Short and medium time experience with a tined, multilumen steroid eluting defibrillation lead.
Both leads and pulse generators of implantable defibrillators have undergone important improvements during the last years. New leads should be tested against previous models to demonstrate safety and reliability. When introduced in 1995, the Medtronic 6932 pace, sense and defibrillation lead was compared to the alternative larger 6936 lead in a short-term randomized study with a mean follow-up of 2.4 +/- 2.0 months. A subgroup of patients were followed for 23.9 +/- 9.0 months. Three hundred and thirty-six patients were randomized to receive either the 6932 or the 6936 lead. Defibrillation threshold at implant, tested using a binary search protocol, was similar for the two leads. The pacing threshold was significantly lower for the 6932 lead both at implant and at follow-up, probably due to the steroid eluting tip of the electrode. R-wave amplitudes were similar for the leads, as were the complication rates. During about two years of follow-up, both leads performed well, with a slightly lower pacing threshold for the 6932 lead.


Physical and electrical characteristics of Si/SiC quantum dot superlattice solar cells with passivation layer of aluminum oxide.
In this work, we numerically simulate the silicon (Si)/silicon carbide (SiC) quantum dot superlattice solar cell (SiC-QDSL) with aluminum oxide (Al2O3-QDSL) passivation. By exploiting the passivation layer of Al2O3, the high photocurrent and the conversion efficiency can be achieved without losing the effective bandgap. Based on the two-photon transition mechanism in an AM1.5 and a one sun illumination, the simulated short-circuit current (J sc) of 4.77 mA cm-2 is very close to the experimentally measured 4.75 mA cm-2, which is higher than those of conventional SiC-QDSLs. Moreover, the efficiency fluctuation caused by the structural variation is less sensitive by using the passivation layer. A high conversion efficiency of 17.4% is thus estimated by adopting the QD's geometry used in the experiment; and, it can be further boosted by applying a hexagonal QD formation with an inter-dot spacing of 0.3 nm.


Late toxicity of image-guided hypofractionated radiotherapy for prostate: non-randomized comparison with conventional fractionation.
To evaluate the incidence and predictors for late toxicity and tumor outcome after hypofractionated radiotherapy using three different image-guided radiotherapy (IGRT) systems (hypo-IGRT) compared with conventional fractionation without image guidance (non-IGRT). We compared the late rectal and urinary toxicity and outcome in 179 prostate cancer patients treated with hypo-IGRT (70.2 Gy/26 fractions) and 174 non-IGRT patients (80 Gy/40 fractions). Multivariate analysis was performed to define predictors for late toxicity. 5- and 8-year recurrence-free survival (RFS) and overall survival (OS) were analyzed. Mean follow-up was 81 months for hypo-IGRT and 90 months for non-IGRT group. Mainly mild late toxicity was observed: Hypo-IGRT group experienced 65 rectal (30.9% G1/G2; 6.3% G3/G4) and 105 urinary events (56% G1/G2; 4% G3/G4). 5- and 8-year RFS rates were 87.5% and 86.8% (hypo-IGRT) versus 80.4% and 66.8% (non-IGRT). 5- and 8-year OS rates were 91.3% and 82.7% in hypo-IGRT and 92.2% and 84% in non-IGRT group. Multivariate analysis showed that hypo-IGRT is a predictor for late genitourinary toxicity, whereas hypo-IGRT, acute urinary toxicity and androgen deprivation therapy are predictors for late rectal toxicity. Advanced T stage and higher Gleason score (GS) were correlated with worse RFS. A small increase in mild late toxicity, but not statistically significant increase in severe late toxicity in the hypo-IGRT group when compared with conventional non-IGRT group was observed. Our study confirmed that IGRT allows for safe moderate hypofractionation, offering a shorter overall treatment time, a good impact in terms of RFS and providing potentially more economic health care.


Plasma profiles of peripheral monocyte-related inflammatory markers in patients with arterial hypertension. Correlations with plasma endothelin-1.
This study investigates the plasma activity of inflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), C-C chemokines and soluble adhesion molecules, produced by monocyte-endothelial cell adhesive interaction, in patients with arterial hypertension. We studied 66 untreated patients with mild to moderate arterial hypertension (hypercholesterolemic: 34, normocholesterolemic: 32) and 30 sex- and age-matched normocholesterolemic normotensive controls. Plasma concentrations of GM-CSF, macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP-1alpha), RANTES (regulated on activation normally T-cell expressed and secreted), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), as well as plasma endothelin-1 (ET-1), were determined in study population by ELISA and RIA, respectively. Hypertensives exhibited significantly higher levels of GM-CSF (6.5+/-1.3 vs. 2.3+/-0.7 pg/ml, P=0.099), MCP-1 (175+/-31 vs. 120+/-24 pg/ml, P=0.0093), MIP-1alpha (23+/-4 vs. 15+/-2 pg/ml, P=0.0089), RANTES (17+/-4 vs. 14+/-3 ng/ml, P=0.047), sICAM-1 (235+/-39 vs. 187+/-21 ng/ml, P=0.0041), sVCAM-1 (684+/-42 vs. 589+/-23 ng/ml, P=0.0045) and ET-1 (6.1+/-1.5 vs. 2.4+/-0.3 pg/ml, P=0.0095) than those of normotensives. The normocholesterolemic hypertensives had significantly lower levels of GM-CSF, MCP-1, MIP-1alpha, sICAM-1 and sVCAM-1 than hypercholesterolemic hypertensives but higher than normotensives. In hypertensives, ET-1 levels were significantly correlated with mean arterial pressure (r=0.51, P=0.028), MCP-1 values (r=0.45, P=0.047) and sICAM-1 levels (r=0.64, P=0.0090). Significant correlations were also found between LDL cholesterol values and plasma inflammatory factors GM-CSF (r=0.58, P=0.0088), MCP-1 (r=0.49, P=0.040) and sICAM-1 (r=0.53, P=0.034) in the hypercholesterolemic sub-group of hypertensives. Inflammatory markers of monocyte-endothelial cell adhesive interaction are elevated in hypertensives in comparison to normotensives and may be related to plasma ET-1 activity. The coexistence of hypercholesterolemia may enhance this inflammatory process induced by arterial hypertension.


Inhibition of Eimeria tenella replication after recombinant IFN-gamma activation in chicken macrophages, fibroblasts and epithelial cells.
We have previously shown that activation of primary cultures of chicken bone-marrow macrophages and embryo fibroblasts with supernatants of concanavaline A-stimulated or reticuloendotheliosis virus (REV)-transformed chicken spleen cells as source of IFN-gamma significantly decreases Eimeria tenella growth in vitro. In the present study, we used various chicken cell lines, HD11 macrophages and DU24 fibroblasts, both virally transformed, CHCC-OU2 fibroblasts and LMH hepatic epithelial cells, both chemically transformed, to replicate E. tenella in vitro. We confirmed the previous results by showing that HD11 macrophages pre-treated for 24h with recombinant chicken IFN-gamma (either produced in E. coli or by transfected COS cells), at doses ranging from 1000 to 10U/ml, drastically inhibited E. tenella replication as measured by [3H] uracil uptake after a further 70h of culture, as when treated with REV supernatant. Likewise the fibroblast and epithelial cell lines exhibited significant inhibitory activity on E. tenella replication after pre-treatment with recombinant chicken IFN-gamma, but were less sensitive (1000-100U/ml) than when treated with REV supernatant. Recombinant chicken IFN-alpha pre-treatment of all cell lines had no inhibitory effect on parasite development.


Synthesis and phosphorylation of osteopontin by avian epiphyseal growth-plate chondrocytes as affected by differentiation.
The regulation of synthesis and phosphorylation of osteopontin in relation to avian epiphyseal growth-plate chondrocyte differentiation was studied in situ and in culture. Osteopontin gene expression was evaluated in the tibia growth-plate of 3-week-old chickens by in situ hybridization. The gene was expressed mainly at the lower hypertrophic zone where cartilage matrix is calcified and endochondral bone formation is initiated. Within the hypertrophic region, a poorly labeled area separated the layer of osteopontin-positive hypertrophic chondrocytes from those associated with endochondral bone formation. In culture, proliferative chondrocytes show no alkaline phosphatase activity in contrast to ascorbic acid-treated chondrocytes which display the enzyme activity. Chondrocytes not treated with ascorbic acid, exhibited lower levels of osteopontin mRNA than the treated cells. The phorbol ester TPA--an activator of protein kinase C--and to a lesser extent FGF but not EGF, stimulated osteopontin gene expression. Chondrocytes secreted low levels of phosphorylated osteopontin to the medium. EGF treatment resulted in the appearance of phosphorylated osteopontin in the medium, without affecting the synthesis of other proteins. FGF and TGF beta, but not IGF-I or IGF-II, also caused phosphorylation of osteopontin. Ascorbic acid-treated chondrocytes secreted higher levels of phosphorylated osteopontin than the non-treated cells, but addition of FGF or TPA did not stimulate osteopontin phosphorylation any further. Parathyroid hormone caused a dose-dependent attenuation of osteopontin phosphorylation and inhibited the EGF-dependent osteopontin phosphorylation. The results suggest that osteopontin gene expression and phosphorylation in chondrocytes are regulated by separate mechanisms. The response to the various controlling agents varies with the state of differentiation. Both processes--the synthesis and phosphorylation of osteopontin--are under the control of local growth factors which are involved in bone growth and calcification.


Green and environmentally sustainable fabrication of SnS2 quantum dots/chitosan nanocomposite for enhanced photocatalytic performance: Effect of process variables, and water matrices.
Concerns over the availability of clean water and the quality of treated wastewater are significant problems that call for an appropriate solution to improve the water quality. The present work emphasized the synthesis of novel SnS2 quantum dots (QDs) deposited on chitosan via a facile green precipitation method involving neem (Azadirachta indica) leaf extract and investigating its photocatalytic performance for the degradation of Crystal violet (CV) dye under varying reaction parameters, other organic and inorganic salts and water matrices. The crystal structure, surface morphology, and elemental composition of the prepared SnS2 (QDs)/Ch composite were evaluated by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), photoluminescence (PL) and energy dispersive X-ray analysis (EDAX) techniques. The average size of SnS2/Chitosan nanoparticles was calculated to be 8.8 nm using XRD, with the average diameter of SnS2 QDs to be 3.3 nm from TEM. UV-visible spectroscopy was used to investigate its optical properties. The direct band gap of SnS2/Chitosan estimated from Tauc's plot came to be 2.5 eV. The prepared novel SnS2/Ch composite showed outstanding photocatalytic activity for the degradation of CV through the Advanced Oxidation Process (AOP). The fabricated photocatalyst caused 98.60 ± 1.34 % degradation of CV within a short period of 70 min under optimum conditions. The photodegradation reaction followed pseudo-first-order rate kinetics with a rate constant of 0.0815 min-1. Furthermore, the photocatalyst showed high stability and was reusable for up to four cycles. The present work fulfils the aim of designing a novel, green, and efficient visible light-active nano-photocatalyst.


Unravelling the Complexity of Colorectal Cancer: Heterogeneity, Clonal Evolution, and Clinical Implications.
Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease's course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, and BRAF, provide valuable guidance for treatment decisions in patients with metastatic CRC. While high concordance exists between mutational status in primary and metastatic lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable in identifying genetic heterogeneity and predicting prognosis in RAS-mutated metastatic CRC patients. Tumor heterogeneity can arise from genetic and non-genetic factors, affecting tumor development and response to therapy. To comprehend and address clonal evolution and intratumoral heterogeneity, comprehensive genomic studies employing techniques such as next-generation sequencing and computational analysis are essential. Liquid biopsy, notably through analysis of ctDNA, enables real-time clonal evolution and treatment response monitoring. However, challenges remain in standardizing procedures and accurately characterizing tumor subpopulations. Various models elucidate the origin of CRC heterogeneity, highlighting the intricate molecular pathways involved. This review focuses on intrapatient cancer heterogeneity and genetic clonal evolution in metastatic CRC, with an emphasis on clinical applications.


Phase 2 Trial of Metformin Combined With 5-Fluorouracil in Patients With Refractory Metastatic Colorectal Cancer.
Observational and preclinical studies have suggested that metformin has antitumor effects in solid tumors, including colorectal cancer (CRC). However, the effects of metformin in CRC have not been tested in clinical trials. This was a single-center, single-arm phase 2 clinical trial where histologically confirmed CRC patients with measurable and progressing metastatic disease previously treated with 5-fluorouracil (5-FU), irinotecan, oxaliplatin, and an anti-epidermal growth factor receptor (if the tumor was RAS wild type) were enrolled to receive metformin 850 mg orally continuously 2 times a day plus 5-FU 425 mg/m2 and leucovorin 50 mg intravenously weekly until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was disease control rate at 8 weeks. Among 50 patients included, 11 (22%) met the primary end point. The median progression-free survival was 1.8 months and the median overall survival 7.9 months. Analyzing only the 11 patients who experienced disease control at 8 weeks, their median progression-free survival was 5.6 months and their median overall survival was 16.2 months. There was a trend for prolonged median survival for obese patients (12.4 vs. 5.8 months) and those longer off 5-FU. The treatment was well tolerated; the main adverse effects were diarrhea, nausea, vomiting, and myelotoxicity. Metformin and 5-FU showed an overall modest but intriguing activity in patients with refractory CRC in this phase 2 study. Some patients experienced long-term disease control. Further trials are needed to confirm these results, particularly in obese patients with CRC.


Effect of nano-delivery systems on the bioavailability and tissue biodistribution of vitamin E tocotrienols.
Vitamin E is one of the most important essential vitamins to support the regulation of oxidative stress in human body. Tocotrienols are part of the vitamin E family. The potentials of tocotrienols as nutraceutical ingredient are largely understated due to low oral bioavailability, which is a common problem associated with fat-soluble bioactive compounds. Nanoencapsulation technology offers innovative solutions to enhance the delivery mechanisms of these compounds. In this study, the effect of nanoencapsulation on the oral bioavailability and tissue distribution of tocotrienols were investigated using two types of formulations, i.e. nanovesicles (NV-T3) and solid lipid nanoparticles (NP-T3). At least 5-fold increment in maximum plasma concentrations, evident with dual-peak pharmacokinetic profiles, were observed after oral administration of nano-encapsulated tocotrienols. Plasma tocotrienol composition showed a shift from α-tocotrienol dominant in control group (Control-T3) to γ-tocotrienol dominant after nanoencapsulation. Tissue distribution of tocotrienols was found to be strongly influenced by the type of nanoformulation. Both nanovesicles (NV-T3) and nanoparticles (NP-T3) showed elevated accumulation in the kidneys and liver (5-fold) compared to control group while selectivity for α-tocotrienol was evident for NP-T3. In brain and liver of rats given NP-T3, α-tocotrienol emerged as the dominant congener (>80%). Acute oral administration of nanoencapsulated tocotrienols did not show signs of toxicity. The study concluded enhanced bioavailability and selective tissue accumulation of tocotrienol congeners when delivered via nanoencapsulation.


Exploring the mechanism of IR-UV double-resonance for quantitative spectroscopy of protonated polypeptides and proteins.
Spectroscopic fingerprint: Infrared–ultraviolet double resonance photodissociation is used for conformational assignment of the electronic spectra of a cold protonated decapeptide (see picture). A mechanism of the IR–UV depletion spectroscopy is proposed and a procedure of using it for measurements of absolute absorption cross-sections of vibrational transitions is elaborated.


The rheological properties of self-emulsifying systems, water and microcrystalline cellulose.
The rheological properties of mixtures of equal parts of a range of ratios of a self-emulsifying system (MP) and water (W) added to microcrystalline cellulose (MCC), have been measured by an extrusion capillary rheometer. These measurements allow assessment of both the shear and tension components of flow plus the elastic behaviour of the wet powder masses, although the results for the estimation of shear stress require careful interpretation due to the limitation of the measuring system and the assumptions made in their derivation. The results indicate that there are three regions of behaviour of the systems, which are all significantly different from the mixtures containing only W and MCC. At low MP contents (1.5--23%), the masses increase in their resistance to shear and elongational flow and have lower elasticity. These similarities in behaviour occur in spite of considerable increase in the viscosity of the MPW mixtures and a change to non-Newtonian flow of the fluid. The behaviour of the 46% MP system is intermediate between these systems and the high MP concentrations (69, 80 and 92%). These latter systems show less resistance to shear and elongational flow than the first group of concentrations, but show considerably higher levels of elasticity. As the resistance to shear decreases, so does the impairment of the surface of the extrudate. There is clear evidence of a systematic change in behaviour of the wet powder masses as the values for the angle of entry of the wet mass into the die when plotted against the ratio of the resistance to die entry (upstream pressure loss) to the shear stress within the die, is linear on a log/log scale. Also, the values of compliance of the systems as a function of shear stress fall on a common curve. Changes in the ratio of the MPW to MCC for a system for a single level of MP (46%) resulted in a change in the values of the rheological parameters but not the type of behaviour. As all these wet powder masses had been shown previously to form pellets by the process of extrusion/spheronization, it is clear that systems with a wide range of rheological characteristics can be processed and no single rheological parameter can be used to provide complete characterisation of the processability of such systems.


A trade-off between kinematic and dynamic control of bimanual reaching in virtual reality.
Bimanual coordination is an essential component of human movement. Cooperative bimanual reaching tasks are widely used to assess the optimal control of goal-directed reaching. However, little is known about the neuromuscular mechanisms governing these tasks. Twelve healthy, right-handed participants performed a bimanual reaching task in a three-dimensional virtual reality environment. They controlled a shared cursor, located at the midpoint between the hands, and reached targets located at 80% of full arm extension. Following a baseline of normal reaches, we placed a wrist weight on one arm and measured the change in coordination. Relative contribution (RC) was computed as the displacement of the right hand divided by the sum of displacements of both hands. We used surface electromyography placed over the anterior deltoid and biceps brachii to compute muscle contribution (MC) from root mean squared muscle activity data. We found RC was no different than 50% during baseline, indicating participants reached equal displacements when no weights were applied. Participants systematically altered limb coordination in response to altered limb dynamics. RC increased by 0.91% and MC decreased by 5.3% relative to baseline when the weight was applied to the left arm; RC decreased by 0.94% and MC increased by 6.3% when the weight was applied to the right arm. Participants adopted an optimal control strategy that attempted to minimize both kinematic and muscular asymmetries between limbs. What emerged was a trade-off between these two parameters, and we propose this trade-off as a potential neuromuscular mechanism of cooperative bimanual reaching.NEW & NOTEWORTHY This study is the first to propose a trade-off between kinematic and dynamic control parameters governing goal-directed reaching. We propose a straightforward tool to assess this trade-off without the need for computational modeling. The technologies and techniques developed in this study are discussed in the context of upper extremity rehabilitation.


Congenital retinal arterial loops and vitreous hemorrhage.
In two adolescents, mild vitreous hemorrhage occurred from the area of retinal arterial loops near the optic nerve. In both cases the hemorrhage cleared without further complications. This vascular malformation may be associated with secondary complications more frequently than has previously been reported.


Redox regulation of vascular prostanoid synthesis by the nitric oxide-superoxide system.
Oxygen is involved in cell signaling through oxygenases and oxidases and this applies especially for the vascular system. Nitric oxide (*NO) and epoxyarachidonic acids are P450-dependent monooxygenase products and prostacyclin is formed via cyclooxygenase and a heme-thiolate isomerase. The corresponding vasorelaxant mechanisms are counteracted by superoxide which not only traps *NO but through the resulting peroxynitrite blocks prostacyclin synthase by nitration of an active site tyrosine residue. In a model of septic shock, this leads to vessel constriction by activation of the thromboxane A2-prostaglandin endoperoxide H2 receptor. This sequence of events is part of endothelial dysfunction in which the activated vascular smooth muscle counteracts and regenerates vessel tone by cyclooxygenase-2-dependent prostacyclin synthesis. Peroxynitrite was found to activate cyclooxygenases by providing the peroxide tone at nanomolar concentrations. Such new insights into the control of vascular function have allowed us to postulate a concept of redox regulation in which a progressive increase of superoxide production by NADPH-oxidase, mitochondria, xanthine oxidase, and even uncoupled NO-synthase triggers a network of signals originating from an interaction of *NO with superoxide.


Endovascular exclusion of renal artery aneurysm.
A patient who was operated for an abdominal aortic aneurysm 7 years earlier presented with recently discovered iliac and renal artery aneurysms. The renal artery had an angulation of 90 , but the aneurysm was successfully excluded using a covered vascular stent graft placed over an extra stiff guidewire. Even in cases of complex anatomy of a renal aneurysm, endovascular treatment should be considered. With development of more flexible and low-profile endoprosthesis with accurate deployment, these have become more usable.


"For Me, 'Normality' is Not Normal": Rethinking Medical and Cultural Ideals of Midlife ADHD Diagnosis.
According to psychiatry, Attention-Deficit/Hyperactivity Disorder (ADHD) is a chronic condition beginning in early life. Psychiatry advocates for early diagnosis to prevent comorbidities that may emerge in untreated cases. "Late"-diagnosis is associated with various hazards that might harm patients' lives and society. Drawing on fieldwork in Israel, we found that 'midlife-ADHDers,' as our informants refer to themselves, express diverse experiences including some advantages of being diagnosed as adults rather than as children. They share what it means to experience "otherness" without an ADHD diagnosis and articulate how being diagnosed "late" detached them from medical and social expectations and allowed some to nurture a unique ill-subjectivity, develop personal knowledge, and invent therapeutic interventions. The timeframe that psychiatry conceives as harmful has been, for some, a springboard to find their own way. This case allows us to rethink 'experiential time'-the meanings of timing and time when psychiatric discourse and subjective narratives intertwine.


Quantitative Prediction of OATP-Mediated Disposition and Biliary Clearance Using Human Liver Chimeric Mice.
Drug biliary clearance (CLbile) in vivo is among the most difficult pharmacokinetic parameters to predict accurately and quantitatively because biliary excretion is influenced by metabolic enzymes, transporters, and passive diffusion across hepatocyte membranes. The purpose of this study is to demonstrate the use of Hu-FRG mice [Fah-/-/Rag2-/-/Il2rg-/- (FRG) mice transplanted with human-derived hepatocytes] to quantitatively predict human organic anion transporting polypeptide (OATP)-mediated drug disposition and CLbile To predict OATP-mediated disposition, six OATP substrates (atorvastatin, fexofenadine, glibenclamide, pitavastatin, pravastatin, and rosuvastatin) were administered intravenously to Hu-FRG and Mu-FRG mice (FRG mice transplanted with mouse hepatocytes) with or without rifampicin as an OATP inhibitor. We calculated the hepatic intrinsic clearance (CLh,int) and the change of hepatic clearance (CLh) caused by rifampicin (CLh ratio). We compared the CLh,int of humans with that of Hu-FRG mice and the CLh ratio of humans with that of Hu-FRG and Mu-FRG mice. For predicting CLbile, 20 compounds (two cassette doses of 10 compounds) were administered intravenously to gallbladder-cannulated Hu-FRG and Mu-FRG mice. We evaluated the CLbile and investigated the correlation of human CLbile with that of Hu-FRG and Mu-FRG mice. We found good correlations between humans and Hu-FRG mice in CLh,int (100% within threefold) and CLh ratio (R2 = 0.94). Moreover, we observed a much better relationship between humans and Hu-FRG mice in CLbile (75% within threefold). Our results suggest that OATP-mediated disposition and CLbile can be predicted using Hu-FRG mice, making them a useful in vivo drug discovery tool for quantitatively predicting human liver disposition. SIGNIFICANCE STATEMENT: OATP-mediated disposition and biliary clearance of drugs are likely quantitatively predictable using Hu-FRG mice. The findings can enable the selection of better drug candidates and the development of more effective strategies for managing OATP-mediated DDIs in clinical studies.


Delving into the Antiurolithiatic Potential of Tribulus terrestris Extract Through -In Vivo Efficacy and Preclinical Safety Investigations in Wistar Rats.
Modern treatment interventions for kidney stones are wrought with side-effects, hence the need for alternative therapies such as plant-based medicines. We have previously documented through in vitro studies that statistically optimized aqueous extract of Tribulus terrestris (Zygophyllaceae family) possesses antiurolithic and antioxidant potential. This provides strong scientific foundation to conduct in vivo efficacy and preclinical safety studies to corroborate and lend further proof to its ability to prevent and cure kidney stones. The preventive and curative urolithiatic efficacy in experimentally induced nephrolithiatic Wistar rats, along with preclinical toxicity was evaluated following oral administration of statistically optimized aqueous extract of T. terrestris. Treatment showed augmented renal function, restoration of normal renal architecture and increase in body weight. Microscopic analysis of urine revealed excretion of small sized urinary crystals, demonstrating that treatment potentially modulated the morphology of renal stones. Tissue enzymatic estimation affirmed the antioxidant efficacy of treatment with reduced free radical generation. Significant upregulation of p38MAPK at both the gene and protein level was noted in hyperoxaluric group and interestingly treatment reversed it. Acute oral toxicity study established the Median Lethal Dose (LD50) to be greater than 2000 mg/kg body weight (b.wt.) No observed adverse effect level (NOAEL) by repeated oral toxicity for 28 days at 750 mg/kg b.wt. was noted. This study lends scientific evidence to the safe, preventive and curative potential of statistically optimized aqueous extract of T. terrestris at a dose of 750 mg/kg b.wt. and suggests that the extract shows promise as a therapeutic antiurolithic agent.


Corrigendum to 'Undetectable viral load within the mastoid during cochlear implantation in a patient with Covid-19'.
[This corrects the article DOI: 10.1016/j.xocr.2021.100273.].


Changes in antizyme-ornithine decarboxylase complexes in tissues of hormone-treated rats.
The presence of antizyme-ornithine decarboxylase complex in thymus and kidney of rats was demonstrated using the method of Y Murakami et al. [(1985) Biochem. J. 225, 689-697]. A very small amount of complex was found in kidney of control rats, accounting for only 1-3% of total enzyme in the tissue, while in thymus, approximately one-third of the total ornithine decarboxylase in thymus occurred as an antizyme-enzyme complex. After treatment with dexamethasone, both free ornithine decarboxylase and antizyme-ornithine decarboxylase decreased in thymus, the free enzyme activity decreasing more rapidly. In kidney, the concentration of the antizyme-ornithine decarboxylase complex increased after dexamethasone treatment, but only after the induction of free enzyme activity had reached its peak and begun to decrease. The pattern of the changes in amount of antizyme-ornithine decarboxylase complex after prolactin treatment differed from those observed in the dexamethasone-treated animals. In both kidney and thymus, the concentration of antizyme-ornithine decarboxylase complex increased concurrently with the induction of free enzyme activity. Both free and complexed ornithine decarboxylase had increased at 2.5 h after prolactin treatment and continued to increase to maximum specific activities at similar rates. In thymus, the amount of ornithine decarboxylase present as a complex reached 70% of the total in the tissue. In both thymus and kidney, the concentration of antizyme-ornithine decarboxylase complex decreased more slowly than did free enzyme activity. Free antizyme was observed only in thymus of dexamethasone-treated animals. The amount of measurable inhibitor was decreased if cycloheximide was given with dexamethasone.


Low dimensional criticality embedded in high dimensional awake brain dynamics.
Whether cortical neurons operate in a strongly or weakly correlated dynamical regime determines fundamental information processing capabilities and has fueled decades of debate. Here we offer a resolution of this debate; we show that two important dynamical regimes, typically considered incompatible, can coexist in the same local cortical circuit by separating them into two different subspaces. In awake mouse motor cortex, we find a low-dimensional subspace with large fluctuations consistent with criticality - a dynamical regime with moderate correlations and multi-scale information capacity and transmission. Orthogonal to this critical subspace, we find a high-dimensional subspace containing a desynchronized dynamical regime, which may optimize input discrimination. The critical subspace is apparent only at long timescales, which explains discrepancies among some previous studies. Using a computational model, we show that the emergence of a low-dimensional critical subspace at large timescale agrees with established theory of critical dynamics. Our results suggest that cortex leverages its high dimensionality to multiplex dynamical regimes across different subspaces.


The clinical utility of the foveal electroretinogram: a review.
The historical development of the foveal electroretinogram is reviewed. The factors required to obtain a local cone electroretinogram with a small focal source of illumination against a lighted background are discussed. From these considerations and various studies of macular degeneration, the optimal size of the foveal source is found to be 5 degrees diameter or less. Applications of the foveal electroretinogram in various diseases are summarized. The foveal electroretinogram is abnormal with reduced acuity in age-related macular degeneration, juvenile macular degeneration (Stargardt's disease), retinitis pigmentosa, and diabetic retinopathy. Normal foveal electroretinograms are found in optic atrophy, amblyopia, and optic neuritis. Foveal electroretinograms are normal or abnormal in Best's disease, central serous retinopathy, and several other diseases discussed.


Tracheal reconstruction with asymmetrically porous polycaprolactone/pluronic F127 membranes.
Congenital and acquired tracheal stenosis continues to be challenging problems. The purpose of this study was to evaluate the efficacy of an asymmetrically porous membrane (APM) to induce tracheal reconstruction by inhibition of granulation tissue growth into the tracheal lumen whereas minimizing graft failure. The APM was fabricated with polycaprolactone (PCL) and pluronic F127 to have nano-size pores at top side, whereas the bottom side had micro-size pores. Fifteen rabbits underwent tracheal defect, which was then reconstructed with the APM. Rabbits were euthanized 1, 4, and 12 weeks postoperatively, and endoscopic, histologic, and radiologic evaluations were conducted. Endoscopy did not reveal granulation ingrowth into tracheal lumen. APM was well incorporated into the surrounding tissue on histologic evaluation. CT scans showed well maintained airways. Off-the-shelf use of APM for tracheal reconstruction seems to be a promising strategy in the treatment of tracheal defects.


Neoadjuvant chemotherapy in patients undergoing neoadjuvant radiation for trunk and extremity soft tissue sarcoma.
Many patients with high-risk soft tissue sarcoma (STS) develop distant metastases. Meta-analyses suggest that chemotherapy confers a small survival benefit, though few studies focus on neoadjuvant chemotherapy (NCT). There has been more frequent use of neoadjuvant radiation therapy (NRT) in STS, but the utility of NCT for these patients remains unclear. Patients with stage II-III trunk/extremity STS who underwent NRT and resection were identified using the National Cancer Database (2006-2019). Predictors of NCT were analyzed using logistic regression. Change in rate of NCT use over time was assessed using log-linear regression modeling. Survival was examined using Kaplan-Meier (KM) and Cox proportional hazard modeling. Of 5740 patients, 25% underwent NCT. The overall median age was 62, 55% of patients were male, and 67% had stage III disease. The most common histological subtypes were fibrosarcoma/myxofibrosarcoma (39%) and liposarcoma (16%). Use of NCT decreased by 4.0% per year throughout the study period (p < 0.01). Predictors of NCT included younger age (median 54, IQR 42-64 vs. median 65, IQR 53-75, p < 0.01), treatment at an academic center (odds ratio [OR] 1.5, p < 0.01), and stage III disease (OR 2.2, p < 0.01). Histologic predictors of NCT included synovial sarcoma (52%) and angiosarcoma (45%). With a median follow-up time of 77 months, NCT was associated with improved 5-year survival compared to NRT alone on KM analysis (70% vs. 63%, p < 0.01). This difference persisted on multivariate analysis (hazard ratio 0.86, p = 0.027) and after propensity matching (70% vs. 65%, p = 0.0064). Despite risk of distant failure in high-risk STS, use of NCT has decreased over time in patients receiving NRT. In this retrospective analysis, NCT was associated with a modestly improved overall survival.


Development of the human sclera. A morphological study.
Differentiation of the sclera in human embryos and fetuses with a gestation age from 6.4 to 24.0 weeks was studied by light and electron microscopy. The developmental route was found to be anteroposterior and directed from inside outwards. Continuous cytological maturation begins anteriorly during week 7.2 with a loss of free ribosomes and polysomes and an increase in the amount of rough-surfaced endoplasmic reticulum (rER) and Golgi complex components. From the region of the future limbus, these cytodevelopmental events progress posteriorly. By week 13 there are no marked differences between anterior and posterior localization. The cytodevelopmental events directed from inside outwards were found to begin during week 7.2, with a marked increase in the addition of glycogen and lipid droplets in the choroidal half of the anterior scleral condensation and from there progressing to the outer (episcleral) half. With the beginning of week 10.9 no more differences were identified between the outer and the inner portions of the sclera. Portions of the ER denuded of ribosomes close to the plasmalemma were observed during the whole gestational period studied. The role of these structures and the involvement of the Golgi complex for the biosynthesis of collagen are discussed. In week 24, the diameter of the collagen fibrils had increased more than three times in comparison with week 6.4. Elastic microfibrils were found beginning with week 7.2, whereas the elastic deposits with central electron-translucent cores were characterized for the first time beginning with week 18.


Ethanol evolution rate: a new parameter to determine the feeding rate for the production of avermectins by Streptomyces avermitilis.
A new parameter ethanol evolution rate (EER) was developed to aid in the determination of glucose feeding rate in avermectin production. The EER characterized the level of primary metabolism and its value was affected mainly by the supply of O2 and glucose. In an abnormal batch, over-feeding of glucose led to 2.5-fold increase of the maximum EER value compared to the normal one, and the production was thus decreased by nearly 80%. Together with other criteria, the EER helped to control utilization of substrate, so it has been successfully used to control glucose feeding in an industrial process.


Nitrogen fertiliser value of bioacidified slurry.
Bioacidification of animal slurry has proven to be a good alternative to traditional acidification with sulfuric acid for reducing ammonia emissions. However, the fertiliser value of the bioacidified slurry is yet to be determined before a whole-system assessment can be made. The N fertiliser value of pig slurry either untreated or bioacidified with glucose and/or fermented brown juice (BJ) was investigated in a pot experiment with maize (Zea mays L.) grown in a greenhouse. The slurry treatments were either pre-acidified with sulfuric acid to pH 6.5 or 5.5 before bioacidification, or bioacidified without pre-acidification. Plant growth was good in all treatments, but the bioacidified treatments showed a lower mineral fertiliser equivalence (MFE) value than the non-bioacidified treatments. Average MFE values were 71 %, 62 %, 59 % and 41 % for the non-bioacidified (noC), glucose (glu), glucose and brown juice (glu + BJ20) and brown juice (BJ50) treatments respectively. This reduction was most likely caused by immobilisation of N due to the addition of easily available C from the substrates. The fertiliser value was not affected by the pH, C/N ratio and C content of the treatments, while a positive correlation was found with NH4 + -N content. Pre-acidification positively affected MFE, probably due to higher nutrient availability. Further studies on the effect of different inclusion rates of substrates for bioacidification and the effect of application method on the fertiliser value, as well as studies under field conditions, are needed before recommendations can be made about bioacidification as an alternative to traditional acidification.


Stability of pharyngeal airway dimensions: tongue and hyoid changes after treatment with a functional appliance.
Because stability is known as the fundamental key of the successful outcome of orthodontics treatment, this study investigated the stability of tongue, hyoid bone and airway dimensions at least two years after active treatment with Faramand functional appliance in patients with class II div 1 malocclusion. The present findings indicate that treatment with functional appliance has the potential to increase pharyngeal airway dimensions and changes in tongue and hyoid position. Importantly, these achieved changes seemed to be maintained in long-term, up to 4 years on average.


[Changes in first-time patients in an outpatient memory clinic -The impact of the declaration of a state of emergency].
With the spread of the new coronavirus infection (COVID-19) and the resulting declaration of a state of emergency, many medical institutions refrained from providing medical care, and patients themselves refrained from visiting hospitals. We also stopped accepting new patients to our outpatient memory loss clinic. We examined whether or not there was any change in the patients who visited our clinic after the state of emergency was lifted. A total of 517 first-time patients ≥65 years old who visited the Center for Comprehensive Care on Memory Disorders at Kyorin University Hospital from July 2019 to June 2021 were included in the study. Patients were grouped by quarter, and their physical characteristics, frailty, and Comprehensive Geriatric Assessment (CGA) findings were compared. Patients who were first seen in July-September 2020 (Q3) had a higher number of medications and greater proportion of frailty than those who were first-time patients in other periods. Regarding the sub-indices, weight loss (48.6%) and the percentage of those complaining of fatigue (37.5%) were significantly higher in Q3 than in other periods. Regarding the CGA findings, the Vitality Index was significantly lower, and among the sub-items, appetite and motivation for activity were lower in Q3 than in other periods. First-time outpatients at the outpatient memory clinic in Q3 of 2020 had a higher rate of frailty and lower motivation than first-time patients at other times.The spread of COVID-19 infection and behavioral restrictions due to the declaration of a state of emergency may have contributed to the progression of frailty among outpatients with memory loss.


Effect of ultrasonic treatments on nanoparticle preparation of acid-hydrolyzed waxy maize starch.
Waxy maize starch was dispersed (14.7% solids) in an aqueous sulfuric acid solution (3.16M), and hydrolyzed by stirring for up to 7 days at 40°C with ultrasonic treatments at different vibration amplitudes (20 and 40%) and durations (30 and 60min/day). The amount of starch nanoparticles in the hydrolyzates isolated after 7 days, measured by a dynamic light scattering detector, was raised from 20% to 70% by an ultrasonic treatment (20% amplitude, 30min). The aggregation of nanoparticles possibly occurring during the hydrolysis was effectively prevented by the ultrasonication. Alternatively, ultrasonic treatments were applied to the re-dispersed suspension of the large microparticles of starch hydrolyzates (2 days) precipitated by a mild centrifugation (500rpm, 10min). By an ultrasonic treatment at 60% vibration amplitude for 3min, the microparticles could be completely transformed to nanoparticles. The inherent crystalline structure of waxy maize starch (A-type in X-ray diffraction) remained after the ultrasonic treatments during acid hydrolysis, but it was disrupted by the ultrasonic treatments for the re-dispersed microparticles.


Usefulness of genetics for clinical reclassification and refinement of prognostic stratification in pulmonary arterial hypertension.
Risk stratification in pulmonary arterial hypertension (PAH) is essential to provide more aggressive treatment for patients at higher risk. Nevertheless, recently introduced simplified prognostic tools neglect the genetic background. Additionally, pulmonary veno-oclusive disease (PVOD) has never been considered in risk assessment strategies. We analyzed consecutive patients in the Spanish registry of PAH (REHAP) genetically tested, between 2011 and 2022. We applied the 4-strata COMPERA 2.0 model, comparing these results with an amplified score including genetics. Cox regression models were compared using Harrel c-statistics. The application of the model was specifically tested in PVOD before inclusion. We identified 298 patients tested genetically among the group of idiopathic, familial, drug-induced PAH and PVOD patients in the REHAP registry. When we analyzed only patients with all available variables of interest at baseline (World Health Organization functional class, 6-minute walk test, B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide) and included in the 4-strata model (n=142), after a median follow-up of 58.2 months, 17.6% of patients died and 11.3% underwent lung transplant. The application of the 4-strata model in our population demonstrated a good prognostic capacity (Harrel c of 0.689), which was not improved by the introduction of genetics (c-index 0.690). This last model showed a tendency for a better identification of patients at intermediate-low and intermediate-high risk, and no differences between intermediate-high and high-risk strata. In this work, the addition of genetics to the COMPERA 4-strata model achieved a similar global prognostic capacity but changed the identification of different risk strata in a cohort of young genetically tested patients.


Intravenous nitroglycerin in the management of retained placenta.
Thirty patients in the third stage of delivery complicated by retained placenta were prospectively managed with intravenous nitroglycerin. We studied the effect of nitroglycerin on the hemodynamics and characteristics of the procedure, and also analyzed labor and maternal and neonatal data. Intravenous nitroglycerin effectively aided the extraction of the retained placenta in all cases. The average procedure time was 5.3 +/- 1.1 min, and the dose range was 50-200 microg. Systolic and diastolic blood pressure fell significantly from 111 +/- 7.5 to 103 +/- 6 mm Hg and from 74 +/- 6.7 to 67 +/- 6.6 mm Hg, respectively (p<0.05). Although statistically significant, this was not evident clinically and there were no complications. Intravenous nitroglycerin at a dose of 200 microg or less is safe, effective and predictable in the management of retained placenta and could obviate the need of general anesthesia.


The effect of digitonin-containing fixatives on the retention of free cholesterol and cholesterol esters.
The influence of several fixation and dehydration procedures on the retention of free cholesterol and cholesterol esters was studied in filter paper preparations. The retention of free cholesterol by the filter paper proved to be decreased by the addition of digitonin to the aldehyde fixative (aqueous phase) and was only slightly enhanced by partial dehydration (alcoholic phase, up to 70% ethanol). Furthermore, digitonin or the presumably formed cholesterol-digitonide complex bound hardly any osmium oxides in glass-fibre paper. Up to 26% of the cholesterol esters was mobilized during the aqueous phase when digitonin was added to the aldehyde fixative. When the glass-fibre papers containing the digitonin cholesterol-ester-osmate complexes were stored in distilled water after fixation, the fluid became turbid. Particulate material isolated from this turbid solution showed ultrastructurally a close resemblance to the 'whorls' observed by several authors in tissue fixed by a digitonin-containing aldehyde fixative. Digitonin also changed the ultrastructural appearance of liposomes, containing lecithin: cholesterol: phosphatidic acid; in a molar ratio 7:2:1. Our observations lead to the conclusion that the use of digitonin-containing fixatives should be abandoned, because they give results which cannot be interpreted. By the use of K4 [Fe(CN)6] containing OSO4 in the post-fixation step were able to demonstrate an increase in the visualization of membranous structures (liposomes).


Postnatal changes in erythropoietin levels in untransfused premature infants.
The purpose of this study was to determine whether an inappropriately low erythropoietin response in premature infants might be a basis for the anemia of prematurity. Erythropoietin was measured by radioimmunoassay in conjunction with hemoglobin and reticulocyte count in untransfused premature infants between birth and 60 days of age. The 27 infants had a mean gestational age of 31 weeks and a mean birth weight of 1378 gm. Between 2 and 30 days, mean erythropoietin concentration was 9.7 mU/ml, significantly and substantially lower than 15.2 mU/ml in 15 concurrently studied healthy adults (P less than 0.01). Subsequently, from 30 to 60 days, values rose gradually to a mean of 17.2 mU/ml, which did not differ significantly from the mean value in adults. Hemoglobin values fell from a mean of 12.9 gm/dl during the first month to 9.0 gm/dl between 30 and 60 days. Thus, during the second postnatal month, preterm infants had essentially the same erythropoietin values as in adults despite a mean hemoglobin concentration that averaged less than two thirds the adult value. This failure to mount a greater erythropoietin response may help to explain why hemoglobin declines to such low values at 2 months of age.


Association of Prefrailty and Frailty With All-Cause Mortality, Acute Exacerbation, and Hospitalization in Patients With Chronic Obstructive Pulmonary Disease: A Meta-Analysis.
To evaluate the impact of prefrailty and frailty on all-cause mortality, acute exacerbation, and all-cause hospitalization in patients with chronic obstructive pulmonary disease (COPD). Meta-analysis. Two authors independently searched PubMed, Web of Science, and Embase databases until December 27, 2022,to identify studies that reported the predictive value of prefrailty and frailty in COPD patients. All-cause mortality, acute exacerbation, and all-cause hospitalization. Ten studies reporting on 11 articles enrolling 13,203 patients with COPD were included. The prevalence of frailty ranged from 6.0% to 51%. When compared with nonfrailty, the pooled adjusted hazard ratio (HR) of all-cause mortality was 1.48 (95% CI 0.92-2.40) for prefrailty and 2.64 (95% CI 1.74-4.02) for frailty, respectively. The pooled adjusted odds ratio (OR) of all-cause hospitalization was 1.35 (95% CI 1.05-1.74) for prefrailty and 1.65 (95% CI 1.05-2.61) for frailty. In addition, frailty significantly predicted all acute exacerbation (OR 2.20, 95% CI 1.26-3.81) but not moderate to severe acute exacerbation (OR 1.42, 95% CI 0.94-2.17) in patients with stable COPD. However, the pooled results of all-cause hospitalization were not reliable in leave-1-out sensitivity analyses. Frailty significantly predicts all-cause mortality in patients with COPD, even after adjustment for common confounding factors. Assessment of frail status in COPD patients may improve secondary prevention and allow early intervention. However, future studies are warranted to validate the impact of frailty defined by a standardized definition of frailty on acute exacerbation and all-cause hospitalization.


Functional influence of areas 17, 18, and 19 on lateral suprasylvian cortex in kittens and adult cats: implications for compensation following early visual cortex damage.
The aim of the present study was to investigate the mechanisms of physiological compensation that is seen in the posteromedial lateral suprasylvian (PMLS) cortex of cats that received visual cortex (areas 17, 18, and 19) damage early in life. The strategy was to compare the response properties of PMLS neurons just after visual cortex damage (before any compensation has occurred) with the properties of PMLS neurons in normal cats and cats with long-standing visual cortex damage. Fourteen animals (aged 8 weeks, 18 weeks, 26 weeks, or adult) received a unilateral visual cortex lesion and recordings were made from ipsilateral PMLS cortex within about 24 h. An additional 4 adult cats were studied within either 24 or 3 h of a bilateral visual cortex lesion. Results from these animals were compared with results from normal cats and cats with long-standing visual cortex damage studied previously in this laboratory. At all ages studied, an acute visual cortex lesion reduced the percentage of direction-sensitive cells in PMLS cortex from nearly 80% in normal cats to about 20% after the lesion. In 8- and 18-week-old kittens, nearly all of the remaining PMLS cells responded best to stimulus movement but were not direction sensitive. In 26-week-old and adult cats, the remaining cells were divided between those that responded to movement without a directional preference and those that responded as well to stationary flashed stimuli as to moving stimuli. The presence of receptive-field surround inhibition was not affected significantly by an acute lesion at any age. In addition, few PMLS cells were orientation selective to elongated slits of light in cats with an acute lesion, just as in normal cats. The ocular dominance distributions of PMLS neurons also were normal following an acute visual cortex lesion at all ages studied. These results suggest that the influences of areas 17, 18, and 19 on the response properties of PMLS neurons are the same when the properties first reach maturity as in adult cats. The results also suggest that the mechanisms of physiological compensation for an early visual cortex lesion differ for different response properties. Compensation of direction sensitivity and orientation selectivity (an anomalous property) develops de novo after the early lesion. In contrast, compensation of ocular dominance appears to be due to the maintenance of a preexisting property that is present immediately after the lesion. Thus, plasticity after early visual cortex damage represents multiple developmental changes in the remaining visual pathways.


Synthesis and time-gated fluorometric application of a europium(III) complex with a borono-substituted terpyridine polyacid ligand.
A new europium(III) complex with a borono-substituted terpyridine polyacid ligand, (4'-borono-2,2':6',2″-terpyridine-6,6″-diyl) bis(methylenenitrilo) tetrakis(acetate)-Eu(3+) (BTTA-Eu(3+)), has been designed and synthesized as a luminescence probe for hydrogen peroxide (H(2)O(2)). The complex is highly luminescent in aqueous buffers to display a typical Eu(3+) emission pattern with a sharp emission peak at 610 nm and a long luminescence lifetime of 1.34 ms. Upon reaction with H(2)O(2), the deboronation derivative of BTTA-Eu(3+), (4'-hydroxy-2,2':6',2″-terpyridine-6,6″-diyl) bis(methylenenitrilo) tetrakis(acetate)-Eu(3+) (HTTA-Eu(3+)), can be generated. It was found that the luminescence of BTTA-Eu(3+) was pH-insensitive, whereas that of HTTA-Eu(3+) was pH-dependent and could be remarkably weakened in neutral and basic buffers, which allowed BTTA-Eu(3+) to be a luminescence probe for the time-gated luminescence detection of H(2)O(2) in neutral and basic buffers. The H(2)O(2)-BTTA-Eu(3+) system was applied to monitor the kinetics of the palladium-catalyzed Suzuki cross-coupling reaction between BTTA-Eu(3+) and bromobenzene, which suggested a useful strategy for the application of time-gated luminescence technique in catalysis reaction researches.


Mosaic increments for predicting the gas chromatographic retention data of the chlorobenzenes.
The chlorinated organic compounds are very important from the point of view of the chemical industry and environmental protection, and therefore the gas chromatographic analysis of these compounds is very interesting for analytical chemists. In this paper we studied the relationship between the molecular structure and gas chromatographic retention on several stationary phases having different polarity and at several temperatures of benzene and 12 chlorobenzene compounds as model compounds. A coding system involving primary (mosaic increments) and secondary (bond increments)calculation methods was developed. The retention indices of benzene and the chlorobenzenes calculated on HP-5 at 120 degrees C shows a better performance of the mosaic increments (average absolute deviation delta of 1.7 retention index units) compared with the bond increments (delta = 11.7 retention index units). Retention factors, k, calculated with mosaic increments for chlorobenzenes on SPB-1 and WAX-10, at 140 degrees C, yield average relative errors of epsilon = 0.9 and 3.5%, respectively. Therefore, the presented paper provides a new possibility for precalculation of the retention data.


Minimal dose of cyclosporin A for tracheal allografts.
Minimizing immunosuppression after allotransplantation is desirable. We assessed the minimal dose of cyclosporin A for viable tracheal allografts in 50 dogs. Each tracheal transplant, consisting of a six-ring segment of cervical trachea, was harvested and heterotopically implanted into the omentum. In group I (n = 10), transplantation into each dog's own omentum was performed as a control. The remaining 40 tracheal segments were randomly assigned to four recipient groups receiving either no treatment (group II, n = 10), 10 mg.kg-1.day-1 of cyclosporin A (group III, n = 10), 15 mg.kg-1.day-1 of cyclosporin A (group IV, n = 10), or 20 mg.kg-1.day-1 of cyclosporin A (group V, n = 10). After 10 or 28 days, the tracheal segments were evaluated histologically. Epithelial regeneration in group IV was significantly better than that in groups I, II, or III on posttransplantation day 10. Only group IV showed no difference in epithelial viability from group I on posttransplantation day 28. In terms of vascularity, groups IV and V exhibited no differences from group I as evidenced by vascular endothelial morphology. We conclude that an appropriate dose of 15 mg.kg-1.day-1 of cyclosporin A may be used to maintain tracheal allograft viability.


Software interface between SAS and the GDDM interactive chart utility.
Data from temporary or permanent SAS-data-sets on disk are transferred to the GDDM Interactive Chart Utility (ICU). Within the ICU these data can be displayed graphically, including all features of modification, supported by the ICU. The transfer is accomplished by a user written SAS procedure, which transforms the data from SAS internal format to the structure required to call the ICU from a PL/1 program. The interface provides interactive menu driven graphics from SAS-data-sets without the need to use SAS control language. The implementation refers to the CMS operating system.


Carbon-13 NMR of fluorocyclopropanes.
Carbon-13 and hydrogen NMR data are presented for several cyclopropanes with one to four fluorine atoms attached to the ring. Substituents directly attached to a ring carbon are found to unshield that carbon to an extent increasing with their electronegativity, but remote substituents may have an opposite effect. Relative orientation of the substituent groups, especially if they are bulky, also has a strong influence on the ring-carbon shifts. Chemical shifts of carbons in methyl groups attached to the ring change to an extent which is additive in the effects of gem and cis substituents. One-bond coupling of ring carbons with fluorines is affected both by geminal and vicinal substituents, in a way generally related to their electronegativity. It is tentatively concluded that two-bond coupling between ring carbons and ring-attached fluorines depends in magnitude primarily on what groups are cis to the fluorine. Two-bond coupling between a carbon atom in a ring-attached methyl and the hydrogen gem to the methyl appears to be vanishingly small, but there is appreciable three-bond coupling of the methyl carbons to vicinal hydrogens.


Breast MRI: Are T2 IR sequences useful in the evaluation of breast lesions?
To evaluate the potential role of signal intensities calculated in T2 images as an adjunctive parameter in the analysis of mass-like enhancements classified as BIRADS (Breast Imaging Reporting and Data System) assessment categories 2, 3, 4 or 5 with the standard T1 criteria. After a retrospective review of 338-breast Magnetic Resonance Imaging (MRI) performed for the evaluation of a suspicious lesion we selected a group of 65 mass-like enhancements ranging from 5 to 20mm, classified as BIRADS assessment categories 2, 3, 4 or 5, histologically proved. In all cases we calculated the ratio between the signal intensity (SI) of the nodule and the pectoralis major muscle (LMSIR, lesion to muscle signal intensity ratio) with a multiROIs (region of interest) analysis on T2 images. A ROC analysis was performed to test the ability of the two diagnostic parameters separately considered (BIRADS and LMSIR) and combined in a new mono-dimensional variable obtained by a computerized discriminant function. Histological examination assessed 34 malignant lesions (52.3%) and 31 benign lesions (47.7%). The evaluation of ROC curves gave the following results: BIRADS area under the curve (AUC) 0.913, S.E. 0.0368, LMSIR AUC 0.854, S.E. 0.0487, combined BIRADS-LMSIR AUC 0.965, S.E. 0.0191 with a definitive increase in the AUC between the overall ROC area and those of the two diagnostic modalities separately considered. T2-weighted SI assessment with LMSIR measurement improves the diagnostic information content of standard breast MRI and can be considered a promising potential tool in the differential diagnosis of mass-like enhancements judged as borderline lesions (BIRADS 3 and 4).


The effect of work environment on burnout among nursing directors: A cross-sectional study.
Identifying the relationship between burnout status and hospital size and workplace environment among hospital nursing directors. Although the demands on nursing staff and managers are increasing, nursing directors' burnout is an under-researched topic. An anonymous survey was conducted with 205 nursing directors across all 654 hospitals in Tokyo, Japan. The survey instruments were the Japanese version of the Burnout Scale, the Organizational Justice Questionnaire, the Nursing Work Empowerment Scale and the Workplace Support Scale. Nursing directors who were close to burnout were from smaller rather than large hospitals. Correlations were found between emotional exhaustion and interactional justice, age, resources, moral support from hospital executives, and self-reflection support from subordinates. Regarding depersonalization, correlations were found with interactional justice, age and work support from subordinates. Regarding participants' personal accomplishment, correlations were found with procedural justice, interactional justice and opportunities. Nursing directors of smaller hospitals tend to experience greater burnout. The impact of work environment on burnout is greater than that of facility and individual characteristics. To mitigate burnout, hospitals should ensure high organizational justice, provide access to resources and opportunities, and encourage moral support from executives and work support from subordinates.


Dual regulation of IRF4 function in T and B cells is required for the coordination of T-B cell interactions and the prevention of autoimmunity.
Effective humoral responses to protein antigens require the precise execution of carefully timed differentiation programs in both T and B cell compartments. Disturbances in this process underlie the pathogenesis of many autoimmune disorders, including systemic lupus erythematosus (SLE). Interferon regulatory factor 4 (IRF4) is induced upon the activation of T and B cells and serves critical functions. In CD4(+) T helper cells, IRF4 plays an essential role in the regulation of IL-21 production, whereas in B cells it controls class switch recombination and plasma cell differentiation. IRF4 function in T helper cells can be modulated by its interaction with regulatory protein DEF6, a molecule that shares a high degree of homology with only one other protein, SWAP-70. Here, we demonstrate that on a C57BL/6 background the absence of both DEF6 and SWAP-70 leads to the development of a lupus-like disease in female mice, marked by simultaneous deregulation of CD4(+) T cell IL-21 production and increased IL-21 B cell responsiveness. We furthermore show that DEF6 and SWAP-70 are differentially used at distinct stages of B cell differentiation to selectively control the ability of IRF4 to regulate IL-21 responsiveness in a stage-specific manner. Collectively, these data provide novel insights into the mechanisms that normally couple and coordinately regulate T and B cell responses to ensure tight control of productive T-B cell interactions.


Minthostachys verticillata Griseb (Epling.) (Lamiaceae) essential oil orally administered modulates gastrointestinal immunological and oxidative parameters in mice.
Minthostachys verticillata (Griseb.) Epling (Lamiaceae) is a plant used in folk medicine for digestive or respiratory disorders. In addition, it is incorporated as condiment, in foods, as beverage flavoring or mate. The ethnopharmacological interest of M. verticillata resides in its essential oil (EO). Part of group has demonstrated the immunomodulatory ability of EO giving this oil a biological potential not known until that moment and conducted studies to evaluate their possible application in diseases of veterinary interest. However, the immunomodulatory effects of EO administered orally have not been fully characterized. This study evaluated the impact of EO oral administration on gastrointestinal and immune health through measurement of immunological and oxidative parameters in mice. The EO was extracted from the leaves, slender stems and flowers of M. verticillata by hydrodistillation and chemical analyzed by gas chromatography-mass spectrometry (GC-MS). Prior to in vivo study, the cytotoxic effect of EO was determined using the human colon carcinoma Caco-2 cell line. For in vivo study, three groups of male Balb/c mice (n = 3) were orally administered with saline solution (control group) and EO (5 or 10 mg/kg/day) during 10 consecutive days. Subsequently, histological and hematological parameters, cytokines production, oxidative markers and CD4+ and CD8+ T cells were evaluated. The chemical analysis of EO revealed the presence of a high content of monoterpenes, being the main pulegone (76.12%) and menthone (14.28%). The EO oral administration improved mice growth performance and modulated systemic adaptive immune response by increasing in the total leukocyte number. A high percentage of CD4+ T cells were observed whereas the number of CD8+ T cells was not altered. EO did not alter the morpho-physiology of intestine and improved total antioxidant capacity by decreasing MDA concentrations. In addition, EO decreased the IL-6 levels and increased in the IL-4 and IL-10 concentrations. Results indicate that M. verticillata EO modulate inflammatory and oxidative parameters constituting a natural alternative which could be applied to improve gastrointestinal and immune functionality in animals.


Clonidine and modification of perioperative outcome.
Perioperative cardiac risk reduction using perioperative beta-blockade is being widely adopted. Recent research has identified a second-line agent, perioperative clonidine, that can be used to reduce the risk of perioperative cardiac mortality. Perioperative clonidine has some advantages over perioperative beta-blockers because it has less risk of bronchospasm in asthmatics and it comes in a transcutaneous form that can be used in patients who are not taking oral medications ('NPO'). Clonidine has been used for many purposes, including reduction of blood pressure in hypertension, reduction in alcohol and drug withdrawal phenomena, reduction in nicotine withdrawal symptoms during smoking cessation, analgesia, reduction in stress response, and now as an anti-ischemic agent to reduce the risk of perioperative myocardial ischemia and perioperative mortality. Administration of perioperative clonidine can reduce the risk of perioperative myocardial ischemia and mortality in patients undergoing non-cardiac surgery. Perioperative clonidine comes in a patch form that can be used in patients who are not taking medications by mouth, and can be used when beta-blockers are contraindicated (for asthmatics or patients with high-grade atrioventricular block).


The effect of interleukin-6 and soluble interleukin-6 receptor protein on the bone resorptive activity of human osteoclasts generated in vitro.
The role of interleukin-6 (IL-6) in the regulation of bone resorption is controversial and has not been studied using human tissue in vitro. This study exploits a recently described in vitro model, whereby osteoclasts, defined as cells that resorb bone, can be generated from human bone marrow, and investigated the effect of IL-6 and its soluble receptor on bone resorption, in the presence of 1,25-dihydroxyvitamin D3 [1,25(OH)2 vitamin D3]. Human bone marrow was cultured to form a confluent stroma, sedimented onto devitalized bone slices, and recharged with non-adherent bone marrow cells. 1,25(OH)2 vitamin D3 increased bone resorption, whereas IL-6 failed to induce a similar stimulatory effect. Both IL-6 at 100 ng/ml and soluble IL-6 receptor protein in the absence of exogenous IL-6 inhibited the stimulatory effect of 1,25(OH)2 vitamin D3. Bone resorption was never observed when non-adherent haemopoietic cells were cultured in the absence of stroma but in the presence of IL-6, which indicates that IL-6 cannot replace the stromal factor(s) required for the formation of cells capable of resorbing bone. These results suggest that IL-6 at high concentrations is not a critical cytokine in stimulating osteoclastic bone resorption.


An approach to the multiple-minima problem in protein folding by relaxing dimensionality. Tests on enkephalin.
An algorithm for locating the region in conformational space containing the global energy minimum of a polypeptide is described. Distances are used as the primary variables in the minimization of an objective function that incorporates both energetic and distance-geometric terms. The latter are obtained from geometry and energy functions, rather than nuclear magnetic resonance experiments, although the algorithm can incorporate distances from nuclear magnetic resonance data if desired. The polypeptide is generated originally in a space of high dimensionality. This has two important consequences. First, all interatomic distances are initially at their energetically most favorable values; i.e. the polypeptide is initially at a global minimum-energy conformation, albeit a high-dimensional one. Second, the relaxation of dimensionality constraints in the early stages of the minimization removes many potential energy barriers that exist in three dimensions, thereby allowing a means of escaping from three-dimensional local minima. These features are used in an algorithm that produces short trajectories of three-dimensional minimum-energy conformations. A conformation in the trajectory is generated by allowing the previous conformation in the trajectory to evolve in a high-dimensional space before returning to three dimensions. The resulting three-dimensional structure is taken to be the next conformation in the trajectory, and the process is iterated. This sequence of conformations results in a limited but efficient sampling of conformational space. Results for test calculations on Met-enkephalin, a pentapeptide with the amino acid sequence H-Tyr-Gly-Gly-Phe-Met-OH, are presented. A tight cluster of conformations (in three-dimensional space) is found with ECEPP energies (Empirical Conformational Energy Program for Peptides) lower than any previously reported. This cluster of conformations defines a region in conformational space in which the global-minimum-energy conformation of enkephalin appears to lie.


[The prevalence of Toxoplasma antibodies among the patients with symptoms of toxoplasmosis at the hospital of the Faculty of Medicine, University of Cukurova].
The antibodies of Toxoplasma gondii were screened with Indirect Haemagglutination (IHA) method during 1983-1987 by different departments of faculty of medicine. University of Cukurova with the symptoms of toxoplasmosis. Of overall 4200 sera, 1327 belonged to babies, and 2873 to adults which were contained of 663 males and 2210 females. The rate of T.gondii antibodies found was 45.74% in babies, 39.67% in males and 53.53% in females all above 1/64 and high titers. Overall 48.88% (2053/4200) sera were positive for T.gondii antibodies.


An unusual case of anti-Borrelia burgdorferi immunoglobulin G seroconversion caused by administration of intravenous gammaglobulins.
Administration of gammaglobulins to individuals without specific anti-Borrelia burgdorferi antibodies may lead to immunoglobulin G (IgG) conversion as detected by enzyme-linked immunosorbent assay (ELISA). In some cases however, complementary techniques such as Western blot or avidity will be of prime importance in distinguishing the start of an infection from the passive immunization induced by the gammaglobulins. In all cases, the key element before reaching conclusions in relation to any of these investigations remains the confrontation between the clinical context and the biological findings. This is the scenario that has been followed in our observation.


Expression and functional analysis of cytochrome P450 genes in the integument of the oriental armyworm, Mythimna separata (Walker).
Mythimna separata is a devastating agricultural pest that has recently developed insecticide resistance. Integument-specific cytochrome P450s were reported to participate in cuticle formation and could be potential targets for pesticide synthesis. The transcriptome of integuments of M. separata larvae was constructed, generating a total of 38 058 unigenes with an average length of 1243 bp. These unigenes are enriched in functional categories such as lipid transport and metabolism, and secondary metabolites biosynthesis, transport and catabolism. Amongst unigenes, cytochrome P450s were identified and 66 unique P450s with complete open reading frames were named. These P450s were divided into 17 families and 32 subfamilies, containing conserved motifs such as helix C, helix I, helix K, and the heme-binding region. RNA-Seq and RT-qPCR analyses showed different expression levels of P450s in integuments of M. separata larvae. Further RT-qPCR analysis of P450s among different tissues showed that five P450s, especially CYP4G199, were specifically highly expressed in integuments. Moreover, knockdown of CYP4G199 disturbed cuticle formation, leading to imperfection in larval cuticle, and prevented pupation of M. separata. Transcriptome of larval integuments provided sequence and expression of genes in M. separata. CYP4G199 is specifically highly expressed in larval integuments and is important for cuticle formation in M. separata.


A business imperative.
Diversity is no longer optional; it's necessary for health care institutions that want to succeed. There's no one-size-fits-all approach, but good strategies have a few things in common.


Effect of microenvironment pH of aluminum hydroxide adjuvant on the chemical stability of adsorbed antigen.
The rate of acid-catalyzed hydrolysis of glucose-1-phosphate (G1P) when adsorbed to aluminum hydroxide adjuvant was significantly slower than the rate of hydrolysis of a solution of G1P at the same pH. It was concluded that the positively charged aluminum hydroxide adjuvant (iep 11.4) electrostatically attracted anions including hydroxyls to form a double layer surrounding the adjuvant particles. Thus, the pH of the microenvironment surrounding the aluminum hydroxide adjuvant was higher than the bulk pH. Adsorbed G1P hydrolyzed at a rate associated with the pH of the microenvironment of the surface of the adjuvant rather than with the pH of the bulk solution. Comparison of the rate constant for the hydrolysis of adsorbed G1P to the pH-stability profile of G1P in solution revealed that adsorbed G1P hydrolyzed at a rate associated with a pH that was approximately two pH units higher than the bulk pH. The results suggest that the chemical stability of antigens that degrade by pH-dependent mechanisms can be optimized by modifying the surface charge of the aluminum-containing adjuvant to produce the pH of maximum stability in the microenvironment of the adjuvant.


Long-term follow-up of patients with unresectable locally advanced non-small cell lung cancer treated with chemoradiotherapy: a retrospective analysis of the data from the Japan Clinical Oncology Group trials (JCOG0003A).
To clarify the long-term survival data and factors that are correlated with survival outcome of unresectable locally advanced non-small cell lung cancer (NSCLC) following chemoradiotherapy, we analyzed patients who entered the Japan Clinical Oncology Group (JCOG) clinical trials for unresectable locally advanced NSCLC. Between October 1989 and August 1997, 240 patients (male 207, female 33; PS (performance status) 0 58, PS 1 172, PS 2 9, unknown 1; stage IIB 2, IIIA 62, IIIB 175, unknown 1) entered the 6 trials. All patients received chemotherapy and radiotherapy. The associations between survival outcome and treatment-related factors were analyzed using Cox regression analysis. Median survival times and 5-year survival rates in the trials were 11.9-19.7 months and 0-17.6%, respectively. Median survival time was 16.1 months and the 5- and 7-year survival rates of all 240 patients were 14.4% and 12.0%, respectively. No deaths were observed 7 years after initiation of the treatment or later. For stage IIIA and IIIB patients, the 5-year survival rates were 16.3% and 13.4%, respectively. Node status and age were significantly associated with survival, but no factors of the treatment were associated with survival of patients with unresectable locally advanced NSCLC. The present retrospective analysis showed that approximately 12% of patients with unresectable locally advanced NSCLC could be cured by various chemoradiotherapy regimens.


A simple method for the demonstration of factors in bovine colostrum capable of causing anaemia in lambs reared free from maedi on bovine colostrum.
Previous studies demonstrated that the anaemia encountered in lambs reared on bovine colostrum and a milk substitute was associated with the presence of immune complexes on lamb erythrocytes. In the present study the usefulness of a panel of 20 sheep sera for the detection of "anti-sheep" factors in bovine colostrum by double immunodiffusion in agarose was investigated. Utilising this method, 353 batches of bovine colostrum have been examined, 132 of which were declared safe for use in the rearing of lambs. When fed to lambs, only 2 samples (1.5%) caused anaemia as compared with up to 20% before this test was introduced. Experiments designed to determine whether the bovine colostra, declared anaemia-prone, would indeed cause anaemia when fed to lambs, showed our method to fully discriminate between safe and unsafe colostra for the rearing of lambs. In a follow-up collaborative study, set up to cover most of the Netherlands, the general validity of the test system described was demonstrated, using 114 batches of safe colostrum to feed 723 lambs. Further experiments are needed to determine the exact nature of the factor(s) involved in this phenomenon.


Determination of tumour hypoxia with [18F]EF3 in patients with head and neck tumours: a phase I study to assess the tracer pharmacokinetics, biodistribution and metabolism.
The aim of this study was to assess the pharmacokinetics, biodistribution and metabolism of [(18)F]EF3, a labelled 2-nitroimidazole hypoxia marker, in ten patients with head and neck cancer. [(18)F]EF3 was administered intravenously (group 1, n=5, mean dose+/-SD: 324+/-108 MBq; group 2, n=5, mean dose+/-SD: 1,134+/-138 MBq) to patients (nine male, one female). Blood and urine samples and whole-body PET scans were obtained from 20 s to 4-6 h. Radioactivity was determined in several regions of interest. No serious adverse event was reported. [(18)F]EF3 concentration in blood exhibited a bi-exponential decline. [(18)F]EF3 was mainly eliminated in the urine. By 7 h 40 min after injection, 53+/-14% of the injected dose was collected in the urine. There was no significant difference between the low- and high-dose groups. A progressive accumulation occurred also in the colon, indicating a hepatobiliary excretion. Except in organs involved in the elimination of [(18)F]EF3, the tumour-to-organ ratio remained close to or below unity in muscle, lungs, heart and brain at various times after injection. In one patient, tumour hypoxia was observed with a tumour-to-blood ratio ranging from 1.4 to 1.9. Last, [(18)F]EF3 remained very stable after injection, with percentage of native tracer above 87% in the serum and 84% in the urine. Administration of [(18)F]EF3 in head and neck cancer patients is feasible and safe. Uptake and retention in tumour was observed, indicating the presence of hypoxia.


Triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio is an independent predictor of the severity of hyperlipidaemic acute pancreatitis.
The incidence of acute pancreatitis caused by hyperlipidaemia is increasing. A quick and easy diagnosis of the severity of hyperlipidaemic acute pancreatitis (HTGP) is important to improve patient prognosis and reduce mortality. Previous studies reported that insulin resistance (IR) is associated with acute pancreatitis. Our study aimed to investigate the correlation between the triglycerides to high-density lipoprotein cholesterol (TG/HDL-C) ratio and HTGP. Patients' laboratory and clinical parameters were obtained from the institutional pancreatitis database. Univariate and multivariate logistic regression analyses were applied to evaluate the risk factors for the severity of HTGP and the efficacy of four clinical scoring systems: Ranson's Criteria, Acute Physiology and Chronic Health Evaluation II (APACHE II), the Bedside Index for Severity in Acute Pancreatitis (BISAP), and Marshall. Of 290 patients, 134 (46.2%) were diagnosed with moderately severe to severe HTGP. The TG/HDL-C ratio was higher in the moderately severe to severe HTGP subgroup than in the mild HTGP subgroup. Among the independent risk factors, such as amylase, albumin, aspartate transaminase (AST), systemic inflammatory response syndrome (SIRS), and TG/HDL-C ratio, the TG/HDL-C ratio had the highest area under the curve (AUC) (0.727, 95% CI, 0.571-0.701). In comparison with other clinical scoring systems, the TG/HDL-C ratio has a relatively preferable predictive ability. Our findings suggest that the TG/HDL-C ratio is positively correlated with HTGP severity and could be used as a simple indicator of severe HTGP.


Novel evidence for the prognostic impact of β-blockers in solid cancer patients receiving immune checkpoint inhibitors.
Cancer immunotherapy based on immune checkpoint inhibitors (ICIs) has made encouraging achievements in both clinical trials and real-world studies. The β-blockers, as common concomitant medications in clinical practice, have been suggested to exert anti-cancer effects in various human malignancies. This study aimed to clarify the prognostic impact of β-blockers in solid cancer patients receiving ICI therapy. A systematic literature review and meta-analysis was firstly performed based on databases including PubMed, Cochrane Library, Web of Science, Embase, and Clinicaltrials.gov before August 1th 2022. The association of β-blocker use with overall survival (OS) or progression-free survival (PFS) was determined using the hazard ratios (HRs) coupled with 95% confidence intervals (CIs). Then, a retrospective study enrolling 194 patients was performed to validate the results of the meta-analysis. A total of 11 studies enrolling 10,156 patients were included in the meta-analysis. The pooled analysis demonstrated β-blocker use was not significantly correlated with either OS (HR = 0.97(0.85-1.11)) or PFS (HR = 0.98(0.90-1.06)). Similar results were also observed in the subgroup analysis stratified by cancer type, age, sample size and ICI therapy, except for the OS (HR = 0.61(0.45-0.83)) and PFS (HR = 0.65(0.44-0.96)) in the studies with sample size less than 200. The retrospective study indicated no significant correlation between β-blocker use and the clinical outcome in the entire cohort and lung cancer subgroup. However, β-blocker use was found to be significantly associated with better objective response to ICI-based therapy in the entire cohort (odds ratio (OR) = 0.42(0.19-0.94), p = 0.036) and lung cancer subgroup (OR = 0.25(0.08-0.83), p = 0.024). Although both our up-to-date meta-analysis and retrospective study suggested β-blocker use has no significant impact on the overall prognosis of solid cancer patients receiving ICIs, β-blocker use may be associated with improved anti-cancer efficacy of ICIs. Considering study limitations, more clinical validations and mechanism investigations are of great necessity for clarifying the role of β-blockers in ICI-based therapy.


Reuse of disposable sphincterotomes for diagnostic and therapeutic ERCP: a one-year prospective study.
Although previous studies have documented that single-channel sphincterotomes can be sterilized and used up to 10 times, no studies have prospectively evaluated the reuse of disposable sphincterotomes. Five- and six-French double-channel sphincterotomes marketed as one-time-use only were manually cleaned, sterilized with ethylene oxide, and used up to 10 times. Over a 1-year period, total number of uses as a cannulation or cutting device, reason for sphincterotome dysfunction, possible infectious complications were evaluated, and cost-savings associated with reuse were evaluated. The mean number of times sphincterotomes could be used in our institution was 3.4; a broken or stiff cutting wire was the main reason for discard. There were two infectious complications during the study period. Both were experienced by patients with unrelieved obstruction treated with new sphincterotomes. Contingent on the method used, total savings related to sphincterotome reuse was approximately $66,000. Double-channel sphincterotomes marketed as one-time-use items can be reused safely when properly cleaned. Reuse was associated with significant cost savings in our institution.


Gene expression profiling of the effects of intravenous immunoglobulin in human whole blood.
Intravenous immunoglobulin (IVIG) is involved in many complex mechanisms that act in synergy including expression and function of Fc receptors, complement activation, the cytokine network, interaction with the anti-idiotypic network and modulation of B and T cell activation. To gain insight into the early effects of IVIG on this broad range of activities at the gene level we performed DNA microarray analysis. Human whole blood was incubated in vitro for 4 h followed by extraction of RNA which was hybridized to a chip containing 8793 genes. About 75 upregulated genes and 21 downregulated genes were identified using a cut off for the false discovery rate of 5%. These genes are associated with a wide range of cellular immune functions in line with the broad mechanism of action of IVIG. A striking upregulation of a series of genes coding for chemokines was measured. This finding was confirmed at the protein level as pharmacologically relevant concentrations of CXCL9 and CXCL10 were measured in serum. Interestingly, IVIG shows a partial overlap of its gene expression program with lipopolysaccharide. Our data suggests multiple hypotheses regarding the pharmacology of IVIG that must be validated by complementary studies.


Brainstem tuberculoma: A delayed IRIS.
We describe a twenty six years old lady with tuberculous meningitis who developed new onset left ptosis and binocular diplopia with features of left fascicular 3rd nerve palsy after 9 months of anti tubercular therapy (ATT) and imaging revealed new onset tuberculoma in the mid-brain. Tuberculoma responded to steroids while continuing ATT. Formation of new tuberculoma as a part of immune reconstitution inflammatory syndrome (IRIS) is possible even after prolonged therapy of 9 months, which responded well to only steroids without altering ATT.


TRANSDIRE: data-driven direct reprogramming by a pioneer factor-guided trans-omics approach.
Direct reprogramming involves the direct conversion of fully differentiated mature cell types into various other cell types while bypassing an intermediate pluripotent state (e.g. induced pluripotent stem cells). Cell differentiation by direct reprogramming is determined by two types of transcription factors (TFs): pioneer factors (PFs) and cooperative TFs. PFs have the distinct ability to open chromatin aggregations, assemble a collective of cooperative TFs and activate gene expression. The experimental determination of two types of TFs is extremely difficult and costly. In this study, we developed a novel computational method, TRANSDIRE (TRANS-omics-based approach for DIrect REprogramming), to predict the TFs that induce direct reprogramming in various human cell types using multiple omics data. In the algorithm, potential PFs were predicted based on low signal chromatin regions, and the cooperative TFs were predicted through a trans-omics analysis of genomic data (e.g. enhancers), transcriptome data (e.g. gene expression profiles in human cells), epigenome data (e.g. chromatin immunoprecipitation sequencing data) and interactome data. We applied the proposed methods to the reconstruction of TFs that induce direct reprogramming from fibroblasts to six other cell types: hepatocytes, cartilaginous cells, neurons, cardiomyocytes, pancreatic cells and Paneth cells. We demonstrated that the methods successfully predicted TFs for most cell conversions with high accuracy. Thus, the proposed methods are expected to be useful for various practical applications in regenerative medicine. The source code and data are available at the following website: http://figshare.com/s/b653781a5b9e6639972b. Supplementary data are available at Bioinformatics online.


Regional expression of brain derived neurotrophic factor (BDNF) is correlated with dynamic patterns of promoter methylation in the developing mouse forebrain.
Brain Derived Neurotrophic Factor (BDNF) plays an important role in brain development and plasticity. BDNF gene expression is known to be dynamically regulated during development, but the regulatory controls of normal differential expression are not well understood. Methylation of CpG dinucleotides within gene promoters is emerging as an important epigenetic control mechanism of transcription, and the BDNF complex promoter contains several CpG dinucleotides. We determined BDNF expression in the developing mouse forebrain and examined whether there were correlated patterns of methylation at CpG dinucleotides within the BDNF promoter. The data show that BDNF is dynamically expressed in the mouse forebrain and that expression is correlated with differential methylation specifically at CpG dinucleotides in eIV of the mouse BDNF promoter. These studies demonstrate that DNA methylation of this regulatory region may be an important mechanism controlling differential expression of BDNF during forebrain development.


Reliability of quantitative multiparameter maps is high for magnetization transfer and proton density but attenuated for R1 and R2 * in healthy young adults.
We investigate the reliability of individual differences of four quantities measured by magnetic resonance imaging-based multiparameter mapping (MPM): magnetization transfer saturation (MT), proton density (PD), longitudinal relaxation rate (R1 ), and effective transverse relaxation rate (R2 *). Four MPM datasets, two on each of two consecutive days, were acquired in healthy young adults. On Day 1, no repositioning occurred and on Day 2, participants were repositioned between MPM datasets. Using intraclass correlation effect decomposition (ICED), we assessed the contributions of session-specific, day-specific, and residual sources of measurement error. For whole-brain gray and white matter, all four MPM parameters showed high reproducibility and high reliability, as indexed by the coefficient of variation (CoV) and the intraclass correlation (ICC). However, MT, PD, R1 , and R2 * differed markedly in the extent to which reliability varied across brain regions. MT and PD showed high reliability in almost all regions. In contrast, R1 and R2 * showed low reliability in some regions outside the basal ganglia, such that the sum of the measurement error estimates in our structural equation model was higher than estimates of between-person differences. In addition, in this sample of healthy young adults, the four MPM parameters showed very little variability over four measurements but differed in how well they could assess between-person differences. We conclude that R1 and R2 * might carry only limited person-specific information in some regions of the brain in healthy young adults, and, by implication, might be of restricted utility for studying associations to between-person differences in behavior in those regions.


Inhibition of Balbiani ring transcription following differential arrest of Balbiani ring-coded translation.
A differential inhibition of the synthesis of secretory proteins, mainly fractions formed in giant translation units, can be obtained in Chironomus salivary gland cells with low concentrations of the ribosome translocation inhibitor, cycloheximide with or without emetine. Both treatments also lead to puff regression and inhibition of transcription specific to the large Balbiani rings, BR1 and BR2, the loci for the giant secretory proteins. The amount of 75S BR RNA transcribed is also reduced in the cytoplasm and in the poly(A) RNA relative to other transcripts. The half-life of 75S RNA is, however, prolonged so that there is little if any decrease in the cytoplasmic content of 75S RNA. The effect on the Balbiani rings may be due to control emanating from the translational process.


Adolescent: provider connectedness and STI risk reduction following a brief alcohol intervention: findings from a randomized controlled trial.
Given the frequent co-occurrence between alcohol use and sexual behavior among adolescents, alcohol interventions may play a role in helping prevent sexually transmitted infections (STIs) in this age group. Psychotherapy "common factors" are one potential active ingredient in intervention efficacy. Thus, the purpose of this study was to evaluate the influence of a critical common factor, adolescent: provider connectedness, on STI risk reduction at 3 months post-intervention. Community-based youth (N = 168) were randomized to two 60-min individual sessions of either motivational interviewing (MI) or brief adolescent mindfulness (BAM). Logistic regressions predicted post-intervention positive STI from adolescent: provider connectedness, intervention condition, and their interaction. Path analytic models tested post-intervention hazardous drinking as a mediator of the association between adolescent: provider connectedness and reduction in STI risk at 3-month follow-up. Stronger adolescent: provider connectedness reduced risk of STI at 3 months post-intervention, with no differences by treatment condition. A mediational relationship between adolescent: provider connectedness and STI risk via hazardous drinking was not observed. Psychotherapeutic common factors, including adolescent: provider connectedness, may be important in mitigating adolescent health risk in behavioral interventions, above and beyond intervention condition and beyond the target behavior of the intervention.


Combined fluorescence-guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nanocluster.
Glioblastoma multiforme (GBM) is the most common primary intracranial malignancy; survival can be improved by maximizing the extent-of-resection. A near-infrared fluorophore (Indocyanine-Green, ICG) was combined with a photosensitizer (Chlorin-e6, Ce6) on the surface of superparamagnetic-iron-oxide-nanoparticles (SPIONs), all FDA-approved for clinical use, yielding a nanocluster (ICS) using a microemulsion. The physical-chemical properties of the ICS were systematically evaluated. Efficacy of photodynamic therapy (PDT) was evaluated in vitro with GL261 cells and in vivo in a subtotal resection trial using a syngeneic flank tumor model. NIR imaging properties of ICS were evaluated in both a flank and an intracranial GBM model. ICS demonstrated high ICG and Ce6 encapsulation efficiency, high payload capacity, and chemical stability in physiologic conditions. In vitro cell studies demonstrated significant PDT-induced cytotoxicity using ICS. Preclinical animal studies demonstrated that the nanoclusters can be detected through NIR imaging in both flank and intracranial GBM tumors (ex: 745 nm, em: 800 nm; mean signal-to-background 8.5 ± 0.6). In the flank residual tumor PDT trial, subjects treated with PDT demonstrated significantly enhanced local control of recurrent neoplasm starting on postoperative day 8 (23.1 mm3 vs 150.5 mm3, p = 0.045), and the treatment effect amplified to final mean volumes of 220.4 mm3 vs 806.1 mm3 on day 23 (p = 0.0055). A multimodal theragnostic agent comprised solely of FDA-approved components was developed to couple optical imaging and PDT. The findings demonstrated evidence for the potential theragnostic benefit of ICS in surgical oncology that is conducive to clinical integration.