Evidence that 2-aminoethoxydiphenyl borate provokes fibrillation in perfused rat hearts via voltage-independent calcium channels.
We tested whether 2-aminoethoxydiphenyl borate (2-APB) induces arrhythmia in perfused rat hearts and whether this arrhythmia might result from the activation of voltage-independent calcium channels. Rat hearts were Langendorff perfused and beat under sinus rhythm. An isovolumic balloon inserted into the left ventricle was used to record mechanical function while bipolar electrograms were recorded from electrodes sutured to the base and the apex of hearts. Western and immunofluorescence analyses were performed on rat left ventricular protein extracts and left ventricular frozen sections, respectively. Rat ventricular myocytes express Orai 1 and Orai 3, and ventricle also contains the Orai regulator Stim1. Rat hearts (n=5) perfused with Krebs-Henseleit (KH) alone maintained sinus rhythm at 4.8 ± 0.1 Hz and stable mechanical function. By contrast, perfusing hearts (n=5) with (KH+22 μM 2-APB) provoked a period of tachycardic ectopy at rates of up to 10.8 ± 0.2 Hz. As perfusion with (KH+22 μM 2-APB) continued, the rate of spontaneous ventricular depolarization increased to 21.8 ± 1.2 Hz and became disorganized. Heart mechanical function collapsed as developed pressure decreased from 87 ± 8.8 to 3.5 ± 1.9 mm Hg. Flow rate did not change between normal (16.6 ± 0.9 ml/min) and fibrillating (17.4 ± 0.8 ml/min) hearts. The addition of 20 μM 1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl-1H-imidazole (SKF-96365) to (KH+22 μM 2-APB) perfusates (n=4) restored sinus rhythm and heart mechanical output. These data indicate that activating myocardial voltage-independent calcium channels, possibly the Orais, may be a novel cause of ventricular arrhythmia.


Butane-1,4-diyl dications stabilized by steric factors: electrochiroptical response systems based on reversible interconversion between dihydro[5]helicene-type electron acceptors and electron-donating 1,1'-binaphthyls.
Incorporation in the dihydro[5]helicene framework prevents deprotonation of the title dications by steric factors, thus allowing their isolation as deeply colored stable salts. Based on the reversible interconversion with the electron-donating binaphthylic diolefins, they constitute a new class of electrochromic systems, in which C-C bond making/breaking is accompanied by two-electron transfer. Optically pure (R)-binaphthylic donors are interconvertible with the 1,4-dications with the R,R-configuration. The very large molar ellipticity makes it possible for them to be used as electrochiroptical response systems, by which the electrochemical input is transduced into two spectral outputs, i.e. UV-Vis and circular dichroism. Structurally related push-pull-type bis(quinonemethide)s also exhibit a similar multi-output electrochemical response.


pH-sensitive poly(glutamic acid) grafted mesoporous silica nanoparticles for drug delivery.
pH-sensitive poly(L-glutamic acid) grafted mesoporous silica nanoparticles (MSN-PLGA) were prepared by the surface-initiated N-carboxyanhydride polymerization method. The resultant MSN-PLGA was well dispersed in aqueous medium and showed high drug loading efficiency, superior stability, and significantly higher drug release rates. The cumulative release of doxorubicin hydrochloride (DOX) from DOX-loaded MSN-PLGA (DOX@MSN-PLGA) was pH-dependent and the release rate was much higher at pH 5.5 than that at pH 7.4. The cytotoxicity results indicated that the blank MSN-PLGA was biocompatible and the DOX@MSN-PLGA had potent in vitro cytotoxicity effect similar to free DOX. Overall, these results demonstrate that MSN-PLGA is a promising platform to build pH controlled drug delivery systems for cancer therapy.


Improved expression of kinases in Baculovirus-infected insect cells upon addition of specific kinase inhibitors to the culture helpful for structural studies.
As exemplified by three cases, we show that the addition of a small molecular weight inhibitor to the culture of Baculovirus-infected insect cells can dramatically improve the expression of a recombinant kinase. The expression of the tyrosine kinase KDR was sevenfold higher and mainly in a soluble form, when the KDR inhibitor PTK/ZK was added to the culture at the time of Baculovirus infection. The expression of the catalytic domain of the serine/threonine kinase PKCtheta, which is otherwise not possible with the Baculovirus expression system, was expressed mainly soluble at 120mg/L by the addition of the PKC inhibitor BIM XI to the culture of Baculovirus-infected insect cells. For Abl kinase, the expression could also be significantly increased by the addition of the Abl kinase inhibitor STI571 to the culture. For all three kinases, this method had previously been applied by us for the improved production of kinase/inhibitor complex protein, leading to the co-crystal structures. It is shown here at the cases KDR-PTK/ZK and PKCtheta-BIM XI, that the stimulatory effect of an inhibitor on kinase expression is applicable under many culture conditions. The presented method represents a valuable tool to obtain structural knowledge on kinase-inhibitor complexes.


Identification of a transmissible plasmid from an Argentine Sinorhizobium meliloti strain which can be mobilised by conjugative helper functions of the European strain S. meliloti GR4.
We describe in this work the identification and the conjugal properties of two cryptic plasmids present in the strain Sinorhizobium meliloti LPU88 isolated from an Argentine soil. One of the plasmids, pSmeLPU88b (22 kb), could be mobilised from different S. meliloti strains to other bacteria by conjugation only if the other plasmid, pSmeLPU88a (139 kb), was present. This latter plasmid, however, could not be transferred via conjugation (frequency <10(-9) transconjugants per recipient) contrasting with the conjugal system from the previously described strain GR4, where one plasmid is mobilisable and a second one (helper) is self-transmissible. Despite the differences between the two systems, the conjugative helper functions present in the cryptic plasmids of strain GR4 were active in the mobilisation of plasmid pSmeLPU88b from strain LPU88. Contrasting with this, plasmid pSmeLPU88b was not mobilised by the helper functions of the broad-host-range plasmid RP4. Eckhardt gel analysis showed that none of the plasmids from strain GR4 were excluded in the presence of plasmid pSmeLPU88b suggesting that they all belong to different incompatibility groups for replication. The small plasmid from strain LPU88, pSmeLPU88b, was only able to replicate in members of the Rhizobiaceae family such as Rhizobium leguminosarum, Rhizobium tropici and Agrobacterium tumefaciens, but not in Escherichia coli or Pseudomonas fluorescens. The observation suggests that most likely plasmid pSmeLPU88b was not received from a phylogenetically distant bacterium.


Up from 'false positives' in genetic-and other-epidemiology.
Published 'positive' results of epidemiological studies on possible associations (descriptive or causal) are ever more commonly 'false positives' and, thus, false warrants for claiming discovery. More common examination of a multitude of possible associations is widely seen to be the principal cause of this trend. I dispute this explanation and take the principal basis for the trend to be the ever decreasing prior plausibility of the associations that are reported on; and publication bias leading to missing 'negatives' in the published results exacerbates the appearance of the problem. The problem is, however, eminently remediable. We epidemiologists, as a collective of researchers, should leave behind the decision-oriented, inference-denying cult of statistical 'significance' adduced by Neyman and Pearson, and in its stead we should embrace the Fisherian culture of focusing on the production of statistical evidence, for use in inference by our readers. I recommend a simple, objective measure of evidence, suitable for readers' Bayesian-type inferences about the existence of an association.


Coronary computed tomography angiography in a patient with atrial fibrillation, case report.
Atrial fibrillation (AF) is the most common persistent arrhythmia. It is associated with wide range of cardiac clinical conditions. Because of variable duration of cardiac cycle resulting in reduced image quality, AF has been considered relative contraindication for performing coronary computed tomography angiography (CCTA). However, recent reports have suggested that newer dual source scanner with higher temporal resolution can be used in patients with AF (Oncel et al., 2007; Wolak et al., 2008; Rist et al., 2009). Image quality can be maintained if heart rate is lowered to less than 70 beats per minute. However, high heart rate can still be challenging. Mapping systolic phase with the use of absolute delay reconstruction algorithm has been shown to provide better image quality. In this article, we present a case of patient with chronic AF and in whom coronary examination was required before going to repair of aortic root dissection. CCTA, with the use of absolute delay reconstruction algorithm, provided diagnostic image quality of the coronary arteries.


A systematic review of SNAPO (Smoking, Nutrition, Alcohol, Physical activity and Obesity) randomized controlled trials in young adult men.
To investigate the effectiveness of Smoking, Nutrition, Alcohol, Physical activity and Obesity (SNAPO) interventions in young men exclusively. The secondary aim was to evaluate the recruitment, retention and engagement strategies. A search with no date restrictions was conducted across seven databases. Randomized controlled trials recruiting young men only (aged 18-35 years) into interventions targeting any SNAPO risk factors were included. Ten studies were included (two nutrition, six alcohol use, two targeting multiple SNAPO risk factors). Six studies (two nutrition, three alcohol use and one targeting multiple SNAPO risk factors) demonstrated significant positive short-term intervention effects, but impact was either not assessed beyond the intervention (n=3), had short-term follow-up (≤6 months) (n=2) or not sustained beyond six months (n=1). Overall, a high risk of bias was identified across studies. Only one study undertook a power calculation and recruited the required sample size. Adequate retention was achieved in three studies. Effectiveness of engagement strategies was not reported in any studies. Despite preliminary evidence of short-term effectiveness of SNAPO interventions in young men, few studies characterized by a high risk of bias were identified. High quality SNAPO interventions for young men are warranted.


Children's Physical Activity and Depression: A Meta-analysis.
Research regarding the protective effects of early physical activity on depression has yielded conflicting results. Our objective was to synthesize observational studies examining the association of physical activity in childhood and adolescence with depression. Studies (from 2005 to 2015) were identified by using a comprehensive search strategy. The included studies measured physical activity in childhood or adolescence and examined its association with depression. Data were extracted by 2 independent coders. Estimates were examined by using random-effects meta-analysis. Fifty independent samples (89 894 participants) were included, and the mean effect size was significant (r = -0.14; 95% confidence interval [CI] = -0.19 to -0.10). Moderator analyses revealed stronger effect sizes in studies with cross-sectional versus longitudinal designs (k = 36, r = -0.17; 95% CI = -0.23 to -0.10 vs k = 14, r = -0.07; 95% CI = -0.10 to -0.04); using depression self-report versus interview (k = 46, r = -0.15; 95% CI = -0.20 to -0.10 vs k = 4, r = -0.05; 95% CI = -0.09 to -0.01); using validated versus nonvalidated physical activity measures (k = 29, r = -0.18; 95% CI = -0.26 to -0.09 vs k = 21, r = -0.08; 95% CI = -0.11 to -0.05); and using measures of frequency and intensity of physical activity versus intensity alone (k = 27, r = -0.17; 95% CI = -0.25 to -0.09 vs k = 7, r = -0.05; 95% CI = -0.09 to -0.01). Limitations included a lack of standardized measures of physical activity; use of self-report of depression in majority of studies; and a small number of longitudinal studies. Physical activity is associated with decreased concurrent depressive symptoms; the association with future depressive symptoms is weak.


Effect of menstrual cycle and gender on ventilatory and heart rate responses at the onset of exercise.
To clarify the luteal-follicular and male-female differences in ventilatory and heart rate responses at the onset of exercise, seven women and seven men performed voluntary exercise and passive movement for 20 s (brief voluntary exercise and brief passive movement) and voluntary exercise for 3 min (long voluntary exercise) in a sitting position. Voluntary exercise consisted of alternate flexion-extensions of both lower legs with a weight corresponding to about 2.5% of the subjects' body mass attached to each ankle, at a frequency of about 60 times min(-1). Passive movement was carried out without weights by experimenters pulling ropes attached to both of the subjects' ankles, in the same way as voluntary exercise. During these exercises and movements, minute inspiratory ventilation ( V(I)) and heart rate (HR) were continuously measured by breath-by-breath and beat-to-beat techniques. We calculated relative changes of V(I) and HR (Delta V(I) and DeltaHR). Additionally, we averaged Delta V(I) and DeltaHR obtained during the exercise and movement for each subject, and performed a correlation analysis between the averaged Delta V(I) and DeltaHR. It was clarified that: (1) Delta V(I) and DeltaHR in the follicular phase were almost equal to those in the luteal phase; (2) there were no significant male-female differences in these parameters; (3) significant positive correlations were found in both genders only during brief voluntary exercise. We conclude that ventilatory and HR responses at the onset of voluntary exercise and passive movement are not affected by the menstrual cycle or gender.


Remodeling Lymphatic Vessels in Intrinsically Aged Skin on SKH-1 Mouse Using Low Dose 5-aminolevulinic Acid Photodynamic Therapy via VEGF-C/VEGFR3 Pathway.
Decline of lymphatic vessel (LV) density and function in intrinsically aged skin can lead to harmful substance accumulation and fluid imbalance. Whether it will be improved by low dose ALA-PDT needs to be investigated. To investigate the effect of low dose ALA-PDT on remodeling LVs in intrinsically aged skin. Low dose ALA-PDT with 3 sessions were applied on the dorsal skin of intrinsically aged SKH-1 mice (15 months old). Skin biopsies were obtained from young mice (4 months old, Young-control), intrinsically aged mice before PDT (Old-pre-PDT), and after PDT at different time points (Old-PDT-24h, Old-PDT-1w, Old-PDT-4w), and skin phenotypes were evaluated by dermoscopy. The structure of LVs and extracellular matrix were evaluated via immunofluorescence staining and HE. The drainage function of LVs was evaluated by Evans Blue assay in vivo. The expression of Calcium-binding EGF domain-containing protein 1 (CCBE1), VE-cadherin, and the activation of VEGF-C/VEGFR3 signaling pathway were evaluated by ELISA and Western Blot. The density of LVs decreased and the lymphatic clearance was significantly delayed in aged skin. Low dose ALA-PDT increased the density of LVs and blood vessels. The clearance of Evans Blue assay showed the drainage function of LVs was improved after PDT treatments in vivo. The VE-cadherin and VEGF-C/VEGFR3 pathway up-regulated in intrinsically aged skin after ALA-PDT treatments. LVs in intrinsically aged skin were remodeled and their function were restored by low dose ALA-PDT via up-regulating the VEGF-C/VEGFR3 pathway and stimulating the expression of VE-cadherin.


Stimulation of mitogen-activated protein kinase by oncogenic Ras p21 in Xenopus oocytes. Requirement for Ras p21-GTPase-activating protein interaction.
p21ras plays an important role in the control of cell proliferation. The molecular mechanisms implicated are unknown. We report that the injection of oncogenic Lys12 Ras into Xenopus laevis oocytes promoted the activation of mitogen-activated protein kinase (MAP kinase) after a lag of about 90 min. MAP kinase activity was 10-fold higher 4 h after injection of oncogenic Lys12 Ras than after injection of nononcogenic Gly12 Ras. The stimulated MAP kinase activity remained at a plateau for at least 18 h. Maximal stimulation was obtained with 5 ng of Lys12 Ras, which is similar to the amount that elicits germinal vesicle breakdown. DEAE-Sephacel chromatography of extracts from Lys12 Ras-injected oocytes showed one peak of MAP kinase. MAP kinase activation by Lys12 Ras was associated with tyrosine phosphorylation of MAP kinase (p42). As previously shown, the S6-kinase II (likely pp90rsk), which is activated in vitro by MAP kinase, was also activated by oncogenic Lys12 Ras. Lys12 Ras with an additional mutation (Glu38) in the effector region that binds GTPase-activating protein (GAP) did not promote MAP kinase or S6 kinase activations. Thus, GAP may be involved downstream to Ras in these activation processes. Our results indicate that the Ras-GAP complex promotes MAP kinase activation in oocytes. This supports the idea that Ras-GAP controls MAP kinase, a kinase implicated in the action of various stimuli.


Effect of zero-valent iron and a redox mediator on removal of selenium in agricultural drainage water.
Effective and economical removal of selenium (Se) in agricultural drainage water is very important in Se bioremediation. Zero-valent iron (ZVI) and a redox mediator [anthraquinone-2,6-disulfonate (AQDS)] were assessed for their ability to enhance the removal of Se(VI) or Se(IV) (500 microg/L) in synthetic drainage water by Enterobacter taylorae. The results showed that E. taylorae was capable of using inexpensive sucrose to remove Se from the drainage water. During a 7-day experiment, Se(VI) was almost entirely reduced to Se(0) and transformed to organic Se in the drainage water with sucrose levels of 500 to 1000 mg/L. Addition of ZVI to the drainage water increased the removal of total soluble Se to 94.5-96.5% and limited the production of organic Se. Addition of AQDS to the drainage water with or without ZVI decreased Se(VI) removal, but enhanced the removal of Se(IV), suggesting that E. taylorae only can use anthrahydroquinone-2,6-disulfonate (AHQDS, a reduced form of AQDS) to respire Se(IV), and not Se(VI). These results show that ZVI has promising application potential in the bioremediation of Se in Se-contaminated water.


The emotional lexicon of individuals diagnosed with antisocial personality disorder.
This study investigated the specific emotional lexicons in narratives created by persons diagnosed with antisocial personality disorder (ASPD) to test the hypothesis that individuals with ASPD exhibit deficiencies in emotional language. Study participants consisted of 60 prison inmates with ASPD, 40 prison inmates without ASPD, and 60 men without antisocial tendencies who described situations involving love, hate and anxiety depicted by photographs. The lexical choices made in the narratives were analyzed, and a comparison of the three groups revealed differences between the emotional narratives of inmates with ASPD, inmates without ASPD, and the control group. Although the narratives of the individuals with ASPD included more words describing emotions and higher levels of emotional intensity, the valence of these words was inappropriate. The linguistic characteristics of these narratives were associated with high levels of psychopathy and low emotional reactivity.


Effect of phosphate on glucosamine production by ethanolic fungus Mucor indicus.
In this study, the effect of phosphorous compound concentration on the production of glucosamine by Mucor indicus was investigated. Changes in the yield of ethanol, the major metabolite of the fungus, were also followed besides. The alkali insoluble material of the biomass of the fungus mainly contained phosphates and polymers of glucosamine and N-acetyl glucosamine, i.e., chitin and chitosan. Yields of glucosamine (78-113 g/kg dry fungal biomass) and ethanol (200-370 g/kg glucose) were significantly affected by the phosphorous concentration. The results showed that lower concentrations of phosphorous favored the production of glucosamine while higher ethanol as well as biomass yields was obtained at higher concentrations. The best concentration was 0.5 g/l where glucosamine yield was 0.37 g/l (11 % of the biomass). At this phosphate concentration, ethanol and biomass yields were 360 and 76 g/kg glucose, respectively. On average, proteins comprised 51.5 % of the biomass. Glycerol was the second important metabolite during the fermentation by the fungus which appeared at lower yields (20-34 g/kg glucose).


Effects of Mindfulness on Obligatory Exercise During the Return of Injured Athletes to Sports: The Mediating Roles of Self-Criticism and Competitive State Anxiety.
Despite the Advances in sports training methods and medicine, they have not reduced the recurrence rate of athletes' injuries significantly, and obligatory exercise may be an important reason for their re-injury. The purpose of this study was to investigate the effects of mindfulness on obligatory exercise behavior, self-criticism, and competitive state anxiety in athletes recovering from injury, and explain their interactions. The study adopted the snowball and convenience sampling methods. From November to December 2022, a total of 265 high-level sports players in South China were selected, and ultimately, 208 valid data samples were obtained. Maximum likelihood estimation was used to analyze the data and test the hypotheses proposed using 5000 bootstrap samples to test the mediating effects of the structural equation model. The results demonstrated that there were positive correlations between self-criticism and obligatory exercise (standardized coefficients = 0.38, p < 0.001), as well as competitive state anxiety and self-criticism (standardized coefficients = 0.45, p < 0.001). Mindfulness and obligatory exercise were correlated negatively (standardized coefficients = -0.31, p < 0.001), but there was no significant relation between competitive state anxiety and obligatory exercise (standardized coefficients = 0.05, p > 0.01). Self-criticism and competitive state anxiety mediated mindfulness's positive effects on obligatory exercise in part (standardized indirect effect = -0.16, p < 0.01), and this explanatory power was higher than in any previous study (R2 = 0.37). The irrational beliefs in Activating events-Beliefs-Consequence (ABC) theory play an important role in explaining athletes' obligatory exercise, and mindfulness has a positive effect on reducing obligatory exercise behavior.


Control of neurulation by the nucleosome assembly protein-1-like 2.
Neurulation is a complex process of histogenesis involving the precise temporal and spatial organization of gene expression. Genes influencing neurulation include proneural genes determining primary cell fate, neurogenic genes involved in lateral inhibition pathways and genes controlling the frequency of mitotic events. This is reflected in the aetiology and genetics of human and mouse neural tube defects, which are of both multifactorial and multigenic origin. The X-linked gene Nap1l2, specifically expressed in neurons, encodes a protein that is highly similar to the nucleosome assembly (NAP) and SET proteins. We inactivated Nap1l2 in mice by gene targeting, leading to embryonic lethality from mid-gestation onwards. Surviving mutant chimaeric embryos showed extensive surface ectoderm defects as well as the presence of open neural tubes and exposed brains similar to those observed in human spina bifida and anencephaly. These defects correlated with an overproduction of neuronal precursor cells. Protein expression studies showed that the Nap1l2 protein binds to condensing chromatin during S phase and in apoptotic cells, but remained cytoplasmic during G1 phase. Nap1l2 therefore likely represents a class of tissue-specific factors interacting with chromatin to regulate neuronal cell proliferation.


Expression of insulin-like growth factor II mRNA binding protein 3 (IMP3) in enchondroma and chondrosarcoma.
Atypical cartilaginous tumor and enchondroma are similar in histopathologic aspects. Although the clinical course, radiologic and pathologic examinations enable distinction in most cases, difficulties are still encountered by the pathologists. There is no known biomarker to help make a distinction between benign and malignant cartilaginous tumors. Insulin-like growth factor II mRNA binding protein (IMP3) is a member of an oncofetal family of proteins that is expressed in different human malignancies and rapidly emerging as a prognostic and diagnostic marker in surgical pathology. In this study, IMP3 expression was examined by immunohistochemistry in 36 enchondromas and 42 chondrosarcomas of different histologic grades. The results showed that all 36 cases of enchondroma were negative for IMP3, while it was overexpressed in 15 of 42 chondrosarcomas (36%) (P<0.01). Significant higher levels of IMP3 were detected in grade III chondrosarcomas (6 of 7; 85.7%) when compared to low-grade tumors (6 of 19; 31.5% in grade II and 3 of 16; 18.7% in Atypical Cartilaginous Tumor). We proved statistically significant difference in IMP3 expression between enchondromas and ACTs (P=0.025). Our study clearly demonstrated differentiation-dependent expression of IMP3 in chondrosarcoma, and suggests IMP3 as a novel marker for differentiating problematic cases of enchondroma from well-differentiated chondrosarcomas. To our knowledge, this study is the first study to clarify expression of IMP-3 in chondromas and chondrosarcomas.


Severe hyperglycemic hyperosmolar nonketotic coma in a nondiabetic patient receiving aripiprazole.
Aripiprazole is commonly used as an atypical antipsychotic. It has been associated with abnormalities in glucose metabolism. Severe diabetic complications associated with its use occur rarely. We present a case of a patient without a history of diabetes mellitus who presented to the emergency department in severe hyperosmolar nonketotic coma while using aripiprazole.


Primary Thyroid Mucoepidermoid Carcinoma (MEC) Is Clinically, Prognostically, and Molecularly Different from Sclerosing MEC with Eosinophilia: A Multicenter and Integrated Study.
Mucoepidermoid carcinoma (MEC) and sclerosing MEC with eosinophilia (SMECE) are rare primary thyroid carcinomas. In this study, we aimed to present our multicenter series of MEC and SMECE and integrated our data with published literature to further investigate the clinicopathological characteristics and prognoses of these tumors. We found 2 MECs and 4 SMECEs in our multicenter archives. We performed fluorescence in situ hybridization (FISH) to determine the MAML2 gene rearrangement. We screened for mutations in BRAF, TERT promoter, and RAS mutations using Sanger sequencing and digital polymerase chain reaction. Histopathologically, MECs and SMECEs were composed of two main cell types including epidermoid and mucin-secreting cells, arranged in cords, nests, and tubules. SMECEs were characterized by a densely sclerotic stroma with abundant eosinophils. We did not detect any MAML2 fusion in any of our cases. Two MEC cases harbored concomitant BRAF p.V600E and TERT C228T mutations. RAS mutations were absent in all cases. Concurrent foci of another thyroid malignancy were more commonly seen in MECs (p < 0.001), whereas SMECEs were associated with chronic lymphocytic thyroiditis (p < 0.001). MECs and SMECEs had equivalent recurrence-free survival (RFS) but MECs conferred significantly dismal disease-specific survival (DSS) as compared to SMECEs (p = 0.007). In conclusion, MECs and SMECEs not only shared some similarities but also demonstrated differences in clinicopathological characteristics, prognoses, and molecular profiles. SMECEs had a superior DSS in comparison to MECs, suggesting that they are low-grade cancers. This could help clinicians better evaluate patient outcomes and decide appropriate treatment plans.


Topologically optimized concentric-nanoring metalens with 1 mm diameter, 0.8 NA and 600 nm imaging resolution in the visible.
Metalenses can achieve diffraction-limited focusing via localized phase modification of the incoming light beam. However, the current metalenses face to the restrictions on simultaneously achieving large diameter, large numerical aperture, broad working bandwidth and the structure manufacturability. Herein, we present a kind of metalenses composed of concentric nanorings that can address these restrictions using topology optimization approach. Compared to existing inverse design approaches, the computational cost of our optimization method is greatly reduced for large-size metalenses. With its design flexibility, the achieved metalens can work in the whole visible range with millimeter size and a numerical aperture of 0.8 without involving high-aspect ratio structures and large refractive index materials. Electron-beam resist PMMA with a low refractive index is directly used as the material of the metalens, enabling a much more simplified manufacturing process. Experimental results show that the imaging performance of the fabricated metalens has a resolution better than 600 nm corresponding to the measured FWHM of 745 nm.


The unique association between the level of peripheral blood monocytes and the prevalence of diabetic retinopathy: a cross-sectional study.
The attraction and influx of monocytes into the retina has been considered a critical step in the development of diabetic retinopathy (DR). However, large population studies about the association between peripheral blood monocyte levels, an inexpensive and easily measurable laboratory index, and DR are limited. Thus, we aimed to investigate the association between peripheral blood monocyte levels and DR. A total of 3223 participants out of 3277 adults with diabetes were enrolled from seven communities in China in this cross-sectional survey. Participants underwent several medical examinations, including the measurement of anthropometric factors, blood pressure, routinely analyzed leukocyte characteristics, glucose, lipid profiles, urine albumin/creatinine ratio and fundus photographs. The prevalence of DR among the participants in the highest quartile of peripheral blood monocyte levels significantly decreased by 41% (OR 0.59; 95% CI 0.43, 0.81) compared with the participants in the first quartile (P for trend < 0.05). However, there were no associations between the monocyte level and the prevalence of cardiovascular and cerebrovascular diseases (CVD) and diabetic kidney disease (DKD) (both P for trend > 0.05). Associations between leukocyte, neutrophil and lymphocyte levels and DR were also not found (all P for trend > 0.05). These associations were all fully adjusted for age, sex, education status, duration of diabetes history, current smoking, BMI, HbA1c, dyslipidemia, systolic blood pressure and insulin therapy. Decreased peripheral blood monocyte levels were associated with increased odds of DR after adjusting for potential confounders in diabetic adults. However, causation remains to be demonstrated.


Direct multi-elemental analysis of cerebrospinal fluid samples by LA-ICP-MS employing an aerosol local extraction cryogenic ablation cell.
A novel method for direct high-throughput analysis of multi-elements in cerebrospinal fluid (CSF) samples by laser ablation inductively coupled plasma mass spectrometry with an aerosol local extraction cryogenic ablation cell (ALEC-LA-ICP-MS) was developed. Microliter-level CSF samples were frozen by a designed cryogenic ablation cell and directly analyzed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) without time-consuming pretreatment. Compared with the precision obtained at room temperature (20℃), that obtained at low temperature (- 25℃) was significantly improved; the RSDs were reduced from 8.3% (Zn) to 32.6% (Mn) to 2.2% (Pb) to 6.5% (Mn) with six times parallel determination. To meet the analytical requirement of the micro-volume CSF samples, the laminar flow aerosol local extraction strategy was adopted to improve the transmission efficiency of aerosols, and the signal intensity was increased by four times compared with the standard commercial ablation cell. The standard solution with 0.4% bovine serum albumin (BSA) matrix was used as matrix-match external standard, and Rh was added into the samples as internal standard. The limits of detection (LODs) ranged from 0.17 μg·L-1 (Mn) to 8.67 μg·L-1 (Mg). Standard addition recovery experiments and the determination of CRM serum L-1 and L-2 were carried out to validate the accuracy of the method; all results indicated there were excellent accuracy and precision in the proposed method. The matrix-scanning function in the GeoLas software combined with the microwell plate realizes the high-throughput automatic analysis. Twenty-four CSF samples from different patients were determined; the results showed that there might be a correlation between the metal elements in CSF and the diseases, which means that the proposed method has potential in the diagnosis of neurological diseases.


25-gauge lens-sparing vitrectomy for stage 4A retinopathy of prematurity.
To evaluate the feasibility of performing lens-sparing vitrectomies using 25-gauge instruments for the management of stage 4A retinal detachments in Retinopathy of Prematurity (ROP). 13 eyes of 10 patients with stage 4A retinal detachments underwent a lens-sparing pars plicata vitrectomy. All patients were operated using a three port transconjunctival 25-gauge sutureless technique. The sclerotomies were made 0.5 to 1.0 mm posterior to the limbus through the pars plicata. Core vitrectomy and membrane peeling were performed. A partial fluid-air exchange was used at the end of the procedure in the majority of the cases. The anatomic status of the retina was determined by ophthalmoscopy during routine follow up visits or under general anesthesia. Per-operative complications were recorded. Eight of the infants were female and two were male. The average postmenstrual age at birth was 26.4 weeks and the average postgestational age at time of surgery was 39.3 weeks (range, 33-44). Three out of the 13 eyes (23%) had zone I ROP. With a mean follow-up of 17 months (range, 4-36) 12 out of the 13 eyes (92%) achieved successful retinal reattachment. One eye developed post operative hypotony with a small choroidal detachment that resolved spontaneously. Surgical intervention with a three port 25-gauge transconjunctival sutureless vitrectomy is an effective technique to attach the retina in patients with stage 4A retinal detachment in ROP.


[Effect of the type of extraction solution and length of storage on the distribution of lactate dehydrogenase isoenzymes in piglet liver homogenate].
Type of extraction solution applied to preparation of homogenate of piglet liver is of negligible importance, if immediately follows electrophoretic separation of tissue material. --Storage of liver homogenates in frozen state over 30 days involves insignificant changes of distribution of LD isoenzymes in 0.25 M sucrose, distinct changes in 0.1 M Tris-buffer, pH 7,5, and important ones in mercaptoaethanol-containing extraction solution, applied to preparation of tissue homogenates.


Durability of anti-spike antibodies after vaccination with mRNA SARS-CoV-2 vaccine is longer in subjects with previous infection: could the booster dose be delayed?
The long-term effectiveness of BNT162b2/Pfizer vaccine remains undetermined. This observational prospective study was designed to verify durability of antibodies against the viral receptor-binding domain (RBD) spike (S)-protein (RBD S-Protein IgG) after the second-dose administration of the vaccine among Health Care Workers (HCWs). In all HCWs at the Poliambulanza Foundation Hospital Brescia (Italy) were quantified the levels of RBD S-Protein IgG (Abbott Diagnostics) at 45 and 240 days after the second-dose vaccine. Previous infection was defined as antibodies against SARS-CoV-2 nucleocapsid positivity (Abbott Diagnostics) before vaccination. The Mann-Whitney U test was used to compare mean levels of RBD S-Protein IgG among previously infected and uninfected HCWs. The mean level of the RBD S-protein IgG detected 45 days after the second dose of the vaccine was 30,041 AU/mL (95% CI 145-80,000) for the 250 previously infected HCWs and it was significantly higher (p < 0.001) than that observed in the 1121 previously uninfected subject with the mean level of 10,604 AU/mL (95% CI 165-62,241). Similarly, at 240 days in previously infected subjects the antibody titer was of 8145 AU/mL (95% CI 347-80,000) and significantly higher (p < 0.001) than that observed in the 1121 previously uninfected HCWs with a mean antibody level of 1271 AU/mL (95% CI 50-80,000). When comparing the change in mean antibody levels overtime, the previously infected HCWs presented a 72.9% reduction in RBD S-protein IgG while in the previously uninfected HCWs the reduction was 88.0%. In addition, in the HCWs group without previous infection we reported 53 new SARS-CoV-2 infections and they had a mean level of RBD S-protein IgG antibodies of 1039 AU/mL (95% CI 157-4237) at 240 days. No new infections were found in previously SARS-CoV-2 infected subjects. We report that the mean level of post vaccinal RBD S-protein IgG was significantly higher in the previously infected HCWs than in previously uninfected subjects at 45 and 240 days after the second-dose vaccine. Moreover, our data suggest that the risk of a new SARS-CoV-2 infection was higher in the previously uninfected HCWs than in those who had already contracted natural viral infection. The limitations of this study prevent us to draw definitive conclusions on the antibody titers and on the role of a previous SARS-CoV-2 infection in influencing the levels of post-vaccine RBD S-protein IgG. The booster dose of the vaccine could be delayed after the second dose in previously naturally infected subject and it could have an important strategic impact on the organization of the future COVID-19 vaccination campaign.


Neuropsychiatric Features in Primary Mitochondrial Disease.
Mitochondrial diseases are a clinically heterogeneous group of disorders that ultimately result from dysfunction of the mitochondrial respiratory chain. There is some evidence to suggest that mitochondrial dysfunction plays a role in neuropsychiatric illness; however, the data are inconclusive. This article summarizes the available literature published in the area of neuropsychiatric manifestations in both children and adults with primary mitochondrial disease, with a focus on autism spectrum disorder in children and mood disorders and schizophrenia in adults.


Natural cycle increases the live-birth rate compared with hormone replacement treatment for frozen-thawed single euploid blastocyst transfer.
A number of studies have compared the clinical outcomes between the two endometrial preparation methods: natural cycles (NCs) and hormone replacement treatment (HRT) before frozen embryo transfer, but the results were conflicting. In order to mitigate the potential effect of embryos per se, several researchers have worked on this subject for euploid blastocyst transfer, but the results were still inconsistent. Therefore, the present study was aimed to investigate the clinical outcomes between HRT and NC for autologous single vitrified-warmed euploid blastocyst transfer based on our data. A total of 598 frozen-thawed single euploid blastocyst transfer cycles in the assisted reproductive center of Northwest Women's and Children's Hospital from January 2014 to May 2021 were retrospectively analyzed. Women were stratified into the NC (n = 125) or HRT (n = 473) group according to the patient's preference and the physician's guidance. Multivariate regression models and subgroup analysis were constructed to analyze the association between endometrial preparation and live birth. Women in the NC group had a higher live birth rate (68.80% versus 58.35%, P = 0.034) and a lower risk of total pregnancy loss (8.51% versus 21.14%, P = 0.005) when compared with women in the HRT group. The biochemical pregnancy rate (75.20% versus 74.00%, P = 0.784) and clinical pregnancy rate (74.40% versus 69.98%, P = 0.334) were similar between the two groups (NC versus HRT). NC was associated with an increased odds of live birth compared with HRT by different multivariable analysis models (Model 1: adjusted odds ratio [aOR], 95% confidence interval [CI]: 0.57, 0.36 - 0.90; Model 2: aOR, 95%CI: 0.57, 0.35 - 0.92). In addition, the increased chance of live birth in the NC group was found in all subgroups. No major obstetrical complications and two malformation livebirths were reported. In women undergoing single euploid frozen blastocyst transfers, the NC group was associated with a lower pregnancy loss rate and an ultimately higher live birth rate than the HRT group. Although HRT is convenient for both clinicians and patients, the lower live birth rate should be taken into account and NC might be the first choice of endometrial preparation method.


Stromal tumours of the gastrointestinal tract: a clinicopathological and ploidy analysis of 33 cases.
The clinicopathological and DNA flow cytometric data of 33 patients with stromal tumours of the gastrointestinal tract (STGIT) were analysed to select pathological features of prognostic value. Tumours had been previously classified as benign (21 cases) or malignant (12 cases). Data relating to poor prognosis statistically were local invasion, pathological grade, size greater than 10 cm, mitotic index (MI) and necrosis. Pathological grade was related to local invasion. Aneuploidy did not correlate with poor survival although a common trend was detected between both. DNA content may help to predict prognosis of STGIT, but its real value has not yet been clearly established. Currently, stage (invasion), size, MI and pathological grade remain the most useful prognostic factors.


Correlates of suicide and violence risk 1: the suicide risk measure.
A measure of suicide risk was developed using items reported to discriminate suicidal patients from controls in various studies. The new self-report scale was administered to 82 outpatients, 157 inpatients, and 83 college students. Using total scores, significant differences were found between the college sample and the two patient samples. The scale also discriminated between patients who reported one or more past suicide attempts and those who reported none. An independent cross-validation showed that half of the items continued to discriminate between patient and control groups. Sensitivity and specificity estimates were also determined. The test does not attempt to predict a specific rare event, i.e., suicide. It attempts to describe the degree to which a given individual reveals a set of characteristics that are similar to a suicide prototype.


The correlation of breakpoint cluster region rearrangement and p210 phl/abl expression with morphological analysis of Ph-negative chronic myeloid leukemia and other myeloproliferative diseases.
The chromosome 22 derivative, the Philadelphia (Ph) chromosome, results from a reciprocal translocation t(9;22) (q34;q11) and is associated with chronic myeloid leukemia (CML). The translocation can be identified at the DNA level in Ph-positive CML by using a probe to the breakpoint cluster region (bcr). In addition, as a result of this translocation an abl-related 210-kd protein with protein tyrosine kinase (PTK) activity is produced. We analyzed 28 cases of Ph-negative CML for rearrangement of the chromosome 22 sequences and found that eight of the 28 show rearrangement of the bcr. When 12 of the Ph-negative cases were independently reviewed, five were indistinguishable from Ph-positive CML on the basis of morphology, peripheral blood film and clinical details. These five also showed bcr rearrangement. The other seven were reclassified as six atypical CML (aCML) and one chronic myelomonocytic leukemia (CMML). None of these seven showed bcr rearrangement. In addition 11 cases of bcr- CML were assayed for abl-related PTK, and no detectable activity was present, whereas p210 phl/abl PTK was observed both in Ph-positive (three cases examined) and Ph-negative, bcr + (four cases examined) CML. Therefore, bcr + CML, whether or not the Ph chromosome is cytogenetically apparent, involves a similar molecular alteration and produces the 210-kd protein with enhanced PTK activity. Furthermore, these cases can be distinguished from Ph-negative bcr- CML by careful evaluation of clinical and hematologic data.


Core-Shell Gold/Silver Nanoparticles for Localized Surface Plasmon Resonance-Based Naked-Eye Toxin Biosensing.
The localized surface plasmon resonance (LSPR) phenomenon provides a versatile property for biodetection. Herein, this unique feature was employed to build a homogeneous optical biosensor to detect staphylococcal enterotoxin A (SEA) in solution down to very low levels by naked-eye readout. If the initial position of the LSPR band is located in the cyan region, even a small red shift (∼2-3 nm) induced by a refractive index change close to the surface of nanoparticles (NPs) could make the light absorption transit from cyan to green and become visually detectable via a concomitant change in the complementary colors. In this work, we aimed at synthesizing two types of NPs based on compositionally complex core-shell NPs-Ag shells on AuNPs (Au@AgNPs) and Ag inside gold nanoshells (Ag@AuNPs). By controlling the thickness of the shells and their surface chemistry with anti-SEA antibody (Ab), the LSPR band was tuned to near 495 and 520 nm for Ag@AuNPs and Au@AgNPs, respectively. The two particle systems were subsequently applied to spectroscopically and visually detect anti-SEA Ab-SEA interactions. Upon the addition of SEA, large red shifts of the LSPR band were observed spectroscopically and the limits of detection (LODs) were estimated to be 0.2 and 0.4 nM for Au@AgNPs and Ag@AuNPs, respectively. Although the two sets of NPs gave almost identical LODs, the Ag@AuNPs whose initial position of the LSPR band was tuned in the cyan to green region (∼500 nm) displayed a substantially more distinct color change from orange to red, as revealed by the naked eye. We foresee significant potential to this strategy in medical diagnostics and environmental monitoring, especially when basic laboratory infrastructure is sparse or nonexistent.


Ophthalmic applications of lipid-based drug nanocarriers: an update of research and patenting activity.
Ophthalmic diseases collect great attention by researchers and pharmaceutical technologists, since they can dramatically worsen the quality of life. Because of the limited duration of action on the eye surface, and anatomical/physiological barriers to drug penetration from it into the inner eye structures, conventional ocular formulations are generally unable to perform at their best. Nanotechnology approaches can represent a solution to improve the therapeutic efficiency, compliance and safety of ocular drugs. In this respect, lipid-based nanocarriers are among the most interesting systems. Their composition and production methods make them highly biocompatible and safe formulations. This review illustrates the developments achieved in ocular drug delivery using lipid-based nanocarriers, with a critical revision of recent scientific articles and filed patents.


Short-term-toxicity of 4-methyl-1-phenylpentan-2-ol in rats.
Groups of 15 male and 15 female rats were given diets to provide intakes of 0 (control), 10, 40 or 160 mg 4-methyl-1-phenylpentan-2-ol/kg/day for 13 wk. No effects attributable to treatment were seen in the 10-mg/kg/day dose group. At 40 mg/kg/day the only finding was a decrease in serum glucose in males. This was of questionable toxicological significance. At 160 mg/kg/day a reduction in weight gain, probably due to unpalatability, a mild proteinuria in the females, an increased relative liver weight in males, increased caecal weights, a reduction in serum glucose and a lower reticulocyte count were recorded. No changes were observed in the histopathological examination. The no-untoward-effect level established in this study was 10 mg/kg/day.


How is my child doing - parental understanding of their children when a parent has cancer.
To explore the difficulties parents face when understanding their children's reactions to parental cancer and parents' reactions to their children's perceived needs. Qualitative interviews with cancer patients and their partners. Eleven patients and seven partners took part. Their children were aged 1-15 years. Eight patients were mothers and cancer was diagnosed median 28 (7-104) months ago. Inductive analysis with systematic text condensation. Parents were groping in the dark when understanding their children's reactions. They observed signs of distress in their children, but often avoided communication about emotional reactions. We suggest parental difficulties in containing own and children's emotions as an important cause for this situation. Parents lacked relevant support offers for the family as a unit. Identification of children's difficulties cannot be based on parental evaluation alone. We suggest family support as part of standard care for patients with minor children.


Integrated mangrove-shrimp cultivation: Potential for blue carbon sequestration.
Globally, shrimp farming has had devastating effects on mangrove forests. However, mangroves are the most carbon-rich forests, with blue carbon (i.e., carbon in coastal and marine ecosystems) emissions seriously augmented due to devastating effects on mangrove forests. Nevertheless, integrated mangrove-shrimp cultivation has emerged as a part of the potential solution to blue carbon emissions. Integrated mangrove-shrimp farming is also known as organic aquaculture if deforested mangrove area does not exceed 50% of the total farm area. Mangrove destruction is not permitted in organic aquaculture and the former mangrove area in parts of the shrimp farm shall be reforested to at least 50% during a period of maximum 5 years according to Naturland organic aquaculture standards. This article reviews integrated mangrove-shrimp cultivation that can help to sequester blue carbon through mangrove restoration, which can be an option for climate change mitigation. However, the adoption of integrated mangrove-shrimp cultivation could face several challenges that need to be addressed in order to realize substantial benefits from blue carbon sequestration.


Evaluation of NucliSens-AmpliScreen methodology to detect subtypes G of HIV-1 and 4c/4d of HCV in the screening of blood donors.
Albeit, the NucliSens Extractor combined with the Ampliscreen was validated for application in NAT minipool screening, a study to evaluate the reliability of the procedure in relation to subtypes G of human immunodeficiency virus (HIV)-1 RNA and 4c/4d of hepatitis C virus (HCV) RNA should be performed, due to their genetic differences and the high frequency in our country. Samples from patients infected with subtypes G of HIV-1 RNA and 4c/4d of HCV RNA were diluted with negative plasma and tested eight times for each concentration. For nucleic acid extraction we used an automated silica-based extraction method (NucliSens Extractor) and for amplification and detection the AmpliScreen HIV-1 version 1.5 and AmpliScreen HCV version 2.0 (Roche Diagnostic Systems) were applied. The sensitivity for HIV-1 RNA genotype G using the NucliSens-AmpliScreen method-95% detection limit (95% CI) of 25 (18-50) copies per ml-is comparable with those described for genotypes B and E and to that obtained by the Multiprep procedure. In the case of HCV, the sensitivity of the method was also similar, when we compared the detection limits obtained for genotype 4c/4d-95% detection limit (95% CI) of 34 (24-71) IU/ml-with the genotype 1 published. The data presented here suggest that these infections will not be missed because of genetic variation, as the platform exhibited similar limits of detection for the subtypes evaluated, meeting the sensitivity requirements set by the regulatory bodies.


Development of a liquid chromatography-mass spectrometry method for the high-accuracy determination of creatinine in serum.
An LC-MS method for the high-accuracy determination of creatinine in serum has been developed and used to provide results for an international measurement evaluation programme (IMEP) and the Comité Consultatif pour la Quantité de Matière (CCQM) international inter-laboratory studies. An assessment of different sample preparation methods, including ion-exchange chromatography, solid-phase extraction, plasma ultrafiltration and ethanol protein precipitation, revealed that no bias or reduced precision was associated with the quicker less extensive clean-up methods, when using liquid chromatography-isotope dilution mass spectrometry (LC-IDMS) for quantitation. A number of different calibration regimes were also investigated. External calibration was shown to provide adequate calibration for most routine analysis with a relative associated expanded uncertainty (k=2) of 6% at the 95% confidence level. The use of a non-isotopically labelled internal standard was shown to improve the relative expanded uncertainty (k=2) to 4%. However, the difference in retention time between the internal standard and the creatinine was such that a matrix interferent produced an observed bias of over 16%. The use of an isotopically labelled internal standard was shown to reduce any bias to less than 0.2% with an expanded uncertainty (k=2) of less than 0.3%. The developed method was then used, in a blind trial organised jointly by IMEP and CCQM, to determine the amount of creatinine in human serum. The method performed well against the established reference method of ion-exchange chromatography followed by derivatisation gas chromatography (GC)-IDMS. The observed difference between the values determined by LC-IDMS and the key comparison reference value (average of all the submitted results) was less than 0.3%. The biggest advantage of the described method is in the speed of analysis. With a chromatographic run time of less than 10 min and sample preparation consisting of a simple protein precipitation, without the need for a derivatisation stage, the analysis is vastly simpler then the conventional GC-IDMS reference method.


Relating costs to the user value of farmland biodiversity measurements.
The impact of agricultural management on global biodiversity highlights the need for farm-scale monitoring programmes capable of determining the performance of agriculture practices. Yet the identification of appropriate indicators is a challenging process and one that involves considering a number of different aspects and requirements. Besides the attention given to scientific effectiveness, relevant but less studied issues related to biodiversity measurements include the economic feasibility of monitoring programmes and the relevance of indicators for different end-users. In this paper, we combine an analytic assessment of costs and a stakeholder-based evaluation of the usefulness of a set of biodiversity-related parameters (habitat mapping, vegetation, bees, earthworms, spiders, and a farmer questionnaire) tested for scientific consistency in 12 European case studies and on more than 14,000 ha of farmland. The results point to the possibility of meeting the expectations of different end-users (administrators, farmers and consumers) with a common indicator set. Combining costs and usefulness also suggests the possibility of designing more efficient monitoring approaches involving private agencies and networks of volunteers and farmers for the field data collection at different stages of a monitoring programme. Although complex, such an approach would make it possible to enhance the effectiveness of available funds for farmland biodiversity monitoring.


GEMOX: An Active Regimen for the Treatment of Luminal and Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer.
Pretreated metastatic breast cancer (MBC) remains a formidable challenge with unmet needs both in terms of prolonged survival and quality-of-life-related issues. We collected data from 27 MBC patients treated with gemcitabine and oxaliplatin (GEMOX) at our institution between June 2009 and April 2015. The patients were heavily pretreated, and all had previously been exposed to anthracyclines and taxanes. We achieved a complete response in 1 patient (4%), a partial response in 7 patients (26%) and stable disease in 12 patients (44%), while 6 patients (22%) experienced progressive disease. The response of 1 patient (4%) could not be evaluated because she interrupted her treatment during the first cycle due to a major reaction to oxaliplatin. We observed grade 4 hypertransaminasaemia in only 1 patient (4%) and grade 2 neuropathy in 16 patients (59%). Grade 3 leuconeutropenia was observed in 5 patients (18%). The median progression-free survival was 5.9 months and the median overall survival was 9.6 months. GEMOX is an efficient and well-tolerated salvage regimen for MBC patients.


Lymphoblastoid interferon in chronic hepatitis C patients who were "non responders" to recombinant interferon alpha (rIFN alpha).
The aim of this study was to investigate whether there is a variable responsiveness of the hepatitis C virus and/or of the affected host to different types of interferon. We treated 21 patients affected by chronic hepatitis C who failed to respond to recombinant alpha interferon, after a four-month interval, with lymphoblastoid interferon. Alanine transaminase (ALT) serum level was normal in 9 patients (43%) at the end of treatment. At the end of a 12 months treatment-free follow-up serum ALT remained normal in 3 patients, 4 patients relapsed and 2 dropped-out. As yet there are no reports of differences in the therapeutic efficacy of the two types of interferon used in our study. The good response to the lymphoblastoid interferon in our non responders to recombinant alpha interferon may be due to the immune modulation induced by the four-month wash-out interval between the two therapies or to a different virus sensitivity to this interferon.


The use of levonorgestrel - IUD in the treatment of uterine myoma in Thai women.
This study was designed to evaluate the potential usefulness of the levonorgestrel-releasing intrauterine device (LNG - IUD ; Mirena) in treating women with uterine myomas. Prospective before-and-after (comparing) study. Department of Obstetrics and Gynecology King Chulalongkorn Memorial Hospital. Sixteen women with uterine myomas who intended to receive treatment with the LNG IUD. Clinical and ultrasound examinations were performed prior to and at 1, 3 and 6 months after the LNG IUD insertion. Myoma and Uterine volume, menstrual blood loss assessed with pictorial blood loss assessment charts and hematocrit. Use of the LNG IUD was associated with a statistically significant reduction in the total myoma volume, average uterine size and marked reduction in menstrual blood loss. After 6 months of use, the median total myoma volume decreased from 19.82 mL to 11.63 mL (p < 0.05), median pictorial blood loss assessment chart score declined from 89 to 3 (p < 0.05). Hematocrit level increased over 6 months of use. The most common side effects were bleeding disturbances (68.8%). No pregnancies occurred during the study. The LNG IUD was associated with a profound reduction in myoma and uterine volume. For women with myomas of this size, the LNG IUD provides effective medical treatment of bleeding.


The Role of Chinese Herbs and Acupuncture on the Inflammation Reaction After Cerebral Ischemia.
As a complex pathological process, immune inflammatory reaction plays an important role in the injury by cerebral ischemia. Inflammatory mediators can promote each other to coregulate the immune inflammatory reaction. Inflammatory cytokines play a pivotal role in regulating the immune inflammatory reaction process. Chinese herbs and acupuncture can exert a protective effect against neuronal damage by cerebral ischemia by inhibiting the production and expression of inflammatory cytokines and adhesion molecules, effectively blocking the inflammatory reaction and reducing the apoptosis of nerve cells.


The costs of mobilisation and collection of peripheral blood stem cells in multiple myeloma and lymphoma in an European country: results from The Gruppo Italiano Trapianto Midollo Osseo (GITMO) and Società Italiana di Emaferesi e Manipolazione Cellulare (SIdEM) survey.
Scarce information is available about the cost of mobilisation/collection of peripheral blood stem cells for patients undergoing autologous transplant for relapsed Lymphoma or Multiple Myeloma. This paper reports the consumption of resources and costs collected through a survey among Italian Centres who adhere to the GITMO and SIdEM scientific societies. General transplant information was extracted from the European Promise database. Resources used alongside the phases of mobilisation/collection were retrieved. Resources for each of the process phases were quantified and averaged across centres and a unit cost value was attributed, based on administrative data from 3 centres, tariffs and market values. 25/89 Centres (34% of 2009 Promise transplants) provided data according to their standard practice. The mean cost/patient of the process of cell mobilisation/collection was € 6830 ± 1802 for Multiple Myeloma and € 7304 ± 1542 for Lymphoma. The organisational path for PBSC mobilisation/collection appears complex and cumbersome, spread amongst different treatment settings, with many different healthcare professionals being involved and considerable amounts of time and resources being currently dedicated to the management of patients requiring autologous transplantation.


Low oxygen tension and autologous plasma enhance T-cell proliferation and CD49d expression density in serum-free media.
As cellular immunotherapy with ex vivo expanded cells becomes more widely used to treat a variety of illnesses, optimization of culture parameters, to maximize cell production and function, is essential for continued success. The effects of reduced oxygen tension and autologous plasma on T-cell expansion, receptor expression, apoptosis, and cytolytic activity in serum-free media were investigated. PBMCs derived from whole blood samples were activated with anti-CD3 and anti-CD28 MAb in serum-free (AIM V) medium containing IL-2, and maintained at 5% and 20% oxygen tension. In some cases cultures were supplemented with 2% autologous plasma. Low oxygen enhanced T-cell expansion 13- and 4.8-fold in serum-free and plasma-supplemented media, respectively. Autologous plasma also had a beneficial effect on T-cell cultures. Plasma-supplemented cultures expanded 74-fold more than serum-free cultures at low oxygen tension, and 43-fold more at high oxygen tension. Several samples expanded very poorly under serum-free conditions, and reasonable cell numbers were obtained only from plasma-supplemented cultures. CD49d expression density increased 3-fold to 4-fold in cultures supplemented with plasma. In contrast to our previous findings in serum-containing media, IL-2 receptor expression kinetics were unaffected by oxygen tension. No effects caused by oxygen tension or autologous plasma on expression of other surface antigens (CD4, CD8, CD44, CD95) were observed. Low oxygen tension and autologous plasma greatly increase expansion of T cells, thereby decreasing the time needed for production of cells for prophylaxis. Increased CD49d expression density may translate into improved migration and cytotoxicity.


Adult neurogenesis acts as a neural regularizer.
New neurons are continuously generated in the subgranular zone of the dentate gyrus throughout adulthood. These new neurons gradually integrate into hippocampal circuits, forming new naive synapses. Viewed from this perspective, these new neurons may represent a significant source of "wiring" noise in hippocampal networks. In machine learning, such noise injection is commonly used as a regularization technique. Regularization techniques help prevent overfitting training data and allow models to generalize learning to new, unseen data. Using a computational modeling approach, here we ask whether a neurogenesis-like process similarly acts as a regularizer, facilitating generalization in a category learning task. In a convolutional neural network (CNN) trained on the CIFAR-10 object recognition dataset, we modeled neurogenesis as a replacement/turnover mechanism, where weights for a randomly chosen small subset of hidden layer neurons were reinitialized to new values as the model learned to categorize 10 different classes of objects. We found that neurogenesis enhanced generalization on unseen test data compared to networks with no neurogenesis. Moreover, neurogenic networks either outperformed or performed similarly to networks with conventional noise injection (i.e., dropout, weight decay, and neural noise). These results suggest that neurogenesis can enhance generalization in hippocampal learning through noise injection, expanding on the roles that neurogenesis may have in cognition.


Energy use and carbon footprints differ dramatically for diverse wastewater-derived carbonaceous substrates: An integrated exploration of biokinetics and life-cycle assessment.
Energy neutrality and reduction of carbon emissions are significant challenges to the enhanced sustainability of wastewater treatment plants (WWTPs). Harvesting energy from wastewater carbonaceous substrates can offset energy demands and enable net power generation; yet, there is limited research about how carbonaceous substrates influence energy and carbon implications of WWTPs with integrated energy recovery at systems-level. Consequently, this research uses biokinetics modelling and life cycle assessment philology to explore this notion, by tracing and assessing the quantitative flows of energy embodied or captured, and by exploring the carbon footprint throughout an energy-intensive activated sludge process with integrated energy recovery facilities. The results indicate that energy use and carbon footprint per cubic meter of wastewater treated, varies markedly with the carbon substrate. Compared with systems driven with proteins, carbohydrates or other short-chain fatty acids, systems fed with acetic acid realized energy neutrality with maximal net gain of power from methane combustion (0.198 kWh) and incineration of residual biosolids (0.153 kWh); and also achieved a negative carbon footprint (72.6 g CO2). The findings from this work help us to better understand and develop new technical schemes for improving the energy efficiency of WWTPs by repurposing the stream of carbon substrates across systems.


In vivo preservation of steroid specificity in CWR22 xenografts having a mutated androgen receptor.
In vitro studies of CWR22 tumor cells lack steroid specificity. We sought to determine if CWR22 xenografts also lack steroid specificity. We injected castrated nude mice with CWR22 tumor cells (6 x 10(6) cells) and implanted Alzet osmotic pumps that delivered approximately 1 mg steroid/kg body weight/day. Serum PSA levels were detectable in intact mice and castrated mice treated with testosterone (T), but not in those treated with estradiol (E(2)), progesterone (P), or flutamide (F). T maintained mean tumor weight similar to that in intact mice (P = NS). We observed no tumors in castrated mice or mice treated with E(2), P, or F, and tumor histology was consistent with weights. The mutation of the androgen receptor (H874Y) that occurs in the CWR22 xenograft model of human prostate cancer does not significantly affect in vivo steroid specificity for E(2), P, or F.


Interaction of specifically chemically modified dextrans with transforming growth factor beta1: potentiation of its biological activity.
Transforming growth factor beta (TGFbeta), a potent multifunctional cytokine, is well known to demonstrate heparin binding ability. This study investigated the binding capacity of heparin-like family of chemically modified dextrans to TGFbeta1. Dextran derivatives with various substitution contents in carboxymethyl, benzylamide and sulfate groups were evaluated using a gel mobility shift assay. This structure-function study indicated that a synergistic role of benzylamide and sulfate substituents resulted in an optimal interaction with the growth factor. The effect of these polymers on the biological response of TGFbeta1 was assessed using mink lung epithelial cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct (PAI/Luc). When the growth factor was mixed with 250 microg/mL of carboxymethyl-benzylamide-dextran (DCMB) or carboxymethyl-benzylamide-sulfate-dextran (DCMBSu), the luciferase gene expression was enhanced. Only polymers exhibiting TGFbeta1 binding demonstrated a biological potentiating effect. However, this effect was strongly amplified as the cell plating time increased (35-fold increase with a 2 days plating time versus 1.1-fold increase with a 4 hr plating time at a 0.25 ng/mL concentration of TGFbeta1). TGFbeta1 induced the PAI/Luc construct in a dose-dependent fashion but its effect diminished when added to cells previously cultured for 24 and 48 hr. The results indicated that the potentiating effect required a complex formation between TGFbeta1 and polymers, the action of which seeming to locally maintain TGFbeta1 in an active form. TGFbeta isoforms playing a key role in the process of bone repair, specifically designed functionalized dextrans could potentiate the in vivo TGFbeta1 biological effect and be used in the field of wound healing applications.


Is access to workplace amenities associated with leisure-time physical activity among Canadian adults?
The workplace represents an important setting for increasing physical activity levels. The purpose of the present study was to investigate the relationship between the workplace environment and leisure-time physical activity, using a nationally representative sample of the Canadian population. This study used cross-sectional, self-reported data from 48,916 participants who completed relevant questions on the 2008 Canadian Community Health Survey. Associations between supportive workplace environments for physical activity (e.g., perceived range of amenities available such as a pleasant place to walk, fitness facility, showers, and health program) and leisure-time physical activity level (active, moderately active, inactive) were examined using multinomial logistic regression. Approximately three quarters (n=36,216) of participants had access to at least one amenity that supported physical activity while at work. Females in the lowest age category (18-35 years) who perceived a more supportive workplace environment for physical activity had higher odds of being moderately active (AOR 1.06, 95% CI 1.04-1.08) and active (AOR 1.15, 95% CI 1.13-1.17) as compared to inactive in their leisure time. The strength of this association was slightly higher with age and for males. Since the majority of Canadian adults do not meet recommended levels of physical activity, the workplace offers a promising and modifiable target for increasing opportunities to be physically active. Employers who can provide a more supportive workplace environment for physical activity would benefit, as it can increase employees' physical activity levels and ultimately improve their productivity and overall health. These benefits may be increased for males and with employees' age.


Effect of dipyridoimidazole pretreatment on mutagen activation in rats.
Rats were pretreated with a single oral dose of different mutagenic fractions obtained from glutamic acid pyrolysate: Glu-P-2 (2-amino-dipyrido[1,2-a:3',2'-d]imidazole), Glu-P-3 (3-amino-4,6-dimethyldipyrido[1,2-a:3',2'-d]imidazole), the tar residue and a basic extract (B2). The liver S9 fractions of these animals were used to investigate the mutagenic activation of 3 promutagens (2-aminoanthracene, Glu-P-2 and Glu-P-3) in Salmonella typhimurium strain TA1538. Different factors were analyzed; influence of the structure of the compounds administered, doses, time interval between pretreatment and sacrifice and sex of the rats. Interpretation of the hepatic induction effects was complicated, however, by the fact that simple oral pretreatment with the solvents (DMSO or ethanol) enhances the activation of the substrates tested for mutagenicity. A dose-effect relationship was found between 2-AA mutagenic activation and Glu-P-2 pretreatment. Glu-P-3 induced the activation of 2-AA more than did Glu-P-2, in the male as in the female. The mutagenicity of 2-AA activated with S9 from male rats was found to be optimal after 24 h pretreatment with 20 mg Glu-P-2/kg b.w. The mutagenicity of Glu-P-2 was poorly influenced by the different pretreatments applied to either the males or the females, whereas some dose effect was found in the autoinduction of Glu-P-2 mutagenicity. Compared to Glu-P-2, the mutagenicity of Glu-P-3 was increased at higher levels when tested with S9 from males pretreated with the same compound, but no differences were observed between males and females.


Behaviour of contact allergy and new sensitivities on subsequent patch tests.
Patch tests repeated one or more times over periods of up to 3 years in 208 subjects with allergic contact dermatitis produced evidence of persistent specific sensitivities in almost 50% of cases. In about 25% the reactivity disappeared and over 25% developed new sensitivities. No new sensitivities appeared in 253 patients with non-allergic contact dermatitis or with other types of dermatitis in whom the same patch tests were carried out. The history and follow-up of patients with new sensitivities brought into focus the presumed aetiopathogenetic role of further contacts, especially occupational or after topical applications. Patch tests themselves, provided the correct technique is employed especially as regards the concentration of allergens, do not seem to be responsible for new sensitizations to any significant extent.


Prostaglandin derivatives inhibit the growth of malarial parasites in mice.
New prostaglandin oligomeric derivatives, termed MR-256 and MR-356, were found to inhibit the growth of murine malarial parasites, P. chabaudi and P. vinckei, within red blood cells in vivo. When mice were infected with P. chabaudi, both MR-256 and MR-356 suppressed the growth of parasites, but MR-356 had a greater inhibitory effect than MR-256. With P. vinckei, MR-356 also inhibited the growth of parasites, and improved the survival rate. The effect of MR-256 was much less. A possible inhibitory mechanism of action of these drugs is discussed.


Pregnancy in patients with previous successful renal transplantation.
To evaluate the risk factors affecting pregnancy, perinatal outcomes, and short-term graft condition in women who underwent renal transplantation. Between May 1998 and January 2005, the histories of 20 pregnancies in 17 renal transplant recipients were reviewed retrospectively at the Ministry of Health Aegean Obstetrics and Gynecology Teaching Hospital. There were significant associations between high serum creatinine level (>1.5 mg/dL) prior to pregnancy and preterm delivery (P=0.04), and between short interval between transplantation and pregnancy (<2 years) and increased rate of cesarean sections (P=0.04). There were no significant changes in serum creatinine levels during pregnancy in these women, and there were no acute rejection and graft loss during pregnancy or in the 6 months following delivery. These findings suggest that, although pregnancy does not adversely affect short-term renal allograft function, the rates of obstetric and perinatal complications are increased. Risk factors present before conception are a short interval between renal transplantation and pregnancy and poor renal function.


Decoupling local mechanics from large-scale structure in modular metamaterials.
A defining feature of mechanical metamaterials is that their properties are determined by the organization of internal structure instead of the raw fabrication materials. This shift of attention to engineering internal degrees of freedom has coaxed relatively simple materials into exhibiting a wide range of remarkable mechanical properties. For practical applications to be realized, however, this nascent understanding of metamaterial design must be translated into a capacity for engineering large-scale structures with prescribed mechanical functionality. Thus, the challenge is to systematically map desired functionality of large-scale structures backward into a design scheme while using finite parameter domains. Such "inverse design" is often complicated by the deep coupling between large-scale structure and local mechanical function, which limits the available design space. Here, we introduce a design strategy for constructing 1D, 2D, and 3D mechanical metamaterials inspired by modular origami and kirigami. Our approach is to assemble a number of modules into a voxelized large-scale structure, where the module's design has a greater number of mechanical design parameters than the number of constraints imposed by bulk assembly. This inequality allows each voxel in the bulk structure to be uniquely assigned mechanical properties independent from its ability to connect and deform with its neighbors. In studying specific examples of large-scale metamaterial structures we show that a decoupling of global structure from local mechanical function allows for a variety of mechanically and topologically complex designs.


Chemical shift assignments of the catalytic domain from the yeast proline isomerase Fpr4p.
Yeast Fpr4p belongs to the FK506-binding protein (FKBP) class of peptidyl proline isomerases (PPIases), and has been implicated in regulating the cis-trans conversion of proline residues within histone tails. Here we report the (1)H, (13)C and (15)N chemical shift assignments for the bacterially expressed C-terminal PPIase catalytic domain of Fpr4p. Prediction of secondary structure reveals similarity to domains from other members of the FKBP proline isomerases, including yeast Fpr1p and the prototypic PPIase region from human FKBP12.


Inflammatory myofibroblastic tumor presenting as ileocecal intussusception-A case report.
Inflammatory myofibroblastic tumor (IMFT) is an uncommon mesenchymal solid tumor commonly documented in children and young adults. It is usually located in lungs however, extrapulmonary involvement has also been reported. Here we report a case of IMFT presenting as an ileocecal intussusception. A 55-year-old man presented with a two months history of colicky abdominal pain, more intense at the right inferior abdominal quadrant, and unintentional weight loss of 8kg in the previous four months. Computer tomography showed an image of intussusception at the cecum. Colonoscopy demonstrated a pediculated tubular lesion, with the base near ileocecal valve. We performed a right hemicolectomy. Histopathological examination of the tumor revealed an IMFT. IMFT usually affects lungs with rare gastrointestinal involvement. Clinical presentation is related with location of the neoplasm. Intussusception in adults presents with non-specific symptoms and classical image signs facilitate preoperative diagnosis. IMFT diagnosis is histopathological which usually implies surgical resection. Complete surgical excision, with microscopically clear margins, is the mainstain of treatment, with virtually no local recurrence or metastasis. Gastrointestinal IMFT are rare in the adult population and clinical features depend on its location. Surgical approach with total excision of the neoplasm confirms the diagnosis. Prognosis is good with the main prognostic indicator being the adequacy of the primary excision.


Preexisting antibodies to homologous colonization factors and heat-labile toxin in serum, and the risk to develop enterotoxigenic Escherichia coli-associated diarrhea.
Preexisting serum immunoglobulin (Ig) A and IgG titers against colonization factors and heat-labile toxin of enterotoxigenic Escherichia coli (ETEC) were examined in young adults who subsequently developed ETEC-associated diarrhea and in healthy matched controls. The data suggest an inverse association between the antibody titers against colonization factors, but not heat-labile toxin, and development of ETEC-associated diarrhea.


Toxicity of Hypofractionated Whole Breast Radiotherapy Without Boost and Timescale of Late Skin Responses in a Large Cohort of Early-Stage Breast Cancer Patients.
To report toxicity of hypofractionated whole-breast radiotherapy in a large cohort of early-stage breast cancer (BCaients. From 02/2009-05/2017, 1325 consecutive BCa patients were treated with 40.05 Gy/15 fractions, without boost. Median age was 62 (IQR:51.1-70.5) years. Chemotherapy was prescribed for 28% of patients, hormonal therapy for 80.3%, monoclonal antibodies for 8.2%. Median follow-up was 72.4 (IQR: 44.6-104.1) months. Acute RTOG toxicity was: 69.8% Grade (G) 1, 14.3% G2 and 1.7% G3. Late SOMA-LENT toxicities were: edema-hyperpigmentation (E-H): G1 28.67%, G2 4.41%, G3 0.15%; fibrosis-atrophy-telangiectasia-pain (F-A-T-P): G1 14.6%, G2 3.2%, G3 0.8%, G4 0.1%. Median time to first occurrence was 6 and 18 months, respectively. Aesthetic result after surgery was excellent in 28.7%, good in 41.5%, acceptable in 20.3% and poor in 9.5% of patients. Change in breast appearance after radiotherapy was mild in 6.9%, moderate in 2.3% and marked in 1.3% of patients. Concomitant chemotherapy, obesity, smoking, use of bolus and planning target volume (PTV) were associated with higher acute toxicity. Patients ≥55 years old were less likely to experience acute toxicity. PTV and acute G2 toxicity were associated with ≥G2 E-H. PTV, concomitant chemotherapy, hypertension and ≥G2 acute toxicity were associated with increased risk of F-A-T-P. Hypofractionated whole-breast radiotherapy without boost demonstrated mild acute and late toxicity in a large cohort of consecutive patients. Moderate and marked changes in breast appearance were registered for 3.6% of patients and occurred between 18 to 42 months.


[HerediCaRe: Documentation and IT Solution of a Specialized Registry for Hereditary Breast and Ovarian Cancer].
The national registry "HerediCaRe" for the evaluation and improvement of risk-adjusted prevention in hereditary breast and ovarian cancer is one of six "model registries in health services research" funded by the BMBF. In this paper, we describe and discuss the documentation and IT solution chosen for standardized data collection based on the specific functional requirements previously defined. The documentation is divided into different modules to be used individually for each patient, which are based on a previously defined catalog of documentation items. Due to special functional requirements, a specific data entry application based on ORACLE and ORACLE Forms was developed and implemented. The specific requirements included the integration of graphical pedigree representations, the structured upload of pedigree data and molecular genetic information, the automated transfer of old data from the previous system, as well as the free programmability of complex database queries for central data quality control. A database for patient-independent management of genetic risk variants was seamlessly integrated into the application and linked to the patient-related data. The advantages and disadvantages of the chosen IT solution are critically discussed. Overall, we come to the conclusion that, in view of the complex documentation and the special functional requirements, there are no alternative ready-made software products to the in-house development we have chosen.


[Recruitment maneuvers for patients with lung failure. When, how, whether or not?].
Recruitment maneuvers have been proposed as an adjunct to mechanical ventilation to re-expand collapsed lung regions. Although, in most patients recruitment maneuvers improve gas exchange a controversial discussion on recruitment maneuvers remains. This article reviews the physiological and patho-physiological backgrounds of recruitment maneuvers. The different recruitment maneuvers and possible monitoring are discussed as well as the influence of recruitment on other organs. Furthermore, we discuss whether recruitment maneuvers are useful if patients with acute lung injury or acute respiratory distress syndrome are ventilated with a lung-protective strategy.


Video-assisted thoracoscpic muscle transposition for acute empyema.
Muscle flap transposition is one of the surgical treatment options for empyema with alveolarpleural fistula (APF) or bronchopleural fistula (BPF). This surgical procedure is invasive because it is typically performed by standard thoracotomy. We performed video-assisted thoracoscopic surgery (VATS) debridement, decortication, and obliteration of an empyema cavity using a pedicled latissimus dorsi muscle (LDM) flap harvested through minimal skin incisions for a case of acute empyema with APF. This VATS procedure is effective and less invasive and can be a new option for the thoracoscopic surgical treatment of acute empyema with APF.


Three-dimensional control of the helical axis of a chiral nematic liquid crystal by light.
Chiral nematic liquid crystals--otherwise referred to as cholesteric liquid crystals (CLCs)--are self-organized helical superstructures that find practical application in, for example, thermography, reflective displays, tuneable colour filters and mirrorless lasing. Dynamic, remote and three-dimensional control over the helical axis of CLCs is desirable, but challenging. For example, the orientation of the helical axis relative to the substrate can be changed from perpendicular to parallel by applying an alternating-current electric field, by changing the anchoring conditions of the substrate, or by altering the topography of the substrate's surface; separately, in-plane rotation of the helical axis parallel to the substrate can be driven by a direct-current field. Here we report three-dimensional manipulation of the helical axis of a CLC, together with inversion of its handedness, achieved solely with a light stimulus. We use this technique to carry out light-activated, wide-area, reversible two-dimensional beam steering--previously accomplished using complex integrated systems and optical phased arrays. During the three-dimensional manipulation by light, the helical axis undergoes, in sequence, a reversible transition from perpendicular to parallel, followed by in-plane rotation on the substrate surface. Such reversible manipulation depends on experimental parameters such as cell thickness, surface anchoring condition, and pitch length. Because there is no thermal relaxation, the system can be driven either forwards or backwards from any light-activated intermediate state. We also describe reversible photocontrol between a two-dimensional diffraction state, a one-dimensional diffraction state and a diffraction 'off' state in a bilayer cell.


A novel descriptor based on atom-pair properties.
Molecular descriptors have been widely used to predict biological activities and physicochemical properties or to analyze chemical libraries on the basis of similarity. Although fingerprints and properties are generally used as descriptors, neither is perfect for these purposes. A fingerprint can distinguish between molecules, whereas a property may not do the same in certain cases, and vice versa. When the number of the training set is especially small, the construction of good predictive models is difficult. Herein, a novel descriptor integrating mutually compensating fingerprint and property characteristics is described. The format of this descriptor is not conventional. It has two dimensions with variable length in one dimension to represent one molecule. This format is not acceptable for any machine learning methods. Therefore the distance between molecules has been newly defined for application to machine learning techniques. The evaluation of this descriptor, as applied to classification tasks, was performed using a support vector machine after the features of the descriptor had been optimized by a genetic algorithm. Because the optimizing feature is time-intensive due to the complicated calculation of distances between molecules, the optimization was forced to stop before it was completed. As a result, no remarkable improvement was observed in the classification results for the new descriptor compared with those for other descriptors in any evaluation set used in this work. However, extremely low accuracies were also not found for any set. The novel descriptor proposed in this work can potentially be used to make highly accurate predictive models. This new concept in descriptors is expected to be useful for developing novel predictive methods with quick training and high accuracy.


Effect of labetalol on the uptake of [3H]-(-)-noradrenaline into the isolated vas deferens of the rat.
1 The effects of the combined alpha- and beta-adrenoceptor blocking drug, labetalol, on the uptake of [3H]-(-)-noradrenaline into the isolated vas deferens of the rat have been determined and compared with those of some other alpha-adrenoceptor blocking drugs and cocaine. 2 Labetalol, like cocaine, produced a simple competitive inhibition of [3H]-(-)-noradrenaline uptake and was about 4 times less potent than cocaine. It is concluded that labetalol is a potent inhibitor of uptake1. Phentolamine and thymoxamine also inhibited [3H]-(-)-noradrenaline uptake, and were respectively 8 and 14 times less potent than cocaine. Tolazoline, piperoxan and yohimbine were inactive in concentrations up to 30 microgram/ml. 3 The uptake1 blocking action of labetalol could explain, at least in part, the previously reported difference in its ability to block noradrenaline and phenylephrine vasopressor responses in the anaesthetized dog. 4 The possibility that uptake1 inhibitory concentrations of labetalol could be present in the blood of subjects receiving normal antihypertensive doses of the drug is discussed.


The influence of implant surface roughness on decontamination by antimicrobial photodynamic therapy and chemical agents: A preliminary study in vitro.
The aim of this preliminary study was to analyze the effectiveness of three different protocols of decontamination on five commercial moderate rough implants. The types of implants investigated were: Neoporos Drive CM (CM; Neodent®), Drive CM Acqua (ACQ; Neodent®), SLActive (SLA; Straumann®), Osseotite (OT; Biomet 3i®) and Nanotite (NT; Biomet 3i®). Implant surface properties (n = 2/type of implant; control groups) were analyzed by scanning electron microscopy (SEM) images to determine surface roughness parameters (SRP) and energy disperse X-ray spectrometry to determine the chemical composition. Implants were then inoculated with Aggregatibacter actinomycetencomitans in vitro (n = 6/type of implant;experimental groups) and the contaminated areas were determined in SEM images (500x magnifications). Decontamination of implants was performed in duplicate by three protocols: antimicrobial photodynamic therapy (aPDT), EDTA associated with citric acid (EDTA + CA) and 0.12 % chlorhexidine (CHX). The remaining contaminated area (rCtA) was determined in SEM images (500x magnifications). All quantitative analysis through SEM images were analyzed in ImageJ® software for two-dimensional parameters. No significant differences were found in SRP among implants (control group), except for Rv (lowest valley) between SLA vs. OT (p=0.0031; Kruskal Wallis post hoc Dunn). NT implants showed highest contaminated area vs. ACQ implants (68.19 % ± 8.63 % and 57.32 % ± 5.38 %, respectively; p = 0.0016, Tukey's test). SRP after decontamination showed statistical difference for Ra (arithmetical mean deviation) for all decontamination groups when compared to control (p < 0.05; ANOVA with post-hoc Tukey's multiple comparisons test), only CM implants showed statistical difference when compared decontamination protocols to control with highest modification of SRP for EDTA + AC group. For decontamination analysis, for applicability of different protocols in the same type of implant, only SLA showed statistical significant difference for aPDT vs. EDTA + CA (p = 0.0114; ANOVA with post-hoc Tukey's multiple comparisons test) with lowest rCTA for aPDT, however for ACQ implants the aPDT showed lowest rCTA with no statistical difference (p > 0.05; ANOVA with post-hoc Tukey's multiple comparisons test). No statistical difference was observed between the decontamination protocols at other implant types. It can be suggested that the chemical-physical characteristics of dental implants can be effected by the process of contamination and decontamination by aPDT and chemical agents.


Iron metabolism and iron supplementation in cancer patients.
Iron deficiency and iron deficiency-associated anemia are common complications in cancer patients. Most iron deficient cancer patients present with functional iron deficiency (FID), a status with adequate storage iron, but insufficient iron supply for erythroblasts and other iron dependent tissues. FID is the consequence of the cancer-associated cytokine release, while in absolute iron deficiency iron stores are depleted resulting in similar but often more severe symptoms of insufficient iron supply. Here we present a short review on the epidemiology, pathophysiology, diagnosis, clinical symptoms, and treatment of iron deficiency in cancer patients. Special emphasis is given to intravenous iron supplementation and on the benefits and limitations of different formulations. Based on these considerations and recommendations from current international guidelines we developed recommendations for clinical practice and classified the level of evidence and grade of recommendation according to the principles of evidence-based medicine.


Identification and characterization of errors and incidents in a medical intensive care unit.
To assess the frequency, type, consequences, and associations of errors and incidents in a medical intensive care unit (ICU). Two-hundred and sixteen consecutive patients with predominantly cardiovascular and pulmonary disorders admitted between December 2002 and February 2003 were enrolled. Demographic data, SAPS II, and TISS-28 were obtained for all patients. Prior to patient enrolment all staff members (physicians, nurses, physiotherapists) were repeatedly encouraged to make use of the Incident Report Form (IRF) and detailed descriptions on how, why and when to use the IRF were provided. During the observation period of 64 days, 50 errors involving 32 patients (15%) were reported. Patients subjected to errors were more severely ill (SAPS II 42 +/- 25 vs. 32 +/- 18, P < 0.05), had a higher hospital mortality (38% vs. 9%), and a longer ICU stay (11 +/- 18 vs. 3 +/- 5 days, P < 0.05). Gender, age and TISS-28 were equally distributed. Each day of ICU stay increased the risk by 8% (odds ratio 1.078, 95% confidence interval 1.034-1.125, P < 0.001), and by 2.3% per SAPS II point (odds ratio 1.023, 95% confidence interval 1.006-1.040, P < 0.001). The majority of errors and incidents were judged as 'human failures' (73%), and 46 errors and incidents (92%) as 'avoidable'. The identification and characterization of errors and incidents combined with contextual information is feasible and may provide sufficient background information for areas of quality improvement. Areas with a high frequency of errors and incidents need to undergo process evaluation to avoid future occurrence.


Protective down-regulated states in the human brain: A possible lesson from COVID-19.
The COVID-19 pandemic has created a large population of patients who are slow to recover consciousness following mechanical ventilation and sedation in the intensive care unit. Few clinical scenarios are comparable. Possible exceptions are the rare patients in post-cardiac arrest coma with minimal to no structural brain injuries who recovered cognitive and motor functions after prolonged delays. A common electroencephalogram (EEG) signature seen in these patients is burst suppression [8]. Biophysical modeling has shown that burst suppression is likely a signature of a neurometabolic state that preserves basic cellular function "during states of lowered energy availability." These states likely act as a brain protective mechanism [9]. Similar EEG patterns are observed in the anoxia resistant painted turtle [24]. We present a conceptual analysis to interpret the brain state of COVID-19 patients suffering prolonged recovery of consciousness. We begin with the Ching model and integrate findings from other clinical scenarios and studies of the anoxia-tolerant physiology of the painted turtle. We postulate that prolonged recovery of consciousness in COVID-19 patients could reflect the effects of modest hypoxic injury to neurons and the unmasking of latent neuroprotective mechanisms in the human brain. This putative protective down-regulated state appears similar to that observed in the painted turtle and suggests new approaches to enhancing coma recovery [12].