Evaluation of indigenous bacterial strains for biocontrol of the frogeye leaf spot of soya bean caused by Cercospora sojina.
Assessment of biological control of Cercospora sojina, causal agent of frogeye leaf spot (FLS) of soya bean, using three indigenous bacterial strains, BNM297 (Pseudomonas fluorescens), BNM340 and BNM122 (Bacillus amyloliquefaciens). From cultures of each bacterial strain, cell suspensions and cell-free supernatants were obtained and assayed to determine their antifungal activity against C. sojina. Both mycelial growth and spore germination in vitro were more strongly inhibited by bacterial cell suspensions than by cell-free supernatants. The Bacillus strains BNM122 and BNM340 inhibited the fungal growth to a similar degree (I ≈ 52-53%), while cells from P. fluorescens BNM297 caused a lesser reduction (I ≈ 32-34%) in the fungus colony diameter. The foliar application of the two Bacillus strains on soya bean seedlings, under greenhouse conditions, significantly reduced the disease severity with respect to control soya bean seedlings and those sprayed with BNM297. This last bacterial strain was not effective in controlling FLS in vivo. Our data demonstrate that the application of antagonistic bacteria may be a promising and environmentally friendly alternative to control the FLS of soya bean. To our knowledge, this is the first report of biological control of C. sojina by using native Bacillus strains.


Rapidly developing tolerance to transdermal nitroglycerin in congestive heart failure.
We have reported early attenuation of hemodynamic effects of transdermal nitroglycerin in patients with heart failure. We now report nitroglycerin plasma levels in those same patients. We administered transdermal nitroglycerin, 60 mg/24 h, to eight patients or placebo to seven patients in a double-blind fashion, and monitored pulmonary wedge pressure and nitroglycerin plasma levels for 24 hours. After placebo administration, nitroglycerin plasma levels and pulmonary wedge pressure remained unchanged. During transdermal nitroglycerin administration, the plasma nitroglycerin level rose from 0.04 +/- 0.12 ng/mL at baseline to near peak levels at 2 hours (7.43 +/- 7.21 ng/mL). Between 2 and 24 hours, levels fluctuated at a steady state. Pulmonary wedge pressure fell from 22 +/- 7 mm Hg at control to a nadir of 14 +/- 5 mm Hg at 4 hours (p less than 0.01). Despite persistently high plasma nitroglycerin levels, by 18 hours pulmonary wedge pressure was no longer significantly reduced (20 +/- 9 mm Hg). These results indicate that rapid development of tolerance is the cause of attenuated hemodynamic efficacy of transdermal nitroglycerin.


An efficient scheme for purification of a novel recombinant immunotoxin, rCCK8PE38, for anti-tumour experiments.
rCCK8PE38 is a novel immunotoxin that targets choleystokinin B receptor, which is over-expressed in some tumor tissues. Although we constructed a prokaryotic expression vector to express rCCK8PE38 in our laboratory, thorough purification was necessary to quantitatively assess its anti-tumor effect. In this study, we established a purification protocol to obtain rCCK8PE38 with high purity from E. coli. Three different types of chromatography, hydrophobic chromatography, ion exchange chromatography and size exclusion chromatography, were used in combination. The purification technological parameters of each chromatography type were optimized. The whole process of purification was arranged to minimize the purification steps and achieve purity and bioactivity. Finally, through this optimized scheme, we obtained a recombinant protein with a purity of >95%; then, the protein was stored at -80°C after lyophilization. The purified protein was used in a tumor inhibition experiment and was effective in killing tumor cells that over-expressed choleystokinin B receptor. The results of this study may provide some valuable information about protein purification and lay the foundation for further clinical experiments with rCCK8PE38.


Infarto cerebral embólico como complicación perioperatoria de un mixoma auricular.
Perioperative stroke is one of the complications that can occur during the surgical procedure and up to 30 days after it. A 52-year-old woman with no neurological symptoms and a diagnosis of intracardiac mass. She underwent cardiac surgery with resection of the tumor that was compatible with atrial myxoma. In the immediate postoperative, she presented neurological symptoms and was diagnosed with basal ganglia infarction of embolic etiology. Perioperative stroke appears most frequently in cardiovascular surgery but is rarely reported in heart tumor resection surgery.


Proton pump inhibitors co-prescribed with warfarin reduce warfarin control as measured by time in therapeutic range.
Warfarin is an oral anticoagulant that requires ongoing monitoring with time in therapeutic range (TTR), a common measure of the quality of warfarin control and likelihood of adverse events including bleeds. Numerous factors can influence these warfarin outcomes including drug interactions. Proton pump inhibitors (PPIs) have been reported to interact with warfarin but there remain conflicting reports with regard to the impact on bleeds and limited data on TTR. Therefore, the aim of this study was to determine the effect of PPIs on warfarin control using TTR and bleeds as endpoints. Retrospective data were collected for patients managed by a warfarin management clinic in Queensland. Data collected included current medications, reported bleeds and INR results to calculate TTR. Patients were grouped as taking PPIs or not taking PPIs. Analysis of TTR and bleeds occurred for these groups both before and after exclusions of other medication reported to interact with warfarin. Of the 4494 included patients, almost half (44.5%) were taking PPIs with esomeprazole most commonly (34.8%) prescribed. Patients taking PPIs had significantly reduced TTR compared with patients not taking PPIs both before (78.5 ± 9.7% vs 81.7 ± 10.2%, P < 0.0001) and after (84.4 ± 5.1% vs 89.4 ± 8.0%, P < 0.0001) excluding all other interacting medications with warfarin. Patients taking PPIs also had significantly higher incidence of minor bleeds compared with patients not taking PPIs (32.4% vs 26.1%, P = 0.0487). Patients taking PPIs with warfarin had significantly lower TTRs and higher incidence of minor bleeds. This combination warrants additional caution and monitoring with warfarin control as measured by TTR potentially affected.


A Comparison between Mechanical Thrombectomy and Intra-arterial Fibrinolysis in Acute Basilar Artery Occlusion: Single Center Experiences.
Recent advances in intra-arterial techniques and thrombectomy devices lead to high rate of recanalization. However, little is known regarding the effect of the evolvement of endovascular revascularization therapy (ERT) in acute basilar artery occlusion (BAO). We compared the outcome of endovascular mechanical thrombectomy (EMT) versus intra-arterial fibrinolysis (IAF)-based ERT in patients with acute BAO. After retrospectively reviewed a registry of consecutive patients with acute ischemic stroke who underwent ERT from September 2003 to February 2015, 57 patients with acute BAO within 12 hours from stroke onset were enrolled. They were categorized as an IAF group (n=24) and EMT group (n=33) according to the primary technical option. We compared the procedural and clinical outcomes between the groups. The time from groin puncture to recanalization was significantly shorter in the EMT group than in the IAF group (48.5 [25.3 to 87.8] vs. 92 [44 to 179] minutes; P=0.02) The rate of complete recanalization was significantly higher in the EMT group than in the IAF group (87.9% vs 41.7%; P<0.01). The good outcome of the modified Rankin Scale score≤2 at 3 months was more frequent in the EMT group than in the IAF group, but it was not statistically significant (39.4% vs 16.7%; P=0.06). EMT-based ERT in patients with acute BAO is superior to IAF-based ERT in terms of the reduction of time from groin puncture to recanalization and the improvement of the rate of complete recanalization.


Grape berry position affects the diurnal dynamics of its metabolic profile.
Solar irradiance and air temperature are characterized by dramatic circadian fluctuations and are known to significantly modulate fruit composition. To date, it remains unclear whether the abrupt, yet predictive, diurnal changes in radiation and temperature prompt direct metabolic turn-over in the fruit. We assessed the role of fruit insolation, air temperature, and source-tissue CO2 assimilation in the diurnal compositional changes in ripening grape berries. This was performed by comparing the diurnal changes in metabolite profiles of berries positioned such that they experienced (a) contrasting diurnal solar irradiance patterns, and (b) similar irradiance but contrasting diurnal CO2 assimilation patterns of adjacent leaves. Grape carbon levels increased during the morning and decreased thereafter. Sucrose levels decreased throughout the day and were correlated with air temperature, but not with the diurnal pattern of leaf CO2 assimilation. Tight correlation between sucrose and glucose-6-phosphate indicated the involvement of photorespiration/glycolysis in sucrose depletion. Amino acids, polyamines, and phenylpropanoids fluctuated diurnally, and were highly responsive to the diurnal insolation pattern of the fruit. Our results fill the knowledge gap regarding the circadian pattern of source-sink assimilate-translocation in grapevine. In addition, they suggest that short-term direct solar exposure of the fruit impacts both its diurnal and nocturnal metabolism.


Phosphorescent Molecules That Resist Concentration Quenching in the Solution State: Concentration-Driven Emission Enhancement of Vaulted trans-Bis[2-(iminomethyl)imidazolato]platinum(II) Complexes.
In this paper, we describe the first phosphorescent molecules that do not exhibit the concentration quenching in the homogeneous solution state throughout the entire range of concentrations. A series of newly designed polymethylene-vaulted trans-bis[2-(iminomethyl)imidazolato]platinum(II) complexes (1a, n = 10; 1b, n = 12; 1c, n = 14) was prepared by treating [PtCl2(CH3CN)2] with the corresponding N,N'-bis[(1H-imidazol-2-yl)methylene]-1,ω-alkanediamines. The trans coordination and vaulted structures of 1 have been unequivocally established from X-ray diffraction studies. When the concentration of a clear homogeneous solution of 1a-c in organic solvents increases from the diluted to the saturated state, the emission intensity and quantum efficiency increase continuously without concentration quenching at ambient temperature. This is in contrast to the emission profiles of other analogues 2-4 and typical AIEgens, which show ordinary concentration quenching under the same measurement conditions. The present concentration-driven emission enhancement is observed more intensely in a solution of a racemic mixture of 1 in comparison to that of the optically pure solution. Kinetic studies, 1H NMR, XRD analyses, and DFT calculations revealed that this specifically intense emission enhancement of 1 is attributed to an increase in the contribution of a 3MMLCT to 1GS transition, which is caused by the specific ability for the formation of a cofacial association dimer of 1.


Advanced heart failure in critical patients (INTERMACS 1 and 2 levels): ventricular assist devices or emergency transplantation?
For patients in advanced heart failure, emergency transplantation or ventricular assist devices (VADs) are possible strategies. The aim of this single-centre, retrospective study was to evaluate early and long-term results for these two strategies. From 2005 to 2011, we analysed 49 INTERMACS level 1 and 2 patients, who were divided into the following two groups: group A comprised 26 patients on the waiting list for heart transplantation with urgent conditions; and group B comprised 23 patients who underwent VAD implantation as a bridge to candidacy. In group A, 25 patients underwent transplantation. In group B, 19 patients were supported with left VAD and four with biventricular VAD. Of these 23 patients, 13 underwent transplantation (mean time 279 ± 196 days). The 30 day mortality was 42.3 and 4.3% in group A and B, respectively. Survival at 6 and 12 months was significantly better in group B than in group A (87 vs 53%, P = 0.018 at 6 months; and 77 vs 48%, P = 0.045 at 12 months). Improved outcomes may justify the use of mechanical assistance devices as a bridge to candidacy or bridge to transplantation in INTERMACS 1 and 2 patients in order to avoid high-risk transplants. Evaluation of long-term multicentre outcomes is needed to assess future strategies.


The prognostic and clinical value of morphometry and DNA cytometry in borderline ovarian tumors: a prospective study.
To evaluate if morphometric features (mitotic activity index, volume percentage of epithelium, and DNA ploidy) are prognostic markers in borderline ovarian tumors (BOTs). Ninety-three serous and mucinous consecutive BOTs diagnosed between 1989 and 2002 were studied. In all tumors, mitotic activity index, volume percentage of epithelium, and DNA ploidy were determined prospectively. Consecutively, age at diagnosis, calculated tumor volume, International Federation of Gynecology and Obstetrics (FIGO) stage, and treatment by extensive staging were evaluated after a median follow-up of 52 months. Serous BOTs presented at a younger age (P<0.05), with smaller volume (P<0.001), with higher FIGO stage (P<0.001), and were more frequently bilateral (P<0.001) than mucinous BOTs. Patients with serous BOT (P<0.05) and beyond stage Ia (P<0.01) showed worse recurrence-free survival. No prognostic significance could be established for DNA ploidy or morphometry. The previously claimed prognostic power of DNA ploidy and morphometry could not be corroborated in this prospective study and can therefore not be recommended to direct clinical management in BOTs. In contrast, histologic subtype and FIGO stage seem to be stable prognosticators in BOTs.


Neural cell adhesion molecule polysialylation enhances the sensitivity of embryonic stem cell-derived neural precursors to migration guidance cues.
The development of stem cell-based neural repair strategies requires detailed knowledge on the interaction of migrating donor cells with the host brain environment. Here we report that overexpression of polysialic acid (PSA), a carbohydrate polymer attached to the neural cell adhesion molecule (NCAM), in embryonic stem (ES) cell-derived glial precursors (ESGPs) strikingly modifies their migration behavior in response to guidance cues. ESGPs transduced with a retrovirus encoding the polysialyltransferase STX exhibit enhanced migration in monolayer cultures and an increased penetration of organotypic slice cultures. Chemotaxis assays show that overexpression of PSA results in an enhanced chemotactic migration toward gradients of a variety of chemoattractants, including fibroblast growth factor 2 (FGF2), platelet-derived growth factor, and brain-derived neurotrophic factor (BDNF), and that this effect is mediated via the phosphatidylinositol 3'-kinase (PI3K) pathway. Moreover, PSA-overexpressing ESGPs also exhibit an enhanced chemotactic response to tissue explants derived from different brain regions. The effect of polysialylation on directional migration is preserved in vivo. Upon transplantation into the adult striatum, PSA-overexpressing but not control cells display a targeted migration toward the subventricular zone. On the basis of these data, we propose that PSA plays a crucial role in modulating the ability of migrating precursor cells to respond to regional guidance cues within the brain tissue. Disclosure of potential conflicts of interest is found at the end of this article.


[Osteoid osteoma and labrum injury in a hip of a 29-year-old woman].
Osteoid osteoma is a benign bone tumour most commonly seen in long bones, and CT-scan is the modality of choice showing nidus with surrounding sclerosis. Osteoid osteoma with an intra-articular location in the hip may lack sclerosis, and it may also lack nocturnal pain and pain relieved by non-steroidal anti-inflammatory drugs, which is most commonly seen in osteoid osteoma. This is a case report of a combination of osteoid osteoma and labrum injury in a hip of a 29-year-old woman.


Additional studies concerning the metabolism of packed erythrocytes in CPD adenine.
Studies concerning the relationship between glucose level, hematocrit to which cells were packed (within three hours of initial collection) and adenosine triphosphate (ATP) concentration were undertaken in CPD supplemented with adenine (0.25 mM final concentration). It was found that apparently adequate ATP levels could be maintained in 90 per cent hematocrit packed units at 42 days only if glucose was present in amounts 1.5 times or greater than that provided by CPD. Less tight packing of the units to 70 and 80 per cent hematocrit maintained ATP at greater than 50 per cent of the initial level for a full 42 days of storage when 1.25 times the usual glucose concentration was present in the initial anticoagulant. No difference in 2,3-diphosphoglycerate or pH was found in any of the modified media under study.


Lung function in relation to six-minute walk test in pulmonary hypertension.
Background: Pulmonary hypertension (PH) is a progressive disorder of the pulmonary circulation, associated with diverse medical conditions. Exercise limitation is the most prominent symptom in PH. Exercise capacity, commonly assessed through a six-minute walk test (6MWT), correlates with both functional status and survival in PH. Few studies have analysed the relation between respiratory function and exercise limitation. Therefore, we investigated the relationship between resting pulmonary function, exercise capacity, and exertional desaturation, assessed through the 6MWT, in unselected PH patients. Methods: Fifty consecutive patients with PH diagnosis, referred for pulmonary function testing (lung volume, spirometry, and diffusing capacity for carbon monoxide (DLCO)) and 6MWT, were recruited at Molinette University Hospital, Turin. Results: The majority of the patients (54%) had PH due to left heart disease. Airway obstruction (FEV1/VC-ratio < 0.7) was found in 46% of the patients and they performed significantly worse in the 6MWT than unobstructed patients (307 m vs. 377 m). Patients with PH due to left heart disease also performed significantly poorer 6MWT when airway obstruction was present (305 m vs. 389 m). Twenty-two patients (44%) presented exertional desaturation upon 6MWT. Lower DLCO divided by the alveolar volume (DLCO/VA), FEV1/VC-ratios and resting PaO2-values were significantly correlated with exertional desaturation after adjustments for age, sex, BMI, and smoking habits. DLCO/VA was the main determinant of exertional desaturation in a stepwise regression model. Conclusions: Spirometric parameters of airway obstruction were related to walk distance and exercise-induced desaturation in PH patients. This suggests a place for spirometry in clinical monitoring of PH patients.


Widespread synchronous decline of Mediterranean-type forest driven by accelerated aridity.
Large-scale, abrupt ecosystem change in direct response to climate extremes is a critical but poorly documented phenomenon1. Yet, recent increases in climate-induced tree mortality raise concern that some forest ecosystems are on the brink of collapse across wide environmental gradients2,3. Here we assessed climatic and productivity trends across the world's five Mediterranean forest ecosystems from 2000 to 2021 and detected a large-scale, abrupt forest browning and productivity decline in Chile (>90% of the forest in <100 days), responding to a sustained, acute drought. The extreme dry and warm conditions in Chile, unprecedented in the recent history of all Mediterranean-type ecosystems, are akin to those projected to arise in the second half of the century4. Long-term recovery of this forest is uncertain given an ongoing decline in regional water balance. This dramatic plummet of forest productivity may be a spyglass to the future for other Mediterranean ecosystems.


MicroRNA-regulated protein-protein interaction networks: how could they help in searching for pro-longevity targets?
In spite of enormous efforts and accumulated knowledge, our capabilities for tackling aging and age-related diseases (ARDs), and ultimately to promote longevity, are still very modest. What is lacking--essential data on key players, efficient analytic tools, or both? Here we discuss how the existing data may be integrated and analyzed in the context of microRNA (miRNA)-regulated protein-protein interaction networks. The proposed model highlighted: (1) The strong molecular links between aging, longevity, and ARDs; (2) the possibility and even the preferability of initiating longevity-promoting interventions in adult life; (3) the potentially important role for miRNA- (or small interfering RNA [siRNA]) mediated targeting of certain genes with features of antagonistic pleiotropy; (4) the superiority of systemic interventions to the common single-target approach in curing ARDs and promoting longevity.


Clinical nomogram for lymph node metastasis in pathological T1 esophageal squamous cell carcinoma: a multicenter retrospective study.
Endoscopic resection is increasingly used to treat pathological T1 (pT1) esophageal cancer (EC) patients. However, the procedures are limited by lymph node metastasis (LNM) and remain controversial. We aimed to construct a nomogram to predict the risk of LNM in patients with pT1 esophageal squamous cell carcinoma (ESCC). A total of 243 patients with pT1 ESCC who underwent esophagectomy and lymph node dissection at two different institutes between February 2013 and June 2019 were analyzed retrospectively. Patients were categorized into the negative group and the positive group according to whether there was LNM. Risk factors for LNM were evaluated by univariate and multivariate analyses. The nomogram was used to estimate the individual risk of LNM. Forty-six (18.9%) of the 243 patients with pT1 ESCC exhibited LNM. The LNM rate in patients with stage T1a disease was 5.7% (5/88), and the rate in patients with stage T1b disease was 26.5% (41/155). Multivariable logistic regression analysis showed that tumor differentiation [odds ratio (OR) =1.942, 95% confidence interval (CI): 1.067-3.536, P=0.030], the T1 sub-stage (OR =4.750, 95% CI: 1.658-13.611, P=0.004), the preoperative alanine aminotransferase/aspartate aminotransferase ratio (LSR) (OR =5.371, 95% CI: 1.676-17.210, P=0.005), and the high-density lipoprotein cholesterol (HDL-C) level (OR =5.894, 95% CI: 1.917-18.124, P=0.002) were independent risk factors for LNM. The nomogram had relatively high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.803 (95% CI: 0.732-0.873). The calibration curve showed that the predicted probability of LNM was in good agreement with the actual probability. Clinicopathological and hematological parameters of tumor differentiation, the T1 sub-stage, the preoperative LSR, and the HDL-C level may predict the risk of LNM in T1 ESCC. The risk of LNM can be predicted by the nomogram.


Er,Cr:YSGG Laser as a Means of Orthodontic Adhesive Removal: Myth or Reality?
Objective: This study aimed to compare the effect of Er,Cr:YSGG laser with a tungsten carbide bur in orthodontic finishing on the enamel surface roughness and the heat generated in the pulp chamber. Methods: Before bonding, of 125 intact extracted premolar teeth, 15 teeth were randomly assigned to the control group. Of the remaining 110 bonded teeth, 50 were used to determine the laser parameters, and 60 were included in the main in vitro study. After debonding, the teeth were randomly distributed among four study groups (n = 15) for finishing with laser beams (Er,Cr:YSGG, Waterlase) with and without polishing with Sof-Lex discs, and finishing with a bur (tungsten carbide, Reliance) with and without polishing with Sof-Lex discs. The thermal changes were measured during finishing using a thermo-controller-coupled thermocouple placed in the pulp chamber. Enamel surface roughness was evaluated qualitatively under a scanning electron microscope (SEM) and quantitatively under an atomic force microscope (AFM). Results: The thermal changes of the bur group were significantly higher than those in the laser group (p = 0.0001). Quantitatively, the surface roughness values of all the study groups were significantly higher than those of the control group (p < 0.05), with no significant difference between the study groups (p > 0.05). SEM analysis confirmed the AFM measurements. Conclusions: Er,Cr:YSGG can be recommended as an alternative for a carbide bur for adhesive agent removal after orthodontic debonding, considering its mild thermal effect on the pulp. Polishing with Sof-Lex discs did not significantly reduce the surface roughness, regardless of the finishing procedure.


Treatment of real industrial wastewaters through nano-TiO2 and nano-Fe2O3 photocatalysis: case study of mining and kraft pulp mill effluents.
High quantities of industrial wastewaters containing a wide range of organic and inorganic pollutants are being directly discharged into the environment, sometimes without proper treatment. Nanotechnology has a tremendous potential improving the existing treatments or even develop new treatment solutions. In this study, nano-TiO2 or nano-Fe2O3 was used for the photocatalytic treatment of kraft pulp mill effluent and mining effluent. The experiments with the organic effluent lead to reduction percentages of 93.3%, 68.4% and 89.8%, for colour, aromatic compounds and chemical oxygen demand, respectively, when treated with nano-TiO2/H2O2/UV and nano-Fe2O3/H2O2/UV, at pH 3.0. Significant removal of metals from the mining effluent was recorded but only for Zn, Al and Cd, the highest removal attained with 1.0 g L-1 of nano-TiO2/UV and nano-Fe2O3/UV. Regarding the toxicity of the organic effluent to Vibrio fischeri, it was reduced with the treatments combining the oxidant and the catalyst. However, for the inorganic effluent, the best reduction was achieved using 1.0 g L-1 of catalyst. In fact, the increase in dose of the catalyst, especially for nano-TiO2, enhanced toxicity reduction. Our results have shown that the use of these NMs seemed to be more effective in the organic effluent than in metal-rich effluent.


Immune activation in α1-antitrypsin-deficiency emphysema. Beyond the protease-antiprotease paradigm.
α1-Antitrypsin (AAT) is a potent protease inhibitor, deficiency of which is associated with the presence of emphysema. An imbalance of elastase and antielastase, along with innate inflammation in the lung, is believed to cause lung destruction in α1-antitrypsin deficiency (AATD). It is now apparent that AAT has important immune-regulatory roles that would be lost in AATD, yet adaptive immune responses in the lung have not been investigated in patients with AATD. To assess the adaptive immune response in severe AATD emphysema and compare it with that present in "usual" chronic obstructive pulmonary disease (COPD). The immune inflammatory response in explanted lungs from 10 subjects with AATD was characterized and quantified, and the results were compared with those of 26 subjects with usual COPD and those of 17 smoking and 11 nonsmoking control subjects with normal lung function. Lymphoid follicles (LFs) in AATD and usual COPD were markedly increased when compared with control groups. Molecular analysis of B lymphocytes in LFs showed predominantly mono/oligoclonality. LF number correlated negatively with FEV1/FVC. B lymphocytes and CD4(+) and CD8(+) T lymphocytes were significantly increased in AATD and usual COPD when compared with control groups. IL-32, an important cytokine in induction of autoimmunity, was markedly up-regulated in AATD and usual COPD. An important adaptive immune inflammation, comprising B, CD4(+), and CD8(+) lymphocytes, and LFs, is a prominent feature in AATD. These results change the paradigm of the mechanism of AATD-induced emphysema from a pure elastase-antielastase imbalance to a much more complex one involving the adaptive immune system, similarly to what occurs in usual COPD.


CtIP fusion to Cas9 enhances transgene integration by homology-dependent repair.
In genome editing with CRISPR-Cas9, transgene integration often remains challenging. Here, we present an approach for increasing the efficiency of transgene integration by homology-dependent repair (HDR). CtIP, a key protein in early steps of homologous recombination, is fused to Cas9 and stimulates transgene integration by HDR at the human AAVS1 safe harbor locus. A minimal N-terminal fragment of CtIP, designated HE for HDR enhancer, is sufficient to stimulate HDR and this depends on CDK phosphorylation sites and the multimerization domain essential for CtIP activity in homologous recombination. HDR stimulation by Cas9-HE, however, depends on the guide RNA used, a limitation that may be overcome by testing multiple guides to the locus of interest. The Cas9-HE fusion is simple to use and allows obtaining twofold or more efficient transgene integration than that with Cas9 in several experimental systems, including human cell lines, iPS cells, and rat zygotes.


Immediate postpartum IUD insertions in a Chinese hospital--a two year follow-up.
A data set consisting of 199 immediate postpartum IUD insertions performed at the Xuan Wu Hospital, Beijing, China was analysed in terms of insertion route, category of inserting personnel and device type. IUD expulsion and continuation of use were the outcome events of interest in this study. Based on our findings, the following hypotheses were derived for future confirmative studies: lower expulsion rates and hence, higher continuation rates of immediate postpartum IUD insertions are associated with (1) insertions through the abdominal incision wound for women who had a cesarean delivery as compared to immediate (less than 10 min) vaginal insertions in women with vaginal delivery; (2) obstetrician insertions, as compared to midwife insertions, and (3) use of the Delta T, as compared to that of the Delta Loop. For the derivation of the latter two hypotheses, only the vaginal insertions were studied.


Reproductive Capacity and Scanning Electron Microscopy (SEM) Analyses of the Micromorphological Surfaces of Three Endemic Satureja Species from Bulgaria.
Satureja pilosa Velen., S. coerulea Janka and S. kitaibelii Wierzb. ex Heuff. are Balkan endemic species, and they are distributed in restricted territories, primarily found in dry grasslands, rocky slopes, and stony habitats. This study presents the results of the first embryological and micromorphological analyses of three Satureja species (S. pilosa, S. kitaibelii, and S. coerulea) from the Bulgarian flora. The aim of this study was to establish the features of the male and female reproductive sphere, as well as surface characteristics of leaves, stem, and calyx in order to understand the mode of reproduction, character, size and state of species populations and delimitation. For the embryological study, flowers and flower buds in different developmental stages were collected from plants of natural populations and treated with the classic paraffin method. Reproductive capacity was assessed using the following approaches: (1) acetocarmine test for pollen viability, (2) tetrazolium test (TTZ) for seed viability, and (3) germination test. The surfaces characteristics of leaves, stem, and calyx were analyzed by scanning electron microscopy (SEM). As a result, the study revealed the structures of the male (M) and female (F) generative spheres as well as the processes of gamete development, pollination, and endosperm and embryo formation. It was found that the three Satureja species exhibited a high pollen viability but low seed viability and germination. The SEM analysis showed both common and distinct micromorphology features regarding epidermis, calyx and stem surfaces among the three Satureja species. Notably, the S. coerulea surfaces (leaves, calyx, stem) were clearly distinguishable from the other two Satureja species. Regarding the nutlet surfaces, it was observed that the exocarp surfaces of S. coerulea and S. kitaibelii have a reticulate convex type surface and comprise two types of cells: (1) highly bulging, bubble-like cells; and (2) flat cells with numerous striations. On the other hand, the exocarp of S. pilosa displayed rectangular or polygonal shapes without bubble-like cells, and it had a tabular to slightly convex type surface. Additionally, nutlets (seeds) of both S. coerulea and S. pilosa exhibited distinct papilla formations resembling non-glandular trichomes seen on the ends of the nutlets for S. coerulea and over the entire surface for S. pilosa. The characteristics of the embryological structures and processes, along with the absence of apomixis, characterized the three studied Satureja species as sexually reproducing. The established balanced processes and stable structures contribute to their high reproductive potential and population stability. However, these traits may also decrease their adaptability to environmental changes.


The effect of a dedicated emergency theatre facility on emergency operating patterns.
Following the introduction of a dedicated 24-hour emergency theatre facility in a 500-bed district general hospital, the total amount of emergency general surgery performed after 22.00 hours has been reduced from 37.2 to 13.1%, with a concomitant increase in emergency day-time operating from 22.1 to 51.2%. The majority of the workload was previously performed by the junior grades, and this has remained unchanged. Operative experience has not been diminished with the reduction in night-time surgery, and senior supervision has been enhanced. There has been no significant difference in mortality or morbidity with the changes in operating patterns. Utilization of the theatre staff and time during the night has been improved.


Anticoagulant potential of endothelial cell membrane components.
In this communication some of the important regulatory mechanisms involving endothelial cell surface associated anticoagulant reactions as well as endothelial cell surface expressed receptors which directly contribute to the inhibition of coagulation are reviewed. In particular, the mechanism of action of protease inhibitors such as antithrombin III, heparin cofactor II, or protease nexin I and their possible interaction with glycosaminoglycan components of the endothelial cells is critically summarized. Thrombin binding to endothelial cells, in particular to thrombomodulin, is believed to be a major event in the induction of anticoagulatory mechanisms such as the protein C/protein S system which warrant a balanced hemostatic system. Additional components such as vascular anticoagulant or extrinsic pathway inhibitor may also contribute to the anticoagulant potential of the vessel wall. Furthermore, the modulation of these membrane-associated anticoagulant reactions by other components such as heparin-binding proteins is discussed.


Moyamoya syndrome associated with neurofibromatosis type 1 in a pediatric patient.
Neurofibromatosis type 1 is a multisystem genetic disease of autosomal dominant transmission that reveals important cutaneous manifestations such as café-au-lait spots, multiple neurofibromas, and ephelides in skin fold areas, as well as hamartomatous lesions in the eyes, bones, glands, and central nervous system. Moyamoya disease is a rare progressive vaso-occlusive disorder that occurs with important ischemic cerebrovascular events. Despite the rarity of this association in childhood, children diagnosed with neurofibromatosis type 1 and focal neurologic symptoms should be investigated for moyamoya syndrome. The present study reports the case of a pediatric patient with a rapidly progressive cerebrovascular accident and a late diagnosis of Neurofibromatosis type 1 associated with moyamoya disease.


Striatal plasticity and basal ganglia circuit function.
The dorsal striatum, which consists of the caudate and putamen, is the gateway to the basal ganglia. It receives convergent excitatory afferents from cortex and thalamus and forms the origin of the direct and indirect pathways, which are distinct basal ganglia circuits involved in motor control. It is also a major site of activity-dependent synaptic plasticity. Striatal plasticity alters the transfer of information throughout basal ganglia circuits and may represent a key neural substrate for adaptive motor control and procedural memory. Here, we review current understanding of synaptic plasticity in the striatum and its role in the physiology and pathophysiology of basal ganglia function.


Transforming Undergraduate Student Perceptions of Dementia through Music and Filmmaking.
With nearly 6 million people with dementia (PWD) in the United States, there is a critical need to build an interprofessional dementia workforce. Among the novel approaches to expanding a new workforce, music and the arts show promise for engaging students and trainees. To understand how and why the arts affect attitudes about and engagement with PWD, we examined a service-learning general education undergraduate course centering on music, filmmaking, and dementia. The undergraduate course curriculum brought students to meet with PWD in dementia care settings, build personalized music playlists, coproduce short films about PWD, and write reflective essays. Two researchers independently completed inductive thematic analysis of the films, essays, and course evaluations. Differences were reconciled by consensus. A total of 52 students from three classes completed the course; 24 (46%) were majoring in health sciences. Three key themes emerged: (1) Music helps students connect with people living with dementia in meaningful ways; (2) filmmaking offers students the opportunity to share unique, person-centered stories about dementia and music that empower the voices of PWD; and (3) reflective writing enables students to process new experiences and lessons learned. Unexpectedly, 29 students (56%) reported continued engagement with PWD in their careers, families, and communities after course completion. This study identifies reproducible ways in which undergraduate arts courses thematically focused on dementia not only transform student perceptions about dementia but change the ways in which those students choose to engage with PWD following course completion. Arts and music departments may represent an untapped resource for building a geriatrics workforce. J Am Geriatr Soc 68:1083-1089, 2020.


Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor.
In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a-1x and 1ha-1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.


The humoral immune response is essential for successful vaccine protection against paratuberculosis in sheep.
The role played by the humoral immune response in animals vaccinated against a mycobacterial disease such as paratuberculosis, is not well understood. Sheep vaccinated against Mycobacterium avium subsp. paratuberculosis (MAP) can still become infected and in some cases succumb to clinical disease. The strength and location of the humoral immune response following vaccination could contribute to the ability of sheep to clear MAP infection. We examined the peripheral antibody response along with the localised humoral response at the site of paratuberculosis infection, the ileum, to better understand how this contributes to MAP infection of sheep following vaccination and exposure. Through assessing MAP specific serum IgG1 and IgG levels we show that the timing and strength of the humoral immune response directly relates to prevention of infection following vaccination. Vaccinated sheep that subsequently became infected had significantly reduced levels of MAP specific serum IgG1 early after vaccination. In contrast, vaccinated sheep that did not subsequently become infected had significantly elevated MAP specific serum IgG1 following vaccination. Furthermore, at 12 months post MAP exposure, vaccinated and subsequently uninfected sheep had downregulated expression of genes related to the humoral response in contrast to vaccinated infected sheep where expression levels were upregulated. The timing and strength of the humoral immune response following vaccination against paratuberculosis in sheep directly relates to subsequent infection status. An initial strong IgG1 response following vaccination was crucial to prevent infection. Additionally, vaccinated uninfected sheep were able to modulate that response following apparent MAP clearance, unlike vaccinated infected animals where there was apparent dysregulation of the humoral response, which is associated with progression to clinical disease.


Comparative study of structure and permeability of porous oxide films on aluminum obtained by single- and two-step anodization.
A comparative study of the structure and transport properties of porous aluminum oxide films obtained by single- and two-step anodization was carried out. It is shown that the oxidation regime significantly affect the number of dead-ended channels, which results in more than twice the variation in membrane permeability. The effect is explained by multiple branching of channels on the initial stages of organization of the porous structure. Branching also occurs on later stages governing mass transport properties of porous anodic alumina films. A model describing transport properties of anodic aluminum oxide membranes based on pore branching on domain boundaries was suggested to fit experimental results of permeance of membranes obtained by both single- and two-step anodization.


An ultrastructural analysis of osteochondritic growth plate cartilage in growing swine.
In growing swine, ossification failure due to osteochondrosis has an incidence of nearly 100% in the distal ulna of animals at six months of age, yet the etiology of the disease is understood poorly. In this study, the ultrastructure of the chondrocyte and its pericellular matrix is analyzed in normal growth plates and in growth plates with lesions characteristic of osteochondrosis using aldehyde primary fixatives and osmium-ferrocyanide as the secondary fixative. Chondrocytes in lesion areas fail to undergo normal hypertrophic cell maturation, and they have an accumulation of rough endoplasmic reticulum, lipid droplets and mitochondria. These morphological changes are interpreted to be both variable and nonspecific for osteochondrosis. Within the pericellular matrix of chondrocytes from lesion areas, the most striking abnormality is the presence of a highly condensed matrix with an accumulation of large, irregularly shaped deposits of electron dense material. These morphological alterations are characteristic of a matrix which either is not secreted normally, or in which the highly ordered interactions of diverse macromolecules has been lost. These pericellular matrix changes have not been described in other diseases of growing cartilage. They may be significant in the failure of metaphyseal vascular penetration of the pericellular matrix which is characteristic of osteochondrosis.


Investigating what felt shapes look like.
A recent empirical study claims to show that the answer to Molyneux's question is negative, but, as John Schwenkler points out, its findings are inconclusive: Subjects tested in this study probably lacked the visual acuity required for a fair assessment of the question. Schwenkler is undeterred. He argues that the study could be improved by lowering the visual demands placed on subjects, a suggestion later endorsed and developed by Kevin Connolly. I suggest that Connolly and Schwenkler both underestimate the difficulties involved in rectifying the study they seek to fix. The problem is that the experimental paradigm under consideration fails to account for the role that rational inference plays in newly sighted subjects' ability or inability to recognize spatial properties across modalities. Since answering Molyneux's question requires establishing whether spatial properties can be recognized, across modalities, by newly sighted subjects without recourse to rational inference, this is a problem. Indeed, it is a problem that may be worsened by Schwenkler and Connolly's suggestions regarding the lowering of visual demands on subjects in cross-modal matching tasks.


Poor Outcomes of Acute Hepatitis E in Patients With Cirrhotic Liver Diseases Regardless of Etiology.
Background: Chronic liver diseases (CLDs) have been documented to exacerbate clinical outcomes of acute hepatitis E (AHE). This study aimed to uncover the role of etiology and status of CLD in the adverse outcomes of AHE. We found that superinfection with hepatitis E virus (HEV) in patients with cirrhotic CLD can cause a worsen outcome, leading to exacerbation of AHE, compared with HEV-infected patients without CLD or with noncirrhotic CLD. Additional analysis revealed that the etiology of CLD is not associated with outcomes of AHE patients. These finding suggests that the overall liver status plays a predominant role in determining the outcomes of AHE.


Intercontinental validation of brain volume measurements using MSmetrix.
Background Brain volume assessment has become an important outcome within research and treatment of multiple sclerosis (MS). MSmetrix (Icometrix) has been developed specifically for patients with MS. The original healthy, 'normal' population used for determination of the acceptable brain volume data consisted mainly of Europeans. Methods In the present study, results from 295 completely normal magnetic resonance imaging scans from Brazilian subjects were plotted against the original results in MSmetrix. Results With regard to whole brain volume, only 2% of the healthy adult subjects from Brazil were below the 5th percentile of the graph, and for grey matter volume, only 3% of the subjects were below the 5th percentile of MSmetrix standards. Conclusion MSmetrix may be used across different populations.


AIDS: a global problem.
AIDS has emerged as one of the foremost infectious disease epidemics of the twentieth century. This review summarizes the magnitude of the AIDS problem and the frequency of infection with the causative agent, the human immunodeficiency virus (HIV). The natural history of HIV infection suggests that a high proportion of persons still healthy but infected with HIV will become immunosuppressed over the next decade. These persons are capable of transmitting HIV to others as a venereal disease as well as by blood and blood products. Thus, the epidemic will grow not only because more cases will appear among persons already infected but also because new infections will occur. However, the incidence of new HIV infections within the homosexual community is already slowing because of changing behavior after the advent of AIDS. The spread of HIV infection within the heterosexual community will probably never be as extensive as that in the homosexual community during the early 1980s because of different behavior patterns. Containment of the epidemic will require an effective vaccine as well as changes in personal life style, but it is unlikely these developments will eradicate HIV infection as a public health problem.


Pyrrole-Based Macrocyclic Small-Molecule Inhibitors That Target Oocyte Maturation.
Polo-like kinase 1 (PLK1) plays crucial roles in various stages of oocyte maturation. Recently, we reported that the peptidomimetic compound AB103-8, which targets the polo box domain (PBD) of PLK1, affects oocyte meiotic maturation and the resumption of meiosis. However, to overcome the drawbacks of peptidic compounds, we designed and synthesized a series of pyrrole-based small-molecule inhibitors and tested them for their effects on the rates of porcine oocyte maturation. Among them, the macrocyclic compound (E/Z)-3-(2,16-dioxo-19-(4-phenylbutyl)-3,19-diazabicyclo[15.2.1]icosa-1(20),6,17-trien-3-yl)propyl dihydrogen phosphate (4) showed the highest inhibitory activity with enhanced inhibition against embryonic blastocyst formation. Furthermore, the addition of this compound to culture media efficiently blocked the maturation of porcine and mouse oocytes, indicating its ability to penetrate the zona pellucida and cell membrane. We investigated mouse oocytes treated with compound 4, and the resulting impairment of spindle formation confirmed PLK1 inhibition. Finally, molecular modeling studies with PLK1 PBD also confirmed the presence of significant interactions between compound 4 and PLK1 PBD binding pocket residues, including those in the phosphate, tyrosine-rich, and pyrrolidine binding pockets. Collectively, these results suggest that the macrocyclic compound 4 may serve as a promising template for the development of novel contraceptive agents.


A nondeletional mechanism for central T-cell tolerance.
To be positively selected, immature thymocytes must receive signaling through their T-cell receptor (TCR), and engagement of relatively low-affinity self-peptides permits further T-cell maturation. However, mature T cells no longer overtly respond to such low-affinity antigens, indicating that T cells acquire a higher threshold for activation during thymopoiesis. We wondered whether partial interference in positive selection could produce T cells that respond to the selecting self-peptide. This possibility was tested by injecting procainamide-hydroxylamine (PAHA), a lupus-inducing drug, into the thymus of adult normal mice. Three weeks after the second injection, IgG antichromatin antibodies appeared in the circulation and remained for several months. The murine antichromatin antibodies reacted with the (H2A-H2B)-DNA subnucleosome complex, the predominant specificity in patients with procainamide-induced lupus. In thymus organ and reaggregate cultures, PAHA had no effect on negative selection of T cells with high affinity for a co-present antigen, but acted on CD4+ CD8+ immature T cells as they underwent positive selection. TCR transgenic T cells specific to cytochrome c peptide 88-104 acquired the capacity to respond to the low-affinity analogue at position 99 (lys-->ala) if PAHA was present during their development. PAHA also blocked the capacity of a T-cell line to become anergic after anti-CD3 treatment, suggesting that PAHA prevents the production of negative regulators that accumulate in response to partial signaling through the TCR. These results are consistent with the view that T cells acquire self-tolerance during positive selection, and disruption of this process can result in autoreactive T cells and systemic autoimmunity.


Improvement of the quality and abatement of the biogenic amines of grass carp muscles by fermentation using mixed cultures.
To improve the quality of processed grass carp (Ctenopharyngodon idellus) products and control the accumulation of hazardous substances therein, minced grass carp slices were salted for 6 h at room temperature and then inoculated with mixed starter cultures of Lactobacillus casei, Streptococcus lactis, Saccharomyces cerevisiae Hansen and Monascus anka and fermented for 12 h at 30 degrees C. The changes in some characteristics and biogenic amine contents of the fermented muscles were investigated. During the 12 h fermentation at 30 degrees C, muscles inoculated with mixed starter cultures showed a rapid decrease in pH from 6.0 to 5.1 and suppression of the growth of enterobacteria and pseudomonads. The fermented muscles exhibited better colour, appearance, flavour and overall acceptability than the control (P < 0.05). The changes in non-protein nitrogen and free amino acid contents of the fermented muscles and in their sodium dodecyl sulfate polyacrylamide gel electrophoresis profiles indicated that severe hydrolysis of muscle proteins occurred during fermentation. The accumulation of biogenic amines in the muscles was efficiently reduced by fermentation with mixed starter cultures. Fermentation with mixed starter cultures of L. casei, S. lactis, S. cerevisiae Hansen and M. anka significantly improved the characteristics of grass carp muscles and controlled the accumulation of biogenic amines.


Urethral Reconstruction with Small Intestinal Submucosa Seeded with Oral Keratinocytes and TIMP-1 siRNA Transfected Fibroblasts in a Rabbit Model.
To evaluate the effect of tissue inhibitor of metalloproteinase-1 small interfering RNA (TIMP-1 siRNA) transfected fibroblasts (FB) for urethral reconstruction. A ventral urethral mucosal defect was created. Substitution urethroplasty was performed with small intestinal submucosa (SIS) alone (8 rabbits, group 1), autogenic oral keratinocytes (OK)-seeded SIS (8 rabbits, group 2) or autogenic OK and TIMP-1 siRNA transfected FB-seeded SIS (8 rabbits, group 3). At 1 and 6 months after surgery (4 rabbits at each time point), retrograde urethrogram and histologic analysis were performed to evaluate the outcomes of urethroplasty. TIMP-1 siRNA transfected FB decreased the secretion of type I collagen. Under retrograde urethrography, 5 rabbits in group 1, 6 in group 2 and 7 in group 3 maintained a wide urethral caliber. Histologically, inflammation and fibrosis were observed at 6 months in group 1. The speed of urothelium, smooth muscle and vessel regeneration in group 3 was faster than that in group 2. Comparison of smooth muscle-to-collagen ratio, epithelial layers, smooth muscle content and microvessel density among three groups revealed a significant increase (p < 0.05). TIMP-1 siRNA transfected FB could be used as a source of seed cell for urethral tissue engineering and could prevent the proliferation of urethral scar tissue.


[Biomorphology of the Bacterial Invasion in Chronic pharyngotonsillitis ].
The study investigates whether relapses of chronicpharyngotonsillitis result from new infections caused by theoro-pharyngeal microbial flora or are reactivations of persistent bacterial infections of the tonsils. 90 patients, who were surgically treated for chronicpharyngotonsillitis (age 13 months to 38 years, at least 5 episodes of disease and antibiotic treatment in the past) were included. The surgery was performed in the antibiotic- and symptom-free period (at least 6 weeks after the last exacerbation). Sections of tonsillar tissue were investigated for invasive bacteria using fluorescence in situ hybridization (FISH) with group and species-specific 15/23S RNA based probes. Abundant foci of invasive bacteria were found in 86% of the resected tonsils, despite previous treatment with antibiotica and absent symptoms of ongoing infection. The diffuse infiltration of the tonsils was most predominant in the youger children. Local invasive processes such as abscesses, fissures filled with pus and superficial infiltration of the tonsillar epithelium were more typical for adults. All of the foci were polymicrobial and contained up to 10 different species or groups of bacteria. The local concentrations of invasive bacteria were up to 1012 bacteria/ml. The chronic pharyngotonsillitis is the result of persistent invasive bacterial infections. The polymicrobial nature of the infectious foci enables them to resist the antibiotic treatment and to exacerbate afterwards. The surgical treatment is unavoidable as long as antibiotic treatment fails to clear the infection.


Comparison of statistical methodologies used to estimate the treatment effect on time-to-event outcomes in observational studies.
The use of real-world data became more and more popular in the pharmaceutical industry. The impact of real-world evidence is now well emphasized by the regulatory authorities. Indeed, the analysis of this type of data can play a key role for treatment efficacy and safety. The aim of this work is to assess various methods and give guidance on the comparisons of drugs, mostly with respect to time-to-event data, in non-randomized studies with potentially confounding variables. For that purpose, several statistical methodologies are compared based on simulation studies. These methodologies belong to family classes of methods that are widely used for this type of problem: regression, matching, weighting and subclassification methods. The evaluation criteria used to compare methods performances are the relative bias, the mean square error, the coverage probability and the width of the confidence interval. In this paper, we consider different scenarios of dataset features in order to study the effect of the sample size, the number of covariates and the magnitude of the treatment effect on the statistical methodologies performances. These statistical analyses are conducted within a proportional hazard model framework. Furthermore, we highlight the advantage of using techniques to identify relevant covariates for time-to-event outcomes by comparing two variable selection methods under a frequentist and a Bayesian inference. Based on simulation results, recommendations on each of the family of methods are provided to guide decision making.


Natural occurrence of arsenic in shallow groundwater, Shanyin, Datong Basin, China.
In Shanyin, Shanxi province, China, As concentration in shallow groundwater exceeds guide concentrations, set internationally and nationally at 10-50 microg/L, and may reach 1932.0 microg/L, which has resulted in severe clinical symptoms of arsenic toxity. In this article, chemical characteristics of groundwaters containing anomalous As and mechanisms of arsenic release to shallow groundwaters were studied. Groundwaters containing anomalous As in the study area were characterized by higher pH, higher concentration of phosphate, higher concentration of naphthenic acid, and lower concentrations of sulfate and nitrate. Microbial metabolism of sedimentary organic matter, which is present as high as 1.0% organic C, results in the lower concentrations of sulfate and nitrate. The reactions decrease Eh and produce CO2, which promotes the dissolution of carbonates and increases pH. The clay minerals and colloids including organic matters scavenging arsenic would release arsenic to groundwater in higher pH and lower Eh environment. In addition, the competitive absorption between As and anions (such as phosphate and fluoride) contributes to the release of As from kaolinite, montmorillonite, illite, and Fe oxyhydroxides. Naphthenic acid also promotes mobilization and translocation of As in groundwater systems.


Chandelier-assisted pneumatic retinopexy for rhegmatogenous retinal detachment repair in young adults.
We describe the new technique of chandelier-assisted pneumatic retinopexy in repairing rhegmatogenous retinal detachments in a series of young adults. In the operating room, a 25-gauge trocar cannula is inserted at the pars plana 180° across the preoperatively detected retinal break followed by Chandelier light insertion, which is used in globe fixation and rotation. The retinal periphery is reexamined using scleral indentation and chandelier light endoillumination. Transconjunctival cryopexy is performed around the break followed by paracentesis and pure sulfur hexafluoride gas injection. Twelve eyes of 12 patients were repaired. Their mean (±SD) age was 29.4 (±3.4) years and preoperative corrected distance visual acuity (CDVA) was 0.36 (±0.32). Nine eyes had 1 break while 3 eyes had 2 breaks within 1 clock hour. Mean duration of operation was 11.7 (±1.8) min. No patient experienced major intraoperative complications, but one patient required reoperation. Mean CDVA 6 months postoperatively was 0.63 (± 0.21) (p < 0.05).


Exclusion zones close to wireless communication transmitters aiming to reduce human health risks.
The electromagnetic fields (EMFs) radiated from typical cellular phone transmitter stations are calculated and compared to available guidelines considering thermal and non thermal biological effects. Exclusion zones close to the transmitter station are then estimated. These are three-dimensional figures calculated in comparison to a chosen EMF reference human exposure guideline limit. The volume inside them represents the regions in which the estimated electromagnetic field level is above the limit. Outside the exclusion zone the estimated electromagnetic field is below the limits. This procedure can be very useful in many applications, e.g., when a transmitter station is expected to be placed close to schools, hospitals, or close to areas where people live or work and where they spend much time each day. Owing to the uncertainty in science regarding the minimum non ionizing radiation level below which no adverse health effects can occur, the Precautionary Approach is suggested and it is recommended that EMF human exposure be kept to a minimum.


[A case of advanced colon cancer successfully treated with combination therapy of cetuximab and oxaliplatin, leucovorin, and 5-fluorouracil].
A 65-year-old woman was referred to our hospital for examination of anemia. Colonoscopy showed a type 1 tumor in the ascending colon with nearly complete stenosis that was diagnosed as a tubular adenocarcinoma. Computed tomography (CT) revealed swelling of the regional, periaortic, and celiac lymph nodes and lymphangitis carcinomatosa. The patient was diagnosed as having Stage IV ascending colon cancer, and neoadjuvant chemotherapy was administered to avoid non-curative resection. The patient was treated with cetuximab and oxaliplatin, Leucovorin, and 5-fluorouracil( mFOLFOX6) combination chemotherapy. After 6 courses of chemotherapy, the primary lesion and multiple lymph node swellings greatly reduced in size and lymphangitis carcinomatosa improved. Accordingly, right colectomy with D3 nodal dissection was performed. The patient was recurrence free at her 8-month follow-up examination. Neoadjuvant chemotherapy with molecular targeted drugs is useful in the treatment of patients with unresectable primary cancer.


Prolonged alterations in the serotonin neural system following the cessation of adolescent anabolic-androgenic steroid exposure in hamsters (Mesocricetus auratus).
In hamsters (Mesocricetus auratus), anabolic-androgenic steroid (AAS) exposure during adolescence facilitates offensive aggression that is modulated, in part, by serotonin (5-HT) signaling and development and by signaling and expression of 5-HT1B receptors. To examine whether these effects are persistent or reversible, the authors administered AAS to hamsters, then examined them for aggression at 1, 4, 11, 18, or 25 days following cessation of AAS treatment. Then, 1 day later, hamsters were killed by transcardial perfusion and examined for 5-HT afferents to and 5-HT1B receptor-containing neuronal puncta and somata in areas of the brain altered by AAS, namely, the anterior hypothalamus, ventrolateral hypothalamus, and medial amygdala. Although aggression resulting from AAS exposure returned to control, nonaggressive levels by 18 days following cessation of AAS treatment, alterations in 5-HT afferent innervation and 5-HT1B receptor localization were observed throughout the extended time period examined. These data suggest that adolescent AAS exposure may have long-term, irreversible effects on 5-HT neural systems and that return to nonaggressive behavioral phenotypes following adolescent AAS exposure may not be a function of plasticity in central 5-HT systems.


[Damage of hip prosthesis causing failure in arthroplasty].
Analysis of retrieved hip joint was presented. Bone remodeling considering the distribution of friction products was discussed. Scanning electron microscopy methods were used to perform on structural analysis. We expressed a surface changing prosthetic head as Ra (roughness average). X-Ray Microanalysis was applied to study products of degradation.


Expression profiling of murine intestinal adenomas reveals early deregulation of multiple matrix metalloproteinase (Mmp) genes.
Initiation of intestinal tumours occurs as a consequence of aberrant Wnt signalling. This causes altered expression of a number of genes which provides the mechanistic basis of neoplastic change in normal epithelium. In order to identify these genes, expression profiles of normal intestinal mucosa and intestinal adenomas from multiple intestinal neoplasia (Min) mice were compared. A total of 116 genes were found to show significant changes in expression in adenomas compared with normal mucosa. Functional classification of these genes clearly identified the biological processes of cellular adhesion and matrix remodelling to be profoundly affected. Notably, three members of the matrix metalloproteinase (Mmp) gene family (Mmp10, Mmp13, and Mmp14) were consistently up-regulated in tumour tissue. To extend these data, expression of 17 Mmp genes was defined using quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR). Several Mmp genes were profoundly up-regulated and every tumour showed overexpression of at least four Mmp genes. These results underscore the probable importance of interactions between the intestinal epithelium and stroma in early tumour development. Furthermore, the inferred role of Mmps at the adenomatous stage of tumourigenesis suggests that this may represent the optimal therapeutic window for the use of Mmp antagonists as anti-cancer agents.


N-butyl-2 cyanoacrylate (NBCA) embolus in the graft portal vein after portosystemic collateral embolization in liver transplantation recipient: what is the clinical significance?
Background An N-butyl-2 cyanoacrylate (NBCA) embolus in the graft portal vein was frequently observed after an intraoperative embolization of portosystemic collaterals performed to prevent portal steal in liver transplant (LT) recipients. The radiological and clinical features of NBCA emboli have not yet been described. Purpose To describe radiological and clinical features of NBCA embolus in graft portal vein after portosystemic collateral embolization in LT recipients. Material and Methods A total of 165 consecutive LT recipients who had undergone intraoperative NBCA embolization of varix were found in single institution's computerized databases of a clinical cohort of LT. Patients were evaluated for NBCA emboli (categorized into major and minor emboli according to location) on first postoperative computed tomography (CT). All electronic medical records and radiologic studies including follow-up was evaluated to determine any radiological and clinical abnormality associated with NBCA embolus. Results NBCA emboli were found in 24% (39/165) of recipients. Although most patients had minor emboli (77%, 30/39) without remarkable ultrasonography (US) abnormalities, seven (78%) of nine recipients with major emboli showed intraluminal echogenic lesions in graft portal vein on grayscale US, and five of them (71%) showed partial portal flow obstruction, although none exhibited any abnormality on contrast-enhanced US. Recipients with NBCA portal emboli showed no significant clinical abnormalities and were discharged safely. NBCA embolus eventually disappeared mostly within six months (82%, 32/39). Conclusion NBCA emboli are frequently observed after portosystemic collateral embolization in LT recipients and are not associated with poor clinical outcome. They may mimic ordinary thromboemboli on US.


Carburization of tungsten filaments in a hot-wire chemical vapor deposition process using 1,1,3,3-tetramethyl-1,3-disilacyclobutane.
The alloying of tungsten filament when using 1,1,3,3-tetramethyl-1,3-disilacyclobutane (TMDSCB) in a hot-wire chemical vapor deposition reactor was systematically studied by scanning electron microscopy, Auger electron spectroscopy, analysis of the power consumed by the filament, and in situ mass spectrometric measurements of the gas-phase species produced in the process. Only carburization of the W filament was observed. The carburization is mainly caused by the interaction of methyl radicals with the filament. Graphite as well as both WC and W2C alloys can form on the filament surface, depending on the filament temperatures and source gas pressures. Both WC and graphite are converted to W2C with the diffusion of C into the filament. It is shown that filament carburization affects the consumption rate of the source gas and the intensities of gas-phase reaction products. Gas-phase reactions dominate at T < or = 1400 degrees C. The carburization rate increases with increasing filament temperatures and dominates at T > or = 1800 degrees C.


Isotropic-to-nematic transition in confined liquid crystals: an essentially nonuniversal phenomenon.
Computer simulations are presented of the isotropic-to-nematic transition in a liquid crystal confined between two parallel plates a distance H apart. The plates are neutral and do not impose any anchoring on the particles. Depending on the shape of the pair potential acting between the particles, we find that the transition either changes from first order to continuous at a critical film thickness H=H(x) , or that the transition remains first order irrespective of H . This demonstrates that the isotropic-to-nematic transition in confined geometry is not characterized by any universality class, but rather that its fate is determined by microscopic details. The resulting capillary phase diagrams can thus assume two topologies: one where the isotropic and nematic branches of the binodal meet at H=H(x), and one where they remain separated. For values of H where the transition is strongly first order the shift Deltaepsilon of the transition temperature is in excellent agreement with the Kelvin equation. Not only is the relation Deltaepsilon proportional, variant 1/H recovered but also the prefactor of the shift is in quantitative agreement with the independently measured bulk latent heat and interfacial tension.


Antitumor activity and surface phenotypes of human glioma-infiltrating lymphocytes after in vitro expansion in the presence of interleukin 2.
The present study describes a method for in vitro expansion and characterization of antitumor-reactive lymphoid cells isolated from human malignant astrocytomas. Glioma-infiltrating lymphocytes were separated from 24 glioma specimens and cultured in medium containing interleukin 2 (50 to 2000 units/ml). Within 20 to 42 days after the initiation of culture, 20 of 24 cultures of glioma-derived lymphocytes expanded with a substantial increase in cell numbers, of at least 5 x 10(8) cells up to 5 x 10(9), with a simultaneous elimination of contaminating autologous glioma cells. The expanding glioma-derived lymphocytes consisted of 90 +/- 8% (SD) CD3+ T-cells including both CD4+ and CD8+ subpopulations. CD16 was expressed on 4 +/- 5% of the cells and three cultures studied exhibited 14% +/- 1 of Leu-19-positive cells. After 4 to 8 weeks of proliferation, interleukin 2 receptor expression decreased from 36 +/- 28% to less than 10% and the lymphocytes ceased to grow in all cultures. Glioma-derived effector lymphocytes could lyse almost all the autologous tumor targets as well as allogeneic glioma cells. The cytotoxic activity of long-term cultured peripheral blood lymphocytes obtained from the same patients appeared to be similar to that of glioma-derived lymphocytes in killing autologous tumor cells. In summary, glioma-derived lymphocytes expanded in bulk culture with high concentrations of interleukin 2 (2000 units/ml) consisted predominantly of T-lymphoblasts with the ability to kill autologous glioma cells. The tumor-infiltrating lymphocytes could be expanded to sufficient numbers for possible use in the adoptive immunotherapy of malignant gliomas.


Loving and Leaving Public Health: Predictors of Intentions to Quit Among State Health Agency Workers.
State health agencies play a critical role in protecting and promoting the health and well-being of the people they serve. To be effective, they must maintain a highly skilled, diverse workforce of sufficient size and with proper training. The goal of this study was to examine demographics, job and workplace environment characteristics, job satisfaction, and reasons for initially joining the public health workforce as predictors of an employee's intentions to leave an organization within the next year. This study used a cross-sectional design. Respondents were selected on the basis of a stratified sampling approach, with 5 geographic (paired Health and Human Services [HHS] regions) as the primary strata. Balanced repeated replication was used as a resampling method for variance estimation. A logistic regression model was used to examine the correlates of intentions to leave one's organization within the next year. The independent variables included several measures of satisfaction, perceptions about the workplace environment, initial reasons for joining public health, gender, age, education, salary, supervisory status, program area, and paired HHS region. The sample for this study consisted of 10,246 permanently employed state health agency central office employees who responded to the Public Health Workforce Interests and Needs Survey (PH WINS). Considering leaving one's organization within the next year. Being a person of color, living in the West (HHS regions 9 and 10), and shorter tenure in one's current position were all associated with higher odds of intentions to leave an organization within the next year. Conversely, greater employee engagement, organizational support, job satisfaction, organization satisfaction, and pay satisfaction were all significant predictors of lower intentions to leave one's organization within the next year. Results from this study suggest several variables related to demographics, job characteristics, workplace environment, and job satisfaction that are predictive of intentions to leave. Future researchers and state health agencies should explore how these findings can be used to help with retention of employees in the state health agency workforce.


Targeting Inflammatory Mediators in Epilepsy: A Systematic Review of Its Molecular Basis and Clinical Applications.
Recent studies prompted the identification of neuroinflammation as a potential target for the treatment of epilepsy, particularly drug-resistant epilepsy, and refractory status epilepticus. This work provides a systematic review of the clinical experience with anti-cytokine agents and agents targeting lymphocytes and aims to evaluate their efficacy and safety for the treatment of refractory epilepsy. Moreover, the review analyzes the main therapeutic perspectives in this field. A systematic review of the literature was conducted on MEDLINE database. Search terminology was constructed using the name of the specific drug (anakinra, canakinumab, tocilizumab, adalimumab, rituximab, and natalizumab) and the terms "status epilepticus," "epilepsy," and "seizure." The review included clinical trials, prospective studies, case series, and reports published in English between January 2016 and August 2021. The number of patients and their age, study design, specific drugs used, dosage, route, and timing of administration, and patients outcomes were extracted. The data were synthesized through quantitative and qualitative analysis. Our search identified 12 articles on anakinra and canakinumab, for a total of 37 patients with epilepsy (86% febrile infection-related epilepsy syndrome), with reduced seizure frequency or seizure arrest in more than 50% of the patients. The search identified nine articles on the use of tocilizumab (16 patients, 75% refractory status epilepticus), with a high response rate. Only one reference on the use of adalimumab in 11 patients with Rasmussen encephalitis showed complete response in 45% of the cases. Eight articles on rituximab employment sowed a reduced seizure burden in 16/26 patients. Finally, one trial concerning natalizumab evidenced a response in 10/32 participants. The experience with anti-cytokine agents and drugs targeting lymphocytes in epilepsy derives mostly from case reports or series. The use of anti-IL-1, anti-IL-6, and anti-CD20 agents in patients with drug-resistant epilepsy and refractory status epilepticus has shown promising results and a good safety profile. The experience with TNF inhibitors is limited to Rasmussen encephalitis. The use of anti-α4-integrin agents did not show significant effects in refractory focal seizures. Concerning research perspectives, there is increasing interest in the potential use of anti-chemokine and anti-HMGB-1 agents.


CD1 expression on B-CLL lymphocytes.
In a previous report we showed that D47 CD1a monoclonal antibody positively labelled B-CLL cells of some patients. Six cases were selected to further characterize CD1 antigenic expression at the leukaemic cell surface using flow cytometry with a battery of six CD1a, two CD1b and two CD1c monoclonal antibodies. CLL cells were positively labelled with CD1a antibodies except OKT6 and NA1/34; in all cases they were CD1b negative and CD1c positive. These results suggested that CD1a, c epitopes can be detected on leukaemic B cells in addition to other T cell differentiation antigens. In view of recently published data demonstrating the presence of CD1c molecule in normal B cell subsets, our results further question the relationship of B-CLL with a restricted subpopulation of B cells.


PDGFRα/HER2 and PDGFRα/p53 Co-expression in Oral Squamous Cell Carcinoma.
The purpose of this study was to explore the parallel expression of platelet-derived growth factor receptor α (PDGFRα) and human epidermal growth factor receptor 2 (HER2) or p53 in relation to clinicopathological parameters of oral squamous cell carcinoma (OSCC) to define their role in progressive growth of tumor. Expression of PDGFRα, HER2 and p53 was evaluated in 71 OSCC samples by immunohistochemistry. HER2 status was verified by fluorescence in situ hybridization. PDGFRα and p53 expression were associated with tumor grade (p=0.043 and p=0.040, respectively). HER2 expression was more frequent in advanced (III/IV) cancer (p=0.006). A positive correlation of PDGFRα with HER2 (r=0.267; p=0.024) and with p53 (r=0.266; p=0.025) was noted. PDGFRα/HER2 and PDGFRα/p53 co-expression was found more often in G3 than in G1 and G2 tumors (p=0.008 and p=0.015, respectively). Our study revealed that PDGFRα/HER2 and PDGFRα/p53 co-expression exists in poorly differentiated OSCCs, suggesting that cooperation between these proteins might enhance aggressive behavior of tumor.


Total synthesis of (S)-(+)-tylophorine via enantioselective intramolecular alkene carboamination.
The enantioselective synthesis of (S)-(+)-tylophorine, a potent cancer cell growth inhibitor, has been accomplished in eight steps from commercially available 3,4-dimethoxybenzyl alcohol. A copper (II)-catalyzed enantioselective intramolecular alkene carboamination was employed as the key step to construct the chiral indolizidine ring.


Endoscopic Recession of the Gastrocnemius Tendon.
Gastrocnemius contracture is a common condition associated with painful overload symptoms in the forefoot and midfoot. Multiple techniques have been described for the recession of gastrocnemius tendon in patients who failed nonsurgical treatment. We present an endoscopic recession technique for the release of the gastrocnemius tendon just distal to the level of the musculotendinous junction as a minimally invasive operative option. This technique aims to decrease wound complications, unsightly scar, overlengthening, and postoperative pain, while having versatility for performing with supine or prone positioning.


Comparisons of ergonomic evaluation tools (ALLA, RULA, REBA and OWAS) for farm work.
The purpose of this study was to validate the agricultural lower limb assessment (ALLA) ergonomic checklist, which was developed for various agricultural tasks in Korea. One hundred and ninety-six working postures were selected from the real agricultural tasks to verify ALLA, a lower limb body posture assessment tool, and then evaluated by 16 ergonomic experts. Hit rate, quadratic weighted κ, one-way analysis of variance and t-test analyses were applied to compare ALLA with other assessment tools. ALLA analysis had a superior hit rate with ergonomic expert assessment compared with other assessment tools. Quadratic weighted κ analysis also showed that ALLA provided superior estimates of risk levels for farm working postures. ALLA would be an appropriate assessment tool to estimate risk factors for various lower limb body postures which frequently occur in agricultural tasks in Korea. ALLA is a simple and accurate risk assessment tool that could be usefully applied to identify and mitigate risk factors and work-related musculoskeletal disorders in agricultural tasks, and also to evaluate the effects of control and intervention for working conditions.


Why complex pelvic organ prolapse should be approached abdominally.
This review summarizes the recent clinical trials that address the abdominal approach for treatment of uterine or vaginal vault prolapse following hysterectomy. Open abdominal sacrocolpopexy (ASC) has improved anatomic and sexual functioning outcomes compared with the sacrospinous ligament suspension but this benefit comes with higher costs. Newer studies suggest that minimally invasive approaches to ASC that result in 1 day of hospitalization can be cost-effective. Although most studies demonstrate higher costs when using the robot during laparoscopic surgery, the costs of initial purchase and maintenance become insignificant when a single robot is used at least twice a day (500 procedures annually). Minimally invasive sacrocolpopexy appears to result in less small bowel obstruction and ileus however, intraoperative bowel injury rates are similar. During sacrocolpopexy, placing the sacral suture at the promontory may put the L5-S1 intervetebral disc at risk, while placing the suture 5 mm below the promontory would ensure the suture is at the level of S1 vertebrae. Lastly, the use of cadaveric fascia lata as an alternative to polypropylene mesh for sacrocolpopexy in patients who were followed for 5 years, results in decreased anatomic outcomes, similar subjective outcomes and surprisingly, similar mesh erosion rates. One of the significant benefits of sacrocolpopexy is that it is not a procedure that has been developed for profit. As a result, the procedure has evolved based on modifications suggested by surgeons with no financial gain. Minimally invasive approaches to ASC allow for the benefits of ASC with significant reductions in patient hospitalization.


Primary carnitine deficiency and cardiomyopathy.
Carnitine is essential for the transfer of long-chain fatty acids from the cytosol into mitochondria for subsequent β-oxidation. A lack of carnitine results in impaired energy production from long-chain fatty acids, especially during periods of fasting or stress. Primary carnitine deficiency (PCD) is an autosomal recessive disorder of mitochondrial β-oxidation resulting from defective carnitine transport and is one of the rare treatable etiologies of metabolic cardiomyopathies. Patients affected with the disease may present with acute metabolic decompensation during infancy or with severe cardiomyopathy in childhood. Early recognition of the disease and treatment with L-carnitine may be life-saving. In this review article, the pathophysiology, clinical presentation, diagnosis, treatment and prognosis of PCD are discussed, with a focus on cardiac involvements.


Decrease of isoprene concentrations in blood during general anesthesia.
Isoprene is present in human breath and in human blood. The fact that isoprene concentrations in breath are linked to states of sleep and wakefulness led us to study its concentration in blood of 12 patients before, during, and after general anesthesia. Isoprene concentrations in blood of patients before anesthesia were 3.3 +/- 1.6 micrograms/liter. During anesthesia, isoprene concentrations decreased to 0.9 +/- 0.5 micrograms/liter. One hour after the end of anesthesia isoprene increased to levels similar to or higher than the preanesthetic ones.


The spouses of attempted suicides: a personality study.
The 16 PF was administered to 30 female attempted suicides and their spouses, to 20 male attempted suicides and their spouses and to 50 control men and their spouses. Both the female and male attempted suicides show personality disturbance, but there are also sex differences. The female attempted suicides and their spouses appear to share similar personality characteristics, but the spouses of male attempted suicides appear quite dissimilar from their husbands. The effect of the personality of the spouses is briefly discussed in the context of marital relationships of attempted suicides.


Galvanic vestibular stimulation alters the onset of motor unit discharge.
We have previously shown that galvanic vestibular stimulation (GVS) can modulate the amplitude of the passive soleus H-reflex. This study examined whether the response resulted from a general change in excitability of the motoneuron pool or a specific modulation of individual motor units (MUs). Subjects performed slow isometric plantarflexor actions in a prone lying and kneeling position until the discharge of a single gastrocnemius MU was detected. During randomly selected trials, a 1-mA bipolar, binaural galvanic stimulus was triggered just prior to the start of plantarflexor activity. With the knee extended and the medial gastrocnemius (MG) at a long muscle length, GVS did not have an effect on MU activity. However, when the knee was flexed and the MG muscle was shortened, GVS significantly modified the onset of activation and the initial firing frequency of MUs. This may reflect a change in the gain of the presynaptic inhibitory mechanisms that act on the motoneuron pool once a muscle reaches a shortened, nonoptimal force-producing length. Thus, GVS may provide an important research tool for activating descending vestibulospinal pathways that act on lower-limb motoneurons and may be applied to test the integrity of the spinal cord.


Agenesis of the corpus callosum, abnormal genitalia and intractable epilepsy due to a novel familial mutation in the Aristaless-related homeobox gene.
Mutations in the Aristaless-related homeobox (ARX) gene are associated with a broad spectrum of disorders including X-linked lissencephaly with abnormal genitalia (XLAG) and absent corpus callosum. Here, we describe a family with two male infants suffering from agenesis of the corpus callosum (ACC), intractable epilepsy, and abnormal genitalia. The phenotype of both affected patients differed in severity of the cerebral malformation with one showing no obvious evidence for lissencephaly. Both infants lacked any psychomotor development and died at the age of 17 weeks and 18 months, respectively. Genetic analysis of the ARX gene revealed a novel frameshift mutation in exon 4 (nt1419_1420insAC) leading to a shortened protein lacking the aristaless domain. In summary, analysis of the ARX gene should not only be considered in male patients with typical features of XLAG but also in those presenting with early onset epilepsy, ACC, and abnormal genitalia without obvious neuroradiological features of lissencephaly.


Salidroside pretreatment attenuates apoptosis and autophagy during hepatic ischemia-reperfusion injury by inhibiting the mitogen-activated protein kinase pathway in mice.
Ischemia-reperfusion injury (IRI) contributes to liver damage in many clinical situations, such as liver resection and liver transplantation. In the present study, we investigated the effects of the antioxidant, anti-inflammatory, and anticancer agent salidroside (Sal) on hepatic IRI in mice. The mice were randomly divided into six groups: normal control, Sham, Sal (20 mg/kg), IRI, IRI + Sal (10 mg/kg), and IRI + Sal (20 mg/kg). We measured liver enzymes, proinflammatory cytokines, TNF-α and interleukin-6, and apoptosis- and autophagy-related marker proteins at 2, 8, and 24 hours after reperfusion. Components of mitogen-activated protein kinase (MAPK) signaling, including P-38, jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK), were also measured using an MAPK activator anisomycin to deduce their roles in hepatic IRI. Our results show that Sal safely protects hepatocytes from IRI by reducing levels of liver enzymes in the serum. These findings were confirmed by histopathology. We concluded that Sal protects hepatocytes from IRI partly by inhibiting the activation of MAPK signaling, including the phosphorylation of P38, JNK, and ERK. This ameliorates inflammatory reactions, apoptosis, and autophagy in the mouse liver.


Physical activity frequency and risk of incident stroke in a national US study of blacks and whites.
Regular physical activity (PA) is an important recommendation for stroke prevention. We compared the associations of self-reported PA with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. REGARDS recruited 30 239 US blacks (42%) and whites, aged ≥45 years with follow-up every 6 months for stroke events. Excluding those with prior stroke, analysis involved 27 348 participants who reported their frequency of moderate to vigorous intensity PA at baseline according to 3 categories: none (physical inactivity), 1 to 3×, and ≥4× per week. Stroke and transient ischemic attack cases were identified during an average of 5.7 years of follow-up. Cox proportional hazards models were constructed to examine whether self-reported PA was associated with risk of incident stroke. Physical inactivity was reported by 33% of participants and was associated with a hazard ratio of 1.20 (95% confidence intervals, 1.02-1.42; P=0.035). Adjustment for demographic and socioeconomic factors did not affect hazard ratio, but further adjustment for traditional stroke risk factors (diabetes mellitus, hypertension, body mass index, alcohol use, and smoking) partially attenuated this risk (hazard ratio, 1.14 [0.95-1.37]; P=0.17). There was no significant association between PA frequency and risk of stroke by sex groups, although there was a trend toward increased risk for men reporting PA 0 to 3× a week compared with ≥4× a week. Self-reported low PA frequency is associated with increased risk of incident stroke. Any effect of PA is likely to be mediated through reducing traditional risk factors.


A seed-engineering approach toward a hollow nanoreactor suitable for the confined synthesis of less-noble Ni-based nanocrystals.
A hollow nanoreactor suitable for the cultivation of Ni-nanocrystals was developed through a distinct seed-engineering stratagem, which involved the assembly of a catalytically active Au/Pd-heterojunction-nanocrystal inside the hollow silica nanoshell. The resulting hollow nanoreactor demonstrated a targeted performance in the cavity-confined growth of the catalytic Ni nanocrystal.


Is Cervical Stabilization for All Cases of Chiari-I Malformation an Overkill? Evidence Speaks Louder Than Words!
Chiari I malformation is characterized by the downward displacement of cerebellar tonsils through the foramen magnum. While discussing the treatment options for Chiari I malformation, the points of focus include: (1) Has the well-established procedure of posterior fossa decompression become outdated and has been replaced by posterior C1-2 stabilization in every case? (2) In case posterior stabilization is required, should a C1-2 stabilization, rather than an occipitocervical fusion, be the only procedure recommended? The review of literature revealed that when there is bony instability like atlantoaxial dislocation (AAD), occipito-atlanto-axial facet joint asymmetry or basilar invagination (BI) associated with Chiari I malformation, one should address the anterior bony compression as well as perform stabilization. This takes care of the compromised canal at the foramen magnum and re-establishes the cerebrospinal fluid flow along the craniospinal axis; and also provides treatment for CVJ instability. In the cases with a pure Chiari I malformation without AAD or BI and with completely symmetrical C1-2 joints, however, posterior fossa decompression with or without duroplasty is sufficient to bring about neurological improvement. The latter subset of cases with pure Chiari I malformation have, thus, shown significant (>70%) rates of neurological improvement with posterior fossa decompression alone. A C1-2 posterior stabilization is a more stable construct due to the strong bony purchase provided by the C1-2 lateral masses and the short lever arm of the construct. However, in the cases with significant bleeding from paravertebral venous plexus; a very high BI, condylar hypoplasia and occipitalized atlas; gross C1-2 rotation or vertical C1-2 joints with unilateral C1 or C2 facet hypoplasia, as well as the presence of subaxial scoliosis; maldevelopment of the lateral masses and facet joints (as in very young patients); or, the artery lying just posterior to the C1-2 facet joint capsule (being endangered by the C1-2 stabilization procedure), it may be safer to perform an occipitocervical rather than a C1-2 fusion.


Population Movement as a Risk Factor for Malaria Infection in High-Altitude Villages of Tahtay-Maychew District, Tigray, Northern Ethiopia: A Case-Control Study.
Key goal and targets of the Ethiopia National Malaria Control Program are to achieve malaria elimination within specific geographical areas with historically low malaria transmission and to reach near-zero malaria transmission in the remaining malarious areas by 2020. However, back and forth population movement between high-transmission and low-transmission area imposes challenge on the success of national malaria control programs. Therefore, examining the effect of human movement and identification of at-risk populations is crucial in an elimination setting. A matched case-control study was conducted among 520 study participants at a community level in low malaria transmission settings in northern Ethiopia. Study participants who received a malaria test were interviewed regarding their recent travel history. Bivariate and multivariate analyses were carried out to determine if the reported travel was related to malaria infection. Younger age (adjusted odds ratio [AOR] = 3.20, 95% confidence interval [CI]: 1.73, 5.89) and travel in the previous month (AOR = 11.40, 95% CI: 6.91, 18.82) were statistically significant risk factors for malaria infection. Other statistically significant factors, including lower educational level (AOR = 2.21, 95% CI: 1.26, 3.86) and nonagricultural in occupation (AOR = 2.0, 95% CI: 1.02, 3.94), were also found as risk factors for malaria infection. Generally, travel history was found to be a strong predictor for malaria acquisition in the high-altitude villages. Therefore, besides the existing efforts in endemic areas, targeting those who frequently travel to malarious areas is crucial to reduce malaria infection risks and possibility of local transmissions in high-altitude areas of northern Ethiopia.


Inhospital death is a biased measure of fatal outcome from bloodstream infection.
Inhospital death is commonly used as an outcome measure. However, it may be a biased measure of overall fatal outcome. The objective of this study was to evaluate inhospital death as a measure of all-cause 30-day case fatality in patients with bloodstream infection (BSI). A population-based surveillance cohort study was conducted, and patients who died in hospital within 30 days (30-day inhospital death) were compared with those who died in any location by day 30 post BSI diagnosis (30-day all-cause case fatality). A total of 1,773 residents had first incident episodes of BSI. Overall, 299 patients died for a 30-day all-cause case fatality rate of 16.9%. Most (1,587; 89.5%) of the patients were admitted to hospital, and ten (5.4%) of the 186 patients not admitted to hospital died. Of the 1,587 admitted patients, 242 died for a 30-day inhospital death rate of 15.2%. A further 47 patients admitted to hospital died after discharge but within 30 days of BSI diagnosis for a 30-day case fatality rate among admitted patients of 18.2%. Patients who died following discharge within 30 days were older and more likely to have dementia. The use of inhospital death is a biased measure of true case fatality.


Hypersensitivity myocarditis complicating hypertrophic cardiomyopathy heart.
The present report describes a case of eosinophilic myocarditis complicating hypertrophic cardiomyopathy. The 47-year-old female patient, known to have hypertrophic cardiomyopathy, was admitted with biventricular failure and managed aggressively with dobutamine infusion and other drugs while being assessed for heart transplantation. On transthoracic echocardiogram, she had moderate left ventricular dysfunction with regional variability and moderate mitral regurgitation. The recipient's heart showed the features of apical hypertrophic cardiomyopathy and myocarditis with abundant eosinophils. Myocarditis is rare and eosinophilic myocarditis is rarer. It is likely that the hypersensitivity (eosinophilic) myocarditis was related to dobutamine infusion therapy. Eosinophilic myocarditis has been reported with an incidence of 2.4% to 7.2% in explanted hearts and may be related to multidrug therapy.