Unsupervised unmixing of Raman microspectroscopic images for morphochemical analysis of non-dried brain tumor specimens.
Raman microspectroscopic imaging provides molecular contrast in a label-free manner with subcellular spatial resolution. These properties might complement clinical tools for diagnosis of tissue and cells in the future. Eight Raman spectroscopic images were collected with 785 nm excitation from five non-dried brain specimens immersed in aqueous buffer. The specimens were assigned to molecular and granular layers of cerebellum, cerebrum with and without scattered tumor cells of astrocytoma WHO grade III, ependymoma WHO grade II, astrocytoma WHO grade III, and glioblastoma multiforme WHO grade IV with subnecrotic and necrotic regions. In contrast with dried tissue section, these samples were not affected by drying effects such as crystallization of lipids or denaturation of proteins and nucleic acids. The combined data sets were processed by use of the hyperspectral unmixing algorithms N-FINDR and VCA. Both unsupervised approaches calculated seven endmembers that reveal the abundance plots and spectral signatures of cholesterol, cholesterol ester, nucleic acids, carotene, proteins, lipids, and buffer. The endmembers were correlated with Raman spectra of reference materials. The focus of the single mode laser near 1 μm and the step size of 2 μm were sufficiently small to resolve morphological details, for example cholesterol ester islets and cell nuclei. The results are compared for both unmixing algorithms and with previously reported supervised spectral decomposition techniques.


First-in-human trial of the PI3Kβ-selective inhibitor SAR260301 in patients with advanced solid tumors.
Phosphoinositide 3-kinase (PI3K) β is the dominant isoform for PI3K activity in many phosphatase and tensin homolog (PTEN)-deficient tumor models. This was a first-in-human study to determine the maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of SAR260301, a potent PI3Kβ-selective inhibitor (clinicaltrials.gov identifier NCT01673737). Successive cohorts of patients with advanced solid tumors received increasing doses of oral SAR260301 according to a Bayesian escalation with an overdose-control process based on the occurrence of dose-limiting toxicity in the first 28-day cycle. Adverse events, tumor response, PK, and the effect of food on PK were evaluated. Target engagement was assessed in platelets. Physiologically-based PK modeling was used for exposure predictions. Twenty-one patients received treatment at doses ranging from 100 mg once daily to 440 mg/m2 twice daily. Dose-limiting toxicities included 1 episode of grade 3 pneumonitis (400 mg twice daily) and 1 grade 3 γ-glutamyltransferase increase (600 mg twice daily). The maximum tolerated dose was not reached. The most frequently occurring treatment-related adverse events were nausea, vomiting, and diarrhea (14% each). Pharmacologically active concentrations were reached, but SAR260301 was rapidly cleared, and exposures associated with antitumor activity in preclinical models were not maintained at the highest dose tested. Food further decreased SAR260301 exposure. SAR260301 had an acceptable safety profile, but exposure sufficient to inhibit the PI3K pathway was unachievable because of rapid clearance, and clinical development was terminated. These results demonstrate the importance of PK and pharmacodynamic assessments in early drug development. Cancer 2018;124:315-24. © 2017 American Cancer Society.


Feasibility and safety of same-day discharge after laparoscopic radical hysterectomy for cervix cancer.
To evaluate the safety and feasibility of same day-discharge (SDD) after laparoscopic radical hysterectomy for cervix cancer by determining complication rates and factors associated with post-operative admission. In this retrospective cohort study, patients undergoing laparoscopic radical hysterectomy for cervix cancer at a single institution from January 2006 to November 2015 were identified. Admitted patients were compared to same-day discharge patients. Rates of post-operative complications and readmission were analyzed and regression analysis used to determine factors associated with admission. 119 patients were identified. 75 (63%) were SDD patients (mean stay 156.7±50.2min) and 44 (37%) were admitted patients (mean stay 1.2±0.6days). Ten (13%) SDD patients sought medical attention within 30days post-operatively vs. nine (20%) admitted patients (p=0.17). Reasons SDD patients sought attention included pain (n=1), wound concerns (n=2), vaginal bleeding (n=2), DVT/VTE (n=1), fever (n=2) and fistula (n=2). All patients developed symptoms and presented between 5 and 13days post-operatively thus no complications could have been detected or prevented through initial admission. Four SDD patients were readmitted within 30days of surgery (p=0.25), two required re-operation (p=0.16). Admitted patients were older (p=0.049), had longer operations (p=0.02), increased blood loss (p=0.0004), increased intra-operative complications (p=0.001), surgery later in the day (p=0.004) and before April 2010 (p=0.001). On multivariate analysis, older age (OR1.05, p=0.03), surgery later in the day (OR 7.22, p=0.002) and presence of an intra-operative complication (OR 10.25, p=0.02) were significantly associated with admission. Same-day discharge after laparoscopic radical hysterectomy for cervix cancer is safe, with a low risk of post-operative morbidity and hospital readmission.


TNF-α/IL-10 ratio: An independent predictor for coronary artery disease in North Indian population.
Cytokines are responsible for the modulation of immunological and inflammatory processes and play a significant role in the pathogenesis of coronary artery disease (CAD). Tumor necrosis factor-alpha (TNF-α) are considered as a pro inflammatory and interleukin-10 (IL-10) anti inflammatory have been shown to predict the risk of incident of CAD. Aim of present study is to examine the impact of the TNF-α and Il-10 levels on various components of the CAD. Total 580 subjects were recruited in the present study out of which 290 diagnosed CAD subjects (Age 51.61±9.26; BMI 25.27±3.58) and 290 healthy controls (Age 51.72±9.48; BMI 24.02±7.42). Serum TNF-alpha and IL-10 levels were measured by ELISA. Data of present study revealed that CAD patients had higher frequency (p=0.001) of smoking (38.28%), Alcohol (21.03%), Diabetes (53.45%) and hypertension (48.28%) as compare to controls. Moreover, we have observed highly significant (p<0.05) difference in PR, BMI, DBP, DBP, Glucose, TC, TG, VLDL, LDL, TNF-α and TNF-α/IL-10. However, HDL and IL-10 were found lower in CAD. The findings of present study suggest that the TNF-α/IL-10 ratio may play a vital role in the development of CAD of North Indian population.


Morphological analysis and classification of posterior malleolar fractures based on CT scans.
The aim of the study was to propose a classification system of posterior malleolar fractures by fracture lines with the use of CT scans, including 3D CT reconstruction, which can better understand morphological characteristics, analyze the mechanism and guide the surgeon to choose the optimal approach and fixation. Patients with OTA/AO type 44 fractures involving the posterior malleolus and preoperative CT scans were included. We retrospectively analyzed 128 consecutive patients with posterior malleolar fractures from January 2013 to December 2019 at our institution. CT data were loaded into Mimics software (V20.0, Materialize), in which 3D CT reconstruction, morphological analysis and data measurements were made. Based on the number of fracture lines in 128 consecutive patients, posterior malleolar fractures were classified into three types: type 1 with a single fracture line, type 2 with double fracture lines and type 3 with multiple fracture lines. According to the distribution of the fracture line, type 1 was divided into types 1A, 1B and 1C, and type 2 was divided into types 2A, 2B and 2C. The fracture line from the fibular notch to the posterior rim of the distal tibia was defined as type 1A, and the fracture line to the medial malleolus was defined as type 1B. Type 1C was a small fragment in the posterior rim of the distal tibia. Type 2A was regarded as type 1A with type 1C. It was considered type 2B because another fracture line started from the fracture line of type 1A and extended to the medial malleolus. In type 2C, we could see that the double fracture lines were all from the fibular notch to the posterior rim of the distal tibia and did not cross. Type 3 fractures were comminuted fractures with multiple fracture lines. The morphology of posterior malleolar fractures, involvement of the fibular notch, or the medial malleolus can be obviously assessed by our classification system. We found the relation of the injury mechanism between type 1 and type 2 by comparing the area of the fragment. We have indicated that each type of fracture corresponds to its associated injury mechanism and which surgical approach and fixation can be chosen.


The role of urinary neutrophil gelatinase-associated lipocalin in lupus nephritis.
Urine neutrophil gelatinase-associated lipocalin (uNGAL) has been proposed as a potential biomarker for lupus nephritis (LN) activity. We determined the association between uNGAL with LN activity in systemic lupus erythematosus (SLE) patients compared to the current standard markers of SLE. A total of 100 SLE patients with biopsy-proven LN were recruited-47 with active and 53 inactive LN. uNGAL levels were measured. Renal function test, urinary parameters, lupus serology and calculated renal SLE Disease Activity Index-2K (renal SLEDAI-2K) were analyzed to determine their associations with uNGAL. Normalized uNGAL levels (ng/mg creatinine) were significantly higher in patients with active LN compared to those with inactive disease (p=0.01). uNGAL and renal SLEDAI-2K were associated (r=0.32, p=0.001). Multiple logistic regression showed that only serum creatinine and renal SLEDAI-2K were independent predictors of uNGAL levels (p=0.03 and 0.02 respectively). Analysis of the receiver operating characteristic (ROC) curve showed that uNGAL was a potential biomarker for LN. uNGAL was increased in active LN especially in LN flares. Serial measurements of uNGAL levels may be of value in monitoring response of LN to treatment and for predicting LN flares.


The emerging role of tacrolimus in myasthenia gravis.
To describe and evaluate the available evidence assessing the role of tacrolimus in the management of patients with myasthenia gravis (MG). A literature search of MEDLINE (1946 to September 2014) and EMBASE (1947 to September 2014) was performed using the terms 'tacrolimus' and 'myasthenia gravis'. Citations of retrieved articles were examined for relevance. The search was limited to prospective clinical trials focused on clinical outcomes in patients with generalized MG. Case reports, retrospective evaluations and non-English articles were excluded. A total of 12 studies met inclusion criteria, of which seven articles evaluated tacrolimus in steroid-dependent patients and two examined the utility of tacrolimus in patients failing corticosteroids and cyclosporine. Other studies evaluated early initiation of tacrolimus after thymectomy, effectiveness of tacrolimus in de novo MG and the effectiveness of tacrolimus post-thymectomy in thymoma patients versus nonthymoma. A total of eight trials showed statistically significant improvements in quantitative MG score (QMGS) and postintervention status criteria - Myasthenia Gravis Foundation of America (PSC-MGFA). Of the trials examining steroid reduction with tacrolimus, two reported high rates of complete withdrawal; however, the most robust trial was unable to detect a difference in mean steroid dose. Long-term effects of tacrolimus (up to 5 years) were assessed in eight trials, which consistently showed positive effects on QMGS or reduction in adjunct therapies. There is limited yet promising information to suggest a beneficial role for tacrolimus in reducing QMGS and corticosteroid burden in patients with refractory symptoms or new-onset MG. Long-term use appears to be safe in this population.


EEG error-related potentials encode magnitude of errors and individual perceptual thresholds.
Error-related potentials (ErrPs) are a prominent electroencephalogram (EEG) correlate of performance monitoring, and so crucial for learning and adapting our behavior. It is poorly understood whether ErrPs encode further information beyond error awareness. We report an experiment with sixteen participants over three sessions in which occasional visual rotations of varying magnitude occurred during a cursor reaching task. We designed a brain-computer interface (BCI) to detect ErrPs that provided real-time feedback. The individual ErrP-BCI decoders exhibited good transfer across sessions and scalability over the magnitude of errors. A non-linear relationship between the ErrP-BCI output and the magnitude of errors predicts individual perceptual thresholds to detect errors. We also reveal theta-gamma oscillatory coupling that co-varied with the magnitude of the required adjustment. Our findings open new avenues to probe and extend current theories of performance monitoring by incorporating continuous human interaction tasks and analysis of the ErrP complex rather than individual peaks.


Morphometry of spinal motor neurons in amyotrophic lateral sclerosis with special reference to chromatolysis and intracytoplasmic inclusion bodies.
Lewy body-like hyaline inclusions (LBI), Bunina bodies (BB) and central chromatolysis are characteristic neuropathological features of spinal motor neurons in amyotrophic lateral sclerosis (ALS). Using histometric methods, we studied the spinal motor neurons of 4 patients with sporadic ALS and 3 neurological control patients to determine the possible relationship between these neuropathological features and cytoplasmic, nuclear and nucleolar size. In an ALS patient with a very rapid clinical course, many neurons with LBI were observed. Enlargement of nucleolar size and the nucleolar/nuclear ratio of neurons with LBI or BB were the only histometric difference compared to those of normal-appearing neurons. In ALS patients with an average clinical course, the number of neurons with LBI was lower, the number of neurons with BB was higher, and the nuclear and nucleolar sizes were smaller than those of normal-appearing neurons, particularly in chromatolytic neurons without LBI or BB. These data raise the possibility that motor neurons with LBI may represent an early stage in the neurodegenerative process, when the rate of protein synthesis is elevated as evidenced by their larger nucleolar size. Thus, the causative agent(s) of ALS may initially stimulate protein synthesis while in turn leading to down regulation of certain luxury function genes, culminating in neuronal dysfunction and death.


Author Correction: Methylation of LINE-1 in cell-free DNA serves as a liquid biopsy biomarker for human breast cancers and dog mammary tumors.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


CD-19 CART therapy and orthostatic hypotension: a single center retrospective cohort study.
Chimeric antigen receptor T-cell (CART) therapy is a form of cellular immunotherapy used to treat hematologic malignancies. Major adverse cardiovascular events have been seen in CART patients who have high grade CRS, higher baseline creatinine, and troponin elevation. However, the incidence and factors associated with orthostatic hypotension after CART therapy have not previously been reported in the literature. We looked at patients who underwent CD-19 directed CART therapy at UPMC Shadyside hospital from April 1st 2018 to December 1st 2020. Patients were classified as having orthostatic hypotension if they had recorded orthostatic vital signs that were positive or provider notes indicated that vitals had been taken and were positive in the time period from discharge to 3 months post-CART. Data was analyzed with univariate and multivariate analysis using logistic regression. 79% of patients had orthostatic hypotension after discharge from their CART hospitalization and 64% of those patients were symptomatic. Older age, lower BMI, lower ambulatory diastolic blood pressure and grade 2 CRS were associated with orthostatic hypotension in the univariate analysis. Older age and lower ambulatory systolic blood pressure were associated with orthostatic hypotension in the multivariate analysis. Symptomatic orthostatic hypotension was associated with a history of hypertension in both the univariate and multivariate analysis. Patients with symptoms also had a higher pre-CART ejection fraction but this association was not seen in the regression model. There is a high incidence of orthostatic hypotension after CART therapy even after discharge. Therefore, orthostatic vitals signs and associated symptoms should be assessed in both the inpatient and outpatient setting. Older patients and patients with lower BMIs, lower ambulatory blood pressures, grade 2 CRS, or a history of hypertension may need closer monitoring.


Evaluation of push-out bond strength of BioRoot RCS and AH Plus after using different irrigants: An in vitro study.
The aim of this study was to compare push-out bond strength of root canal spaces filled with AH-Plus and BioRoot RCS after using different irrigants. Eighty single-rooted teeth were decoronated and endodontically treated by crown-down technique using ProTaper Universal rotary files progressively till F4 (40/0.06). Samples were divided into two groups according to the sealer (n = 40): Group A = BioRoot RCS, Group B = AH Plus, further subdivided into four subgroups according to irrigation protocol (n = 10): Group 1A, 1B - 0.9% saline, Group 2A, 2B - 5.25% NaOCl + 17% EDTA, Group 3A, 3B- 17% EDTA +2% chlorhexidine, and Group 4A, 4B - 17% EDTA + 3% green tea extract. Samples were obturated with sealers and prepared for push-out test with root slices of 2 mm thickness using universal testing machine. Data were statistically analyzed using two-way ANOVA, Bonferroni's post hoc analysis, and independent Student's t-test. BioRoot RCS exhibited significantly higher push-out bond strength (n < 0.001). The interaction between irrigants and sealer showed higher bond strength for BioRoot RCS when 17% EDTA+ green tea was used. Within the limitation of the study, it was concluded that bond strength of a sealer was influenced by the irrigants used.


Identifying the needs of Innu and Inuit patients in urban health settings in Newfoundland and Labrador.
Labrador's Innu and Inuit live in nine small, isolated villages, and must travel to the urban centres of Goose Bay, Labrador and/or St. John's, Newfoundland for most health services. This study responds to anecdotal evidence of Aboriginal dissatisfaction with these services from the St. John's Native Friendship Centre Association (SJNFCA); it describes Aboriginal experiences and identifies relevant needs. The study consisted of qualitative interviews (N = 143), conducted by trained local researchers, and nine focus groups. The interviews were narrative-based, appropriate to the Aboriginal culture of participants. Participants were recruited from the client list of the SJNFCA. Almost all study participants experience significant difficulties including profound disorientation, language and communication difficulties, inadequate accommodations, and altered diets. Cross-cultural relations are particularly problematic for the Innu. These findings, and 19 recommendations made to the provincial government (8 main recommendations appear in Table II), could lead to improved services for Innu and Inuit using urban health services. Workshops in development could mean more awareness among health care practitioners.


Enhanced hydrolysis and acidification of waste activated sludge by biosurfactant rhamnolipid.
The effect of biosurfactant rhamnolipid (RL) on hydrolysis and acidification of waste activated sludge (WAS) was investigated. The results indicated that RL could greatly reduce the surface tension of sludge, resulting in stimulating the hydrolysis rate of WAS and enhancing the production of short-chain fatty acids (SCFAs). With the increase of RL dosage from 0.2 to 0.5 g/g DS, the maximum soluble chemical oxygen demand (SCOD), protein and carbohydrate concentration increased correspondingly. After 6 h of hydrolysis, SCOD, protein and carbohydrate concentration increased from 371.9, 93.3 and 9.0 mg/l to 3,994.5, 800.0 and 401.4 mg/l at RL 0.3 g/g DS, respectively. Furthermore, the release of NH4 (+)-N, PO4 (3-)-P and the accumulation of SCFAs also improved in the presence of RL. The maximum SCFAs was 1,829.9 mg COD/l at RL 0.3 g/g DS, while it was only 377.7 mg COD/l for the blank test. The propionic acid and acetic acid were the mainly SCFAs produced, accounting for 50-60% of total SCFAs.


High amounts of fluoride induce apoptosis/cell death in matured ameloblast-like LS8 cells by downregulating Bcl-2.
Excessive fluoride intake during enamel formation may result in enamel fluorosis and apoptosis is regarded to be involved in the process by an unclear mechanism. We hypothesize that excessive fluoride might cause apoptosis in the ameloblasts and fluoride-induced apoptosis varies with the maturation stages of ameloblasts. We set up an in vitro differentiation model of ameloblasts by using retinoic acid (RA) and dexamethasone (DEX) to induce the maturation of mouse ameloblast-like LS8 cells. The mRNA and protein levels of two enamel matrix proteins and two enamel proteinases were downregulated and upregulated, respectively, in the RA/DEX induced cells, indicating RA/DEX induced cells possessed the characteristics of matured ameloblasts. The strengthened endocytosis function and decreased intracellular pH value inside RA/DEX treated ameloblasts confirmed the maturation inducing effect of RA/DEX on ameloblasts. Excessive fluoride inhibited cell proliferation of ameloblasts within 72h. High amounts of fluoride also induced more apoptosis/dead cells and reduced the expression of Bcl-2, but to a different degree in the non-induced cells and RA/DEX induced cells. We inferred that high doses of fluoride may easily target the transitional/early maturation ameloblasts and cause apoptosis or cell death. Bcl-2 might be involved in this process.


Impact of Inert Crowders on Host-Guest Recognition Process.
Biological environments typically contain high concentrations (300-400 mg/mL) of different macromolecules at volume fractions as large as 30%-40%. Biomolecular recognition processes, a ubiquitous biological phenomena, occurring in such crowded heterogeneous media would differ significantly compared to the dilute buffer solutions. Here we quantify the potential impact of inert crowders on prototypical host-guest recognition process by explicit-solvent molecular dynamics (MD) simulations in atomic resolution. We demonstrate that the crowders, when smaller in size, would facilitate the binding process of the guest molecule by decreasing the free energy barrier for binding via excluded volume effect and desolvation of the host receptor. However, the extent of crowder-induced stabilization of a host-guest complex is found to be significantly higher when the guest molecule is sterically constricted to approach the host along a centrosymmetric direction, compared to its unrestricted, freely diffusive movement. A kinetic analysis of the recognition process reveals that the origin of a relatively stronger crowder impact during constricted movement of guest molecule lies in the relatively enhanced residence time of the guest inside the host by crowders. Together, our results suggest that the extent of impact of crowding on recognition processes would be contingent upon the presence or absence of constriction on ligand movement.


No evidence of systematic pre-emptive loggings after notifying landowners of their lands' conservation potential.
Landowners can intentionally impair biodiversity values occurring on their land to pre-empt biodiversity protection. This often leads to significant negative effects on biodiversity. We studied whether landowners in Finland engaged in pre-emptive loggings after they were notified that their wooded mires are candidate sites for a mire protection program. After the notification, harvesting rates of the candidate wooded mires were significantly lower compared to harvesting rates of similar but non-candidate wooded mires. Annual and monthly harvesting rates indicated that notifying landowners of the conservation potential did not launch systematic pre-emptive logging behavior. Nevertheless, part of the candidate wooded mires were logged, so some landowners place more weight on other values than the biodiversity ones. Pre-emptive behavior has been observed in other studies suggesting that many country- or system-specific factors such as cultural background or level of compensation can affect landowners' behavior.


The management of occult hemothorax in adults with thoracic trauma: A systematic review and meta-analysis.
Hemothorax is a common sequelae following thoracic trauma and is associated with significant morbidity and mortality. Current guidelines recommend all traumatic hemothoraces be considered for drainage with tube thoracostomy (TT), regardless of size. With increasing use of computed tomography, smaller hemothoraces not seen on x-ray (defined as an occult hemothorax) are frequently detected. This systematic review was performed to gather data on patients with occult hemothorax managed with TT or without TT (termed expectant management [EM]). MEDLINE, EMBASE, and Cochrane databases from inception to October 2019 were searched for relevant articles. The primary outcome was rates of failure of expectant (conservative) management. Secondary outcomes of interest included predictors of TT insertion, predictors of failure of EM, and morbidity and mortality in patients with occult hemothorax. We screened 1,329 abstracts from which 6 articles reporting 1,405 patients with occult hemothorax were included. Of these patients, 601 (43.68%) were managed initially with TT, and 802 (56.32%) were managed expectantly. Of the 802 patients managed expectantly, 212 failed conservative management and underwent TT insertion (23.1% pooled failure rate estimate [95% confidence interval, 17.1-29.1%]). The presence of concomitant pneumothorax predicted upfront TT insertion. Of the patients who failed EM, the need for mechanical ventilation and the presence of a large hemothorax predicted failure. Mortality was similar in both groups. Conservative treatment of occult hemothorax fails in 23.1% of patients. The presence of hemothorax greater than 300 mL and the need for mechanical ventilation predicted failure of conservative treatment and the need for TT. There was no difference in mortality between EM and TT cohorts. These data suggest that it may be possible to safely observe patients with occult hemothoraces less than 300 mL (1.5 cm pleural stripe) secondary to blunt trauma without upfront TT insertion. Systematic review and meta-analysis, level III.


Nuclear Condensation during Mouse Erythropoiesis Requires Caspase-3-Mediated Nuclear Opening.
Mammalian erythropoiesis involves chromatin condensation that is initiated in the early stage of terminal differentiation. The mechanisms of chromatin condensation during erythropoiesis are unclear. Here, we show that the mouse erythroblast forms large, transient, and recurrent nuclear openings that coincide with the condensation process. The opening lacks nuclear lamina, nuclear pore complexes, and nuclear membrane, but it is distinct from nuclear envelope changes that occur during apoptosis and mitosis. A fraction of the major histones are released from the nuclear opening and degraded in the cytoplasm. We demonstrate that caspase-3 is required for the nuclear opening formation throughout terminal erythropoiesis. Loss of caspase-3 or ectopic expression of a caspase-3 non-cleavable lamin B mutant blocks nuclear opening formation, histone release, chromatin condensation, and terminal erythroid differentiation. We conclude that caspase-3-mediated nuclear opening formation accompanied by histone release from the opening is a critical step toward chromatin condensation during erythropoiesis in mice.


Mukonal exerts anticancer effects on the human breast cancer cells by inducing autophagy and apoptosis and inhibits the tumor growth in vivo.
Mukonal is an active member of carbazole alkaloids isolated from Murraya koenigii. It has been shown to possess remarkable biological and pharmacological activities including anticancer activity. Therefore, the aim of current investigation was to explore anti-breast cancer activity of mukonal and to explore the underlying mechanism. Results indicate that mukonal has potential to induce antiproliferative effects against MDA-MB-231 and SK-BR-3 cells with an IC50 of 7.5 µM. No significant toxicity of mukonal was observed in case of normal breast cells. The antiproliferative effects of mukonal were found to proceed via apoptosis, which was further supported by increased cleavage of PARP and caspase-3 and reduced expression of Bcl-2. Mukonal induced autophagic cells death in breast cancer cells as was evidenced by formation of autophagosomes and enhanced expressions of Beclin-1, LC3B-I and LC3B-II proteins. In vivo examination of anti-breast cancer property of mukonal indicated that it could potentially reduce tumor weight and volume in xenografted mice models. In conclusion, mukonal has a remarkable potential of inhibiting breast cancer via induction of apoptosis and autophagy. Mukonal also inhibited xenografted tumors models in a dose-dependent manner. Therefore, mukonal may prove lead molecule in breast cancer drug discovery and treatment provided further investigations are recommended.


Site-directed isotope labeling and FTIR spectroscopy: assignment of tyrosine bands in the bR-->M difference spectrum of bacteriorhodopsin.
Fourier transform infrared difference spectroscopy has been used extensively to probe structural changes in bacteriorthodopsin and other retinal proteins. However, the absence of a general method to assign bands to individual chemical groups in a protein has limited the application of this technique. While site-directed mutagenesis has been successful in special cases for such assignments, in general, this approach induces perturbations in the structure and function of the protein, thereby preventing unambiguous band assignments. A new approach has recently been reported (Sonar et al., Nature Struct. Biol. 1 (1994) 512-517) which involves cell-free expression of bacteriorhodopsin and site-directed isotope labeling (SDIL). We have now used this method to re-examine bands assigned in the bR-->M difference spectrum to tyrosine residues. Our results show that out of 11 tyrosines in bR, only Tyr 185 is structurally active. This work further demonstrates the power of SDIL and FTIR to probe conformational changes at the level of individual amino acid residues in proteins.


Radiotherapy in conjunction with intravenous infusion of 180 mg of disodium pamidronate in management of osteolytic metastases from breast cancer: clinical evaluation, biochemical markers, quality of life, and monitoring of recalcification using assessments of gray-level histogram in plain radiographs.
To evaluate the clinical improvement and radiographically monitor the effect of local radiotherapy in conjunction with disodium pamidronate (DP) on metastatic osteolytic disease. Thirty-three patients with osteolytic metastasis from advanced breast cancer received radiotherapy with a 6-MV linear accelerator up to a dose of 30 Gy (3 Gy/fraction, 5 d/wk) combined with 24 monthly sessions of a 180-mg DP infusion. Conventional X-rays were obtained during the first six sessions of DP treatment, retaining the same settings for each exposure. The analysis of the image attributes was based on measuring the first-order statistics of the mean value and energy of gray-level histograms in the osteolytic region. The 6-month measurements compared with baseline showed statistically significant differences (p < 0.01, Wilcoxon test) in energy of gray-level histogram (-10.8%), mean value of gray-level histogram (+9.5%), pain score (-5.8 points), Eastern Cooperative Oncology Group status (-2.4 points), urine hydroxyproline/creatinine ratio (-41.7%), urine calcium/creatinine ratio (-58.8%), and bone alkaline phosphatase (-42.4%). Quality of life as determined by the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (version 3) also improved. During follow-up, 88% of patients had complete and 12% partial responses (International Union Against Cancer radiologic criteria). On multivariate analysis, greater changes in the mean value of the gray-level histogram and negative nodal status were predictors for a reduction in the number of skeletal complications after therapy. Flu-like syndrome occurred in 13 patients (39%) and was well managed with mild antipyretics. Image-processing in plain radiographs offers an objective way to assess recalcification. The image-processing indexes, along with the measurements of performance status, quality of life, and biochemical markers, improved significantly. Local radiotherapy combined with long-term high-dose DP up to 180 mg is tolerable and has a high therapeutic response.


Mapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation.
BiP co-chaperones ERdj4, ERdj5, and GRP170 associate in cells with peptides predicted to be aggregation prone. Here, extending these findings to a full-length protein, we examine two Interstitial Lung Disease-associated mutants (ILD) of surfactant protein C (SP-C). The TANGO algorithm, which identifies sequences prone to formation of β strand aggregates, found three such regions in SP-C: the N-terminal transmembrane (TM) domain and two sites in the intermolecular chaperone BRICHOS domain. We show the ILD mutants disrupt di-sulfide bond formation in the BRICHOS domain and expose the aggregation-prone peptides leading to binding of ERdj4, ERdj5, and GRP170. The destabilized mutant BRICHOS domain fails to properly insert its TM region in the ER membrane, exposing part of the N-terminal TM domain site. Our studies with ILD-associated mutant proteins provide insights into the specificity of ERdj4, ERdj5, and GRP170, identify context-dependent differences in their binding, and reveal molecular consequences of disease-associated mutants on folding.


Intervertebral focal surgery for the treatment of non-contiguous multifocal spinal tuberculosis.
The purpose of this study was to assess the clinical efficacy of intervertebral focal surgery by complete debridement, deformity correction, graft fusion, and internal fixation for patients with non-contiguous multifocal spinal tuberculosis. A total of 29 cases with non-contiguous multifocal spinal tuberculosis admitted to the hospital from January 2000 to January 2007 were treated by intervertebral focal surgery. There were 63 foci in 29 cases, averaging 2.2 foci per case, and 146 affected vertebral bodies, averaging 2.3 vertebral bodies per focus. Three cases had one normal intervertebral disc between two foci, and the other 26 cases had two or more normal intervertebral discs between two foci. All cases were followed-up for an average of five years. The kyphosis showed a mean correction rate of 67.7% after surgery. A mean loss rate of correction of 8.2% was observed at the final follow-up. The levels of erythrocyte sedimentation rate and C-reactive protein returned to normal in 27 cases on average at 5.8 months and bone union could be observed at five months after surgery. Eleven cases with nerve damage recovered to E grade at the final follow-up. Intervertebral focal surgery by complete debridement, deformity correction, graft fusion, and internal fixation for patients with non-contiguous multifocal spinal tuberculosis was feasible and effective.


After thirty years of experience with early postoperative intraperitoneal 5-fluorouracil now saying goodbye.
In the management of colorectal and appendiceal peritoneal metastases, intraperitoneal 5-fluorouracil (5-FU) has been used in 3 different ways. It has been used as part of an early postoperative intraperitoneal chemotherapy (EPIC) regimen along with EPIC mitomycin C. This EPIC mitomycin C plus EPIC 5-FU has been shown to be equivalent or inferior to HIPEC. Because it is more work intensive than HIPEC and not superior, its use should be abandoned if HIPEC is available. A second way to use intraperitoneal 5-FU is along with HIPEC. Several studies suggest a survival advantage for the combination of HIPEC with EPIC 5-FU. However, patient ineligibility for EPIC 5-FU in high-risk CRS is more likely the cause for the alleged survival advantage attributed to the combination. A third use of intraperitoneal 5-FU is long-term through a peritoneal access device. This plan for 5-FU use has shown favorable results in three randomized controlled studies. Normothermic intraperitoneal chemotherapy (NIPEC) with 5-FU should be considered as a regional chemotherapy component of a randomized trial for prevention or treatment of peritoneal metastases from colorectal or appendiceal cancer. Intravenous oxaliplatin combined with NIPEC 5-FU has been suggested as a bidirectional adjuvant regimen.


Antifibrillatory action of the narcotic agonist fentanyl.
Morphine, an opiate alkaloid with mixed mu- and delta-agonist properties, raises the ventricular fibrillation threshold in anesthetized dogs by altering autonomic tone. To elucidate further underlying structure-activity relationships, the effect of fentanyl, a nonalkaloid, mu-selective agonist in wide clinical use, was studied. Fentanyl (30 micrograms/kg) was given intravenously to 27 chloralose-anesthetized dogs, and ventricular fibrillation threshold was measured by means of the single-stimulus technique. In the baseline state fentanyl raised the ventricular fibrillation threshold by 14%. When the dogs were subjected to hemorrhagic stress, this effect was amplified to 29% (p less than 0.0001). Bilateral cervical vagotomy abolished fentanyl's antifibrillatory effect, but neither atropine sulfate (0.4 mg/kg/hr) nor atropine methylnitrate (0.5 mg/kg/hr) did so. Fentanyl's influence on the fibrillation threshold during hemorrhage was significantly reduced by bilateral stellate ganglionectomy (p less than 0.005). It is concluded that fentanyl raises the ventricular fibrillation threshold by its known sympathoinhibitory action rather than by its vagal efferent activating effect. The facts that an intact vagus is required and that hemorrhage amplifies the effect suggest that the antifibrillatory effect of fentanyl is mediated through the afferent component of the baroreflex arc.


Adolescents with implantable cardioverter defibrillators: a patient and parent perspective.
An implantable cardioverter defibrillator (ICD) is a device used in the treatment of individuals with life-threatening cardiac conditions. These include genetic disorders such as long QT syndrome, hypertrophic cardiomyopathy, and Brugada syndrome, all of which have the propensity to cause sudden cardiac death. Adults with ICDs consistently report elevated levels of anxiety and depression, as well as negative lifestyle changes associated with the device. Compared to older ICD recipients, young patients face decades of life with the device and the long-term impact and implications are important to consider. This research explores the experiences of adolescents living with an ICD. Parents of these adolescents were also included to explore the impact on them as the primary caregivers. A qualitative approach was chosen to explore the lived experience; semistructured interviews with six adolescents and six parents were conducted from which a number of key themes emerged. The experiences described by participants included the restrictions adolescents face, the ICD shock experience, and ongoing challenges post-ICD implantation. However, both adolescents and parents were able to adjust to life after receiving an ICD and described several benefits associated with having the device. Findings also emerged relating to communication between health professionals and adolescents, and the limitations adolescents impose on themselves post-ICD implantation. These findings have important implications for clinical practice and may help guide medical management for adolescents with ICDs and their families.


Gastroesophageal reflux disease and Barrett's esophagus.
Gastroesophageal reflux disease (GERD) is a common clinical problem. More frequent and extended acidic reflux episodes are characteristic of GERD, although substantial (nonacid) reflux per se is also observed in control individuals. Helicobacter pylori may protect some people from reflux disease, but others do not experience deterioration of GERD as a result of H. pylori eradication, for reasons so far unknown. Medical treatment, preferably with proton-pump inhibitors, is well established and is also recommended in endoscopy-negative forms of the disease, although the efficacy is less marked in comparison with erosive esophagitis. Surgery has emerged as an alternative to medical therapy, but the long-term results do not now appear to be as promising as was initially claimed. A number of new endoscopic techniques for the treatment of GERD have been developed, but the future for these is unclear. Barrett's esophagus develops in some patients with GERD for unknown reasons, and surveillance should be carried out in these patients due to the risk of subsequent malignant transformation. Several new approaches have been developed for detecting premalignant conditions, but these need to be investigated further. Ablative techniques are still under intensive investigation, and appear to be promising, at least in a subset of patients, although they are not devoid of major complications. Whether antireflux therapy, irrespective of the method used, can slow down the development of cancer is still an intriguing and clinically important question.


An inhibitor of acylCoA: cholesterol acyltransferase increases expression of ATP-binding cassette transporter A1 and thereby enhances the ApoA-I-mediated release of cholesterol from macrophages.
The effect of inhibition of acylCoA: cholesterol acyltransferase (ACAT) was studied on high density lipoprotein (HDL) metabolism. An inhibitor of ACAT, MCC-147, was given mouse peritoneal macrophages and expression of ATP-binding cassette transporter A1 (ABCA1) was examined. ABCA1 was increased both at the mRNA and protein levels, only when the cells are cholesterol-loaded and thereby the inhibitor decreased esterified cholesterol and increased unesterified cholesterol. In this condition, the ACAT inhibitor increased reversible binding of apoA-I to the cells and enhanced apoA-I-mediated release of cellular cholesterol and phospholipid, but did not influence nonspecific cellular cholesterol efflux to lipid microemulsion. It was therefore concluded that the ACAT inhibitor increased the release of cholesterol from the cholesterol-loaded macrophages by increasing the expression of ABCA1, putatively through shifting cholesterol distribution from the esterified to the free compartments.


Monoclonal antibodies to porcine zona pellucida antigens and their inhibitory effects on fertilization.
Five hybridomas which produce monoclonal antibodies (Mabs) to porcine zona pellucida (ZP) were established. The immunoglobulin classes were IgG2a from hybridoma B11C8 and IgM from the other four. Using immunofluorescent staining, the Mab from B11C8 stained only porcine oocytes, the Mab from G10G5 stained oocytes of pigs and hamsters but Mabs from C6H1, D3H4, G10F9 stained oocytes of pigs, humans, hamsters, rats and mice. Mabs from B11C8 and G10F9 strongly blocked boar sperm binding to porcine ZP but other Mabs produced only slight blocking. However, no Mabs could block sperm penetration during in vitro fertilization (IVF) of hamster oocytes. When a goat antibody (IgG) to mouse serum gamma-globulin was applied after each Mab as a second antibody, only Mab from G10G5 impaired IVF of hamster oocytes.


Equilibrium statistical distributions for subchains in an entangled polymer melt.
In de Gennes-Doi-Edwards theory for entangled polymeric melts, a length scale r(0) is introduced, giving the equilibrium mesh size of the physical network of chains. Each polymer molecule is then represented as a random walk, with a step size r(0) (a "subchain", made up of n(0) Kuhn segments) dictated by the existence of entanglements. Progressing from this simple picture, an issue that has been constantly overlooked so far, despite its potential relevance, is that of finite-size effects at the de Gennes-Doi-Edwards characteristic length scale. Actually, since a subchain in a melt is a "small", nonmacroscopic system, fluctuations of both its length and its number of Kuhn segments are certainly nonnegligible. An ad hoc theoretical treatment from nonstandard (nano) statistical mechanics and thermodynamics seems then required, to find the anticipated equilibrium statistical distributions of the subchain population. In this contribution, we carefully discuss this topic. Some predictions from the nonstandard fluctuation-inclusive approach on the statistics of subchains are here obtained, and compared with existing simulations, even down to the atomistic level.


Age-related changes in blood pressure, hematological values, concentrations of serum biochemical constituents and weights of organs in the SHR/Izm, SHRSP/Izm and WKY/Izm.
Age-related changes in hematological values, serum biochemical constituents, and weights of various organs in both sexes of the Spontaneously Hypertensive (SHR/Izm), Stroke-prone SHR (SHRSP/Izm), and Wistar Kyoto (WKY/Izm) rat strains, bred under SPF conditions, were examined to obtain fundamental data. The body weights from 3-30 weeks and systolic blood pressure from 6-30 weeks in each strain were measured every week. At the ages of 8, 16, and 30 weeks, the hematological values (erythrocyte, hemoglobin, hematocrit, leucocyte, thrombocyte), serum biochemical constituents (total protein, GOT, GPT, ALP, BUN, creatinine, glucose, total Ca and phosphorus, and ionized Ca, Na, K, and Cl were measured. Also, the organs, brain, heart, lung, thymus, liver, spleen, pancreas, bilateral kidneys, adrenal glands, testes/ovaries, digestive tract, and muscle (soleus) were weighed. The age-related changes as well as the strain and sex differences in each measured item were examined. The body weights of each strain increased, but rate of the increase was less in SHR and SHRSP, and was lowest in SHRSP. The blood pressure of SHR and SHRSP elevated with age, and showed higher in SHRSP than SHR, while that of WKY did not change. There were many strain differences in most measured items at each time point, particularly at 30 weeks. In SHRSP, high values of BUN, creatinine, total and ionized Ca, weights of brain, heart, liver, kidney and digestive duct were observed at most time points indicating that this strain's abnormality of calcium metabolism may be related to functions of the kidney and digestive duct as well as hypertension.


Insights into eco-corona formation and its role in the biological effects of nanomaterials from a molecular mechanisms perspective.
Broad application of nanotechnology inevitably results in the release of nanomaterials (NMs) into the aquatic environment, and the negative effects of NMs on aquatic organisms have received much attention. Notably, in the natural aquatic environment, ubiquitous ecological macromolecules (i.e., natural organic matter, extracellular polymeric substances, proteins, and metabolites) can easily adsorb onto the surfaces of NMs and form an "eco-corona". As most NMs have such an eco-corona modification, the properties of their eco-corona significantly determine the fate and ecotoxicity of NMs in the natural aquatic ecosystem. Therefore, it is of great importance to understand the role of the eco-corona to evaluate the environmental risks NMs pose. However, studies on the mechanism of eco-corona formation and its resulting nanotoxicity on aquatic organisms, especially at molecular levels, are rare. This review systemically summarizes the mechanisms of eco-corona formation by several typical ecological macromolecules. In addition, the similarities and differences in nanotoxicity between pristine and corona-coated NMs to aquatic organisms at different trophic levels were compared. Finally, recent findings about potential mechanisms on how NM coronas act on aquatic organisms are discussed, including cellular internalization, oxidative stress, and genotoxicity. The literature shows that 1) the formation of an eco-corona on NMs and its biological effect highly depend on both the composition and conformation of macromolecules; 2) both feeding behavior and body size of aquatic organisms at different trophic levels result in different responses to corona-coated NMs; 3) genotoxicity can be used as a promising biological endpoint for evaluating the role of eco-coronas in natural waters. This review provides informative insight for a better understanding of the role of eco-corona plays in the nanotoxicity of NMs to aquatic organisms which will aid the safe use of NMs.


Repeated administration of acrylamide for 28 days reduces late-stage progenitor cells and immature granule cells accompanying impaired neurite outgrowth in the adult hippocampal neurogenesis in young-adult rats.
Acrylamide (AA) is a neurotoxicant that causes synaptic impairment in distal axons. We previously found that developmental exposure to AA decreased proliferation of late-stage neural progenitor cells (NPCs) in the hippocampal neurogenesis of the dentate gyrus (DG) in rats. To investigate whether hippocampal neurogenesis is similarly affected by AA exposure in a general toxicity study, AA was administered to 7-week-old male rats via oral gavage at dosages of 0, 5, 10, and 20 mg/kg for 28 days. In the subgranular zone (SGZ) and granule cell layer, AA decreased the densities of doublecortin-positive (+) cells and TOAD-64/Ulip/CRMP protein 4b+ cells per SGZ length. In addition, AA decreased the neurite length of doublecortin+ cells and downregulated genes related to neurite outgrowth (Ncam2 and Nrep) and neurotrophic factor (Bdnf and Ntrk2) in the DG. These results suggest that AA exposure for 28 days decreases type-3 NPCs and immature granule cells in neurogenesis of granule cell lineages involving the impairment of neurite outgrowth in young-adult rats. In the DG hilus, AA increased the density of cholinergic receptor nicotinic beta 2 subunit+ cells. AA also downregulated Reln related to the control of neuronal migration by interneurons in the DG. Furthermore, AA decreased the density of glial fibrillary acidic protein (GFAP)+ astrocytes in the DG hilus and downregulated Gfap and the genes of oligodendrocyte progenitor cells (Cspg4 and Pdgfra). Thus, AA decreased granule cell lineage subpopulations in the late-stage differentiation of hippocampal neurogenesis after young-adult stage exposure, exhibiting a pattern similar to the developmental exposure.


Enhancement of cell permeabilization apoptosis-inducing activity of selenium nanoparticles by ATP surface decoration.
A simple method for preparation of adenosine triphosphate (ATP) surface-functionalized selenium nanoparticles (SeNPs@ATP) with enhanced cell permeabilization and anticancer activity has been demonstrated in the study reported in this article. Spherical SeNPs were decorated with ATP by strong adsorption through an Se-N bond, leading to the highly stable structure of the conjugates. ATP surface decoration significantly enhanced the cellular uptake and anticancer activity of SeNPs. Induction of apoptosis in HepG2 human hepatocellular carcinoma cells by SeNPs@ATP was evidenced by accumulation of the sub-G1 cell population, phosphatidylserine exposure, DNA fragmentation, PARP cleavage and caspase activation. Further studies found that SeNPs@ATP treatment triggered the depletion of mitochondrial membrane potential and reactive oxygen species (ROS) overproduction. Our results demonstrate that the use of ATP as a surface decorator of SeNPs is a novel strategy to achieve anticancer synergy. SeNPs@ATP may be a candidate for further evaluation as a chemotherapeutic agent for human cancers. In this paper, adenosine triphosphate (ATP) surface-functionalized selenium nanoparticles are discussed as cell-penetrating anticancer agents. Conjugates are stable and ATP functionalization greatly enhances the apoptosis induction properties of the selenium nanoparticles in HepG2 human hepatocellular carcinoma cells.


Old wine in new bottles: Drug repurposing in oncology.
Increasing costs, much time consumption and high risk of failure associated with the process of de novo development of new anticancer drugs have prompted the pharmaceutical industry to seek alternative strategies that may facilitate and accelerate the whole process. In particular, the repurposing strategy, known also as repositioning or reprofiling strategy, is a potential source of new treatment options for cancer patients with high unmet medical needs. However, it should be noted that the repurposing strategy, being still a new trend in drug development, should only complement the process of discovering new anticancer drugs, and should not be its alternative. The best repurposable oncological drug candidates are the agents whose original patent protection has already expired, and for which there is a possibility to create a formulation enabling, together with a new therapeutic indication, new patent protection. In this review article we discuss the advantages of the repurposing strategy, and provide an overview of a number of promising candidates, such as artesunate, aspirin, cimetidine, doxycycline, ivermectin, metformin, rapamycin (sirolimus), and thalidomide, that have the potential to be repurposed as anticancer drugs both in cancer prevention and therapy. In addition, we highlight some of the studies regarding the signalling pathways and molecular targets altered by these drugs, and describe the biological mechanisms underlying their anticancer effects.


FTIR, FT-Raman, FT-NMR and quantum chemical investigations of 3-acetylcoumarin.
3-Acetylcoumarin (3AC) was synthesised by a Knoevenagel reaction. Conformational analysis using the B3LYP method was also carried out to determine the most stable conformation of the compound. FTIR and FT-Raman spectra of 3AC have been recorded in the range 4000-400 and 4000-100 cm(-1), respectively. (1)H and (13)C NMR spectra have also been recorded. The complete vibrational assignment and analysis of the fundamental modes of the compound were carried out using the experimental FTIR and FT-Raman data and quantum mechanical studies. The experimental vibrational frequencies were compared with the wavenumbers obtained theoretically from the DFT-B3LYP/B3PW91 gradient calculations employing the standard 6-31G(**), high level 6-311++G(**) and cc-pVTZ basis sets for optimised geometry of the compound. The frontier molecular orbital energies of the compound are determined by DFT method.


Characterizing short stature by insulin-like growth factor axis status and genetic associations: results from the prospective, cross-sectional, epidemiogenetic EPIGROW study.
Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH-IGF-I axis. Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH. We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008-2010). Children (n = 275) aged ≥2 years with SS without defined etiology (≤-2.5 height SD score [SDS]) and ≥1 peak GH ≥7 μg/L) were recruited. Serum IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) levels were measured in a central laboratory. Candidate gene exome sequencing was performed in this cohort and ethnicity-matched controls. Serum IGF-I, IGFBP-3, and ALS levels were highly correlated, but there was a discrepancy between prevalence of IGF-I, IGFBP-3, and ALS deficiencies (53%, 30%, and 0.8%, respectively). An insertion-deletion (Indel) on the IGF1 gene (P = 1.2 × 10(-5), Bonferroni-corrected; case vs control frequency: 0.04 vs 0.112), an Indel on NFKB1 (P = 1.36 × 10(-10); case vs control frequency: 0.464 vs 0.272), and 2 single-nucleotide polymorphisms on ZBTB38 (P < 2.3 × 10(-6)) were associated with SS. At P < 10(-4), single-nucleotide polymorphisms on genes related to protein kinase regulation, MAPK, and Fanconi pathways were also associated with SS. IGF-I deficiency is a common feature in SS without defined etiology; an Indel in the IGF1 gene was associated with SS. However, genes involved in transcriptional regulation (NFKB1 and ZBTB38) and growth factor signaling were also associated, providing further candidates for genetic investigations on individual patients.


A novel strategy for producing compost with enhanced biopesticide properties through solid-state fermentation of biowaste and inoculation with Bacillus thuringiensis.
In the framework of a circular economy, organic solid wastes are considered to be resources useful for obtaining value-added products. Among other potential uses, biodegradable wastes from agricultural, industrial, and domestic sources are being studied to obtain biopesticides through solid-state fermentation (SSF), mainly at the laboratory scale. The suitability of biowaste (source-selected organic fraction of municipal solid waste) for use as a substrate for Bacillus thuringiensis (Bt) growth under non-sterile conditions in a 10 L SSF reactor was determined in this study. An operational strategy for setting up a semi-continuous process yielding a stabilised organic compost-like material enriched with Bt suitable for use as a soil amendment was developed. Concentrations of 1.7·107-2.2·107 and 1.3·107-2.1·107 CFU g-1 DM for Bt viable cells and spores, respectively, were obtained in the final material. As the results confirmed, Bt-enriched compost-like material with potential biopesticide properties can be produced from non-sterile biowaste.


Bayesian Models for Multiple Outcomes in Domains with Application to the Seychelles Child Development Study.
The Seychelles Child Development Study (SCDS) examines the effects of prenatal exposure to methylmercury on the functioning of the central nervous system. The SCDS data include 20 outcomes measured on 9-year old children that can be classified broadly in four outcome classes or "domains": cognition, memory, motor, and social behavior. Previous analyses and scientific theory suggest that these outcomes may belong to more than one of these domains, rather than only a single domain as is frequently assumed for modeling. We present a framework for examining the effects of exposure and other covariates when the outcomes may each belong to more than one domain and where we also want to learn about the assignment of outcomes to domains. Each domain is defined by a sentinel outcome which is preassigned to that domain only. All other outcomes can belong to multiple domains and are not preassigned. Our model allows exposure and covariate effects to differ across domains and across outcomes within domains, and includes random subject-specific effects which model correlations between outcomes within and across domains. We take a Bayesian MCMC approach. Results from the Seychelles study and from extensive simulations show that our model can effectively determine sparse domain assignment, and at the same time give increased power to detect overall, domain-specific and outcome-specific exposure and covariate effects relative to separate models for each endpoint. When fit to the Seychelles data, several outcomes were classified as partly belonging to domains other than their originally assigned domains. In retrospect, the new partial domain assignments are reasonable and, as we discuss, suggest important scientific insights about the nature of the outcomes. Checks of model misspecification were improved relative to a model that assumes each outcome is in a single domain.


Estimated optimal gestational weight gain for pregnant women with gestational diabetes mellitus: a prospective cohort study in China.
We aimed to evaluate the inter-hospital variability of gestational weight gain (GWG) among women with gestational diabetes mellitus (GDM) in China and explore GDM-specific optimal GWG relative to the National Academy of Medicine (NAM) targets. A prospective multicenter University Hospital Advanced Age Pregnant Cohort study was conducted from March 2017 to June 2021 at eight hospitals in China. The range of mean GWG across hospitals and the intraclass correlation coefficient (ICC) were used to evaluate the inter-hospital variability of GWG. For normal-weight and overweight women with GDM, potential optimal GWGs were derived by minimizing the joint risk of small and large for gestational age (SGA and LGA), and the incidences of adverse perinatal outcomes were compared between women who met the optimal GWGs and those who met the NAM targets. A total of 3,013 women with GDM and 9,115 women without GDM were included. The GWG variation among hospitals was larger in women with GDM (range: 10.0-14.1 kg, ICC = 7.1%) than in women without GDM (range: 13.0-14.5 kg, ICC = 0.7%). The estimated optimal GWGs for women with GDM were lower than the NAM targets, as 9.5-14.0 kg for normal-weight and 3.0-7.5 kg for overweight women. Women with GDM who met the optimal GWGs had lower incidences of LGA and macrosomia compared to those who met the NAM targets, with no significant increase in the incidences of SGA, preterm birth, etc. CONCLUSIONS: The marked variation of GWG among hospitals in women with GDM indicates the need to develop optimal GWGs for them. The potential optimal GWGs for women with GDM might be lower than the NAM targets, likely benefiting the perinatal outcomes.


Zinc supplementation in ethanol-treated pregnant rats increases the metabolic activity in the fetal hippocampus.
As a possible preventative measure for brain dysfunction in the fetal alcohol syndrome, the effect of zinc supplementation together with ethanol on the fetal cerebrum, especially the hippocampus, was investigated. Female rats of an ethanol group and a control group received 30% ethanol and water, respectively. During pregnancy half of both groups received 0.01% zinc together with ethanol or water. Fetuses on gestational day 21 were examined biochemically and ultrastructurally. Administration of zinc with ethanol resulted in an increased cerebral weight and cerebral RNA content compared to administration of ethanol alone. However, these better results did not reach those of controls without ethanol. In the cytoplasm of hippocampal neurons from dams only given zinc with ethanol confronting cisternae were frequently observed between the rough endoplasmic reticulum and the rough endoplasmic reticulum or the nuclear envelope. Although the functional roles of the confronting cisternae were not definite, it is reasonable to conclude that the confronting cisternae were a repair mechanism of zinc against the inhibitory effect on RNA and protein syntheses of ethanol. This study shows evidence of prevention of the brain dysfunction on ethanol treatment.


Development, internal reliability and preliminary construct validity of the Dutch Dietary Intention Evaluation Tool for In-patients (DIETI).
Diet is important in prevention and management of non-communicable disease and in particular, cardiovascular disease. Recently, more hospitals gear towards healthier dietary policies, however, a tool to assess the effect of these interventions in patient populations is currently lacking. The Theory of Planned Behavior (TPB) is generally used to assess health-related behavior and offers a framework for development of questionnaires. In this study, we aim to evaluate the reliability, internal consistency and preliminary construct validity of the newly developed Dietary Intention Evaluation Tool for In-hospital patients (DIETI) which is based on the TPB. An expert panel constructed the item list of the DIETI. A total of 312 patients admitted to the cardiology ward filled out the DIETI. Explanatory- and confirmatory factor analysis showed that our tool adequately discerns five TPB-consistent factors regarding a healthy diet in hospitalized patients. (N = 312, for the CFA model χ2 = 313.072 (df = 160, p < 0.001, CFI = 0.939, RMSEA = 0.058). Subsequent analysis of reliability showed satisfactory to strong internal consistency of the questionnaire as a whole and all subscales (Cronbach's alpha for the subscales ranging between 0.65 and 0.88). We conclude that the DIETI is an internally reliable tool to assess behavioral intentions regarding a healthy diet of in-hospital patients. Thus, this questionnaire can be used to evaluate the effect of dietary interventions aimed at hospitalized patients.


Characterisation of technologically proficient wild Lactococcus lactis strains resistant to phage infection.
The aim of this work was to establish whether Lactococcus lactis strains isolated from spontaneous dairy fermentations exhibited useful milk-processing capabilities and resistance to bacteriophage infection in order to be used as components in starter formulations. The 33 out of 100 isolates of L. lactis, originated from farmhouse cheeses, were found to be resistant to a collection of 34 phages belonging to the c2 and 936 groups. Six of the isolates were discarded as potential starters because they were lysogenic and other five because they produced tyramine. Plasmid and chromosomal profiles of the 22 remaining isolates allowed their classification into 16 different strains. All of these were good lactic acid producers from lactose, moderately proteolytic and, in eight cases, diacetyl production from citrate was observed. The mechanism(s) leading to the phenotype of phage resistance was identified for all the strains used in this study. Inhibition of adsorption was the most frequent one, although genetic determinants for some abortive infection systems were also detected (abiB, abiG and abiI). Frequently, more than one mechanism was present in the same strain. One of the strains, L. lactis IPLA542, was selected as a model starter for pilot fermentations. It clotted milk normally both in the absence and in the presence of phage at concentrations that completely abolished the process when promoted by a phage-susceptible strain.


Prevalence and risk factors of dual sensory impairment among community-dwelling older adults in Selangor: A secondary data analysis.
The present study aimed to examine the prevalence of dual sensory impairment, and to identify its risk factors among community-dwelling older adults in Selangor. Secondary analysis was carried out on data collected by the Grand Challenge Project among older adults aged ≥65 years from Selangor. Data on sociodemographic information, medical history, cognitive function and functional performance were obtained through face-to-face interviews using standardized questionnaires. Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart while hearing was assessed using pure-tone audiometry. Descriptive analysis was used to measure the prevalence of the impairments, and logistic regression analysis was used to identify the risk factors. The prevalence of dual sensory impairment and hearing impairment were at 10.5% and 76.2% respectively. Multivariate logistic regression analysis revealed that participants with lower cognitive scores were associated with dual sensory impairment (odds ratio, 0.90; 95% confidence interval, 0.83-0.98), while smoking was found associated with hearing impairment (odds ratio, 6.58; 95% confidence interval, 1.51-28.65). Dual sensory impairment is common among older adults in Selangor. The association between dual sensory impairment and cognitive function suggests the need to have visual and hearing screening on older adults for early detection particularly those at risk of cognitive impairment. The prevalence of hearing impairment was reported high among older adults and smokers appeared to be at higher risk of the impairment. Geriatr Gerontol Int 2020; 20: 911-916.


Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy.
The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infusion of branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE.


Richter's hernia.
Richter's hernia is associated with rapid onset of gangrene and a high mortality. We report a case of a strangulated inguinal Richter's hernia of the cecum requiring a laparotomy and bowel resection. Due to the misleading clinical presentation, a high index of suspicion, particularly in patients with a history of laparoscopic surgery, will minimize delay in diagnosis.


[Maraviroc: clinical trials results].
Just over a decade after identification of chemokine receptors CCR5 and CXCR4 as coreceptors for HIV, maraviroc (Celsentri), the first CCR5 antagonist, has recently obtained its Marketing Authorization in the United States and Europe, for treatment of treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable. CCR5 antagonists, after fusion inhibitor enfuvirtide available since 2003, also belong to entry inhibitors. These molecules, unlike previous antiretrovirals, do not target the virus but its target cell by blocking viral penetration. Maraviroc has shown its clinical efficacy in patients failing other antiretroviral classes. Its safety profile was similar to placebo in two large phase III trials. However, careful assessment of both hepatic and immunologic safety of this new therapeutic class is needed. Viral tropism testing has to be investigated before using maraviroc in the clinic, because CCR5 antagonists are not active against CXCR4 viruses. For the moment indicated for the treatment-experienced patient population, maraviroc could in the future benefit to other types of patients, depending on ongoing trials results.


Toward reprogramming bacteria with small molecules and RNA.
A major goal of synthetic biology is to reprogram bacteria to carry out complex tasks, such as synthesizing and delivering drugs, and seeking and destroying environmental pollutants. Advances in molecular biology and bacterial genetics have made it straightforward to modify, insert, or delete genes in many bacterial strains, and advances in gene synthesis have opened the door to replacing entire genomes. However, rewriting the underlying genetic code is only part of the challenge of reprogramming cellular behavior. A remaining challenge is to control how and when the modified genes are expressed. Several recent studies have highlighted how synthetic riboswitches, which are RNA sequences that undergo a ligand-induced conformational change to alter gene expression, can be used to reprogram how bacteria respond to small molecules.


In ovo exposure to triclosan alters the hepatic proteome in chicken embryos.
The occurrence of triclosan (TCS) in the eggs of wild avian species is an emerging concern. We previously evaluated the effects of in ovo exposure to TCS on the liver transcriptome of chicken embryos and proposed adverse outcome pathways (AOPs). However, the key molecular events identified to be affected need to be verified at the protein level. Herein, we investigated the changes in the spectrum of hepatic proteins in TCS-treated chicken embryos by proteomic analysis to validate the key signaling pathways involved in the AOPs. We identified and quantified 894 unique proteins using matrix-assisted laser desorption/ionization time-of-flight/time-of-flight tandem mass spectrometry. In the 0.1 (low dose), 1 (median dose), and 10 μg triclosan/g egg (high dose) groups, TCS caused significant changes in the levels of 195, 233, and 233 proteins in males and 237, 188, and 156 proteins in females, respectively (fold changes > 1.3 or < 0.7). TCS exposure modulated the expression of proteins, predominantly involved in signaling pathways of lipid and energy metabolism in both genders. Among the proteins associated with TCS metabolism in the liver, phase I (e.g., CYP2C23a) and phase II (e.g., UGT1A1) enzymes mediated by chicken xenobiotic receptor, were only induced in males. In consonance with the malondialdehyde levels, which were increased upon TCS exposure in females in a dose-dependent manner, a battery of antioxidant enzymes, notably SOD2, GST, GSTz1, and PRDX1, was decreased and SOD1 and GSTK1 were increased in the embryos. Taken together, this proteome analysis complements the transcriptome profiling reported in our previous study and authenticates the AOPs proposed for chicken embryos in ovo exposed to TCS.


Correlation between anti-JC-virus and anti-cytomegalovirus, -Epstein-Barr virus and -measles/-rubella/-varicella-zoster-virus antibodies.
Anti-JCV antibody status is used for PML-risk-stratification in MS patients before and during Natalizumab therapy. JCV antibodies can be detected in around 60% of MS patients, however, only a small proportion actually develop PML. As anti-viral antibodies tend to occur unspecifically, the aim of this study was to correlate JCV antibody status and index with other common anti-viral antibodies. A total of 123 samples of MS-patients were tested for anti-JCV antibodies by JCV-Stratify-ELISA at Unilabs, Denmark. The same samples were analyzed for measles, rubella, varicella zoster, EBV, and CMV IgG and IgM antibodies by ELISA, or chemiluminescence-microparticle immunoassay. For all antibody-titers correlations were calculated and group comparisons of JCV-positive and -negative patients were performed. Fifty-three patients (43.1%) were JCV negative and 70 (56.9%) positive. CMV-IgM antibodies were detected in six patients. Otherwise no IgM antibodies were detected. IgG antibodies against measles, rubella, varicella zoster, and EBV were detected in ≥97% of patients and 47 samples (38.2%) tested positive for CMV-IgG. There was no significant correlation between any of the antibody titers including JCV index, however, a significantly higher prevalence (P = 0.003) of CMV-IgG in JCV positive compared to JCV negative patients, whereas no difference was detected for measles, rubella, varicella zoster, and EBV IgG. In conclusion, the JCV antibody response in MS patients seems to be largely independent of any other anti-viral immunity. The only coincidence was found with CMV IgG antibodies which might point towards some immunological cross-reactivity in anti-viral immune response or other mechanisms leading to combined viral infections such as shared transmission. J. Med. Virol. 89:3-9, 2017. © 2016 Wiley Periodicals, Inc.


Preoperative assessment of the elderly patient.
Organ system functional reserve variability increases progressively with age. In elderly patients, cardiopulmonary, central nervous system, and metabolic functional reserve seem to be the most important predictors of the ability to undergo surgery. Directed testing for the assessment of organ system functional reserve and identification of organs at risk, rather than the diagnosis of disease itself, is the primary goal of preoperative evaluation prior to surgery and is essential to the formulation of an effective anesthetic plan. The risks of adverse drug interaction, already high in the elderly, make a thorough review of the indications and dosage of perioperative medication an important part of the preoperative assessment process.


Regulatory roles for SOX11 in development, stem cells and cancer.
The transcription factor SOX11 (SRY-related high-mobility-group (HMG) box 11), a member of the SOXC group, is expressed during embryogenesis but largely absent in most adult differentiated tissues. SOX11 regulates progenitor and stem cell behavior, and often acts together with the other two SOXC group members, SOX4 and SOX12, in regulating developmental processes, including neurogenesis and skeletogenesis. Dysregulation of SOX11 has been implicated in a number of diseases including, neurodevelopmental disorders and osteoarthritis, and a wide variety of cancers. Functions of SOX11 during both development and disease could be attributed to its context-dependent post-transcriptional modifications or interaction with other co-factors. We review the molecular and functional roles of SOX11 during development where similar processes appear to be deregulated in cancers.


Body mass index has a greater impact on pregnancy outcomes than gestational hyperglycaemia.
We evaluated diabetes-related pregnancy outcomes in a cohort of Spanish women in relation to their glucose tolerance status, prepregnancy BMI and other predictive variables. The present paper is part of a prospective study to evaluate the impact of American Diabetes Association (2000) criteria in the Spanish population. A total of 9,270 pregnant women were studied and categorised as follows according to prepregnancy BMI quartiles and glucose tolerance status: (1) negative screenees; (2) false-positive screenees; (3) gestational diabetes mellitus (GDM) according to American Diabetes Association criteria only; and (4) GDM according to National Diabetes Data Group criteria (NDDG). We evaluated fetal macrosomia, Caesarean section and seven secondary outcomes as diabetes-related pregnancy outcomes. The population-attributable and population-prevented fractions of predictor variables were calculated after binary logistic regression analysis with multiple predictors. Both prepregnancy BMI and abnormal glucose tolerance categories were independent predictors of pregnancy outcomes. The upper quartile of BMI accounted for 23% of macrosomia, 9.4% of Caesarean section, 50% of pregnancy-induced hypertension and 17.6% of large-for-gestational-age newborns. In contrast, NDDG GDM accounted for 3.8% of macrosomia, 9.1% of pregnancy-induced hypertension and 3.4% of preterm births. In terms of population impact, prepregnancy maternal BMI exhibits a much stronger influence than abnormal blood glucose tolerance on macrosomia, Caesarean section, pregnancy-induced hypertension and large-for-gestational-age newborns.


MRI-informed prostate biopsy: What the radiologist should know on quality in biopsy planning and biopsy acquisition.
Quality is currently recognized as the pre-requisite for delivering the clinical benefits expected by magnetic resonance imaging (MRI)-informed prostate biopsy (MRI-i-PB) in patients with a suspicion for clinically significant prostate cancer (csPCa). The "quality chain" underlying MRI-i-PB is multidisciplinary in nature, and depends on several factors related to the patient, imaging technique, image interpretation and biopsy procedure. This review aims at making the radiologist aware of biopsy-related factors impacting on MRI-i-PB quality, both in terms of biopsy planning (threshold for biopsy decisions, association with systematic biopsy and number of targeted cores) and biopsy acquisition (biopsy route, targeting technique, and operator's experience). While there is still space for improvement and better standardization of several biopsy-related procedures, current evidence suggests that high-quality MRI-i-PB can be delivered by acquiring and increased the number of biopsy cores targeted to suspicious imaging findings and perilesional area ("focal saturation biopsy"). On the other hand, uncertainty still exists as to whether software-assisted fusion of MRI and transrectal ultrasound images can outperform cognitive fusion strategy. The role for operator's experience and quality assurance/quality control procedures are also discussed.


What do you mean "functional" in ecology? Patterns versus processes.
Use of the term "functional" trait has increased exponentially in ecology. Although accounting for numerous ecological questions, this concept raises several issues. We propose that the term "functional" could be misleading because (1) no rigorous criteria exist to identify "functional" traits and (2) it suggests that only some traits ("functional" ones) can inform our understanding of species functioning, whatever the scale or discipline. Hence, the concept of "functional" trait in ecology is starting to be challenged and it remains unclear why some traits should be considered functional, whereas other traits should not. We argue that the most used "functional" traits are meaningful because they reflect important differences between populations or species, based on synchronic comparisons, that is, irrespective of time (hereafter "pattern" traits). Hence, they are useful for identifying trade-offs and strategies across large numbers of observations, usually at rather coarse scales, and are most often used in analyses of "big data." However, given that many ecological processes occur across short time scales and narrow gradients of climate and resource availability, the efficacy of these traits to inform us about these ecological processes appears questionable. We show that trait measurements that take time explicitly into account (hereafter "process" traits) differ from pattern traits because they quantify the flows of material and energy within a given environment across a defined period of time. Although pattern traits and process traits are both functional, it is important to understand the differences between the approaches. Moreover, better accounting of ontogeny, life form, plasticity, and genetic variability is required to enhance the convergence between pattern and process approaches. This revised framework allows more explicit connections between trait ecology and other biological sciences. It should enhance the study of processes at all scales in order to investigate efficiently the adaptive responses of biological organisms to climate change.


The complete nucleotide sequence of two distinct geminiviruses infecting cucurbits in Vietnam.
We have characterised two distinct geminiviruses that infect cucurbit cultivars in Vietnam. The genomes of both viruses consisted of two circular ssDNA components (DNA-A and DNA-B), with a genome arrangement and coding sequence typical of viruses in the Begomovirus genus in the family Geminiviridae. The sequence of DNA-A of one of the viruses was approximately 97% similar to Squash leaf curl virus-China (SLCV-Ch), for which a DNA-B has yet to be identified. We have named this virus Squash leaf curl virus-Vietnam (SLCV-Vn). The intergenic region of the SLCV-Vn DNA-B contained a 40 nt deletion between the putative AC1 TATA box and the stem loop. A second virus isolated from loofa in southern Vietnam was only 80% similar to SLCV-Vn over the complete DNA-A sequence, however the nucleotide sequence in the coat protein coding regions was 95% similar. We have named this virus Loofa yellow mosaic virus-Vietnam (LYMV-Vn). Other regions of the SLCV-Vn and LYMV-Vn genomes differed markedly, suggesting the coat protein coding region was recombinant. The DNA-B of both viruses were only 60% similar over the complete nucleotide sequence, although the encoded amino acid sequence of the BC1 gene was 90% identical.


Hemorrhagic fever with renal syndrome in the Pomurje region of Slovenia--an 18-year survey.
To determine the etiology of hemorrhagic fever with renal syndrome (HFRS) in the north-eastern part of Slovenia (Pomurje region) together with demographic, epidemiological and clinical data on 25 patients from this region who were diagnosed and treated at the General Hospital in Murska Sobota between 1986 and 2003. Medical records of patients with a discharge diagnosis of HFRS who were either hospitalized or referred to an infectiologist as outpatients were included in this retrospective study. Data on demographic characteristics, clinical manifestations and laboratory parameters were collected from the patients' records. In addition, all available follow-up records were examined and information on general health, blood pressure, basic blood and biochemical examination and urine analysis was collected. Infection with Puumala virus (PUUV) was indicated in 23 patients and Dobrava virus (DOBV) infection in two patients. The median age of patients was 39 years; 19 were male. The patients primarily had outdoor occupations. Most of the HFRS cases occurred between May and August. The most common findings were fever, vomiting, headache, myalgia, chills, cough, back and abdominal pain, and blurred vision. The most prominent laboratory abnormalities were elevated erythrocyte sedimentation rate and C-reactive protein concentration, thrombocytopenia, and leucocytosis with neutrophilia. The signs of renal dysfunction were observed in 24 of the 25 patients. Oliguric renal failure was seen in 13 of 23 (57%) PUUV-infected patients. Six of 23 (26%) patients infected with PUUV and one of two (50%) patients from the DOBV group had hypotension or developed signs of shock. Seven out of 15 (47%) patients had elevated protein concentration in cerebrospinal fluid (CSF). Sinus bradycardia was documented in 7 of 17 (41%) patients with PUUV infection. HFRS is endemic in the north-eastern part of Slovenia; PUUV and DOBV infections coexist, with PUUV being the main causative agent of HFRS. Demographic, clinical and laboratory findings in our patients with HFRS caused by PUUV were mostly in accordance with those published previously, but the ratio of patients with sinus bradycardia, oliguric renal failure and mildly elevated CSF protein concentration was rather high.


Local recurrence, rate and sites of metastases, and time to relapse as a function of treatment regimen, size of primary and surgical history in 62 patients presenting with non-metastatic Ewing's sarcoma of the pelvic bones.
This report reviews the experience of 62 patients who presented between 1972 and 1978 with non-metastatic Ewing's sarcoma of the pelvis and were entered on IESS I. Seventeen patients (27%) developed a local recurrence, 38 patients (61%) demonstrated metastases and 21 (34%) neither. In the dose range 4000 rad to 6000 rad no dose response could be detected for local control of tumor. Forty-six patients (74%) had a biopsy or exploratory surgery only, 5 patients (8%) had an incomplete resection and 11 patients (18%) had a complete resection of their tumor. In the 46 patients having a biopsy only, 13 developed a local recurrence (28%) as compared to 2 of 11 patients undergoing a complete resection (18%). The most common sites for metastases were lung in 19 patients (31%) and bone in 23 patients (37%). No significant difference was noted in the frequency of overall metastases or metastases to any site between those patients receiving one of the three treatment regimens used in IESS I: VAC and Adriamycin (regimen I), VAC alone (regimen II) and VAC plus bilateral pulmonary irradiation (regimen III). At a median follow-up of 135 weeks no significant difference in median survival could be detected in patients with pelvic primaries between regimens I, II and III. The mean diameter of the pelvic primaries was comparable to the nonpelvic, however, one half of the pelvic cases were in the range 10-15 cm. The median time to relapse of the 241 non-pelvic patients on IESS I was 222 weeks as contrasted with the median time to relapse of 92 weeks in the 62 pelvic patients on the same study (p = 0.002). The possible reasons for the poor prognosis of pelvic primary patients are discussed together with treatment policies that might improve the survival of this group of patients.


The significant association of Taq1A genotypes in DRD2/ANKK1 with smoking cessation in a large-scale meta-analysis of Caucasian populations.
Although a number of studies have analyzed the relation between the DRD2/ANKK1 gene Taq1A polymorphism and smoking cessation, the results remain controversial. The primary objective of the present study was to determine whether this variant indeed has any effect on smoking cessation. The A1-dominant model that considers A1/* (*=A1 or A2) and A2/A2 as two genotypes and compares their frequencies in current and former smokers was applied. A total of 22 studies with 11,075 subjects were included in the meta-analyses. Considering the potential influence of between-study heterogeneity, we conducted stratified meta-analyses with the Comprehensive Meta-Analysis statistical software (version 2.0). Results based on either cross-sectional or longitudinal studies consistently showed a statistically significant association between Taq1A A1/* genotypes and smoking cessation. Further, a more significant association of the variant with smoking cessation was detected when both types of studies were combined. However, there was marginal evidence of heterogeneity among studies (I(2)=33.9%; P=0.06). By excluding other ethnicities and subjects with cancer, the meta-analysis on the basis of 9487 Caucasians demonstrated that Taq1A A1/* genotypes indeed were significantly associated with smoking cessation under both the fixed- and random-effects models (pooled OR 1.22; 95% CI 1.11-1.34; P=3.9 × 10(-5) for both models). No evidence of between-study heterogeneity or publication bias was observed. Thus, we conclude that the polymorphism of Taq1A has an important role in the process of abstaining from smoking, and smokers carrying A2/A2 genotype have a higher likelihood of smoking cessation than those who carry A1/A1 or A1/A2.


The relationship of personal competencies, social adaptation, and job adaptation on job satisfaction.
Personal competencies are associated with successful job performance. Job satisfaction is directly related to nursing turnover, and is a critical indicator of their performance and quality of patient care. However, little is known about the relationship between personal competencies, social adaptation, and job adaptation on job satisfaction for nurses. The purpose of this study was to explore the relationship between personal competencies, social adaptation, and job adaptation on job satisfaction for nurses. This study was conducted with secondary data analysis. We targeted nursing alumni in a large university in Taiwan. The target population was nursing alumni, and the sample consisted of 280 from the Office of Student Affairs database. Personal competencies, social adaptation, job adaptation, and job satisfaction were measured using a secondary data analysis. Relationships between the variables were analyzed to determine which variable explained the most variance in job satisfaction. Of the 280 participants, participation of extracurricular activities was reported by 70.4%, and over 22.5% had a leadership role in extracurricular activities. The results demonstrated that nursing alumni with either extracurricular activities involvement or a leadership role had higher level of personal competencies and better job satisfaction. Further, these results showed the number of years in the extracurricular activities (r = 0.174, p = .003), the perceived level of personal competencies (r = 0.341, p = .000), social adaptation (r = 0.411, p = .000) and job adaptation (r = 0.575, p = .000) were positively and significantly correlated with job satisfaction. The job adaptation, the perceived level of personal competencies, and alumni who had a leadership role accounted for 37.1% of variance in job satisfaction. Results of this study suggest that job adaptation, personal competencies, and having had a leadership role in extracurricular activities are important concepts to improving nurses' job satisfaction.


Single-nucleotide polymorphisms in genes related to oxidative stress and ion channels in chickens are associated with semen quality and hormonal responses to thermal stress.
Heat stress causes economic loss of livestock industry in tropical areas. Exploring genetic markers for selection of thermotolerance will benefit chicken production. Oxidative stress and fluid-salt balance are tightly associated with thermotolerance and productivity in domestic animals. The study aimed to identify single-nucleotide polymorphisms (SNPs) in genes related to oxidative stress and ion-channel regulation and their associations with semen quality and hormonal responses. In total, 28 SNPs within 11 candidate genes were identified to associate with hormonal changes and semen quality in both broiler- and layer-type Taiwan country chickens (TCCs) after exposure to acute heat stress at 38 °C for 4 h. Acute heat stress significantly affected plasma levels of triiodothyronine and corticosterone and reduced sperm motility, viability, and concentrations in both strains at Day 1 after exposure. In the B-strain TCCs, five SNPs within NDUFA8 and DAB2IP had significant effects on plasma adrenaline and corticosterone levels, and six SNPs within TRPC1, SLC9A9, and TRPC7 markedly affected plasma corticosterone and triiodothyronine levels. In the L2 strain, 15 SNPs within PSMA2, TPK1, MTF1, and CUL1 exerted effects on plasma corticosterone and triiodothyronine levels. Five SNPs within CUL3, TRPC1, and SLC9A9 in the B strain and two SNPs within MTF1 in the L2 strain were associated with sperm concentrations at Day 1 after exposure to heat stress. In conclusion, acute heat stress impaired semen quality and altered plasma corticosterone and triiodothyronine levels in TCCs. Some SNPs involved in oxidative stress and ion-channel regulation were identified to associate with the hormonal and semen alterations. These SNPs in conjunction with differential hormonal responses and semen quality serve as genetic markers for thermotolerance selection in sire lines of chickens.


The binding of simian virus 40 large T antigen to the polyphosphate backbone of nucleic acids.
Simian virus 40 (SV40) large tumor antigen (T antigen), a phosphoprotein found in nuclei of SV40-infected and -transformed cells, binds nonspecifically to DNA. To study this mechanism the binding properties of T antigen to double-stranded (ds) and single-stranded (ss) DNA-cellulose as well as to phosphocellulose were compared. After incubation of [35S] methionine or [3H] leucine/[32 P] phosphate radioactively-labeled cell extracts at different pH values (6.0, 7.3, 9.0) with DNA- or phosphocellulose, bound and unbound species of T antigen were purified and analyzed by SDS-polyacrylamide gel electrophoresis for both the yield and the possible correlation with protein phosphorylation. T antigens bound with comparable affinities to ds- and ss-DNA-cellulose and phosphocellulose. These results suggest the binding of T antigen to the polyphosphate backbone of DNA as a molecular mechanism for its nonspecific binding. The evidence for this observation was supported by blocking the binding of T antigen to DNA-cellulose by divalent cations (Ca2+, Mg2+). 3H/32P ratios of T antigen obtained by double-labeling cells for various times imply that higher phosphorylated forms of T antigen bound more strongly to ds- and ss-DNA as well as to phosphocellulose. Thus, in the presence of cellular proteins and other components the binding activity of T antigen to the polyphosphate backbone of DNA seems to be positively correlated with its phosphorylation. These observations are consistent with the hypothesis that the binding affinities of SV40 T antigen to host cell DNA may be regulated by its phosphorylation.


[Observations in relation to the epidemic outbreak of cutaneous leishmaniasis in the Ribeira Valley (São Paulo), 1978].
The author relates peculiarities of epidemical irruption of the Tegument Leishmaniasis, occurred in the Ribeira Valley, São Paulo State, Brazil, in 1978. The work is divided into three parts: I--Geographical and ecological aspects of the place where the irruption occurred; II--A concise review of the clinic-epidemiological characteristics of the tegumental leishmaniasis; III--Informations on epidemic level about the epidemical irruption and the setting of the subject in order to debate the probable causes of the event.


Choroidal Thickness in Diabetic Patients Without Diabetic Retinopathy: A Meta-analysis.
To evaluate the relationship between diabetic eyes without diabetic retinopathy and healthy eyes in subfoveal choroidal thickness. Systematic review and meta-analysis. An independent retrospective or prospective clinical study comparing diabetic eyes without diabetic retinopathy and healthy control eyes in the subfoveal choroidal thickness was selected. This study compiled data from publications in PubMed and Web of Science between January 1, 2008, and November 15, 2019. Heterogeneity was statistically quantified by I2 statistics, and meta-analysis was performed using a random-effects model. Seventeen related studies were identified, including a total of 4,213 eyes, which consisted of 1,197 diabetic eyes without diabetic retinopathy and 3,016 healthy eyes. Meta-analysis clearly showed that the subfoveal choroidal thickness of diabetic eyes without retinopathy was significantly thinner than that of healthy control eyes (weighted mean difference = -14.34 μm; 95% confidence interval: -24.37 to -4.32 μm; P < .005). Similar results were obtained in sub-analysis based on the adjustment of the axial length. This study suggests that the subfoveal choroidal thickness was thin in diabetic eyes without retinopathy compared to healthy eyes. Subfoveal choroidal thickness might be an important parameter for the development of diabetic retinopathy in diabetic eyes without retinopathy.