Neural correlate of resting-state functional connectivity under α2 adrenergic receptor agonist, medetomidine.
Correlative fluctuations in functional MRI (fMRI) signals across the brain at rest have been taken as a measure of functional connectivity, but the neural basis of this resting-state MRI (rsMRI) signal is not clear. Previously, we found that the α2 adrenergic agonist, medetomidine, suppressed the rsMRI correlation dose-dependently but not the stimulus evoked activation. To understand the underlying electrophysiology and neurovascular coupling, which might be altered due to the vasoconstrictive nature of medetomidine, somatosensory evoked potential (SEP) and resting electroencephalography (EEG) were measured and correlated with corresponding BOLD signals in rat brains under three dosages of medetomidine. The SEP elicited by electrical stimulation to both forepaws was unchanged regardless of medetomidine dosage, which was consistent with the BOLD activation. Identical relationship between the SEP and BOLD signal under different medetomidine dosages indicates that the neurovascular coupling was not affected. Under resting state, EEG power was the same but a depression of inter-hemispheric EEG coherence in the gamma band was observed at higher medetomidine dosage. Different from medetomidine, both resting EEG power and BOLD power and coherence were significantly suppressed with increased isoflurane level. Such reduction was likely due to suppressed neural activity as shown by diminished SEP and BOLD activation under isoflurane, suggesting different mechanisms of losing synchrony at resting-state. Even though, similarity between electrophysiology and BOLD under stimulation and resting-state implicates a tight neurovascular coupling in both medetomidine and isoflurane. Our results confirm that medetomidine does not suppress neural activity but dissociates connectivity in the somatosensory cortex. The differential effect of medetomidine and its receptor specific action supports the neuronal origin of functional connectivity and implicates the mechanism of its sedative effect.


Reconstructive methods to resolve intractable fistulas that develop after radiation therapy in patients with head and neck cancer.
Radiation therapy (RT) is frequently used for supportive treatment and management of advanced head and neck cancers. This study performed a retrospective review of the treatment methods that were used for intractable draining fistulas in seven patients who had received RT for head and neck cancers. Treatment methods used for two of the seven patients are presented in detail. From 2009 to 2020, seven patients underwent reconstructive surgery for intractable fistulas which occurred after RT for head and neck cancers. Patient characteristics, medical history, treatment method, and treatment outcome were reviewed for each case. The type of surgery performed, failure rate, and treatment period were also analyzed. In this study, a total of seven patients received additional management for radiation-induced fistulas. Patients underwent a mean of 3.3± 1.4 surgeries (maximum: six surgeries) to resolve their fistulas. The mean time interval from the first surgery to the last surgery for the patients to achieve resolution of the fistula was 8.7 months. Loco-regional flaps have performed an average of 1.9± 1.5 times. However, all loco-regional flaps failed. Instead, the patients' intractable fistulas were resolved with the use of distant flaps or free tissue transfers. Fistulas that develop after head and neck cancer treatment following RT are difficult to treat with simple loco-regional flap procedures. Therefore, more aggressive treatment techniques, such as distant flap or free tissue transfer, may be needed to shorten patients' treatment periods and avoid unnecessary surgeries.


Sustainable Production and Activity Determination of Serum-Free Conditioned Medium from Menstrual Blood-Derived Endometrial Stem Cells.
Mesenchymal stem cells (MSCs) have exhibited great potential as a regenerative medicine, and MSC-derived paracrine effects, mainly including the secretion of various bioactive factors, play critical roles in MSC-based therapies. MSC-derived serum-free conditioned medium (MSC-CM) is defined as the secretome of MSC-derived bioactive factors and is considered a new cell-free therapeutic agent for disease treatment. However, the MSC-CM used in previous studies was prepared by a nearly disposable method that the MSCs were discarded after preparing MSC-CM, and the preparation time was variable; simultaneously, the viability changes of MSCs after MSC-CM preparation are still unknown. Therefore, this study takes MenSCs as a research project and aims to explore the suitable period of sustainable MenSC-CM preparation rather than using a disposable method. As expected, our results confirmed that MenSC-CM improves viability of both naïve targeted cells and H2O2-injured targeted cells, and suggested that 36 h is suitable for sustainable MenSC-CM preparation in which the angiogenic factors almost reach to the peak. Simultaneously, the MenSCs used to prepare the MenSC-CM for 36 h also maintained preferable cell viability and could be sustainably used for further MenSC-CM preparation. Moreover, the in vivo results further confirmed the improvement of MenSC-CM on promoting skin wound healing. Consequently, our results not only provide support for optimizing MSC-CM sustainable preparation based on various MSCs but also promote the comprehensive application of MenSCs in the clinic.


Intermolecular Dehydrative [4 + 2] Aza-Annulation of N-Arylamides with Alkenes: A Direct and Divergent Entrance to Aza-Heterocycles.
We disclose that following activation with trifluoromethanesulfonyl anhydride, secondary N-arylamides undergo smooth intermolecular dehydrative [4 + 2] aza-annulation with alkenes under mild conditions to give 3,4-dihydroquinolines, amenable to further functionalization. Meanwhile, conditions have been established to allow divergent one pot synthesis of tetrahydroquinolines and quinolines as well as tricyclic analogues from N-arylamides.


Efficacy of P11-4 for the treatment of initial buccal caries: a randomized clinical trial.
To investigate the safety and efficacy of Self-Assembling Peptide P11-4 (SAP P11-4) compared to placebo or fluoride varnish (FV), a randomized, controlled, blinded, split-mouth study with sequential design was conducted. Subjects presenting two teeth with White-Spot-Lesions (WSLs) were included and teeth were randomly assigned to test or control. Control received placebo at baseline (D0) and test SAP P11-4, all received FV at Day 90 (D90). Standardized photographs were taken at each visit, and WSL size changes were morphometrically assessed. Hierarchical Linear Modelling, considering paired and sequential design, was used to test four hypotheses. SAP P11-4 lesions (test, D90-D0) showed significant WSL size reduction compared to placebo (control, D90-D0; p = 0.008) or FV (control, D180-D90; p = 0.001). Combination of SAP P11-4 and delayed FV after 90 days (test, D180-D0), showed a significant difference compared to FV alone (control D270-D90; p = 0.003). No significant difference on FV efficacy was found when SAP P11-4 was applied 3 months before FV (test D270-D90; control D270-D90, p = 0.70). SAP P11-4 treatment resulted in superior caries regression compared to either placebo or FV, and FV efficacy seems not to be affected by SAP P11-4. SAP P11-4 was found to be a safe and effective WSL treatment.


Synthesis and multiparametric evaluation of thiadiazoles and oxadiazoles as diacylglycerol acyltransferase type 1 inhibitors.
Chemical modulation of a formerly disclosed DGAT-1 inhibitor resulted in the identification of a compound with a suitable profile for preclinical development. Optimisation of solubility is discussed and a PK/PD study is presented.


Replica immunoelectron microscopic study of the upper surface layer in rat mandibular condylar cartilage by a quick-freezing method.
A quick-freezing and deep-etching method in combination with replica immunoelectron microscopy was applied for examining localization of hyaluronic acid and fibronectin on the upper surface layer of rat mandibular condylar cartilage. Rat temporomandibular joints were dissected with articular disks in order to leave the articular cartilage surface intact. The disks were slightly cut with razor blades for exposing the condylar articular cartilage surface. They were quickly frozen with the isopentane-propane cryogen (-193 degrees C) and prepared for freeze-fracturing and deep-etching replica membranes. They were additionally treated with 5% SDS and 0.5% collagenase to keep some antigens attached on the replica membranes. After such a treatment, a routine immunogold method was applied for clarifying the localization of hyaluronic acid and fibronectin in the upper surface layer. Small immunogold particles for hyaluronic acid were mainly localized around upper filamentous networks covered with amorphous materials, but large immunogold ones for fibronectin were localized on deep thicker fibrils. We have revealed the native architecture of the upper surface layer of mandibular condylar cartilage on the replica membranes and also three-dimensional localization of hyaluronic acid and fibronectin by the immunogold method.


Evaluating the relationship between reelin gene variants (rs7341475 and rs262355) and schizophrenia: A meta-analysis.
Studies have suggested that reelin (RELN) polymorphism was associated with the susceptibility of schizophrenia (SZ), but the results remained controversial. Thus, we conducted this meta-analysis to determine whether RELN variants (rs7341475 and rs262355) were associated with SZ risk. Studies were identified through retrieving Web of Science, PubMed and Embase databases from inception to May 2015. The genotype data were extracted to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). For rs7341475, five studies with 4741 SZ patients and 10075 controls are included and the results indicate that carriage of A allele is associated with decreased SZ risk in dominant genetic model (OR=0.90, 95%CI=0.83-0.98) and additive model (OR=0.90, 95% CI=0.84-0.97). Subgroup analysis indicates that the association between rs7341475 and SZ is only significant in Caucasian. For rs262355, four studies with 2017 SZ patients and 3274 controls are included, the results demonstrate that carriage of A allele is associated with increased risk of SZ only in Caucasian (dominant model: OR=1.17, 95%CI=1.01-1.37; additive model OR=1.13, 95%CI=1.02-1.27). This meta-analysis suggests that rs7341475 (A/G) and rs262355 (A/T) polymorphisms in RELN gene are inversely associated with SZ risk.


NMDA receptor subunit and CaMKII changes in rat hippocampus induced by acute MDMA treatment: a mechanism for learning impairment.
Cognitive deficits have been reported in recreational 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") users. In rats and other animal species, acute MDMA administration produces an impairment in passive avoidance and other learning tasks. Different studies have shown that this learning deficit is not strictly related to the pronounced serotonin (5-HT) depletion induced by the drug. This study was aimed at determining if acute MDMA administration induces in the rat hippocampus early molecular changes related to memory impairment in a passive avoidance task. The membrane expression of key molecules in memory consolidation, such as the NR1 and NR2B subunits of the N-methyl-D-aspartate (NMDA) receptor, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1 (PP1) was measured. Some of these studies were also performed after 5-HT depletion induced by the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). Neurochemical studies were performed in rats treated with MDMA and killed 90 min later and also in rats subjected to passive avoidance 30 min after MDMA treatment. Western blotting was used for measuring the levels of NMDA receptor subunits, CAMKII and PP1. Enzyme activity assays were also performed. In hippocampal membrane extracts, passive avoidance training increased NMDA receptor NR1 subunit expression as well as CaMKII levels and phosphorylated CaMKII. In untrained rats, MDMA reduced NR1 and NR2B protein levels, membrane CaMKII levels and enzyme activity, and enhanced PP1 levels and activity. In trained rats, MDMA prevented the learning-specific increase in NR1 subunit expression and membrane CaMKII/pCaMKII levels. After pronounced 5-HT depletion by PCPA, MDMA impaired passive avoidance retention to a similar extent and also prevented the training-associated changes in NR1 levels and CaMKII activity. Diminished function of hippocampal CaMKII and reduced levels of synaptic NMDA receptor subunits appear to be involved in the impairment of passive avoidance learning induced in rats by acute MDMA treatment.


Comparison of quality of life and arm complaints after axillary lymph node dissection vs sentinel lymph node biopsy in breast cancer patients.
The sentinel lymph node biopsy (SLNB) represents a minimal invasive surgical method for axillary staging in patients with primary breast cancer. In a prospective study, evaluation of quality of life (QOL) and arm morbidity was performed before surgery on a total of 56 breast cancer patients. The EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires were used for QOL assessment. Assessment of pain was additionally observed using the McGill Pain Questionnaire. Arm mobility was observed by goniometric measurement of arm movement. Data were collected before surgery (t1), 1 week after discharge (t2) and 9-12 months after surgery (t3). The type of axillary surgery does not seem to affect global QOL at a short-time follow-up, but patients recover sooner after SLNB. Body image and sexual functioning remain stable in both types of axillary surgery. Arm/shoulder pain was reported in 36% of patients after SLNB in comparison to 68% receiving axillary lymph node dissection (ALND), and 'numbness' was reported only in 4% of patients in the SLNB group vs 19.3% after ALND. Abduction, flexion and horizontal adduction of the affected arm show significant impairment after ALND. Breast cancer patients should be counselled about the benefits of SLNB over ALND concerning QOL and postsurgery side effects in a short-term follow-up.


Vessel wall enhancement as a predictor of arterial stenosis progression and poor outcomes in moyamoya disease.
This study aimed to determine the association between vessel wall enhancement and progression of arterial stenosis and clinical outcomes in patients with moyamoya (MMD) using high-resolution magnetic resonance (HRMR) vessel wall imaging. Consecutive participants diagnosed with MMD were prospectively recruited and underwent HRMR at baseline and during follow-up, which had an interval period of ≥ 6 months and were clinically followed up for ≤ 24 months to record the occurrence of ischemic stroke. The relationship between vessel wall enhancement and arterial stenosis progression and stroke occurrence was evaluated. HRMR vessel wall imaging was used to identify 309 stenotic lesions at the internal carotid artery (ICA) in 170 participants (mean age: 37.7 ± 11.3 years old, male: 44.1%). The baseline presence (adjusted odds ratio [aOR] = 3.57, 95% CI = 1.97-6.44, p < 0.001) and progression (aOR = 2.96, 95% CI = 1.29-6.80, p = 0.010) of vessel wall enhancement and middle cerebral artery (MCA) involvement (aOR = 4.98, 95% CI = 1.50-16.52, p = 0.009) were significantly associated with rapid progression of arterial stenosis. Furthermore, vessel wall enhancement (adjusted HR = 3.59, 95% CI = 1.33-9.70, p = 0.011) and rapid progression of arterial stenosis (adjusted HR = 4.52, 95% CI = 1.48-13.81, p = 0.008) were correlated with future stroke occurrence. The baseline presence of vessel wall enhancement was associated with rapid progression of arterial stenosis and increased risk for stroke in MMD patients. Our findings suggest that vessel wall enhancement may serve as a predictor of disease progression and poor outcomes in MMD. • The baseline presence of vessel wall enhancement was significantly associated with the rapid progression of arterial stenosis. • The baseline presence of vessel wall enhancement and rapid progression of arterial stenosis were both correlated with increased risk for future occurrence of stroke. • Our findings suggest that vessel wall enhancement may serve as a predictor of rapid progression of arterial stenosis and poor outcomes in MMD patients.


Regional brain atrophy and aberrant cortical folding relate to anxiety and depression in patients with traumatic brain injury and psychogenic nonepileptic seizures.
Psychogenic nonepileptic seizures (PNES) are characterized by multifocal and global abnormalities in brain function and connectivity. Only a few studies have examined neuroanatomic correlates of PNES. Traumatic brain injury (TBI) is reported in 83% of patients with PNES and may be a key component of PNES pathophysiology. In this study, we included patients with TBI preceding the onset of PNES (TBI-PNES) and TBI without PNES (TBI-only) to identify neuromorphometric abnormalities associated with PNES. Adults diagnosed with TBI-PNES (n = 62) or TBI-only (n = 59) completed psychological questionnaires and underwent 3-T magnetic resonance imaging. Imaging data were analyzed by voxel- and surface-based morphometry. Voxelwise general linear models computed group differences in gray matter volume, cortical thickness, sulcal depth, fractal dimension (FDf), and gyrification. Statistical models were assessed with permutation-based testing at 5000 iterations with the Threshold-Free Cluster Enhancement toolbox. Logarithmically scaled p-values corrected for multiple comparisons using familywise error were considered significant at p < .05. Post hoc analyses determined the association between structural and psychological measures (p < .05). TBI-PNES participants demonstrated atrophy of the left inferior frontal gyrus and the right cerebellum VIII. Relative to TBI-only, TBI-PNES participants had decreased FDf in the right superior parietal gyrus and decreased sulcal depth in the left insular cortex. Significant clusters were positively correlated with global assessment of functioning scores, and demonstrated varying negative associations with measures of anxiety, depression, somatization, and global severity of symptoms. The diagnosis of PNES was associated with brain atrophy and reduced cortical folding in regions implicated in emotion processing, regulation, and response inhibition. Cortical folds primarily develop during the third trimester of pregnancy and remain relatively constant throughout the remainder of one's life. Thus, the observed aberrations in FDf and sulcal depth could originate early in development. The convergence of environmental, developmental, and neurobiological factors may coalesce to reflect the neuropathophysiological substrate of PNES.


Single-cell sorting of microalgae and identification of optimal conditions by using response surface methodology coupled with life-cycle approaches.
Response surface methodology (RSM) has been widely used to identify optimal conditions for environmental microorganisms to maximize degrading pollutants and accumulating biomass. However, to date, environmental impact and economic cost have rarely been considered. In this study, a single cell of microalgae Chlorella sorokiniana ZM-5 was sorted, and its enrichment was carried out for the first time. The optimized conditions by RSM for achieving the highest COD, TN, TP removal and 352.61 mg/g lipid production were 24 h light time, 4.3:1C/N, 7.2 pH, and 30 °C temperature, respectively. Life-cycle approaches were then carried out upon this illustrative case, and the results indicated that the implementation of the above optimal conditions could reduce the total environmental impact by 48.0% and the total economic impact by 10.2%. This study showed the feasibility of applying life-cycle approaches to examine the optimal conditions of a biological process in terms of minimizing environmental impact and economic costs.


[Modulating effect of peptides on the development of skin explants in the organotypical culture].
The necessity of the correction of age-related skin resources reduction triggers search for most physiological means and methods to regulate reparative processes in the skin. It is known that regulation of cellular proliferation processes in tissues of the organism takes place under the effect of different peptides. We have carried out a screening study of the effect of different peptides on skin cells in organotypical skin culture. This study revealed the most effective substances to correct age-related changes in the skin.


Selective MR imaging of labeled human peripheral blood mononuclear cells by liposome mediated incorporation of dextran-magnetite particles.
Human peripheral blood mononuclear cells (PBMCs) were incubated with large unilamellar vesicles (LUV) containing encapsulated dextran-magnetite particles (DMP). This resulted in an efficient incorporation of DMP. Electron microscopy revealed the presence of DMP in cells mainly in phagosomes and secondary lysosomes. DMP-labeled PBMCs showed a strong increase of the transverse relaxation rate (up to 16.6 s-1 for 5 x 10(7) cells/ml) and, accordingly, a great loss of signal intensity in MR imaging. The fraction of DMP containing PBMCs could be enriched by magnetic cell separation. The major population of the DMP containing cells proved to be monocytes. When PBMCs depleted of monocytes were used for labeling, DMP uptake was observed also in the peripheral blood lymphocytes. The labeling of PBMCs presented here may be used in future studies of selective MR imaging of in vivo cell migration in a variety of immunologically compromised tissue states, e.g., tumors, transplantations, and abscesses.


Evaluating therapeutic efficacy against cancer stem cells: new challenges posed by a new paradigm.
Current measures of anticancer drug efficacy reflect bulk cell killing and are poorly suited to detect activity against cancer stem cells (CSCs), which sustain tumor growth. The CSC paradigm necessitates a reexamination of methodologies used to evaluate clinical efficacy of anticancer therapies, as well as strategies employed during preclinical drug development.


Surgical repair for primary pulmonary vein stenosis: Single-institution, midterm follow-up.
Primary pulmonary vein stenosis (PVS) is a rare congenital heart condition and carries a poor prognosis. A retrospective review of 18 patients who underwent surgical therapy for primary PVS (2006-2014) was conducted. According to the degree of stenosis severity, the involved pulmonary veins (PVs) were divided into 3 categories: mild (34 veins), moderate (8), and severe (3). Pericardial patch venoplasty was used in 10 involved veins, endarterectomy in 11, and sutureless pericardial marsupialization in 19. Median surgical age and weight were 19.8 (range: 7-100) months and 7.7 (range: 5.3-20.3) kg, respectively. Bilateral PVS was found in 10 patients (56%), and unilateral in 8 (44%). Moderate or severe stenosis was found more frequently in PVs on the left side (P = .035). Multivein involvement was more common in patients age ≤18 months than in older patients (75% vs 20%, P = .054). No early operative death occurred. Median length of hospital stay was 16 (range: 8-60) days. One subsequent death occurred (6%), at the 2-month follow up after discharge. Median follow-up time for the remaining patients was 29 (range: 2-91) months. Three of the 6 PVs treated for moderate stenosis, compared with 7 of the 34 treated for mild stenosis, developed restenosis, irrespective of the surgical strategy (P = .153). Most surviving patients remained in relatively good condition, in New York Heart Association functional class I or II. Detailed morphologic evaluation of each PV involved is a consideration for surgery, and is closely related to the prognosis. Moderate or severe primary PVS is worse than mild PVS, and no differences were found in effectiveness among endarterectomy, pericardial patch venoplasty, and sutureless pericardial marsupialization in treating primary PVS.


An Overview of Pharmaceutical Excipients: Safe or Not Safe?
A medicine consists of 2 fundamental parts: the active pharmaceutical ingredient and the excipient. Most, if not all, medicines could not be made without the use of excipients. In the early times, the safety of excipients was overlooked and no specific safety tests were generally conducted. This fact has been changed over times and is currently being recognized that the excipient's toxicity is not negligible, because its direct interaction with the active pharmaceutical ingredient or between other excipients may occur, leading to a potential change in the relationship between effectiveness and toxicity. This review is intended to address the general status of the pharmaceutical excipients and to describe the safety assessment. As a summary, this review suggests the interest of simplifying the formulations as much as possible and the interest of reducing the number of excipients necessary to strictly meet the required functions. The risk/benefit ratio of an excipient should be always evaluated on the basis of not only its production and quality but also of its safety. Further research according to Good Manufacturing Practices, Guiding Principles in Toxicology Assessment, Good Laboratory Practices, and Good Distribution Practices requirements are needed and are fundamental for health safety, contributing to a comprehensive picture of this matter.


Oral-facial-digital syndromes: review and diagnostic guidelines.
The oral-facial-digital syndromes (OFDS) result from the pleiotropic effect of a morphogenetic impairment affecting almost invariably the mouth, face and digits. Other organ systems can be involved, defining specific types of OFDS. To date, 13 types have been distinguished based on characteristic clinical manifestations. An updated list of these types is provided and recent molecular data are discussed.


Benign histiocytic tumor of lung. A light- and electron-microscopic study.
We describe an unusual benign pulmonary neoplasm which was composed entirely of histiocytes and a few chronic inflammatory cells and which posed difficult diagnostic problems. The differential diagnosis is discussed, and the usefulness of electron microscopy in interpreting unusual pulmonary tumors is emphasized.


Postoperative C-reactive protein measurement predicts the severity of complications following surgery for colorectal cancer.
Studies have shown that postoperative serum C-reactive protein (CRP) measurement may be useful in predicting the type of complication, infective or otherwise, following surgery for colorectal cancer. It may be that the magnitude of the postoperative CRP is also associated with the severity of the complication. The aim of the present study was to examine the relationship between daily postoperative CRP concentrations and Clavien-Dindo complication grade. Data was recorded prospectively for patients undergoing elective, potentially curative, surgery for colorectal cancer in two hospitals between January 2011 and January 2013, n = 241. All patients had daily CRP measurement following surgery for the first four postoperative days. Complications were retrospectively classified by Clavien-Dindo grade. Of the 241 patients, the majority were male (59%) and were over 65 years old (69%). The majority had colonic (86%) and node negative (65%) disease. One hundred nineteen patients (49%) developed a complication, and 28 (12%) of these were Clavien-Dindo grade 3, 4 or 5. Median and established threshold CRP concentrations on postoperative days 2 (>190 mg/L), 3 (>170 mg/L) and 4 (>125 mg/L) were directly associated with an increase in the Clavien-Dindo grade (all p < 0.001). There was a direct association between exceeding established postoperative day 2, 3 and 4 CRP thresholds and the severity of complications defined by the Clavien-Dindo grade.


A robust linkage analysis method using combined allele sharing and transmission disequilibrium information from case-parent tetrad families.
There are two types of linkage information, the allele sharing information and transmission disequilibrium information, that can be extracted from case-parent tetrad families for deriving statistics for test of linkage. By extracting allele sharing information the mean test can be derived. By extracting transmission disequilibrium information the transmission/disequilibrium test (TDT) can be derived. The power performances of the two tests are different with respect to the extent of linkage disequilibrium. The TDT is more powerful than the mean test when the extent of linkage disequilibrium is moderate to strong, but the mean test has better power performance than the TDT when linkage disequilibrium is weak. Some previous studies have proposed several post-combination analysis methods, which combine the two tests after they are derived using the two types of linkage information respectively, to yield robust test statistics against the interference of linkage disequilibrium. Instead of adopting the post-combination approach, in this paper we investigate the approach of using the pre-combination idea to yield robust statistics for test of linkage. The pre-combination methods combine the two types of linkage information first, and then use the combined information to construct robust test statistics. Simulation studies are conducted to compare the power performances of the proposed pre-combination tests with those of the existing post-combination methods.


Nanoenzyme engineered neutrophil-derived exosomes attenuate joint injury in advanced rheumatoid arthritis via regulating inflammatory environment.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovitis and destruction of cartilage, promoted by sustained inflammation. However, current treatments remain unsatisfactory due to lacking of selective and effective strategies for alleviating inflammatory environments in RA joint. Inspired by neutrophil chemotaxis for inflammatory region, we therefore developed neutrophil-derived exosomes functionalized with sub-5 nm ultrasmall Prussian blue nanoparticles (uPB-Exo) via click chemistry, inheriting neutrophil-targeted biological molecules and owning excellent anti-inflammatory properties. uPB-Exo can selectively accumulate in activated fibroblast-like synoviocytes, subsequently neutralizing pro-inflammatory factors, scavenging reactive oxygen species, and alleviating inflammatory stress. In addition, uPB-Exo effectively targeted to inflammatory synovitis, penetrated deeply into the cartilage and real-time visualized inflamed joint through MRI system, leading to precise diagnosis of RA in vivo with high sensitivity and specificity. Particularly, uPB-Exo induced a cascade of anti-inflammatory events via Th17/Treg cell balance regulation, thereby significantly ameliorating joint damage. Therefore, nanoenzyme functionalized exosomes hold the great potential for enhanced treatment of RA in clinic.


Short-term effect of beinaglutide combined with metformin versus metformin alone on weight loss and metabolic profiles in obese patients with polycystic ovary syndrome: a pilot randomized trial.
To observe the effect of beinaglutide combined with metformin versus metformin alone on weight loss and metabolic profiles in obese patients with polycystic ovary syndrome(PCOS). A total of 64 overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomly assigned to metformin(MET) 850 mg twice a day(BID) or combined MET 850 mg BID with beinaglutide (COMB) starting at 0.1mg three times a day(TID)and increasing to 0.2mg TID two weeks later. The main endpoints were changes in anthropometric measurements of obesity. Glucose and lipid metabolic, gonadal profiles, and antral follicle count changes as secondary outcomes were also observed. 60(93.75%) patients completed the study. In terms of lowering weight, body mass index (BMI),waist circumference(WC) and waist to height ratio(WHtR), COMB treatment outperformed MET monotherapy. Subjects in the COMB arm lost weight 4.54±3.16kg compared with a 2.47±3.59kg loss in the MET arm. In the COMB group, BMI,WC and WHtR were reduced significantly compared with that in the MET group, respectively. COMB therapy is also more favorable in the reduction of fasting insulin(FINS), total testosterone(TT), and homeostasis model assessment-insulin resistance(HOMA-IR) when compared to MET therapy. Antral follicle count and ovarian volume were non-significantly changed in both groups.The most frequent side effects in both groups were mild and moderate digestive symptoms. Itching and induration at the injection site were reported with COMB treatment. Short-term combined treatment with beinaglutide and metformin appears superior to metformin monotherapy in lowering body weight, BMI, WC,WHtR and improving insulin sensitivity and androgen excess in women with PCOS and obesity, with tolerable adverse events. https://www.chictr.org.cn/listbycreater.aspx, identifier ChiCTR2000033741.


Effects of DU 24565 (6-nitroquipazine) on serotoninergic and noradrenergic neurones of the rat brain and comparison with the effects of quipazine.
Rat brain cortex slices were prepared in order to study the influence of DU 24565 (6-nitroquipazine) and quipazine on the accumulation of tritium, and to investigate the effects of DU 24565 on the electrically evoked (3 Hz) tritium overflow from slices preincubated with 3H-serotonin (3H-5-HT) or 3H-noradrenaline (3H-NA). The influence of DU 24565 and quipazine on the activity of MAO was studied in rat brain homogenates, using labelled serotonin as a substrate. In cortex slices preincubated with either 3H-5-HT or 3H-NA, DU 24565 increased the electrically evoked 3H overflow (higher potency in slices preincubated with 3H-5-HT; the percentage of 3H accounted for by unmetabolized 3H-5-HT was also increased). The facilitatory effects of DU 24565 on evoked 3H overflow were abolished when the respective monoamine uptake mechanisms had previously been blocked by citalopram and cocaine, respectively. The inhibitory effects of unlabelled 5-HT and NA on the evoked 3H overflow from cortex slices preincubated with 3H-5-HT were not altered by DU 24565. Similarly, the drug did not affect the inhibition by NA of the evoked 3H overflow from cortex slices preincubated with 3H-NA. Quipazine was a weak and non-selective inhibitor of the accumulation of 3H-5-HT and 3H-NA. DU 24565 was about 65 times more potent and about 1100 times more selective than quipazine as an inhibitor of 3H-5-HT accumulation, and it was also superior to citalopram and paroxetine in this respect.(ABSTRACT TRUNCATED AT 250 WORDS)


PI 3-kinase and MAP kinase regulate bradykinin induced prostaglandin E(2) release in human pulmonary artery by modulating COX-2 activity.
Here we studied the role of phosphoinositide 3-kinase (PI 3-kinase) and mitogen activated protein (MAP) kinase in regulating bradykinin (BK) induced prostaglandin E(2) (PGE(2)) production in human pulmonary artery smooth muscle cells (HPASMC). BK increased PGE(2) in a three step process involving phospholipase A(2) (PLA(2)), cyclooxygenase (COX) and PGE synthase (PGES). BK stimulated PGE(2) release in cultured HPASMC was inhibited by the PI 3-kinase inhibitor LY294002 and the p38 MAP kinase inhibitor SB202190. The inhibitory mechanism used by LY294002 did not involve cytosolic PLA(2) activation or COX-1, COX-2 and PGES protein expression but rather a novel effect on COX enzymatic activity. SB202190 also inhibited COX activity.


Treatment of Blepharospasm/Hemifacial Spasm.
The treatment of both hemifacial spasm (HFS) and blepharospasm (BEB) requires making the appropriate clinical diagnosis. Advance imaging and electrophysiologic studies are useful; however, one's clinical suspicion is paramount. The purpose of this review is to summarize current and emerging therapies for both entities. Botulinum toxin (BTX) remains the first-line therapy to treat both conditions. If chemodenervation has failed, surgery may be considered. Due to the risks associated with surgery, the benefits of this option must be carefully weighed. Better surgical outcomes are possible when procedures are performed at tertiary centers with experienced surgeons and advanced imaging techniques. Microvascular decompression is an efficacious method to treat HFS, and myectomy is an option for medication-refractory BEB; the risks of the latter may outweigh any meaningful clinical benefits. Oral agents only provide short-term relief and can cause several unwanted effects; they are reserved for patients who cannot receive BTX and/or surgery. Transcranial magnetic stimulation has gained some traction in the treatment of BEB and may provide safer non-invasive options for refractory patients in the future.


Long-term right ventricular changes in mustard-exposed patients: A historical cohort.
Mustard gas (MG) is a chemical warfare agent widely used in the Iran-Iraq War. Its catastrophic effects on the lungs, eyes, and skin have been well studied. However, it also affects the cardiovascular system. We aimed to evaluate the long-term effect of MG on right ventricular (RV) function. All patients presenting to the university clinics between May 2014 and September 2015 were consecutively evaluated to enter the study based on the inclusion criteria (documented proof of chemical injury, no past or present cardiovascular disease, not a current smoker, and no history of sleep apnea). A comparable control group of veterans without MG exposure was randomly selected. All patients underwent echocardiographic measurement of RV size and function by a blinded cardiologist. We included 23 patients in the MG-exposed group and 19 subjects in the control group, with a mean age of 48.6 years. Mean chemical injury severity score was 29.7% and mean time from the MG exposure was 29.2 years. The main complaint of MG-exposed patients pertained to respiratory symptoms (91%). Pulmonary artery pressure was higher (32.83 vs. 28.95 mmHg) and RV strain was lower (-17.05% vs. -20.72%) in the MG-exposed than in the control group (P < .05). Our results present baseline RV values for MG-exposed patients and show mild but significant changes after 3 decades. Further cellular and molecular studies are needed to evaluate underlying mechanisms of MG cardiotoxicity.


Latency of auditory P300 correlates with self-control as measured by the Sixteen Personality Factor Questionnaire.
The reception, processing, and storage of information about experience define personality. The present study investigated the relationship between auditory event-related potentials (AERP) and personality traits. The AERP were recorded using a standard auditory oddball paradigm, and personality was evaluated by Cattell's Sixteen Personality Factor Questionnaire (16PF) in 20 healthy young male subjects. The P300 latency was found to be significantly associated with rule consciousness (factor G in the 16PF), perfectionism (factor Q3), and self-control (factor SC): it was negatively correlated with G score (r = -0.56, P = 0.01), Q3 score (r = -0.67, P = 0.001), and SC score (r = -0.65, P = 0.002). Moreover, the P300 amplitude and N100 amplitude were negatively correlated with reasoning (factor B; r = -0.46, P = 0.044; and r = -0.72, P = 0.002, respectively). These results indicate that the personality traits of self-control, perfectionism, high superego, and reasoning are related to information processing in the brain.


Value of dual Doppler echocardiography for prediction of atrial fibrillation recurrence after radiofrequency catheter ablation.
Increasing evidence has been presented which suggests that left ventricular (LV) diastolic dysfunction may play an important role in the development of atrial fibrillation (AF). However, the potential for LV diastolic dysfunction to serve as a predictor of AF recurrence after radiofrequency catheter ablation remains unresolved. Dual Doppler and M-PW mode echocardiography were performed in 67 patients with AF before ablation and 47 patients with sinus rhythm. The parameters measured within identical cardiac cycles included, the time interval between the onset of early transmitral flow peak velocity (E) and that of early diastolic mitral annular velocity (e') (TE-e'), the ratio of E to color M-mode Doppler flow propagation velocity (Vp)(E/Vp), the Tei index, the ratio of E and mitral annular septal (S) peak velocity in early diastolic E/e'(S) and the ratio of E and mitral annular lateral (L) peak velocity E/e'(L). A follow-up examination was performed 1 year after ablation and patients were divided into two groups based on the presence or absence of AF recurrence. Risk estimations for AF recurrence were performed using univariate and multivariate logistic regression. TE-e', E/Vp, the Tei index, E/e'(S) and E/e'(L) were all increased in AF patients as compared with the control group (p < 0.05). At the one-year follow-up examination, a recurrence of AF was observed in 21/67 (31.34%) patients. TE-e' and the Tei index within the recurrence group were significantly increased as compared to the group without recurrence (p < 0.001). Results from multivariate analysis revealed that TE-e' can provide an independent predictor for AF recurrence (p = 0.001). Dual Doppler echocardiography can provide an effective and accurate technique for evaluating LV diastolic function within AF patients. The TE-e' obtained within identical cardiac cycles can serve as an independent predictor for the recurrence of AF as determined at 1 year after ablation.


Neural correlates of fear of movement in high and low fear-avoidant chronic low back pain patients: an event-related fMRI study.
The fear-avoidance model postulates that in chronic low back pain (CLBP) a fear of movement is acquired in the acute phase, which leads to subsequent avoidance of physical activity and contributes to the pain syndrome's becoming chronic. In the present event-related functional magnetic resonance imaging (fMRI) study of the neural correlates of the fear of movement, 60 women (30 CLBP patients, 15 healthy controls, and 15 women with spider phobia; mean age 46.8±9.8 years) participated. The CLBP patients were divided into a high and low fear-avoidant group on the basis of the Tampa Scale of Kinesiophobia. The participants viewed photographs depicting neutral and aversive (back-stressing) movements, generally fear-inducing and neutral pictures from the International Affective Picture System, and pictures of spiders while fMRI data were acquired. It was hypothesized that the high fear-avoidant CLBP patients would show fear-related activations when viewing the aversive movements and that they would differ from CLBP patients with low fear-avoidance and controls in this regard. No such activations were found for high or low fear-avoidant CLBP patients. The random-effects analysis showed no differences between high and low fear-avoidant CLBP patients or high fear-avoidant CLBP patients and controls. Normal fear-related activations were present in the high fear-avoidant CLBP patients for the generally fear-inducing pictures, demonstrating the validity of the stimulation paradigm and a generally unimpaired fear processing of the high fear-avoidant CLBP patients. Our findings do not support the fear component of the fear avoidance model.


Search mechanism of a stream grazer in patchy environments: the role of food abundance.
The search behavior of the grazing stream insect Baetis tricaudatus (Ephemeroptera: Baetidae) was examined in field and laboratory experiments. Regardless of food abundance in experimental habitats, nymphs spent significantly more time in food patches than predicted if they had moved randomly with respect to patches. A significant reduction in movement rate within patches relative to movement rate between patches largely accounted for these results. The movement pattern within patches was highly systematic and in agreement with predictions of optimal foraging theory since food was uniformly distributed within patches. Between-patch search movements were affected by food abundance in the most recently grazed patch. Search intensity after departure from a patch was positively related to food abundance in the patch while movement rate after patch departure was inversely related to patch food level. These effects produced between-patch movement patterns that were suboptimal in the experimental habitats because they resulted in revisitation of previously depleted patches. However, differences between experimental and natural habitats in the spatial occurrence of patch types suggest that Baetis between-patch search behavior may be adaptive in natural habitats.


Gonorrhea.
During a 10-year period from 1976 to 1985, N. gonorrhoeae demonstrated remarkable genetic resiliency in developing clinically important antimicrobial resistance through a variety of chromosomal mutations and by acquiring either entire plasmids or resistance determinants on plasmids from other species. Gonococcal resistance is widespread, and few communities will be spared all types. None of the newer diagnostic technologies has provided any performance or cost advantages over traditional Gram-stained smears and cultures. The two most important components of a control program are (1) the National Gonococcal Isolate Surveillance project and (2) treatment with ceftriaxone, 125 or 250 mg intramuscularly, which is active against all known types of resistance and will cure all forms of uncomplicated gonorrhea, including the more difficult-to-treat infections of the pharynx and anorectum. Fear of AIDS has had a powerful motivating effect on sexual behavior, and in the United States has been associated with an overall reduction in incidence of gonorrhea in homosexual men of over 95%. After peaking in 1985, incidence of gonorrhea in white heterosexual men and women has declined as well. A diagnosis of gonorrhea in 1990 implies recent high-risk behavior for acquiring HIV infection. The gonorrhea epidemic in the United States is rapidly contracting down around poor urban minorities; although this is not good, at least it tells us where to target our resources.


Non-invasive detection of candidate pregnancy protein biomarkers in the feces of captive polar bears (Ursus maritimus).
Currently, there is no method of accurately and non-invasively diagnosing pregnancy in polar bears. Specific proteins may exhibit altered profiles in the feces of pregnant bears, but predicting appropriate candidate proteins to investigate is speculative at best. The objective of this study was to identify potential pregnancy biomarker proteins based on their increased abundance in the feces of pregnant polar bears compared to pseudopregnant females (controls) using two-dimensional in-gel electrophoresis (2D-DIGE) and mass spectrometry (MS). Three 2D-DIGE gels were performed to evaluate fecal protein profiles from controls (n=3) and pregnant polar bears (n=3). There were 2224.67±52.39 (mean±SEM) spots resolved per gel. Of these, only five proteins were elevated in the pregnant group (P<0.05), and seven additional spots tended to be higher (0.05<P<0.10). All 12 were submitted for MS analysis and the identities of 11 were ascertained with a >99.9% confidence interval. The 11 spots represented seven distinct proteins, five of which were significantly more abundant in the pregnant group: IgGFc-binding protein, filamin-C, carboxypeptidase B, transthyretin, and immunoglobulin heavy chain variable region. To our knowledge, this was the first study that employed 2D-DIGE to identify differentially expressed proteins in fecal samples to characterize a physiological condition other than those related to gastrointestinal disorders. These promising results provided a strong foundation for ensuing efforts to develop a non-invasive pregnancy assay for use in both captive and wild polar bears.


α-Hemolysin suppresses osteogenesis by inducing lipid rafts accumulation in bone marrow stromal cells.
α-hemolysin (Hla) is considered an essential virulent factor for Staphylococcus aureus (S. aureus) toxicity, the mechanism by which Hla affect bone metabolism is poorly understood. In this study, 2-month-old C57BL/6 mice were treated with Hla (40 μg/kg, i.p.) or S. aureus (1 × 106 CFU/ml, 100 μl, i.v.) with the presence or absence of methyl-β-cyclodextrin (MβCD) (300 mg/kg, i.p.). MicroCT analysis showed progressive bone loss from week 2 to week 4 after Hla treatment, accompanied by a decreased osteoblasts and increased osteoclasts in femoral metaphysis in mice. Further, Hla stimulated the expression of Caveolin-1 in vivo and in vitro, activated lipid rafts accumulation in cell membrane of bone marrow stromal cells (BMSCs), and suppressed osteogenesis of BMSCs. Destruction of lipid rafts with MβCD or inhibition of Caveolin-1 with Daidzein blocked the detrimental effect of Hla on osteogenesis of BMSCs. Importantly, treating mice with MβCD rescued the loss of osteoblasts and increased osteoclastogenesis induced by Hla as well as the bone loss induced by S. aureus infection. Together, we demonstrate that Hla induces bone destruction directly by suppressing osteogenesis and indirectly by stimulating osteoclastogenesis, and that lipid rafts may mediate the detrimental effect of Hla and S. aureus on osteogenesis and bone formation.


[How to manage a claim for medical and technical error].
The fast modifications in French medical legislation, the increasing number of litigations and the professional consequences for the practitioner warrant the necessity to recall the "how to manage" a claim for medical error. Four cases of legal action against oncologists are presented. The importance of quality and traceability of the given information, the essential pieces of the medical file, the description of the different process steps and of the contradictory meeting are presented and discussed. Beyond the control of medical and technical risks, the practitioners in general and the radiation oncologist in particular should learn on the daily management of the risk related to medical claim.


High gradient magnetic separation of erythrocytes.
The high gradient magnetic separation technique has been applied to separate paramagnetic erythrocytes from a cell suspension that also contained diamagnetic cells. Paramagnetism was induced in the red blood cells by oxidizing the iron atoms in the cell hemoglobin to the ferric state (methemoglobin). Diamagnetic cells were either untreated erythrocytes, containing oxyferrohemoglobin, or leukocytes in a suspension of mouse spleen cells. Cell suspensions were passed through a column containing 40 micron diameter stainless steel wire in a high magnetic field (33 kG). The paramagnetic cells were retained on the surface of the wire while the diamagnetic cells passed through. Elution of the paramagnetic cells was accomplished by removing the column from the magnet, in effect turning off the field.


Structural elucidation of fritillahupehin from bulbs of Fritillaria hupehensis Hsiao et K.C. Hsia.
A novel diterpenoid ester, fritillahupehin (1) and three known fatty acids, palmitic acid (2), lignoceric acid (3) and azelaric acid (4), have been isolated from the bulbs of Fritillaria hupehensis Hsiao et K.C. Hsia. The structure of fritillahupehin has been established to be ent-kauran-16beta-yl lignocerate by means of spectroscopic and chemical evidence. Compounds 2-4 were isolated from Fritillaria sp. for the first time.


Physiologically-based pharmacokinetic modeling to predict drug-drug interaction of enzalutamide with combined P-gp and CYP3A substrates.
Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide's net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in Cmax for apixaban and a 45% decrease in AUC and a 25% decrease in Cmax for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety.


A phase II trial of mitomycin C and 5-fluorouracil as second-line therapy in advanced breast cancer.
Fifty-five patients who had relapsed or progressed from chemotherapy for advanced disease were treated with mitomycin C and 5-FU on a 6 weekly regimen. After a median of 2 cycles of therapy the overall response rate was 12% with no complete responses. Significant leucopenia but no thrombocytopenia was seen and despite the low overall response rate the regimen was tolerable and did produce responses in patients primarily resistant to Adriamycin combination chemotherapy. Low overall activity indicates the need for more effective second line treatment.


Bioactivities of 7'‑ethoxy‑trans‑feruloyltyramine from Portulaca oleracea L. and its metabolism in rats using ultra‑high‑performance liquid chromatography electrospray coupled with quadrupole time‑of‑flight mass spectrometry.
This research aims to study the antioxidation and anticholinesterase activities of 7'-ethoxy-trans-feruloyltyramine (ETFT), which was an alkaloid isolated from Portulaca oleracea for the first time. Furthermore, its main metabolites and metabolic pathways in rats were also explored. The antioxidation and anticholinesterase effects of ETFT were, respectively, examined using 1,1-diphenyl-2-picrylhydrazyl assay and modified Ellman's method. The results showed that ETFT exhibited both the good antioxidant and anticholinesterase effects. Its main metabolites in rats were implemented, and nine metabolites were finally found in the rat's plasma and urine, including the oxidation, reduction, hydrolysis, glucuronidation, sulfation, and glutathionylation process.


Immuno-genomic-radiomics to predict response of biliary tract cancer to camrelizumab plus GEMOX in a single-arm phase II trial.
Immunotherapy is an option for the treatment of advanced biliary tract cancer (BTC), although it has a low response rate. In this post hoc analysis, we investigated the predictive value of an immuno-genomic-radiomics (IGR) analysis for patients with BTC treated with camrelizumab plus gemcitabine and oxaliplatin (GEMOX) therapy. Thirty-two patients with BTC treated with camrelizumab plus GEMOX were prospectively enrolled. The relationship between high-throughput computed tomography (CT) radiomics features with immuno-genomic expression was tested and scaled with a full correlation matrix analysis. Odds ratio (OR) of IGR expression for objective response to camrelizumab plus GEMOX was tested with logistic regression analysis. Association of IGR expression with progression-free survival (PFS) and overall survival (OS) was analysed with a Cox proportional hazard regression. CT radiomics correlated with CD8+ T cells (r = -0.72-0.71, p = 0.004-0.047), tumour mutation burden (TMB) (r = 0.59, p = 0.039), and ARID1A mutation (r = -0.58-0.57, p = 0.020-0.034). There was no significant correlation between radiomics and programmed cell death protein ligand 1 expression (p >0.96). Among all IGR biomarkers, only four radiomics features were independent predictors of objective response (OR = 0.09-3.81; p = 0.011-0.044). Combining independent radiomics features into an objective response prediction model achieved an area under the curve of 0.869. In a Cox analysis, radiomics signature [hazard ratio (HR) = 6.90, p <0.001], ARID1A (HR = 3.31, p = 0.013), and blood TMB (HR = 1.13, p = 0.023) were independent predictors of PFS. Radiomics signature (HR = 6.58, p <0.001) and CD8+ T cells (HR = 0.22, p = 0.004) were independent predictors of OS. Prognostic models integrating these features achieved concordance indexes of 0.677 and 0.681 for PFS and OS, respectively. Radiomics could act as a non-invasive immuno-genomic surrogate of BTC, which could further aid in response prediction for patients with BTC treated with immunotherapy. However, multicenter and larger sample studies are required to validate these results. Immunotherapy is an alternative for the treatment of advanced BTC, whereas tumour response is heterogeneous. In a post hoc analysis of the single-arm phase II clinical trial (NCT03486678), we found that CT radiomics features were associated with the tumour microenvironment and that IGR expression was a promising marker for tumour response and long-term survival. Post hoc analysis of NCT03486678.


Active bio-based food-packaging: Diffusion and release of active substances through and from cellulose nanofiber coating toward food-packaging design.
Cellulose nanofibers (CNFs) were recently investigated for the elaboration of new functional food-packaging materials. Their nanoporous network was especially of interest for controlling the release of active species. Qualitative release studies were conducted, but quantification of the diffusion phenomenon observed when the active species are released from and through CNF coating has not yet been studied. Therefore, this work aims to model CNF-coated paper substrates as controlled release system for food-packaging using release data obtained for two model molecules, namely caffeine and chlorhexidine digluconate. The applied mathematical model - derived from Fickian diffusion - was validated for caffeine only. When the active species chemically interacts with the release device, another model is required as a non-predominantly diffusion-controlled release was observed. From caffeine modeling data, a theoretical active food-packaging material was designed. The use of CNFs as barrier coating was proved to be the ideal material configuration that best meets specifications.


Mannosylerythritol lipids: production, downstream processing, and potential applications.
Mannosylerythritol lipids (MELs) are biosurfactants produced by various fungal species. Depending on the degree of acetylation and further chemical modifications, these glycolipids can show remarkable biological properties, including the increase of water retention in the stratum corneum suppression of melanogenic enzymes tyrosinase-1 and -2, reversion of UV-A radiation-induced aquaporin-3 suppression, skin whitening, and anti-aging effects. These applications of MELs require high purity, which is usually reached by liquid-liquid extraction followed by chromatography, obtaining ≥95% purity. This worked aimed to critically discuss the current state of the art and trends on the production of MELs, including post-production treatment as enzymatic conversion. In addition, their application as skincare or pharmaceutical agents and agricultural biostimulants.


Drug substitution therapy: a new approach in preventing the spread of HIV/AIDS in Malaysia.
The prevalence of HIV/AIDS among drug addicts in Malaysia is high, especially among intravenous drug users. The present treatment and rehabilitation of drug addiction is considered as a failure. The government finally decided to start on Drug Substitution Therapy in early 2005 as an effort to prevent the spread of HIV/AIDS in the country.


Photocatalytic performance of 3D engineered chitosan hydrogels embedded with sulfur-doped C3N4/ZnO nanoparticles for Ciprofloxacin removal: Degradation and mechanistic pathways.
Ciprofloxacin, a biotoxic micropollutant, is ubiquitously found in the water environment, which is a global concern. This study developed polymeric S-C3N4/ZnO-Chitosan (indexed as SCZ-CH) hydrogels for degrading Ciprofloxacin. The SCZ-CH hydrogels provided the Ciprofloxacin degradation efficiencies of ~93% and ~69% in UV and visible lights, respectively, at optimum conditions (SCZ-CH hydrogels with 2 g/L SCZ, 20 mg/L initial concentration, pH 5, and room temperature). In addition, immobilized SCZ-CH hydrogels structures enable easy separation of the SCZ catalyst from water. The spectroscopic and microscopic analyses of SCZ-CH hydrogels show multifaceted properties, like high oxygen concentrations, crystallinity, stacked structure, high roughness, and improved bandgap energy, which are responsible for the enhanced photocatalytic activity. The effects of water matrix and experimental conditions on Ciprofloxacin degradation were also studied, which suggested that the catalyst dose and solution pH have significant effects on photocatalytic activity. SCZ-CH hydrogels have shown good mineralization efficiency (~98%) and reusability (up to 10 cycles) for Ciprofloxacin removal. Superoxide radicals played an essential role in the degradation of Ciprofloxacin. The Ciprofloxacin molecules get degraded by driving radicals through oxidation, defluorination, substitution, and breaking of the rings. The proposed SCZ-CH hydrogels can be effectively used at a large scale to treat micropollutants.


Traumatic injuries: radiological hemostatic intervention at admission.
Blunt trauma victims and selected patients with penetrating trauma are systematically investigated after resuscitation and hemodynamic stabilization with cross-sectional imaging. Computed tomography is a good predictor of the need for hemostatic arteriographic embolization, based on contrast medium extravasation observed on CT. In centers admitting polytrauma patients, the CT and angiography units should be installed together within the emergency environment. Trauma-dedicated interventional radiologists should be on call for optimal patient management. Posttraumatic retroperitoneal and pelvic bleeding is a primary indication for angiographic hemostasis, together with orthopedic fixation of pelvic bone fractures. Angiography should be carried out rapidly, before the patient decompensates for considerable blood loss. In patients with visceral bleeding, arterial embolization can obviate primary surgery or potentializes surgical intervention and contributes to changing hierarchy of injuries to be treated surgically. Failure to achieve primary hemostasis may occur according to the type of specific organ injury and coagulation and metabolic parameters of the patient. Postembolization complications are few and are usually non-life-threatening and rarely carry definitive sequelae.


Glutamate induces the expression and release of tumor necrosis factor-alpha in cultured hypothalamic cells.
Tumor necrosis factor-alpha (TNFalpha) affects several CNS functions such as regulation of sleep, body temperature, and feeding during pathology. There is also evidence for TNFalpha involvement in physiological sleep regulation, e.g., TNFalpha induces sleep and brain levels of TNFalpha increase during prolonged wakefulness. The immediate cause of enhanced TNFalpha production in brain is unknown. We investigated whether glutamate could signal TNFalpha production because glutamate is a neurotransmitter associated with cell activation and wakefulness. We used primary cultures of fetal rat hypothalamic cells to examine the expression and release of TNFalpha. Immunostaining for neuron specific enolase revealed that the cultures were 50-60% neuronal and 40-50% non-neuronal cells. TNFalpha was detected in both the media and cells under basal conditions. Stimulation of the cells with 1 mM glutamate for 2 h produced an increase in media content of TNFalpha, whereas cell content was elevated at earlier time points. Using trypan blue exclusion and MTT assays, there was no evidence of cell toxicity with this stimulation protocol. Immunocytochemical staining revealed that TNFalpha was expressed by approximately 25% of the neurons and approximately 75% of the glial cell in the culture. Stimulation of the cultures with glutamate did not increase the percentage of cells expressing TNFalpha. We conclude that TNFalpha is constitutively expressed and released by healthy cultures of hypothalamic cells and that activation of the cells with a non-toxic challenge of glutamate increases TNFalpha production. These findings support the hypothesis that TNFalpha can participate in normal physiological regulation of sleep and feeding.


Adverse effect of maternal caffeine ingestion on fetal cerebrum in rat.
This study was undertaken to determine whether maternal caffeine ingestion is or is not a risk factor in fetal cerebral development using experimental rat models. Pregnant rats of the Wistar strain were given 0.04% caffeine in drinking water before and/or during pregnancy for various numbers of days. Control rats received water for the same periods. There was no reduction of maternal body weight, fetal body weight or fetal total brain weight. Low fetal cerebral weight and placental weight were observed when dams were given caffeine before mating for long times and/or throughout pregnancy. DNA, RNA and protein contents per cerebrum were also reduced in fetuses from dams given caffeine throughout pregnancy or for the last 6 gestational days. Cerebral DNA and protein contents as expressed per wet weight were higher and significantly lower respectively in the fetuses from dams given caffeine throughout pregnancy when compared to controls. Activity of thymidine kinase was not significantly decreased in caffeine-treated fetuses. There was a positive correlation between maternal serum and fetal cerebral caffeine levels. Additionally a negative correlation between maternal caffeine levels and fetal survival rates which decreased in litters from dams given caffeine throughout pregnancy was demonstrated. Our rat model indicates maternal caffeine ingestion during pregnancy is associated with reduction of fetal cerebral weight and protein content without reduction of body weight.


A Multi-Stakeholder Perspective on Factors Affecting Successful Transition to Adulthood for Youth with Severe Emotional Disturbances.
This study elicited the perspectives of youth, caregivers, service providers and researchers to explore how communities can best support the transition to adulthood for youth ages 16-21 with mental health and functional impairments, who are at risk of disconnecting from health and human services. Framed by Relational Systems Evaluation (RSE) and Positive Youth Development (PYD), our study demonstrates the importance of engagement with youth experts. Group Concept Mapping (GCM), a collaborative multiphase mixed-methods approach, was used as a systematic process for participants to make meaning of qualitative data using multidimensional scaling and hierarchical cluster analysis (Kane and Trochim in Concept mapping for planning and evaluation, Sage Publications Inc., Thousand Oaks, 2007). Across all participant groups, Life Skills were perceived as highly important and highly feasible for a successful transition to adulthood. However, Positive Social Support & Connectedness were viewed as less important and less feasible by all groups. When examined closely, youth perspectives differed from caregiver and provider perspectives in the factors they prioritized and deemed feasible. Our findings have implications for community mental health services and positive youth development program practitioners.


Trajectory control in targeted force impulses. VI. Independent specification of response amplitude and direction.
The preceding study of this series (Hening, Favilla and Ghez 1988) examined the time course of the processes by which human subjects use information from a target to set the amplitude of an impulse of isometric elbow force. In that study, subjects were provided with separate cues to time response initiation and to inform them of the required amplitude of the response. When the time between target presentation and response initiation was too brief for them to incorporate information from the target, subjects produced default responses whose amplitudes reflected their prior experience. At longer latencies, subjects specified response amplitude with a gradual time course, starting earlier and ending later than an average reaction time. The present study now examines how two distinct response features, amplitude and direction, are specified following presentation of a target. We sought to answer three main questions. What are the features of responses that are produced before target information is available? Are direction and amplitude specified serially or in parallel? Does the specification of one response feature interfere with the specification of the other? Six normal subjects were studied. They were trained to initiate impulses of isometric elbow force in synchrony with the last of a predictable series of regular tones. The amplitudes and directions were to match those of visual targets requiring flexions or extensions with one of three amplitudes. The targets were presented at random times (0-400 ms) before the last tone. Target directions and amplitudes were either predictable (simple condition) or unpredictable (choice condition). In the simple condition, response amplitudes and directions were independent of the interval between target presentation and response onset (S-R interval). In the choice condition, both amplitude and direction varied with the S-R interval. At short S-R intervals (less than 100 ms), the direction of the subjects' responses was not related to that of the target. The amplitudes of the responses were near the centers of the two target ranges. With increasing S-R intervals, the proportion of correct direction responses gradually increased. Over the same range of S-R intervals, the amplitudes of both right and wrong direction responses to the different targets separated and converged on their respective target amplitudes. Specification of both direction and amplitude was complete at S-R intervals greater than 300 ms. The time course of amplitude specification in this bidirectional paradigm was prolonged over that in a paradigm where response direction was predictable.(ABSTRACT TRUNCATED AT 400 WORDS)


Enzymatic membrane reactor in xylose bioconversion with simultaneous cofactor regeneration.
In this study, we present the concept of co-immobilization of xylose dehydrogenase and alcohol dehydrogenase from Saccharomyces cerevisiae on an XN45 nanofiltration membrane for application in the process of xylose bioconversion to xylonic acid with simultaneous cofactor regeneration and membrane separation of reaction products. During the research, the effectiveness of the co-immobilization of enzymes was confirmed, and changes in the properties of the membrane after the processes were determined. Using the obtained biocatalytic system it was possible to obtain 99% xylonic acid production efficiency under optimal conditions, which were 5 mM xylose, 5 mM formaldehyde, ratio of NAD+:NADH 1:1, and 60 min of reaction. Additionally, the co-immobilization of enzymes made it possible to improve stability of the co-immobilized enzymes and to carry out xylose conversion in six consecutive cycles and after 7 days of storage at 4 °C with over 90% efficiency. The presented data confirm the effectiveness of the co-immobilization, improvement of the stability and reusability of the biocatalysts, and show that the obtained enzymatic system is promising for use in xylose bioconversion and simultaneous regeneration of nicotinamide cofactor.


Combined superficial & deep fractional skin treatment for photodamaged skin--a prospective clinical trial.
Deep microthermal zones targeted by Fractional CO(2) lasers stimulate fibroblast activity, whereas superficial microthermal zones target the epidermal layer pigment. The new combination modality enables targeting both deep and superficial disorders. The study is designed to evaluate the improvement in photodamage and determine downtime. This IRB approved study was aimed to evaluate histology phenotype of combined deep and superficial skin resurfacing. A 120-micron, focused CO(2) laser beam was used to create both deep and superficial fractional skin resurfacing using ultrapulse and continuous wave laser modes, respectively. Fifteen patients (skin types II-V) underwent combined treatment and returned for assessment at 1 week, 1 and 3 months to evaluate the clinical outcome. Additional histological analysis of human tissue was performed to elucidate the combined impact on tissue. Pre-clinical histologies demonstrated the ability to achieve fractional discrete 1.3-mm-diameter spots of superficial ablation with a uniform shallow and narrow area of coagulation while maintaining the deep, fractional 120-micron-ablation spot capabilities. Histologies of the human tissue confirmed the ability to control both superficial and deep fractional treatment using a single handpiece. Pigmentation was greatly reduced at the 1 month follow-up with significant textural improvement. No unexpected AEs or SAEs were reported. The new modality enables combined superficial and deep fractional impact and improvements that are demonstrated at both the phenotype and tissue level.


Knowledge, attitude, and practice assessment toward COVID-19 among communities in East Nusa Tenggara, Indonesia: A cross-sectional study.
This research aimed to assess the knowledge, attitude and practice toward COVID-19 among East Nusa Tenggara (NTT) population and identify associated sociodemographic factors. A cross-sectional study was performed among communities in 22 regencies of NTT between October-November 2021 using a structured and validated questionnaire that consists of 22-items of knowledge, 6-items of attitude and 13-items of practice related COVID-19 questions. A cut off point of at least 70% was employed to categorize good knowledge, attitude, and practice. The percentages of survey respondents showing good knowledge, attitude and practice toward COVID-19 were 79.8, 72.7, and 94.6%, respectively. There was a significant positive, though weak, linear correlation between knowledge and practice scores (ρ = 0.097; p = 0.049). Knowledge was strongly associated with regency of residence (Cramer's V = 0.266; p = 0.010), education (Cramer's V = 0.312; p < 0.001), and occupation (Cramer's V = 0.313; p < 0.001). Attitude and practice had strong relationship with regency of residence (Cramer's V = 0.289; p = 0.024) and education (Cramer's V = 0.272; p < 0.001), respectively. Nearly all survey participants showed good precautionary behaviors, but there was still a quarter of respondents indicated poor knowledge and attitude. There was also a positive relationship between knowledge and practice scores thereby indicating the importance of local public health advocates to distribute information uniformly especially to the groups with inadequate knowledge toward COVID-19 as a means to control the virus transmission.


Right ventricular afterload in repaired D-TGA is associated with inefficient flow patterns, rather than stenosis alone.
Treatment of D- transposition of great arteries (DTGA) involves the Arterial Switch Operation (ASO), which can create PA branch stenosis (PABS) and alter PA blood flow energetics. This altered PA flow may contribute to elevated right ventricular (RV) afterload more significantly than stenosis alone. Our aim was to correlate RV afterload and PA flow characteristics using 4D flow cardiac magnetic resonance (CMR) imaging of a mock circulatory system (MCS) incorporating 3D printed replicas. CMR imaging and clinical characteristics were analyzed from 22 ASO patients (age 11.9 ± 8.7 years, 68% male). Segmentation was performed to create 3D printed PA replicas that were mounted in an MRI-compatible MCS. Pressure drop across the PA replica was recorded and 4D flow CMR acquisitions were analyzed for blood flow inefficiency (energy loss, vorticity). In post-ASO patients, there is no difference in RV mass (p = 0.07), nor RV systolic pressure (p = 0.26) in the presence or absence of PABS. 4D flow analysis of MCS shows energy loss is correlated to RV mass (p = 0.01, r = 0.67) and MCS pressure differential (p = 0.02, r = 0.57). Receiver operating characteristic curve shows energy loss detects elevated RV mass above 30 g/m2 (p = 0.02, AUC 0.88) while index of PA dimensions (Nakata) does not (p = 0.09, AUC 0.79). PABS alone does not account for differences in RV mass or afterload in post-ASO patients. In MCS simulations, energy loss is correlated with both RV mass and PA pressure, and can moderately detect elevated RV mass. Inefficient PA flow may be an important predictor of RV afterload in this population.


Ability of the oriental fruit moth Grapholita molesta (Lepidoptera: Tortricidae) to detoxify juglone, the main secondary metabolite of the non-host plant walnut.
Many plant species produce toxic secondary metabolites that limit attacks by herbivorous insects, and may thereby constrain insect expansion to new hosts. Walnut is a host for the codling moth Cydia pomonella, which efficiently detoxifies the main walnut defensive compound juglone (5-hydroxy-1,4-naphthoquinone). The oriental fruit moth Grapholita molesta, which also belongs to the tribe Grapholitini, does not feed on walnut. We tested the performance of G. molesta, a highly invasive species, on artificial diets containing juglone at levels mimicking those found in walnut over the growing season. Juglone-fed G. molesta survived relatively well to adulthood, but larval and adult body weights were reduced, and larval developmental time was prolonged in a dose-dependent fashion. Chemical analysis of frass from larvae that had been fed a juglone-containing diet suggests that G. molesta reduces juglone to non-toxic 1,4,5-trihydroxynaphthalene in its gut. This unexpected tolerance of G. molesta to high levels of juglone may facilitate expansion of the host range beyond the current rosacean fruit trees used by this invasive pest.


Review with video of a laparoscopic transabdominal preperitoneal (TAPP) repair for giant inguinoscrotal hernia.
Giant inguinoscrotal (GIS) hernias are rarely encountered in clinical settings and are often associated with mental neglect for many years. This type of hernia is defined as "giant" if it descends below the mid-point of the inner thigh of a patient in an upright position. The laparoscopic repair approach of a GIS hernia is technically challenging. It has been claimed that laparoscopic surgery has several advantages over the open surgical approach, with less pain and an earlier recovery. The aim of this video is to evaluate the efficacy of TAPP (laparoscopic transabdominal preperitoneal) in order to treat a GIS hernia. A 65-year-old male without a relevant past medical history was admitted to the emergency service with abdominal pain, belching and nausea. He denied any other symptoms, and no previous surgical operations were recorded. Physical examination showed a large mass in the left scrotum below the mid-point of the inner thigh of the patient in an upright position. A CT scan confirmed the diagnosis of a GIS. A laparoscopic TAPP procedure was decided upon as the best course of treatment. The patient underwent a successful repair procedure. The operation time was 150 min. No intraoperative blood transfusion was necessary. The patient's diet was resumed on the first day post surgery, and the postoperative hospital stay was three days. Laparoscopic TAPP repair is a safe and feasible method for surgically managing GIS hernias.


Prognostic value of extranodal extension and other lymph node parameters in patients with upper tract urothelial carcinoma.
We assessed the prognostic value of extranodal extension and other lymph node parameters in a large multicenter cohort of patients with lymph node metastasis after radical nephroureterectomy. We retrospectively analyzed the records of 222 patients with lymph node metastasis treated with radical nephroureterectomy for upper tract urothelial carcinoma without neoadjuvant therapy. Each lymph node metastasis was microscopically evaluated for extranodal extension. A median of 4 lymph nodes (IQR 8) was removed. Two lymph nodes (IQR 2) were positive. Lymph node density was 51.3% (IQR 71.7%). Overall 110 patients (49.5%) had extranodal extension, which was associated with more advanced pT stage (p = 0.026). On multivariable analysis extranodal extension was associated with disease recurrence (p = 0.01) and cancer specific mortality (p = 0.013). When stratified by a 30% cutoff, lymph node density was associated with disease recurrence and cancer specific mortality on univariable but not multivariable analysis (p = 0.048 and 0.049, respectively). Adding extranodal extension to a multivariable model including pT stage and tumor architecture improved predictive accuracy for disease recurrence from 70.3% to 74.5% (p <0.001). Adding extranodal extension to a multivariable model including age, pT stage and tumor architecture improved predictive accuracy for cancer specific mortality from 70.6% to 74.4% (p <0.001). Extranodal extension is a powerful predictor of clinical outcomes in patients with upper tract urothelial carcinoma with lymph node metastasis. While other lymph node parameters seem to have limited clinical value, extranodal extension could help risk stratify patients with upper tract urothelial carcinoma and lymph node metastasis for better counseling and clinical trial design.


Managing end stage lung disease in children.
Over the course of a career most physicians will manage only a handful of children through End Stage Lung Disease. Nonetheless, the approach of the physician to this challenge will have a profound impact on the children and families they encounter. Managing the end of life well can bring personal growth and professional satisfaction. In this review we highlight aspects of the Palliative Care approach and its integration with restorative and life-prolonging care. We review the role of active treatment, respiratory support, symptom management and psychosocial aspects of the management of End Stage Lung Disease.


Student evaluation of instruction: a challenge to medical technology educators.
Through ever increasing political and economic pressures, accountability is in the foreground of higher education today. Demands are increasing for formal evaluation of instructor effectiveness in classrooms and laboratories. The general concept of teacher evaluation by students is discussed and a form which can be used for evaluation is presented.


Girls' physical activity and sedentary behaviors: Does sexual maturation matter? A cross-sectional study with HBSC 2010 Portuguese survey.
The purpose of this study was to examine the relationship between girls' sexual maturation (age of menarche) and physical activity and sedentary behaviors. Data were collected from a national representative sample of girls in 2010 (pre-menarcheal girls n = 583, post-menarcheal girls n = 741). Physical activity (times/week and hours/week) and screen-based sedentary time (minutes/day) including television/video/DVD watching, playing videogames, and computer use were self-reported. Pre-menarcheal girls engaged significantly more times in physical activity in the last 7 days than post-menarcheal girls (3.5 ± 1.9 times/week vs. 3.0 ± 1.7 times/week, P < 0.001). There was no significant difference between pre-menarcheal and post-menarcheal girls in time (hours/week) spent in physical activity. Post-menarcheal girls spent significantly more minutes per day than pre-menarcheal girls watching TV, playing videogames, and using computers on weekdays (TV: 165.2 ± 105.8 vs. 136.0 ± 106.3, P < 0.001; videogames 72.0 ± 84.8 vs. 60.3 ± 78.9, P = 0.015; computer: 123.3 ± 103.9 vs. 82.8 ± 95.8, P < 0.001) and on weekends (TV: 249.0 ± 116.2 vs. 209.3 ± 124.8, P < 0.001; videogames: 123.0 ± 114.0 vs. 104.7 ± 103.5, P = 0.020; computer: 177.0 ± 122.2 vs. 119.7 ± 112.7, P < 0.001). After adjusting analyses for age, BMI, and socioeconomic status, differences were still significant for physical activity and for computer use. Specific interventions should be designed for girls to increase their physical activity participation and decrease time spent on the computer, for post-menarcheal girls in particular. Am. J. Hum. Biol. 28:471-475, 2016. © 2015 Wiley Periodicals, Inc.


Relating wrist accelerometry measures to disability in older adults.
This analysis assessed the extent to which: (1) wrist accelerometer measures were associated with difficulty performing specific activities of daily living and instrumental activities of daily living and (2) these measures contributed important information about disability beyond a typical self-reported vigorous activity frequency question. We used data from the National Social Life, Health and Aging Project (NSHAP) accelerometry sub-study (n=738). Activity was assessed using two wrist-accelerometer measures assessed over 3 days (routine activity expressed as mean count/15s epoch during wake time, and immobile time expressed as the proportion of wake time spent immobile), and self-reported average vigorous activity frequency. The association between routine activity, immobile time and difficulty performing fourteen activities of daily living (ADLs) and instrumental activities of daily living (IADLs) plus two summary measures (any ADL or IADL difficulty), was assessed using logistic regression models, with and without controlling for self-reported vigorous activity. Self-reported activity was mildly correlated with routine activity (r=0.27) and immobile time (r=-0.21). Routine activity, immobile time, and self-reported vigorous activity were significantly associated with twelve, ten, and fourteen disability measures, respectively. After controlling for self-reported activity, significant associations remained between routine activity and eight disabilities, and immobile time and six disabilities. Wrist accelerometry measures were associated with many ADL and IADL disabilities among older adults. Wrist acclerometry in older adults may be useful to help assess disability risks and set individualized physical activity targets.


Clinical experience with pentoxifylline in occlusive cerebrovascular disorders.
Pentoxifylline--3,7-dimethyl-1(5-oxo-hexyl) xanthine--a new vasodilator compound, was tried in 28 cases of occlusive cerebrovascular disease. A similar group of 24 patients were given xanthinol nicotinate. Although in terms of degree of improvement there was no significant difference in the two treatment groups, improvement was earlier in the group treated with pentoxifylline. No significant side effects were observed with any of the two drugs used in the present study.


Induction of thermotolerance in T cells protects nuclear DNA topoisomerase I from heat stress.
In this study, we have demonstrated that topoisomerase I DNA relaxing activity is protected against a severe heat shock in T cells made thermotolerant by a prior modest heat treatment. However, following a severe heat-shock challenge and incubation at 37 degrees C, topoisomerase activity in the control population eventually returned to levels similar to those detected in thermotolerant cells. This recovery of topoisomerase activity appears to result from the renaturation of heat-inactivated enzyme rather than from synthesis of new protein because the rate of recovery of catalytic activity was not inhibited by the presence of the protein synthesis inhibitor, cycloheximide.


Brain areas involved with obsessive-compulsive disorder present different DNA methylation modulation.
Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive actions, that presents the involvement of the cortico-striatal areas. The contribution of environmental risk factors to OCD development suggests that epigenetic mechanisms may contribute to its pathophysiology. DNA methylation changes and gene expression were evaluated in post-mortem brain tissues of the cortical (anterior cingulate gyrus and orbitofrontal cortex) and ventral striatum (nucleus accumbens, caudate nucleus and putamen) areas from eight OCD patients and eight matched controls. There were no differentially methylated CpG (cytosine-phosphate-guanine) sites (DMSs) in any brain area, nevertheless gene modules generated from CpG sites and protein-protein-interaction (PPI) showed enriched gene modules for all brain areas between OCD cases and controls. All brain areas but nucleus accumbens presented a predominantly hypomethylation pattern for the differentially methylated regions (DMRs). Although there were common transcriptional factors that targeted these DMRs, their targeted differentially expressed genes were different among all brain areas. The protein-protein interaction network based on methylation and gene expression data reported that all brain areas were enriched for G-protein signaling pathway, immune response, apoptosis and synapse biological processes but each brain area also presented enrichment of specific signaling pathways. Finally, OCD patients and controls did not present significant DNA methylation age differences. DNA methylation changes in brain areas involved with OCD, especially those involved with genes related to synaptic plasticity and the immune system could mediate the action of genetic and environmental factors associated with OCD.


Efficient secretion of two fungal cellobiohydrolases by Saccharomyces cerevisiae.
Two different cellobiohydrolases, CBHI and CBHII, of the filamentous fungus Trichoderma reesei both hydrolyse highly crystalline cellulose. Cellulolytic strains of the yeast Saccharomyces cerevisiae were constructed by transferring cDNAs coding for these enzymes into yeast on an expression plasmid. These cellulolytic yeasts were able to secrete efficiently the large, heterologous proteins to the culture medium. The recombinant cellulases were observed to be heterogeneous in Mr due, at least partly, to variable N-glycosylation. Recombinant CBHII was able to bind to crystalline cellulose, although slightly less efficiently than the native enzyme. Both of the two recombinant cellulases were able to degrade amorphous cellulose. In a fermenter cultivation, around 100 micrograms/ml of CBHII was secreted into the yeast growth medium.


MicroRNA Regulation of TRAIL in Renal Carcinoma: Tiny Juggernauts at Work.
Renal Carcinoma (RC) is the ninth most prevalent cancer in men. Advancements in high- throughput technology have begun to scratch the surface of the complex landscape of renal cancer. Development, progression, invasion and metastasis are the key mechanism modulated by the microRNAs (miRNAs). Recent pieces of evidence have delineated the role of these micro steering wheels in the regulation of vital processes of RC biology, therefore miRNAs can be implemented as a new therapeutic target for RC. MiRNAs also negatively affect the process of apoptosis in cancer cells leading to their survival and growth. The role of dysregulated mRNAs in hindering the TRAIL- mediated apoptotic pathway is also known. Therapeutic interventions targeting tumor-suppressive miRNAs to promote apoptosis through extrinsic/intrinsic pathways seem a promising approach for advanced stage and metastatic renal cancers. This article aims to discuss RC-specific microRNAs, their roles in the TRAIL pathway and highlight the distinguished microRNAs that could serve as a diagnostic biomarker and therapeutic targets for this cancer.


A Continuous Gradient Chemical Reduction Strategy of Graphene Oxide for Highly Efficient Evaporation-Driven Electricity Generation.
Spontaneously harvesting electricity through a water evaporation process is renewable and environmentally friendly, and provides a promising way for self-powered electronics. However, most of evaporation-driven generators are suffering from a limited power supply for practical use. Herein, a high-performance textile-based evaporation-driven electricity generator based on continuous gradient chemical reduced graphene oxide (CG-rGO@TEEG) is obtained by a continuous gradient chemical reduction strategy. The continuous gradient structure not only greatly enhances the ion concentration difference between the positive and negative electrodes but also significantly optimizes the electrical conductivity of the generator. As a result, the as-prepared CG-rGO@TEEG can generate a voltage of 0.44 V and a considerable current of 590.1 µA with an optimized power density of 0.55 mW cm-3 when 50 µL of NaCl solution is applied. Such scale-up CG-rGO@TEEGs can supply sufficient power to directly drive a commercial clock for more than 2 h in ambient conditions. This work offers a novel approach for efficient clean energy harvesting based on water evaporation.


AT1 receptor blockade prevents cardiac dysfunction after myocardial infarction in rats.
Myocardial infarction (MI) can induce severe alterations of contractile function that can, in turn, lead to heart failure. In a previous study, we have demonstrated that TNF-alpha was involved in cardiac contractile dysfunction 7 days after coronary artery ligation in rats. Since Angiotensin II type 1 (AT1) receptor can be involved in TNF-alpha production, we have investigated whether early short-term treatment with irbesartan, an AT1 receptor blocker, is able to limit TNF-alpha production within the heart and to improve cardiac function and geometry following MI in rats. Male Wistar rats were subjected to permanent coronary artery ligation and received either a placebo or irbesartan (50 mg/kg/day) per os daily from day 3 to day 6 after surgery. On day 7, cardiac TNF-alpha was significantly reduced in MI rats receiving irbesartan (p < 0.05). Moreover, irbesartan improved residual LV end-diastolic pressure under both basal conditions and after volume overload (p < 0.01). In addition, a significant leftward shift of the pressure-volume curve in the irbesartan-treated group was found versus placebo. Finally, infarct expansion index was also significantly improved by irbesartan (p < 0.01). In conclusion, early, short-term AT1 receptor blockade limits post-infarct cardiac TNF-alpha production and diminishes myocardial alterations observed 7 days after MI in the rat.


[The treatment of 432 patients with pituitary adenomas via transsphenoidal approach].
To study some clinical features of 432 cases of pituitary adenomas treated by transsphenoidal microsurgery between July 1982 and October 1996. Pathological examination, immunohistochemical examination and electronmicroscopic examination were done in 424, 29 and 103 cases respectively. Hyperprolactinemia was found in many so-called non-functioning adenomas besides in prolactinomas. The dura maters were invaded by tumors in 78 cases (the incidence of dural invasion was 65.5%). Hyperprolactinemia is not peculiar to prolactinomas, and differential diagnosis is necessary when hyperprolactinemia exists. The involvement of the dura mater of sellar floor is an important mark that the adjacent tissues were invaded by pituitary adenomas. The outcome of surgical treatment is significantly different between the patients with dural invasion and without invasion.


Initial evaluation of the Chronic Pain Acceptance Questionnaire - 2.
Greater acceptance of chronic pain is associated with lesser levels of pain-related distress and disability and better overall functioning. Pain acceptance is most often assessed using the Chronic Pain Acceptance Questionnaire (CPAQ), which includes both an eight-item short form (CPAQ-8) and a twenty item parent measure (CPAQ-20). This study derived a two-item CPAQ for use in busy clinical settings and for repeated measurement during treatment, the CPAQ-2. An Item Response Theory (IRT) approach was used to identify the strongest items from the CPAQ-20, one from each of its two subscales. Next, regression analyses were conducted to evaluate the utility of the CPAQ-2 by examining variance accounted for in the CPAQ-8, CPAQ-20, and in measures of depression, pain-related fear, physical disability, and psychosocial disability. Four clinical databases were combined (N = 1,776) for the analyses. Items 9 and 14 were identified as the strongest CPAQ-20 items in the IRT analyses. The sum score of these two items accounted for over 60% of the variance in the CPAQ-8 and CPAQ-20. Furthermore, this score accounted for significant variance in measures of depression, pain-related fear, physical disability, and psychosocial disability after controlling for data collection method (i.e. in clinic or online), participant age, education, pain duration and usual pain. Finally, the amount of variance accounted for by the CPAQ-2 was comparable to that accounted for by both the CPAQ-8 and CPAQ-20. These results provide initial support for the CPAQ-2 and suggest that it is well-suited as a brief assessment of chronic pain acceptance. SIGNIFICANCE: The most frequently used measure of pain acceptance is the CPAQ, which includes both an eight-item short form, the CPAQ-8, and a longer twenty item parent measure, the CPAQ-20. The present study sought to derive a two-item measure of the CPAQ for use in busy clinical settings and for repeated measurement during treatment, the CPAQ-2. An IRT approach was used to identify the strongest items from the CPAQ-20, one from each of its two subscales in a large sample of 1,776 individuals with chronic pain. The two item measure accounted for significant variance in measures of depression, pain-related fear, physical disability, and psychosocial disability. The brief measure will be useful in assessing pain acceptance in busy clinical setting and longitudinal designs.