Defining progression in nonmuscle invasive bladder cancer: it is time for a new, standard definition.
Despite being one of the most important clinical outcomes in nonmuscle invasive bladder cancer, there is currently no standard definition of disease progression. Major clinical trials and meta-analyses have used varying definitions or have failed to define this end point altogether. A standard definition of nonmuscle invasive bladder cancer progression as determined by reproducible and reliable procedures is needed. We examine current definitions of nonmuscle invasive bladder cancer progression, and propose a new definition that will be more clinically useful in determining patient prognosis and comparing treatment options. The IBCG (International Bladder Cancer Group) analyzed published clinical trials and meta-analyses that examined nonmuscle invasive bladder cancer progression as of December 2012. The limitations of the definitions of progression used in these trials were considered, as were additional parameters associated with the advancement of nonmuscle invasive bladder cancer. The most commonly used definition of nonmuscle invasive bladder cancer progression is an increase in stage from nonmuscle invasive to muscle invasive disease. Although this definition is clinically important, it fails to include other important parameters of advancing disease such as progression to lamina propria invasion and increase in grade. The IBCG proposes the definition of nonmuscle invasive bladder cancer progression as an increase in T stage from CIS or Ta to T1 (lamina propria invasion), development of T2 or greater or lymph node (N+) disease or distant metastasis (M1), or an increase in grade from low to high. Investigators should consider the use of this new definition to help standardize protocols and improve the reporting of progression.


Why Is Theory of Mind Important for Referential Communication?
This research studies the relation between children's Theory of Mind (ToM) and the communicative behaviour and strategies used in a referential communication task. A total of 46 children (aged 6 to 10) were administered 6 ToM tasks, and they also participated in pairs in a cooperative task. Each pair built 4 construction models. Results showed that several ToM skills were related to the communicative behaviours of requesting clarification and giving information. In addition, the most used communicative strategy was Joint review, in which participants reviewed together the location of their blocks. This strategy was the most related to ToM abilities and to cooperative success. The importance of ToM for developing the communicative behaviours and strategies necessary for cooperation is discussed.


Publisher's Note: Enhanced Tunneling Electroresistance in Ferroelectric Tunnel Junctions due to the Reversible Metallization of the Barrier [Phys. Rev. Lett. 116, 197602 (2016)].
This corrects the article DOI: 10.1103/PhysRevLett.116.197602.


Assessment of safety and the immune response to the CD4 "internal antigen" mouse anti-idiotypic Mab 16D7 in four patients with SLE.
We have analyzed the immune response elicited with the human CD4 internal antigen anti-idiotypic monoclonal antibody 16D7 in four patients with active systemic lupus erythematosus and assessed the safety of the treatment. Patients I and 2 received three 2-mg 16D7 subcutaneous (SC) injections at 3-week intervals and mainly developed IgGI, whereas IgG1, IgG3, and IgG4 were detected in the sera of the other two patients (3 and 4) who received the same amount of 16D7 on days 0, 28, and 70. 16D7-F(ab')2 isotypic determinant-specific antibodies levels, evaluated by sera reactivity with the 16D7-isotype matched anti-idiotypic monoclonal antibody 14D6-F(ab')2, were low or undetectable in patient 1 and became detectable following the first and second boosters in patient 3 and patients 2 and 4, respectively. The highest level was seen in patients 3 and 4. The focusing pattern (spectrotype) of 16D7 idiotypic-specific antibodies suggested that multiple V genes are involved or many somatic mutations occur. Once established, each patient's spectrotype remained stable. Although spectrotype were individually distinct, all four patients produced CD4-specific antibodies, indicating that this response crosses the genetic barrier. Disease relapsed after 11 (patient 2), 40 (patients 3 and 4), and 125 (patient 1) weeks. The lack of side effects and the prolonged periods of disease control (33 and 103 weeks after the last booster) warrants an extension of this study.


The Ras-like protein R-Ras2/TC21 is important for proper mammary gland development.
R-Ras2/TC21 is a GTPase with high sequence and signaling similarity with Ras subfamily members. Although it has been extensively studied using overexpression studies in cell lines, its physiological role remains poorly characterized. Here we used RRas2-knockout mice expressing β-galactosidase under the regulation of the endogenous RRas2 promoter to investigate the function of this GTPase in vivo. Despite its expression in tissues critical for organismal viability, RRas2(-/-) mice show no major alterations in viability, growth rates, cardiovascular parameters, or fertility. By contrast, they display a marked and specific defect in the development of the mammary gland during puberty. In the absence of R-Ras2/TC21, this gland forms reduced numbers of terminal end buds (TEBs) and ductal branches, leading to a temporal delay in the extension and arborization of the gland tree in mammary fat pads. This phenotype is linked to cell-autonomous proliferative defects of epithelial cells present in TEBs. These cells also show reduced Erk activation but wild type-like levels of phosphorylated Akt. Using compound RRas2-, HRas-, and NRas-knockout mice, we demonstrate that these GTPases act in a nonsynergistic and nonadditive manner during this morphogenic process.


Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone.
Oxycodone is metabolized in the liver by means of O-demethylation to form oxymorphone in a reaction catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). This enzyme is expressed as 2 phenotypes (extensive and poor metabolizers). Several drugs are metabolized by CYP2D6, and clinically relevant drug interactions may occur. The aim of this study was to evaluate the role of oxymorphone in mediating the opioid effects of oxycodone by means of blocking CYP2D6 with quinidine. Ten healthy extensive metabolizers were administered 20 mg controlled-release oxycodone after premedication with placebo or 200 mg quinidine in this randomized, double-blind crossover study. A dose of 100 mg quinidine was administered 6 hours later. Plasma opioid concentrations, subjective pharmacodynamic ratings, and psychomotor function were assessed for 24 hours after drug administration. No oxymorphone was detected at any time after quinidine premedication in 8 of 10 subjects. Plasma oxycodone (difference not significant) and noroxycodone (P < .01) concentrations were greater after quinidine pretreatment. Prevention of the production of oxymorphone by quinidine did not affect the psychomotor or subjective drug effects of oxycodone. No difference in number of adverse effects was observed after the 2 pretreatments. A significant reduction in plasma oxymorphone levels did not substantially alter the pharmacodynamic effects of oxycodone. Analgesia was not evaluated because pain was not present.


In situ diagnostics of the crystal-growth process through neutron imaging: application to scintillators.
Neutrons are known to be unique probes in situations where other types of radiation fail to penetrate samples and their surrounding structures. In this paper it is demonstrated how thermal and cold neutron radiography can provide time-resolved imaging of materials while they are being processed (e.g. while growing single crystals). The processing equipment, in this case furnaces, and the scintillator materials are opaque to conventional X-ray interrogation techniques. The distribution of the europium activator within a BaBrCl:Eu scintillator (0.1 and 0.5% nominal doping concentrations per mole) is studied in situ during the melting and solidification processes with a temporal resolution of 5-7 s. The strong tendency of the Eu dopant to segregate during the solidification process is observed in repeated cycles, with Eu forming clusters on multiple length scales (only for clusters larger than ∼50 µm, as limited by the resolution of the present experiments). It is also demonstrated that the dopant concentration can be quantified even for very low concentration levels (∼0.1%) in 10 mm thick samples. The interface between the solid and liquid phases can also be imaged, provided there is a sufficient change in concentration of one of the elements with a sufficient neutron attenuation cross section. Tomographic imaging of the BaBrCl:0.1%Eu sample reveals a strong correlation between crystal fractures and Eu-deficient clusters. The results of these experiments demonstrate the unique capabilities of neutron imaging for in situ diagnostics and the optimization of crystal-growth procedures.


Speculative Considerations about Some Cardiology Enigmas.
Enigmas often lead to hypotheses and speculations. For this reason, especially for the sake of the reader's motivation, we opted for the plain discussion of some cardiology enigmas. The present text was aimed to discuss speculatively some cardiology enigmas. Text was freely designed in the context of coronary artery and heart valve diseases. The results were presented as the combination enigma/hypothesis. 1) The absence of arteriosclerosis in intramyocardial coronary arteries/ endothelium-myocardial interaction (crosstalk); 2) The unique and always confirmed superior evolution of the internal thoracic artery as coronary graft/ higher NO basal release 3) The prophylactic left internal thoracic artery graft in mildlystenosed coronary lesions/need of more accurate functional imaging techniques; 4) The high incidence of perioperative atrial fibrillation in patients with coronary artery disease/atrial ischemia associated to left circumflex coronary lesions; 5) The handling of disease-free saphenous vein grafts at the time of reoperation/biological serendipity with graft vein segments; 6) The possible aortic stenosis protection against coronary artery disease/ endothelium-myocardium interaction (crosstalk) improving NO release. The discussed topics associated with their respective speculative hypothesis remain as enigmas, but would become motivations for investigations.


Albiflorin ameliorates inflammation and oxidative stress by regulating the NF-κB/NLRP3 pathway in Methotrexate-induced enteritis.
Methotrexate (MTX) treats various diseases but also damages intestinal barrier and leads to enteritis. Albiflorin (ALB) has a variety of pharmacological effects, including antioxidant, anti-inflammation and anti-apoptosis. In the present study, we evaluated the therapeutic effect of ALB on MTX-induced enteritis and investigated the possible mechanisms involved. Male SD rats were intraperitoneally injected with 7 mg/kg MTX for three consecutive days to establish the enteritis model. ALB (20 or 40 mg/kg/day) was intragastrically administrated since two days prior MTX treatment and lasted for six days. We found that ALB treatment increased body weight and intestinal weight of rats with MTX injection. The disease activity index (DAI) score was also decreased after ALB administration. In histological examination, ALB treatment attenuated inflammatory cells infiltration and promoted survival of goblet cells. In detection of inflammatory-associated factors, ALB treatment decreased CD68+ cells infiltration, inhibited myeloperoxidase activity, and suppressed intercellular cell adhesion molecule-1 and cyclooxygenase-2 expression. Additionally, ALB reduced malondialdehyde, glutathione levels, inhibited superoxide dismutase activity and suppressed reactive oxygen species production. Moreover, ALB treatment effectively inhibited NLRP3, as well as caspase 1 p20 and interleukin (IL)-1β and 18 expression. Finally, nuclear factor-κB (NF-κB) p65 phosphorylation and nuclear translocation were also demonstrated to be blocked upon ALB treatment. In conclusion, our findings indicated that ALB alleviated MTX-induced enteritis via inhibiting the NF-κB/NLRP3 pathway.


[Presence of bacterial endotoxins in drinking and bottled water, with monitoring of eventual contaminations].
83 samples of drinking water of different source were examined with LAL-test, valuing some characteristics of the water (bacterial count, Coliform, pH, dissolved CO2) which might influence the test. Quantity higher than 0.5 ng/ml of endotoxin were detected in 40 of 44 mineral water samples and 37 of 39 tap water samples. The results are discussed.


Ultrasonography Shows Age-related Changes and Related Factors in the Tongue and Suprahyoid Muscles.
To investigate age and other factors related to the deterioration of the muscles used for swallowing, including the tongue and suprahyoid muscles. Cross-sectional study. This study included 146 participants: 47 younger adults (23 men and 24 women; age range 23-44 years) recruited from a dental hospital and 99 community-dwelling older adults (37 men and 62 women, age range 65-86 years). Age (<65 years or ≥65 years), body mass index (BMI), skeletal muscle mass index (SMI), and tooth loss (Eichner classification) were measured. The cross-sectional areas (CSAs) of the tongue, geniohyoid muscle, and anterior belly of the digastric muscle were measured using an ultrasonic diagnostic apparatus. The correlation between each muscle's CSA and strength was examined. Multiple regression analyses were performed separately for each sex using each muscle CSA as the dependent variable and age, BMI, SMI, and the Eichner classification as explanatory variables. Older men had a significant positive correlation between tongue pressure and CSA (r = 0.35, P = .031). Jaw opening force was positively correlated with geniohyoid muscle CSA (r = 0.41, P = .001) in older women. In the multiple regression analysis, age, BMI, and SMI were significantly associated with tongue CSA in men. Age was significantly and inversely associated with suprahyoid muscle CSA in both men and women. No explanatory variables were significantly associated with geniohyoid muscle CSA except age. The tongue increased in volume, and the suprahyoid muscles underwent atrophy with age. The study results suggest that interventions to prevent dysphagia associated with aging should be tailored toward specific muscles. Direct muscle training is required for the suprahyoid muscles, whereas the maintenance of tongue muscle mass and function, as well as training for the tongue, requires attention to ensure optimal nutritional status and whole-body skeletal muscle mass.


Higgs alignment from extended supersymmetry.
We consider the effective type-II two-Higgs doublet model originating from Dirac gaugino models with extended supersymmetry in the gauge sector, which is automatically aligned in the simplest realisations. We show that raising the scale at which the extended supersymmetry is manifest and including quantum corrections actually improves the alignment. Using an effective field theory approach including new threshold corrections and two-loop RGEs, plus two-loop corrections to the Higgs mass in the low-energy theory, we study the implications from the Higgs mass and other experimental constraints on the scale of superpartners. We contrast the results of the minimal Dirac gaugino model, where alignment is automatic, with the hMSSM and the MRSSM, where it is not, also providing an hMSSM-inspired analysis for the new models.


Ketamine patient-controlled analgesia for dysesthetic central pain.
Case report. To describe the first use of intravenous (IV) ketamine as the sole agent in a patient-controlled analgesic delivery system (ie PCA) in a patient with cervical syringomyelia. A tertiary-care university teaching hospital in New York City. A 41-year-old tetraplegic female on high-dose opioids suffering from intractable dysesthetic central pain received her best pain relief from a low-dose ketamine infusion after failing trials with multiple neuropathic medications. After several weeks of titrating her infusion rate up and down, she was switched to an IV ketamine PCA device. The patient was maintained on an IV ketamine PCA for almost 1 year under the following settings: 2.7 mg/h basal rate; 2.7 mg/h demand dose; 15 min lockout period. Although she continues to report some pain, it has dramatically decreased since the ketamine PCA was instituted, enabling us to significantly reduce her opioid dosage. Ketamine PCA may be a viable treatment option in patients suffering from intractable central pain. The rationale for this treatment, along with dosing guidelines and possible drawbacks, is discussed.


Frequency-dependent changes in the paired-pulse index in the hippocampus of the freely moving adult male rat.
The paired-pulse index (PPI) has been widely used as a measure of modulation of cellular excitability in the hippocampal trisynaptic circuit. This paper presents a quantification of the changes in this measure of neuronal modulation as a result of the application of pulse trains having six different train frequencies (0.1, 1, 5, 8, 15, and 30 Hz) to one of the major efferent pathways to the dentate gyrus, the medial perforant path (MPP). Our findings indicate that the modulation of the first leg of the hippocampal trisynaptic circuit is dependent on the frequency of the "burst train" applied to the perforant pathway. This methodological finding is of importance to all investigators studying hippocampal plasticity via LTP or LTD approaches. The different synaptic mechanisms implicated in being responsible for the changes in the PPI are also discussed.


Expression of the death-associated gene RP-8 in granule cell neurons undergoing postnatal cell death in the cerebellum of weaver mice.
RP-8 is one of several mRNAs elevated during apoptosis in immature thymocytes. We used in situ hybridization to look for RP-8 mRNA in the cerebella of weaver mice. In the weaver mouse cerebellar granule cells fail to differentiate and instead die during the first two weeks of postnatal development [30]. We demonstrate that the dying cells exhibit DNA degradation, a characteristic feature of apoptosis. RP-8 is expressed in the weaver cerebellum during the period of granule cell death, and is limited to cells in the same region where apoptotic granule cells are located. Thus, RP-8 expression, first associated with PCD in thymocytes, correlates with granule cell death in the weaver cerebellum.


Capitalization and proximity to agricultural and natural lands: evidence from Delaware.
This paper offers an applied study assessing the price impacts of proximity to open space in a residential property market. Data are collected in an urban-influenced region of Delaware, USA, which has experienced rapid population growth--an 85 percent increase in number of households and 92 percent increase in population between Census 1990 and Census 2000--but also maintains substantial agricultural land use. In agreement with previous literature the results show the protection of agricultural and natural lands is capitalized into the value of neighboring properties. Surprisingly however, in this rapidly growing region the open space that is not protected from development offers no distinguishable effect on property values. This is likely because in a rapidly developing region all unprotected land is seen as potentially developable.


Detrended fluctuation analysis detects altered coordination of running gait in athletes following a heavy period of training.
To investigate whether functional overreaching affects locomotor system behaviour when running at fixed relative intensities and if any effects were associated with changes in running performance. Prospective intervention study. Ten trained male runners completed three training blocks in a fixed order. Training consisted of one week of light training (baseline), two weeks of heavy training designed to induce functional overreaching, and ten days of light taper training designed to allow athletes to recover from, and adapt to, the heavy training. Locomotor behaviour, 5-km time trial performance, and subjective reports of training status (Daily Analysis of Life Demands for Athletes (DALDA) questionnaire) were assessed at the completion of each training block. Locomotor behaviour was assessed using detrended fluctuation analysis of stride intervals during running at speeds corresponding to 65% and 85% of maximum heart rate (HRmax) at baseline. Time trial performance (effect size ±95% confidence interval (ES): 0.16±0.06; p<0.001), locomotor behaviour at 65% HRmax (ES: -1.12±0.95; p=0.026), and DALDA (ES: 2.55±0.80; p<0.001) were all detrimentally affected by the heavy training. Time trial performance improved relative to baseline after the taper (ES: -0.16±0.10; p=0.003) but locomotor behaviour at 65% HRmax (ES: -1.18±1.17; p=0.048) and DALDA (ES: 0.92±0.90; p=0.045) remained impaired. Locomotor behaviour during running at 65% HRmax was impaired by functional overreaching and remained impaired after a 10-day taper, despite improved running performance. Locomotor changes may increase injury risk and should be considered within athlete monitoring programs independently of performance changes.


Management of ACL Reconstruction Complicated by MRSA Osteomyelitis Requiring a Gastrocnemius Perforator Flap: A Case Report.
A 21-year-old woman presented with sepsis from methicillin-resistant Staphylococcus aureus, patellar osteomyelitis, and 6 × 4 × 2-cm proximal anteromedial soft-tissue defect 1 week after bone-tendon-bone autograft anterior cruciate ligament reconstruction (ACL-R). She underwent multiple irrigation and debridement (I&Ds), hardware removal, bone grafting with antibiotic-loaded tricalcium phosphate beads, and medial gastrocnemius perforator flap with plastic surgery. At 18 months after her initial ACL-R, single-stage revision ACL-R with quadriceps autograft was performed. When acute ACL-R infection does not respond to initial I&D and Intravenous (IV) antibiotics, retained hardware and graft tissue must be removed expeditiously to prevent sepsis, osteomyelitis, and soft-tissue defects.


The association of age, body mass index, and frailty with vestibular schwannoma surgical morbidity.
To evaluate whether increased body mass index (BMI), age, or frailty influence vestibular schwannoma (VS) short-term surgical morbidity. The 2005-2017 National Surgical Quality Improvement Program database was queried for patients with VS undergoing surgical resection. Age was stratified according to age <50, 50-64, and ≥65, while BMI was stratified based on a threshold of 30. Frailty score (0-5) was indicated based on functional status, diabetes, chronic obstructive pulmonary disease, congestive heart failure, and hypertension. A total of 1405 patients were included consisting of 56.7 % females with a mean age of 50.7 ± 13.8 years and mean BMI of 29.4 ± 6.6. Patients <50 (n = 604), 50-64 (n = 578), and ≥65 (n = 223), had different duration of surgery (428 ± 173 vs. 392 ± 149 vs. 387 ± 154 min; p < 0.001) and 30-day mortality rates (0.7 % vs. 0% vs. 1.8 %; p = 0.01). However, post-operative length of stay (LOS) (p = 0.16), readmission (p = 0.08), reoperation (p = 0.54), and complication rates were similar. Post-operative myocardial infarction (p = 0.03) and wound infection (p = 0.02) were more commonly observed in the obese cohort (BMI≥30) but readmission (p = 0.18), reoperation (p = 0.44), and complication rates were similar to those with BMI<30. Severely obese patients (BMI≥35) also had higher rates of deep vein thrombosis (p = 0.004). Frailty score 0 (n=921), 1 (n=375), and 2-4 (n=109) was associated with LOS (4.7±3.5 vs. 5.3 ± 4.1 vs. 6.7 ± 6.6 days, p < 0.001) and prolonged intubation rates (1.0 % vs. 2.4 % vs. 3.7 %; p = 0.03). Increased age, BMI, and frailty among VS patients were associated with different post-operative complication rates, operation time, or LOS. Knowledge of these can optimize care for at-risk patients.


Is there a place for Traditional Chinese Medicine (TCM) in the treatment of recurrent pregnancy loss?
Recurrent pregnancy loss (RPL) impacts a couple's quality of life, mental health and constitutes a large economic burden for care. Traditional Chinese Medicine (TCM) is an integrated systematic medical practice with wide clinical applications that has been predominantly used throughout Asian countries for over 2000 years. However, the efficacy of TCM in the treatment of RPL remains unclear due not only to a lack of experimental evidence, but also a lack of comprehensive summarized conclusions. Therefore, the current manuscript reviews recent relevant publications of the clinical use of TCM in RPL and illustrates its potential mechanisms. All publications (in both Chinese and English), especially randomized controlled trials (RCTs), on the use of TCM in RPL for the last ten years and research on its mechanisms were included. This review also describes our understanding of the problems and challenges in the modernization of TCM research.


Sensitive and specific detection of Salmonid alphavirus using real-time PCR (TaqMan).
Pancreas disease is responsible for major economic losses in the European salmonid farming industry. It was previously believed that a single subtype (salmon pancreas disease virus) of the virus species Salmonid alphavirus (SAV) was responsible for all outbreaks of pancreas disease in the UK and Norway. However, the recent discovery that pancreas disease in Norway is caused by a new and distinct subtype of salmonid alphavirus, exclusively found in Norway, has advocated the need for better diagnostic tools. In the present paper, three real-time PCR assays for all known subtypes of salmonid alphavirus have been developed; the Q_nsP1 assay is a broad-spectrum one that detects RNA from all subtypes, the Q_SPDV assay specifically detects the salmon pancreas disease virus subtype, and the Q_NSAV assay only detects the new Norwegian salmonid alphavirus subtype. The results demonstrated the assays to be highly sensitive and specific, detecting <0.1TCID50 of virus stocks. Regression analysis and standard curves calculated from the Ct-values from 10-fold serial dilutions of virus stocks showed that the assays were highly reproducible over a wide range of RNA input. Thirty-nine field samples were tested in triplicate and compared with traditional RT-PCR. Overall, the real-time assays detected 35 positive compared to 29 positives in standard RT-PCR, and were thus shown to be more sensitive for detecting salmonid alphaviruses in field samples.


Correlated light and electron microscopy observations of the uterine epithelial cell actin cytoskeleton using fluorescently labeled resin-embedded sections.
In order to perform correlative light and electron microscopy (CLEM) more precisely, we have modified existing specimen preparation protocols allowing fluorescence retention within embedded and sectioned tissue, facilitating direct observation across length scales. We detail a protocol which provides a precise correlation accuracy using accessible techniques in biological specimen preparation. By combining a pre-embedding uranyl acetate staining step with the progressive lowering of temperature (PLT) technique, a methacrylate embedded tissue specimen is ultrathin sectioned and mounted onto a TEM finder grid for immediate viewing in the confocal and electron microscope. In this study, the protocol is applied to rat uterine epithelial cells in vivo during early pregnancy. Correlative overlay data was used to track changes in filamentous actin that occurs in these cells from fertilization (Day 1) to implantation on Day 6 as part of the plasma membrane transformation, a process essential in the development of uterine receptivity in the rat. CLEM confirmed that the actin cytoskeleton is disrupted as apical microvilli are progressively lost toward implantation, and revealed the thick and continuous terminal web is replaced by a thinner and irregular actin band, with individually distinguishable filaments connecting actin meshworks which correspond with remaining plasma membrane protrusions.


Lactobacillus rhamnosus Restores Antiviral Signaling and Attenuates Cytokines Secretion from Human Bronchial Epithelial Cells Exposed to Cigarette Smoke and Infected with SARS-CoV-2.
Individuals with chronic obstructive pulmonary disease (COPD) are more susceptible to exacerbation crisis triggered by secondary lung infections due to the dysfunction of antiviral signaling, principally via suppression of IFN-γ. Although the probiotic is known for controlling pulmonary inflammation in COPD, the influence of the Lactobacillus rhamnosus (Lr) on antiviral signaling in bronchial epithelium exposed to cigarette smoke extract (CSE) and viruses, remains unknown. Thus, the present study investigated the Lr effect on the antiviral signaling and the secretion of inflammatory mediators from bronchial epithelial cells (16HBE cells) exposed to CSE and SARS-CoV-2. The 16HBE cells were cultured, treated with Lr, stimulated with CSE, and infected with SARS-CoV-2. The cellular viability was evaluated using the MTT assay and cytotoxicity measured by lactate dehydrogenase (LDH) activity. The viral load, TLR2, TLR3, TLR4, TLR7, TLR8, MAVS, MyD88, and TRIF were quantified using specific PCR. The pro-inflammatory mediators were measured by a multiplex biometric immunoassay, and angiotensin converting enzyme 2 (ACE2) activity, NF-κB, RIG-I, MAD5, and IRF3 were measured using specific ELISA kits. Lr decreased viral load, ACE2, pro-inflammatory mediators, TLR2, TLR4, NF-κB, TLR3, TLR7, and TLR8 as well as TRIF and MyD88 expression in CSE and SARS-CoV-2 -exposed 16HBE cells. Otherwise, RIG-I, MAD5, IRF3, IFN-γ, and the MAVS expression were restored in 16HBE cells exposed to CSE and SARS-CoV-2 and treated with Lr. Lr induces antiviral signaling associated to IFN-γ secreting viral sensors and attenuates cytokine storm associated to NF-κB in bronchial epithelial cells, supporting its emerging role in prevention of COPD exacerbation.


Occurrence of xerophilic fungi in bakery gingerbread production.
The production process of a coconut type of gingerbread was examined for possible sources of contamination with xerophilic fungi. In the production flow chart, critical control points were found at which some effective steps could be made to eliminate undesirable fungal contamination, affected by water activity and temperature, and to prevent mould spoilage of the products. The following xerophilic fungi were detected, isolated and identified: Eurotium amstelodami, E. chevalieri, E. herbariorum, E. rubrum and Wallemia sebi. The resistance of these fungi against elevated temperature and preserving agents was investigated. It was found that Eurotium species were more resistant than W. sebi. Preservation against xerophilic fungi was more effective with the use of propionic acid than with potassium sorbate.


Curative resection for adenocarcinoma of the gastro-esophageal junction following neo-adjuvant chemotherapy-thoraco-abdominal vs. trans-abdominal approach.
This study compares the short- and long-term outcomes between the left thoraco-abdominal and trans-abdominal approaches for radical resection of adenocarcinoma of the gastro-esophageal junction (GEJ) (Siewert types II and III) following neo-adjuvant chemotherapy. A retrospective analysis of a prospectively maintained database of patients from May 2008 to December 2016. Demographic variables, perioperative outcomes, and survival were compared between two approaches. Of the 792 patients, who underwent total/proximal gastrectomy during the specified time interval, 162 had Siewert's type II/III lesions, of which 147 received neoadjuvant chemotherapy and were included in the study. Ninety-two and 55 patients underwent definitive surgery through trans-abdominal and left thoraco-abdominal approach respectively. On baseline endoscopy, 81.8% of patients in the left thoraco-abdominal group had lower esophageal mucosal infiltration as compared to 41.3% in the trans-abdominal group (p < 0.001). Both groups were comparable in terms of duration of surgery, blood loss, complications, severity of complications (Clavien-Dindo grade), duration of hospital stay, R0 resection rate, length of proximal margin, and lymph node yield. At a median follow-up of 24 months, there was no difference in recurrence rate and survival between the groups. Both left thoraco-abdominal and trans-abdominal are comparable surgical approaches for tumors involving the GEJ in terms of morbidity, perioperative, and long-term oncological outcomes. In patients with lower esophageal involvement, the left thoraco-abdominal approach is a feasible alternative with no added overall morbidity or mortality and can be preferred especially in cases, where a safe proximal margin and anastomosis is deemed technically challenging.


Phenotypic heterogeneity within the first complementation group of UV-sensitive mutants of Chinese hamster cell lines.
A DNA-repair mutant was characterized that has the extraordinary and interesting properties of extreme sensitivity to UV killing combined with a high level of nucleotide excision repair. The mutant V-H1 isolated from the V79 Chinese hamster cell line appeared very stable, with a reversion frequency of about 3.5 X 10(-7). Genetic complementation analysis indicates that V-H1 belongs to the first complementation group of UV-sensitive Chinese hamster ovary (CHO) mutants described by Thompson et al. (1981). This corresponds with data on cross-sensitivity and mutation induction after UV irradiation published by this group. Surprisingly, the mutant V-H1 shows only slightly reduced (to approximately 70%) unscheduled DNA synthesis (UDS) after UV exposure, while the other two mutants of this complementation group are deficient in UDS after UV. In agreement with the high residual UDS, in V-H1 also the amount of repair replication in response to UV treatment is relatively high (approximately 50%). It has also been shown that the incision step of the nucleotide excision pathway takes place in V-H1 (with a lower rate than observed in wild-type cells), whereas another mutant (UV5) of the same complementation group is deficient in incision. This heterogeneity within the first complementation group indicates that the repair gene of this complementation group may have more than one functionally important domain or that the gene is not involved in the incision per se but is involved in e.g. preferential repair of active genes.


Short-term effects of light and heavy load interventions on service velocity and precision in elite young tennis players.
This study was conducted to investigate the acute effects of a complex throwing intervention set-up, with light or heavy loads, on the service velocity of elite junior tennis players. On 3 separate test days, 13 elite juniors (mean (SD) 12.3 (0.8) years, 149 (9) cm, 37.5 (5.5) kg) performed four sets of six serves with different between-set conditions. In a cross-over design, the players performed respectively 6, 4 and 2 maximum effort throws with a 200 g ball (LI, light intervention), 6, 4 and 2 maximum effort throws with a 600 g ball (HI, heavy intervention) and no throws (NI, no intervention) during the 2 min in between-set period. Participants were instructed to serve, with maximum speed, to a target near the midline of the deuce court service box. A two-factor analysis of variance was used to determine the effects of intervention type and set number on "service velocity", "service precision" (eg, percentage of serves in) and "service touch" (11 point rating scale). Mean (SD) service velocity decreased significantly in HI (124.3 (7.8) km/h) as compared to NI (126.6 (9.3) km/h, p<0.05, effect size d = 0.26), yet no such differences were found between LI (125.2 (7.9) km/h) and NI. Service velocity also remained constant between sets (p = 0.406). Service precision and service touch were unaffected by the interventions. Under the conditions of our study, a heavy throwing intervention during service training has no beneficial effect on service velocity in young elite tennis players (under 14).


New methods for three dimensional mapping of brain waves.
The representation of spatiotemporal pattern of brain electrical activity is an important issue in the research of neural assemblies. This paper describes methods of parametric 3D head or brain modeling and its corresponding interpolation for functional imaging based on brain waves. The 3D interpolation method is an extension of cortical imaging technique. It can be used with features of either transformed domains or higher order statistics of brain waves on realistic head or brain models. The simulating result suggests that it is a better method in comparison with the global nearest neighbor technique. With those techniques, an example of brainwave imaging was given using partial coherence of event-related potentials estimated by multivariate autoregressive model.


Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing.
Gluten-free diet (GFD) is the only management for coeliac disease (CD). Available methods to assess GFD compliance are insufficiently sensitive to detect occasional dietary transgressions that may cause gut mucosal damage. We aimed to develop a method to determine gluten intake and monitor GFD compliance in patients with CD and to evaluate its correlation with mucosal damage. Urine samples of 76 healthy subjects and 58 patients with CD subjected to different gluten dietary conditions were collected. A lateral flow test (LFT) with the highly sensitive and specific G12 monoclonal antibody for the most dominant gluten immunogenic peptides (GIP) and a LFT reader were used to quantify GIP in solid-phase extracted urines. GIP were detectable in concentrated urines from healthy individuals previously subjected to GFD as early as 4-6 h after single gluten intake, and remained detectable for 1-2 days. The urine assay revealed infringement of the GFD in about 50% of the patients. Analysis of duodenal biopsies revealed that most of patients with CD (89%) with no villous atrophy had no detectable GIP in urine, while all patients with quantifiable GIP in urine showed incomplete intestinal mucosa recovery. GIP are detected in urine after gluten consumption, enabling a new and non-invasive method to monitor GFD compliance and transgressions. The method was sensitive, specific and simple enough to be convenient for clinical monitoring of patients with CD as well as for basic and clinical research applications including drug development. NCT02344758.


Induction of responsiveness to IL 2 in Con A-stimulated rat lymphoid cells requires synergistic action of IL 1 and the accessory cell membrane.
Rat spleen or lymph node cells stimulated with Con A and cultured at a low density of 1 x 10(5) cells per ml proliferated in response to IL 2-containing supernatants and thus expressed receptors for IL 2. Cells depleted of accessory cells either by passage over a glassbead-column or by treatment with the lysosomotropic agent leucine methyl ester (Leu-OMe) did not proliferate in response to IL 2-containing supernatants. The diminished proliferative response after adherent cell depletion could be reconstituted by the addition of peritoneal exudate cells (PEC). Reconstitution could also be achieved by synergistic action of IL 1 and paraformaldehyde-fixed peritoneal exudate cells, indicating an important role for the accessory cell membrane in the induction of IL 2-mediated proliferation.


Co-occurrence of germline BRCA1 and CDH1 pathogenic variants.
We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the first report of such an association.Family description: The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer. She was tested for several genes associated with hereditary breast cancer. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified. This complex situation is challenging for genetic counselling and management of at-risk individuals.


Postdischarge surveillance to identify subsequent methicillin-resistant Staphylococcus aureus infections in colonized children.
Some hospitals screen and identify high risk patients for methicillin-resistant Staphylococcus aureus (MRSA) colonization. We performed postdischarge surveillance, including a telephone survey, and estimated a 9.5% incidence of infection in MRSA-colonized children in the year following discharge. Interventions are needed to reduce MRSA infections in colonized children after hospital discharge.


Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8+ T Cells.
Intratumoral CD8+ T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T-cell-mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self-degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME-responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2-like tumor-associated macrophages, and 3) downregulating PD-L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8+ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti-PD-1 antibodies.


Volatility and mixing states of ultrafine particles from biomass burning.
Fine and ultrafine carbonaceous aerosols produced from burning biomasses hold enormous importance in terms of assessing radiation balance and public health hazards. As such, volatility and mixing states of size-selected ultrafine particles (UFP) emitted from rice straw, oak, and pine burning were investigated by using volatility tandem differential mobility analyzer (VTDMA) technique in this study. Rice straw combustion produced unimodal size distributions of emitted aerosols, while bimodal size distributions from combustions of oak (hardwood) and pine (softwood) were obtained. A nearness of flue gas temperatures and a lower CO ratio of flaming combustion (FC) to smoldering combustion (SC) were characteristic differences found between softwood and hardwood. SC emitted larger mode particles in higher numbers than smaller mode particles, while the converse was true for FC. Rice straw open burning UFPs exhibited a volatilization behavior similar to that between FC and SC. In addition, internal mixing states were observed for size-selected UFPs in all biomasses for all combustion conditions, while external mixing states were only observed for rice straw combustion. Results for FC and open burning suggested there was an internal mixing of volatile organic carbon (OC) and non-volatile core (e.g., black carbon (BC)), while the SC in rice straw produced UFPs devoid of non-volatile core. Also, it was found that volatility of constituting OC in FC and SC particles was different.


The interplay between affect and theory of planned behavior variables.
To assess whether affective evaluations of health behaviors moderate or mediate the influence of theory of planned behavior (TPB) variables on intention. For each of 20 health behaviors, respondents (N=300) completed questionnaire measures of affective evaluation, attitude, subjective norm, perceived behavioral control, and intention. Analyses using path modeling revealed that affective evaluation of the behaviors did not moderate the influence of the TPB variables on intention, but it partially mediated the influence of attitude and perceived behavioral control on intention. These results emphasize the importance of affective evaluation as a target for health communication.


Dose and time effects of nicotine treatment on the capillary blood flow and viability of random pattern skin flaps in the rat.
The deleterious effects of nicotine treatment on skin haemodynamics and survival of 4 X 10 cm acute random pattern skin flaps constructed on the dorsum of the rat were studied. Rats were injected subcutaneously with 0.2 ml of saline containing varying doses (0, 1, 2, 4 or 8 mg kg-1; bid) of nicotine for 5 weeks, starting 4 weeks before flap surgery. It was observed that nicotine treatment at the dose of 2 mg kg-1 (bid), or higher, significantly (p less than 0.05) decreased the length and area of skin flap survival compared with the control. This dose of nicotine treatment also significantly (p less than 0.05) decreased the capillary blood flow and distal perfusion in the skin flaps compared with the control. However, the detrimental effect of nicotine treatment on the survival of acute random pattern skin flaps was not seen if the treatment was started 2 instead of 4 weeks preoperatively. It is concluded that nicotine may cause hypoperfusion and necrosis in acute random pattern skin flap surgery, and the deleterious effects are time-dependent.


Enhancing geneticists' perspectives of the public through community engagement.
Given the rapid pace of genetic and genomic research and technology development, public engagement on scientific issues may be mutually beneficial to the research community and the general public. The public may benefit from a greater understanding of concepts and new applications, and researchers can build awareness of public knowledge, perceptions, and potential concerns about genomic research and applications. We developed and piloted a public engagement program called Genome Diner to facilitate dialog between genetic/genomic researchers (n = 40) and middle school students (n = 76) and their parents (n = 83) from the local community. Program impact was assessed through pre- and post-Diner surveys for each group. After participation in Genome Diner, researchers' views were positively affected regarding the (adult) public's level of understanding of genetic concepts, beliefs about relevance of research, and the importance of researcher-community interaction. Through an interactive discussion with students and parents, researchers gained valuable insight into public perspectives about genome research. The engagement format of the Genome Diner program presents a novel method of fostering trust and relationships between the two groups and to inform both the public and the researchers, whose work may depend on public opinion and participation.


Ion-selective electrode for measuring low Ca2+ concentrations in the presence of high K+, Na+ and Mg2+ background.
In this work, ion-selective electrodes for calcium ion were investigated. Two ionophores were used in the membranes: ETH 1001 and ETH 129. An internal filling solution buffered for primary ion was used that allowed the lower detection limit to be decreased down to 10(-8.8) M. Theoretical and experimental electrode characteristics pertaining to both primary and interfering ions are discussed. Better behavior was obtained with the electrode prepared with ETH 129 in the membrane. This electrode would be the most likely candidate for obtaining a low Ca(2+) detection limit in measurements performed with high K(+), Na(+), Mg(2+) background, which is found inside the cells of living organisms, for example. The potentiometric response of the electrode in solutions containing main and interfering ions is in good agreement with simulated curves obtained using the Nernst-Planck-Poisson (NPP) model.


ST18 affects cell-cell adhesion in pemphigus vulgaris in a tumour necrosis factor-α-dependent fashion.
Pemphigus vulgaris (PV) is a life-threatening mucocutaneous autoimmune blistering disease. We previously showed that genetic variants within the ST18 gene promoter area confer a sixfold increase in the propensity to develop PV. ST18, a transcription factor, was found to be overexpressed in the epidermis of patients with PV. In addition, it was found to promote autoantibody-mediated abnormal epidermal cell-cell adhesion and secretion of proinflammatory mediators by keratinocytes. To delineate the mechanism through which ST18 contributes to destabilization of cell-cell adhesion. We used quantitative reverse-transcriptase polymerase chain reaction, immunofluorescence microscopy, a luciferase reporter system, site-directed mutagenesis, chromatin immunoprecipitation (ChIP) and the dispase dissociation assay. The ChIP and luciferase reporter assays showed that ST18 directly binds and activates the TNF promoter. Accordingly, increased ST18 expression contributes to PV pathogenesis by destabilizing cell-cell adhesion in a tumour necrosis factor (TNF)-α-dependent fashion. In addition, dual immunofluorescence staining showed increased expression of both ST18 and TNF-α in the skin of patients with PV carrying an ST18-associated PV risk variant, which was found to be associated with a more extensive PV phenotype. Our findings suggest a role for TNF-α in mediating the deleterious effect of increased ST18 expression in PV skin.


BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine.
One of the most devastating consequences of methamphetamine abuse is increased risk of psychosis. Brain-derived neurotrophic factor has been implicated in both psychosis and neuronal responses to methamphetamine. We therefore examined persistent psychosis-like behavioral effects of methamphetamine in brain-derived neurotrophic factor heterozygous mice. Mice were chronically treated with methamphetamine from 6 to 9 weeks of age, and locomotor hyperactivity to an acute D-amphetamine challenge was tested in photocell cages after a 2-week withdrawal period. Methamphetamine-treated wild-type mice, but not brain-derived neurotrophic factor heterozygous mice, showed locomotor sensitization to acute 3mg/kg D-amphetamine. Qualitative analysis of exploration revealed tolerance to D-amphetamine effects on entropy in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice, but not wild-type mice. Chronic methamphetamine exposure induces contrasting profiles of behavioral changes in wild-type and brain-derived neurotrophic factor heterozygous mice, with attenuation of behaviors relevant to psychosis in methamphetamine-treated brain-derived neurotrophic factor heterozygous mice. This suggests that brain-derived neurotrophic factor signalling changes may contribute to development of psychosis in methamphetamine users.


Non-uniform changes in magnetic resonance measurements of the semitendinosus muscle following intensive eccentric exercise.
This study was designed to determine the regional differences of magnetic resonance (MR) measurements in the hamstrings [biceps femoris muscle long head (BFl) and short head (BFs), semimembranosus muscle (SM), and semitendinosus muscle (ST)] following eccentric knee-flexion exercise. Twelve male volunteers performed eccentric knee-flexion exercise. Maximum isometric torque, plasma creatine kinase (CK) activity, muscle soreness, and MR images of the hamstrings were measured before and immediately following exercise, and on the first, second, third and seventh days following the exercise. Cross-sectional areas (CSAs) and transverse relaxation times (T2s) of the hamstrings were measured from the T2-weightened MR imaging sequences of 30% (proximal), 50% (middle), and 70% (distal) areas of the thigh length. The CSA of the ST at proximal and middle regions had significantly increased on the third day, but no significant changes were found for the BFl or SM. Immediately following exercise, T2 values had increased significantly in the BFs, BFl, and ST. On the third day, T2 values of only ST increased significantly at proximal, middle and distal regions. Significant differences of T2 values between proximal and distal regions in the ST were found for the second, third and seventh days following the exercise. These results suggest that because of the anatomical characteristics of the muscles, the degrees of response following the exercise differed among the muscles and the regions of ST muscle.


Transcription factor RFX1 is ubiquitinated by E3 ligase STUB1 in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease caused by complex interactions between genes and the environment. The expression level of transcription factor regulatory factor X 1 (RFX1) is reduced in T cells from SLE patients. RFX1 can regulate epigenetic modifications of CD70 and CD11a and plays an important role in the development of SLE. However, the mechanisms that mediate reduction of RFX1 in SLE are unclear. Here, we demonstrate that RFX1 protein expression can be tightly regulated by polyubiquitination-mediated proteosomal degradation via STIP1 homology and U-box containing protein 1 (STUB1). The E3 ligase STUB1 is upregulated in CD4(+)T cells of SLE patients compared to healthy subjects. Overexpression of STUB1 in CD4(+)T cells leads to upregulation of levels of CD70 and CD11a in T cells. The modulation of STUB1 activity may provide a novel therapeutic approach for SLE.


Resilience and its correlates among medical students in the Eastern part of India during the coronavirus disease 2019 (COVID-19) pandemic.
There is a great deal of psychological pressure on medical students, which results in depression, addiction, and suicide. Resilience plays a significant role in coping with psychological distress. The study aimed to determine the resilience level of medical students in Kolkata and factors related to it. A cross-sectional study was conducted among undergraduate students of a medical college in the eastern part of India during October 2020. Resilience was assessed using the validated "Adult Resilience Measure-R." Data were collected on Google Forms and analyzed using SPSS (version 16.0). Logistic regression analysis was performed to find factors associated with low resilience. The study revealed that one-fourth (25.2%) of the participants had low-level resilience. Nearly half (44.9%) of them perceived their mental health status as having worsened during the lockdown. Students who did not enjoy staying at home during the lockdown and who spent <10 h of their time with their family members had higher odds of low resilience. In multivariable analysis, not enjoying staying at home during the lockdown remained the only significant predictor of low resilience. Students should spend more time with their parents and family members and learn coping skills. Appropriate resilience training programs have to be integrated into the medical curriculum to help in coping with future challenges.


Augmented image guidance improves skull base navigation and reduces task workload in trainees: a preclinical trial.
Our group has developed an augmented image guidance system that incorporates intraoperative cone-beam computed tomography (CBCT), virtual or augmented displays, and image registration. We assessed the potential benefits of augmented endoscopy derived from this system for use during skull base navigation. Specifically, we wished to evaluate target localization accuracy and the effect on task workload and confidence. Prospective, sequential, paired preclinical trial. A single cadaver head underwent computed tomography, and critical structures were contoured. The specimen was reimaged after endoscopic dissection and deformable registration allowed contours to be displayed on postablation CBCT imaging. A real-time virtual view including anatomical contours was provided parallel to the real endoscopic image. Twelve subjects were asked to endoscopically localize seven skull base landmarks in a conventional manner. The same exercise was then performed with augmented endoscopy. Precise three-dimensional (3D) localization was recorded with a tracked probe. The NASA task load index was completed after each exercise. A short questionnaire was also administered. The real-time augmented image guidance system aided localization in 85% of responses and increased confidence in 97%. There was a significant reduction in mental demand, effort, and frustration when the technology was employed, with an increase in perceived performance (P < .05). Three dimensional navigational precision was improved for all landmarks. Real-time augmented image-guided surgery increases accuracy and confidence in trainee surgeons and decreases task workload during skull base navigation. This technology shows great promise in assisting in skull base surgery even for experienced surgeons.


Engineering the product profile of a polysialyltransferase.
Oligo- and polysaccharides have myriad applications as therapeutic reagents from glycoconjugate vaccines to matrices for tissue engineering. Polysaccharide length may vary over several orders of magnitude and is a critical determinant of both their physical properties and biological activities. Therefore, the tailored synthesis of oligo- and polysaccharides of defined size is a major goal for glycoengineering. By mutagenesis and screening of a bacterial polysialyltransferase (polyST), we identified a single-residue switch that controls the size distribution of polymeric products. Specific substitutions at this site yielded distributive enzymes that synthesize polysaccharides with narrow size distribution ideal for glycoengineering applications. Mechanistic investigation revealed that the wild-type enzyme has an extended binding site that accommodates at least 20 residues of the growing polymer; changes in affinity along this binding site allow fine-tuning of the enzyme's product distribution.


Successful topical treatment of hand warts in a paediatric patient with tea tree oil (Melaleuca alternifolia).
Tea tree oil (TTO) (Melaleuca alternifolia) has been used recently as an effective topical application for the treatment of skin infections due to a variety of aetiological microbial agents, including mainly bacterial infections. We detail the first report in the peer-reviewed literature of the successful treatment with TTO of a paediatric patient with warts on her right middle finger. TTO was applied topically once daily to the lesions for 12 days, with a successful outcome, including complete re-epithelization of the infected areas. The case highlights the potential use of TTO in the treatment of common warts due to human papilloma virus.


Proximal humeral nail for treatment of 3- and 4-part proximal humerus fractures in the elderly population: effective and safe in experienced hands.
Optimal treatment of 3- and 4-part proximal humerus fractures (PHFs) remains controversial. Although commonly recommended for less comminuted PHFs, the outcomes of treatment with proximal humerus nailing (PHN) are more equivocal. The purpose of this study was to report on radiographic and clinical outcomes of patients undergoing PHN fixation of 3- and 4-part PHFs at minimum one-year follow-up. Our hypothesis was that the findings would demonstrate satisfactory radiographic and clinical outcomes, with low rates of complications and revision surgeries. Between 2008 and 2016, 121 patients with comminuted, low-energy, osteoporotic, PHFs underwent fixation via Targon PHN (Aesculap, Tuttlingen, Germany). Of these, 60 patients met inclusion and exclusion criteria and were included in this analysis (mean age 72; range 65-85). All completed a minimum 1-year follow-up (range 12.5-82 months). Patients with 3-part PHFs were compared to patients with 4-part PHFs. Clinical, radiographic, and functional outcomes were assessed at postoperative visits. Patient reported outcomes included pain, the American Shoulder and Elbow Surgeons (ASES) score and the Simple Shoulder Test (SST). Radiographic union and revision and complication rates were assessed. Overall, 37 (62%) fractures were classified as Neer 3 and 23 (38%) were classified as Neer 4. Both groups achieved similar postoperative range of motion. Patients with 3-part fractures reported significantly lower postoperative pain (0.76 ± 1.8 vs. 1.65 ± 2.2, p = 0.0047). Patients with 3-part fractures reported significantly better ASES scores (82.4 ± 19.2 vs. 70.8 ± 21.9, p = 0.02) and non-statistically significant higher SST scores (8.4 ± 3.2 vs. 7.43 ± 3.8, p = 0.14). Adequate fracture union was achieved in 53 fractures (88.3%). Three patients (5%) had varus malunion or greater tuberosity displacement, one (1.7%) had mechanical failure, and three (5%) had radiographic evidence of avascular necrosis. Between groups, there was no difference in failure rates. Proximal humeral nails can successfully be used by experienced surgeons in fixation of comminuted and displaced proximal humeral fractures in selected patients with osteoporosis. While patients with both 3- and 4-part fractures demonstrate fracture union with satisfactory outcomes, patients with 3-part fractures demonstrate significantly higher postoperative functional scores.


Social anxiety as a risk factor for unprotected intercourse among gay and bisexual male youth.
The current study proposed that social anxiety, which may be elevated among gay and bisexual youth, may increase their risk for unprotected sexual intercourse. Social anxiety predicted increased probability of having engaged in unprotected insertive anal intercourse in the past six months. Further examination suggested that social anxiety continued to be associated with unprotected insertive anal intercourse above and beyond the effects of communication about condom use and social support variables. Findings suggest the need to consider the impact of social fears when designing HIV prevention interventions.


Assessing environmental thresholds in relation to plant structure and nutritional value for improved maize calendar ensuring food security.
The environment has been continuously changed, and it's a bitter truth that we can't minimize anthropogenic activities to mitigate harmful impacts on the environment. The changing environment is a great threat to food security by affecting crop yields. However, there is no comprehensive study to assess the environmental impact on the nutritional quality of the crops. In this study, we have investigated the nutritional profile and yield of maize crops around the globe and synchronized the findings with physiological reasoning. The study enlightens the time-scale activities of maize plant enzymes and describes their response to changing environments. The study also explained time-scale-based changes in the physiological conditions of maize crops against environmental dynamics around the globe. It also detected the impact of climate change on the deterioration of the nutritional quality of maize. The current study reports the activities of three different enzyme classes. It was noted that the photosynthesis-related enzyme activities were boosted after a sudden increase in carbon dioxide concentration. However, the drought years (2005-2010) decreased photosynthesis and increased oxidative enzyme activities. Overall, the glycemic index of the maize crop has been increased during the last four decades. However, the crop production threshold levels have been raised more quickly. The nutritional index values are alarming and have frequently been recorded under the threshold levels in recent years. The study paves a path for maize toward nutritional contents richness, ensuring food security and nutritional security in the future.


Atomically resolved electronic properties in single layer graphene on α-Al2O3 (0001) by chemical vapor deposition.
Metal-free chemical vapor deposition (CVD) of single-layer graphene (SLG) on c-plane sapphire has recently been demonstrated for wafer diameters of up to 300 mm, and the high quality of the SLG layers is generally characterized by integral methods. By applying a comprehensive analysis approach, distinct interactions at the graphene-sapphire interface and local variations caused by the substrate topography are revealed. Regions near the sapphire step edges show tiny wrinkles with a height of about 0.2 nm, framed by delaminated graphene as identified by the typical Dirac cone of free graphene. In contrast, adsorption of CVD SLG on the hydroxyl-terminated α-Al2O3 (0001) terraces results in a superstructure with a periodicity of (2.66 ± 0.03) nm. Weak hydrogen bonds formed between the hydroxylated sapphire surface and the π-electron system of SLG result in a clean interface. The charge injection induces a band gap in the adsorbed graphene layer of about (73 ± 3) meV at the Dirac point. The good agreement with the predictions of a theoretical analysis underlines the potential of this hybrid system for emerging electronic applications.


Ultra low-level measurements of actinides by sector field ICP-MS.
In the present work, a double-focusing sector field inductively coupled plasma-mass spectrometer was optimised for ultra trace and isotopic analyses of actinide long-lived isotopes in low concentration solutions of the fgml(-1) to the ngml(-1) range. Sensitivities of about 3GHz/(microgml(-1)), with as low a background as 0.1cps, were obtained for U using a conventional concentric pneumatic nebuliser. Detection limits are below the fg range for 239Pu and 240Pu. With natural U, a precision lower than 0.5% RSD is currently obtained for 235U/238U isotopic ratio at the 200pgml(-1) level.


Participation-focused interventions for stroke rehabilitation: a scoping review protocol.
The objectives of this scoping review are to i) identify adaptive stroke rehabilitation interventions using metacognitive or self-management approaches targeting participation as an outcome; ii) determine the explicit and implicit theories underlying these interventions; and iii) ascertain the elements in each intervention. This review will develop a catalogue of these interventions, improving the understanding of how these interventions work, thereby facilitating efficient development and testing of participation-focused interventions. Stroke rehabilitation interventions can be categorized as those aiming to correct impairment and those seeking participation improvement despite impairment. Impairment-focused interventions include a relatively small number of well-defined elements, generally based on motor learning or other types of learning theory. Participation-focused interventions span a large group of diverse interventions. The underlying theory is typically varied and often implicit, but many of these interventions are based on metacognitive or self-management approaches. An examination of the underlying theory and elements of participation-focused interventions would allow researchers to more effectively advance the science of these approaches. The review will include published papers describing rehabilitation interventions using metacognitive or self-management approaches to improve participation among adults who have experienced a stroke. The search will include JBI Evidence-Based Practice Database, MEDLINE, Embase, CINAHL, PsycINFO, OTSeeker, and PEDro databases. Studies will be selected according to a three-step process, including i) managing search results and removing duplicates, ii) title and abstract screening, and iii) full text screening. The extracted data will be presented in table form and narrative summary, aligning with the objectives and scope of this review.


[Comparative morphological studies on porphyria cutanea tarda and erythropoietic protoporphyris].
Porphyria cutanea tarda and erythropoietic protoporphyria have common morphological features. Six patients with porphyria cutanea tarda and three patients with erythropoietic protoporphyria were studied with the electron microscope. Ultrastructural finding of connective tissue, basal lamina, and blood vessels are discussed.


Predicting Stock Price Falls Using News Data: Evidence from the Brazilian Market.
Market participants use a wide set of information before they decide to invest in risk assets, such as stocks. Investors often follow the news to collect the information that will help them decide which strategy to follow. In this study, we analyze how public news and historical prices can be used together to anticipate and prevent financial losses on the Brazilian stock market. We include an extensive set of 64 securities in our analysis, which represent various sectors of the Brazilian economy. Our analysis compares the traditional Buy & Hold and the moving average strategies to several experiments designed with 11 machine learning algorithms. We explore daily, weekly and monthly time horizons for both publication and return windows. With this approach we were able to assess the most relevant set of news for investor's decision, and to determine for how long the information remains relevant to the market. We found a strong relationship between news publications and stock price changes in Brazil, suggesting even short-term arbitrage opportunities. The study shows that it is possible to predict stock price falls using a set of news in Portuguese, and that text mining-based approaches can overcome traditional strategies when forecasting losses.


STAT3 signaling is induced by intercellular adhesion in squamous cell carcinoma cells.
The signal transducer and activator of transcription-3 (STAT3) frequently activated during tumor progression has been linked to enhanced cell growth. In squamous cell carcinoma of the head and neck (HNSCC), STAT3 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways. In the present study, we have examined the potential mechanism by which cell-cell contact initiates STAT3 activation. Using a panel of HNSCC cell lines, Ca(+2)-dependent cell-cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of STAT3-Y705 and STAT1-Y701. This intercellular adhesion-induced STAT3 activation was mediated by JAK and Src signaling and partially by EGFR signaling. In addition, immunolocalization studies revealed initial formation of phosphorylated STAT3-Y705 at nascent E-cadherin cell junctions with eventual translocation to the nucleus in cell aggregates. Adhesion-mediated STAT activation in monolayer and cell aggregate cultures required functional E-cadherin. These results indicate that, in HNSCC cells, cadherin-mediated intercellular adhesion induces STAT signaling that may modulate cell survival and resistance to apoptosis during tumor progression.


Inputs from three brainstem sources to identified neurons of the mouse inferior colliculus slice.
A total of 40 neurons from of the central nucleus of the mouse inferior colliculus (IC) were recorded intracellularly from brain slices to determine input properties by electrical stimulation of the ipsilateral lateral lemniscus (LL), commissure of Probst (CP), and commissure of the IC (CoIC) together with cellular morphology (in 25 neurons) by biocytin injection and staining. Nine neurons had oriented (bipolar), 16 neurons non-oriented (multipolar) dendritic trees of various sizes. Axon collaterals of a given neuron often ran in several directions to provide multiple input to adjacent isofrequency laminae, the lateral nucleus of the IC, the brachium of the IC, the LL, the CP, and the IC commissure. Neurons were classified by spike response patterns to depolarizing current injection into onset- and sustained-spiking cells. The former had significantly shorter membrane-time constants, significantly less frequently and smaller hyperpolarizations after spike occurrence, and more Ca2+-humps. These properties and their preferred position in the dorsolateral ICC suggest a participation in binaural temporal processing. Almost all oriented cells showed only excitatory post-synaptic potentials (EPSPs) after LL stimulation, while in non-oriented cells inhibitory post-synaptic potentials (IPSPs) after the EPSPs were significantly more frequent. Neurons with largest dendritic trees and many dorsalward projecting axon collaterals were found in the ventral IC. There, neurons had average 4 ms (two synapses) shorter response latencies to LL stimulation than dorsally located neurons. Thus, neurons in the central and dorsal IC may receive mono- and disynaptic input from ventrally located neurons.


Blended Learning Methods for Surgical Education.
The emergence and maturation of the concept of blended learning in public and military education may prove equally valuable in CME surgical education and training. Creating a learner-centric environment in which multiple modes of education are encouraged, available, integrated, and accredited can increase the level of competence achieved in CME courses. This paper defines a framework for blended surgical training using principles developed for the military and it is applied in courses at a major post-graduate surgical education center.


Severe duodenal stenosis due to rupture of pancreaticoduodenal artery aneurysm.
When a patient complains of nausea, gastrointestinal endoscopy tends to be the first-choice diagnostic method. However, physicians must rule out the possibility of aneurysm rupture by careful physical assessment before performing gastrointestinal endoscopy, which can be extremely dangerous.


Lessons from the history of light microscopy.
Historically, the late arrival of optical microscopy is something of a puzzle, although it may be a testament to the fact that the development of new technology is driven by the desire for scientific knowledge, and not the other way around. The explorations that began in the 17th century are by no means complete, but who is carrying them forward now?


3D-Printed Multidrug-Eluting Stent from Graphene-Nanoplatelet-Doped Biodegradable Polymer Composite.
Patients with percutaneous coronary intervention generally receive either bare metal stents or drug-eluting stents to restore the normal blood flow. However, due to the lack of stent production with an individual patient in mind, the same level of effectiveness may not be possible in treating two different clinical scenarios. This study introduces for the first time the feasibility of a patient-specific stenting process constructed from direct 3D segmentation of medical images using direct 3D printing of biodegradable polymer-graphene composite with dual drug incorporation. A biodegradable polymer-carbon composite is prepared doped with graphene nanoplatelets to achieve controlled release of combinatorics as anticoagulation and antirestenosis agents. This study develops a technology prototyped for personalized stenting. An in silico analysis is performed to optimize the stent design for printing and its prediction of sustainability under force exerted by coronary artery or blood flow. A holistic approach covering in silico to in situ-in vivo establishes the structural integrity of the polymer composite, its mechanical properties, drug loading and release control, prototyping, functional activity, safety, and feasibility of placement in coronary artery of swine.


[Add-on-LUCAS2™ resuscitation at NEF Innsbruck].
The study goals were to analyze the course and compare it with patients who were only resuscitated manually as well as to record the influencing factors in patients in whom the mechanical chest compression aid LUCAS2™ was used as an add-on treatment at the NEF Innsbruck. Retrospective history data analysis of patients in the study period from 01.01.2014 to 31.12.2019 of the NEF Innsbruck from the German Resuscitation Register (GRR), in which LUCAS2™ was used as an add-on treatment according to an emergency doctor's order. A total of 123 add-on LUCAS2™ applications (18.8%) were performed in 653 resuscitations. Of all patients 16.2% survived the first 30 days. By using add-on-LUCAS2TM application 7.3% (9/123) of all add-on LUCAS2TM resuscitations and 1.4% (n = 9) of all CPR survived. Cardiac arrest was observed in 8/9 add-on LUCAS2™ 30-day survivors and bystander CPR was performed and 8/9 showed ventricular fibrillation as the primary rhythm. Compared to manual CPR alone, add-on LUCAS2™ resuscitation was used highly significantly (p < 0.001) more frequently in younger, male patients, in public, in shockable initial rhythms and during transport, and significantly more frequently in observed cardiac arrest (p < 0.05). The 30-day mortality with additive lysis treatment was 100%. By using add-on LUCAS2™ CPR a percentage increase in survival rate can be achieved and thus appears advantageous (1.4% in our study). This means that high-quality CPR can be carried out on patients with favorable prognostic factors, even with technically complex rescue operations (turntable ladder, staircase, transport in an ambulance) and thus transport can be made possible; however, there is a higher admission rate under CPR and thus the treatment target decision is shifted to the shock room.


An interesting case of bilateral bifid insertion of superior rectus muscle as an intra-operative finding in a patient with oculocutaneous albinism.
We report a case of bilateral bifid insertion of superior rectus muscles, in a patient with oculocutaneous albinism as an incidental intraoperative finding during eye muscle surgery. The muscle was successfully operated on and the patient did well postoperatively. To our knowledge, this is the first report of this anomaly.


Natural history of obstructive airways disease and hypoxia: implications for therapy.
Chronic irreversible obstructive airways disease (COAD) is the end result of a number of disorders: airway damage from tobacco smoke, atmospheric pollution and occupational dust and fume, bronchiectasis, cystic fibrosis, bronchial asthma and a number of congenital disorders of defective airway defence. The clinical features include sputum, wheeze, breathlessness and infective and noninfective airway inflammation. The pathological consequences are airways obstruction, emphysema and respiratory failure. Except in bronchiectasis, the volume of daily sputum and bronchial infection is less than 20-30 years ago. At autopsy, bronchial gland hypertrophy is now an inconstant feature. Bronchial infection probably contributes little to airways obstruction, but the load of activated neutrophils in bronchiectasis is an important feature. Wheeze comes late to many patients with COAD. It is associated with less reversibility to bronchodilator drugs and more fixed airways obstruction compared to the conventional asthmatic and is probably of different aetiology. Breathlessness is of variable severity when the forced expiratory volume (FEV1) falls below 1.0 liters resulting in disability ranging from manageable to severe. The FEV1 declines an average by 70-80 ml/year (normal approx. 25 ml/year) until the value falls below 1.0 liters, then the rate of decline slows to a plateau which can persist for several years. During this period, hyperinflation, breathlessness and respiratory failure continue to worsen. Significant respiratory failure may be a terminal event or be present for many years. Arterial oxygen tension (PaO2) slowly declines in most patients--"pink puffers" generally have a minimal rate of fall until weeks or months before death, "blue bloaters," by contrast, several times as great.(ABSTRACT TRUNCATED AT 250 WORDS)


Hard to wake up? The cerebral correlates of sleep inertia assessed using combined behavioral, EEG and fMRI measures.
The first minutes following awakening from sleep are typically marked by reduced vigilance, increased sleepiness and impaired performance, a state referred to as sleep inertia. Although the behavioral aspects of sleep inertia are well documented, its cerebral correlates remain poorly understood. The present study aimed at filling this gap by measuring in 34 participants the changes in behavioral performance (descending subtraction task, DST), EEG spectral power, and resting-state fMRI functional connectivity across three time points: before an early-afternoon 45-min nap, 5 min after awakening from the nap and 25 min after awakening. Our results showed impaired performance at the DST at awakening and an intrusion of sleep-specific features (spectral power and functional connectivity) into wakefulness brain activity, the intensity of which was dependent on the prior sleep duration and depth for the functional connectivity (14 participants awakened from N2 sleep, 20 from N3 sleep). Awakening in N3 (deep) sleep induced the most robust changes and was characterized by a global loss of brain functional segregation between task-positive (dorsal attention, salience, sensorimotor) and task-negative (default mode) networks. Significant correlations were observed notably between the EEG delta power and the functional connectivity between the default and dorsal attention networks, as well as between the percentage of mistake at the DST and the default network functional connectivity. These results highlight (1) significant correlations between EEG and fMRI functional connectivity measures, (2) significant correlations between the behavioral aspect of sleep inertia and measures of the cerebral functioning at awakening (both EEG and fMRI), and (3) the important difference in the cerebral underpinnings of sleep inertia at awakening from N2 and N3 sleep.


Increases of CRF in the amygdala are responsible for reinstatement of methamphetamine-seeking behavior induced by footshock.
Recent evidence suggests the involvement of corticotropin-releasing factor (CRF) in drug abuse. Here, we evaluated whether CRF modulates the reinstatement of methamphetamine (METH)-seeking behavior induced by stress using a drug-self administration paradigm in rats. Rats were trained to lever-press for intravenous METH (0.02 mg/infusion) accompanied by light and tone (drug-associated cues) and then underwent extinction training (saline substituted for METH without cues). Under the extinction condition, the inhibitory effects of a CRF receptor antagonist on the stress-induced reinstatement of METH-seeking behavior were assessed. Anxiety-like behaviors during METH withdrawal in METH self-administered rats were also evaluated. The non-selective CRF receptor antagonist α-helical CRF(9-41) attenuated METH-seeking behavior induced by footshock stress. CRF levels both in the amygdala and in plasma were significantly increased on day 10 of withdrawal after METH self-administration. However, plasma corticosterone concentrations were unchanged during the withdrawal. In addition, METH-seeking behavior was not affected by an inhibitor of corticosterone synthesis, metyrapone. In the elevated plus maze test, METH self-administered rats showed a decrease in the duration of time spent in the open arms on day 10 of withdrawal. The increased CRF levels in the amygdala may, at least in part, contribute to the footshock-induced reinstatement of METH-seeking behavior and the increase in anxiety-like behavior. The present findings indicate that CRF receptor antagonists would be useful as a therapeutic agent for METH-dependence.


Screening for Syphilis Infection in Nonpregnant Adults and Adolescents: US Preventive Services Task Force Recommendation Statement.
In 2014, 19,999 cases of syphilis were reported in the United States. Left untreated, syphilis can progress to late-stage disease in about 15% of persons who are infected. Late-stage syphilis can lead to development of inflammatory lesions throughout the body, which can lead to cardiovascular or organ dysfunction. Syphilis infection also increases the risk for acquiring or transmitting HIV infection. To update the 2004 US Preventive Services Task Force (USPSTF) recommendation on screening for syphilis infection in nonpregnant adults. Screening for syphilis in pregnant women was updated in a separate recommendation statement in 2009 (A recommendation). The USPSTF reviewed the evidence on screening for syphilis infection in asymptomatic, nonpregnant adults and adolescents, including patients coinfected with other sexually transmitted infections (such as HIV). The USPSTF found convincing evidence that screening for syphilis infection in asymptomatic, nonpregnant persons at increased risk for infection provides substantial benefit. Accurate screening tests are available to identify syphilis infection in populations at increased risk. Effective treatment with antibiotics can prevent progression to late-stage disease, with small associated harms, providing an overall substantial health benefit. The USPSTF recommends screening for syphilis infection in persons who are at increased risk for infection. (A recommendation).


[Bacillus subtilis protease: isolation, immobilization and properties].
During the cultivation of B. subtilis strain 3H under optimum conditions (adequate nutrient medium, seed culture, temperature, the level of dissolved oxygen) protease was produced. Protease could be obtained in the purified form by means of gel chromatography and ultrafiltration. The isolated protease was immobilized on polyglucin and stabilized by intramolecular cross-linking with the use of glutaraldehyde. The comparison of native protease modified with polyglucin and glutaraldehyde, as well as with polyglucin, revealed advantages in the stability of the latter.


Measurement of vertical and horizontal vibrations of a probe for acoustic evaluation of food texture.
Two-dimensional (vertical and horizontal) vibrations of a wedge-type probe upon food rupture were evaluated separately using two accelerometers placed perpendicular to a guide rod of a swing-arm device for texture evaluation of the flesh of three varieties of apples and three types of potato chips. Voltage signals from the accelerometers were filtered using a half-octave band-pass filter. The energy texture index (ETI), based on kinetic energy of the vertical or horizontal probe vibrations, was calculated over low to high frequency bands (no. 1-21). The spectra for the flesh of the three varieties of apples included two common peaks for vertical ETI at band no. 11 (1,120-1,600 Hz) and 19 (17,920-25,600 Hz) and horizontal ETI at band no. 1 (0-10 Hz) and 15 (4,480-6,400 Hz). The spectra for the three types of potato chips had a common ETI peak at band no. 11 (1,120-1,600 Hz) for horizontal ETI and at no. 15 (4,480-6,400 Hz) for vertical ETI. The three apple varieties gave rise to different intensities of vertical and horizontal ETIs while the two peaks were maintained. The thick potato chip type had higher vertical and horizontal ETIs than the thin and soft varieties in most bands; however, the thin type had the highest vertical ETIs only in lower bands (0-200 Hz). The soft type had the lowest vertical and horizontal ETI. The above results suggest that different food textures can be distinguished by two-dimensional vibration analyses of probe insertion into a food sample based on frequency bands.


Efficacy of functional foods mixture in improving hypercholesterolemia, inflammatory and endothelial dysfunction biomarkers-induced by high cholesterol diet.
Hypercholesterolemia associated with cardiovascular diseases is a global health issue that could be alleviated by functional foods. This study aimed to explore the effects of a high-cholesterol diet on lipid profile, cardiac, inflammatory, and endothelial dysfunction biomarkers, and the possible improvement by functional foods mixture. Male albino rats weighing 100-150 g were randomly divided into four equal groups: 1st control, giving a normal diet; the 2nd received high-cholesterol diet for 8 weeks, the 3rd received the high-cholesterol diet + functional foods mixture, and the 4th administered high-cholesterol diet +atorvastatin (20 mg) orally. The results showed a significant increase in lipid profile and cardiac biomarkers levels (lactate dehydrogenase, creatine kinase and homocystein), also inflammatory markers, as, tumor necrotic factor alpha and chronic reactive proteins were elevated, moreover, vascular adhesion molecule-1 and nitric oxide synthase were disturbed in high-cholesterol diet compared with normal group. While administration of atorvastatin and functional foods mixture ameliorated these alterations. Administration of functional foods mixture and atorvastatin were effective in treating hypercholesterolemia, reduce the risk of inflammation and cardiovascular biomarkers with a high safety margin. These efficiencies may be due to its active ingredient that improve the imbalance in the measured biomarkers.


[Doppler findings in intracranial vascular disorders. Differential diagnosis of extracranial and intracranial vascular occlusions (author's transl)].
Directional Doppler sonography of the carotid arteries in the neck (selective for the common carotid artery, external and internal carotid arteries) and of the supratrochlear artery permits reliable diagnoses and localizations of extracranial stenoses and occlusions of these arteries. In addition, severe intracranial vascular disorders may also be detected by these methods. Characteristic combinations of Doppler results are described in occlusions of the trunk of the middle cerebral artery, cerebral circulatory breakdown, large arteriovenous angiomas of one hemisphere and carotidcavernous fistulas, and are compared with angiographic findings. The knowledge of these Doppler findings is indispensable for the differential critical evaluation of such disorders found at the level of the neck arteries and at the fronto-orbital terminal branches of the ophthalmic artery.


Immunotherapy with dendritic cells loaded with glioblastoma stem cells: from preclinical to clinical studies.
Different approaches have been explored to raise effective antitumor responses against glioblastoma (GBM), the deadliest of primary brain tumors. In many clinical studies, cancer vaccines have been based on dendritic cells (DCs) loaded with peptides, representing one or more specific tumor antigens or whole lysates as a source of multiple antigens. Randomized clinical trials using DCs are ongoing, and results of efficacy are not yet available. Such strategies are feasible and safe; however, immune-suppressive microenvironment, absence of appropriate specific epitopes to target, and cancer immunoediting can limit their efficacy. The aim of this review is to describe how the definition of novel and more specific targets may increase considerably the possibility of successful DC immunotherapy. By proposing to target glioblastoma stem-like cells (GSCs), the immune response will be pointed to eradicating factors and pathways highly relevant to GBM biology. Preclinical observations on efficacy, and preliminary results of immunotherapy trials, encourage exploring the clinical efficacy of DC immunotherapy in GBM patients using high-purity, GSC-loaded DC vaccines.


[Euthanasia].
The problem of euthanasia emerges again and again in today's Europe. The Dutch type of regulation of euthanasia could be introduced into the Hungarian legal system. Today, in Hungary, the ethical guidelines of the chamber of medicine, the criminal law and the administrative health law also forbid active euthanasia. In Hungary, the criminal code reform of 2012 missed to liberalise the regulation of euthanasia. Such liberalisation awaits bottom-up support from the part of the society. In Europe, active euthanasia is legal only in the Netherlands, Belgium, Luxemburg and Switzerland. In Hungary, a passive form of euthanasia is legal, i.e. a dying patient may, under strict procedural circumstances, refuse medical treatment. The patient is not allowed to refuse medical treatment, if she is pregnant and foreseeably capable to give birth to her child.


HDAC5-mediated deacetylation and nuclear localisation of SOX9 is critical for tamoxifen resistance in breast cancer.
Tamoxifen resistance remains a significant clinical challenge for the therapy of ER-positive breast cancer. It has been reported that the upregulation of transcription factor SOX9 in ER+ recurrent cancer is sufficient for tamoxifen resistance. However, the mechanisms underlying the regulation of SOX9 remain largely unknown. The acetylation level of SOX9 was detected by immunoprecipitation and western blotting. The expressions of HDACs and SIRTs were evaluated by qRT-PCR. Cell growth was measured by performing MTT assay. ALDH-positive breast cancer stem cells were evaluated by flow cytometry. Interaction between HDAC5 and SOX9 was determined by immunoprecipitation assay. Deacetylation is required for SOX9 nuclear translocation in tamoxifen-resistant breast cancer cells. Furthermore, HDAC5 is the key deacetylase responsible for SOX9 deacetylation and subsequent nuclear translocation. In addition, the transcription factor C-MYC directly promotes the expression of HDAC5 in tamoxifen resistant breast cancer cells. For clinical relevance, high SOX9 and HDAC5 expression are associated with lower survival rates in breast cancer patients treated with tamoxifen. This study reveals that HDAC5 regulated by C-MYC is essential for SOX9 deacetylation and nuclear localisation, which is critical for tamoxifen resistance. These results indicate a potential therapy strategy for ER+ breast cancer by targeting C-MYC/HDAC5/SOX9 axis.


Preparation and Electrochemical Properties of Porous Carbon Nanofiber Electrodes Derived from New Precursor Polymer: 6FDA-TFMB.
Porous carbon nanofibers (CNFs) with high energy storage performance were fabricated with a single precursor polymer, 6FDA-TFMB, without the use of any pore-generating materials. 6FDA-TFMB was synthesized, electrospun, and thermally treated to produce binder-free CNF electrodes for electrochemical double-layer capacitors (EDLCs). Highly porous CNFs with a surface area of 2213 m2 g-1 were prepared by steam-activation. CNFs derived from 6FDA-TFMB showed rectangular cyclic voltammograms with a specific capacitance of 292.3 F g-1 at 10 mV s-1. It was also seen that CNFs exhibit a maximum energy density of 13.1 Wh kg-1 at 0.5 A g-1 and power density of 1.7 kW kg-1 at 5 A g-1, which is significantly higher than those from the common precursor polymer, polyacrylonitrile (PAN).


Neurocognitive impairment in HIV-1-infected adults in Sub-Saharan Africa: a systematic review and meta-analysis.
To estimate the burden of HIV neurocognitive impairment (NCI) among adult patients on and off antiretroviral therapy (ART) in Sub-Saharan Africa. Estimates were derived from a random effects meta-analysis of prospective studies reporting HIV status, utilization of ART, and the presence of NCI determined using the International HIV Dementia Scale. Sixteen studies with quality data from seven countries in Sub-Saharan Africa up to June 2012 were included. Among HIV patients, the frequency of NCI pre-ART was 42.37% (95% confidence interval (CI) 32.18-52.56%), and among those on ART for ≥6 months was 30.39% (95% CI 13.17-47.61%). Respective NCI estimates in studies from Uganda were 46.49% (95% CI 30.62-62.37%) and 28.50% (95% CI -1.31-58.30%). NCI was more common among patients with a concomitant psychiatric ailment. HIV-positive patients compared to HIV-negative controls were predisposed to NCI (odds ratio (OR) 6.49, 95% CI 1.68-25.08); the estimated unadjusted attributable risk of HIV infection leading to NCI was 85%. Meta-regression showed no associations between age, gender, CD4 cell counts, or years of education with NCI. Patients on ART were less likely to have NCI compared to HIV-infected pre-ART patients, with OR 0.36 (95% CI 0.19-0.69). In longitudinal studies with the same patients followed before and at ≥6 months after ART, the OR of NCI after ART compared to pre-ART was 0.23 (95% CI 0.14-0.37). The combined burden of NCI among pre-ART and on-ART patients in Sub-Saharan Africa was estimated at 8,121,910 (95% CI 5,772,140-10,471,680). No publication bias was observed, although residual confounding from differing environmental factors, stages of HIV infection, and viral clades might be a limitation. HIV strongly predisposes to NCI leading to a huge burden in Sub-Saharan Africa, and scale-up of ART can substantially reduce it.


[Epidemiological aspects in breast cancer].
Breast cancer represents one of the main public health problem, with a special epidemiological interest, both at the national and international level. A retrospective epidemiological study during the last 11 years (1990-2000) concerning new cases and incidence of the breast cancer at the national level, in Dolj county and in the 1st Surgical Clinic Craiova was made, by using of a comparative analyses which parameters were processed by modern statistic methods. Time evolution equation of the new cases all over the county showed us that more than 208.52 new cases than in the previous year appeared every year. If such an increased rhythm were held, about 6800 new cases would be every year up to 2100. As concerning breast cancer frequency, both at national and local level, a significant increase can be noticed during the last period. At national level the incidence increased from 3.3@100000 in female in 1950 to 29.2@100000 in 1990 up to 46.2@100000 in 2000. We noticed an increase of the incidence with 58.2% at the national level and 86% in Dolj county, in 2000 compared to 1990. By using a comparative analyses on age grouped we could establish a significant frequency of cancer in the patients of 40-49, 50-59 and 60-69 years old, with two frequency peaks for 45-49 and 60-64 subgroups, both at national and county level and also in 1st Surgical Clinic.