The self-regulating synapse: a functional role for the co-existence of neuroactive substances.
Although the co-localizations of neuroactive substances, such as transmitters and peptides, in identified neurons is now a common histochemical phenomenon, the physiological roles and functional significance of such co-existence are largely unknown. Using the vertebrate retina as a model for the central nervous system, we have examined the relationship between co-existence and co-function. We propose here that the co-localization of neuroactive substances in a synaptic terminal provides the structural configuration to ensure the co-release of two or more predetermined substances into the same synaptic cleft, resulting in the capability of the presynaptic neuron to stringently regulate its own activities and output.


Short- and long-term probiotic effects of Enterococcus hirae isolated from fermented vegetable wastes on the growth, immune responses, and disease resistance of hybrid catfish (Clarias gariepinus × Clarias macrocephalus).
This study evaluated the short- and long-term effects of dietary supplementation with Enterococcus hirae strain UPM02 on the growth performance, immunity, and disease resistance of hybrid catfish (Clarias gariepinus × Clarias macrocephalus) against Aeromonas hydrophila infection. In the long-term trial, fingerling fish were fed diets containing 0 (control), 2 × 105, or 2 × 107 CFU/g E. hirae UPM02 for 120 days. Administration of E. hirae UPM02 had significant effects on the specific growth rate (SGR), feed utilization efficiency, body indices (P < 0.05), and gut villus physiology of the catfish. E. hirae UPM02 application also significantly increased the complete blood cell counts, phagocytic activity, respiratory burst, lysozyme activity, and alternative complement pathway hemolytic (ACH50) activity in tested catfish throughout the experimental periods (P < 0.05). Dietary E. hirae UPM02 at both concentrations significantly increased the expression levels of the alpha-2-macroglobulin (α2M), CC chemokines, CXC chemokines, lysozyme c (LYZC), myeloperoxidase (MYE), NF-kappa-B1 p105 subunit (NF-K), and bactericidal permeability-increasing protein (BPIP) genes in the head kidney, liver, and spleen (P < 0.05) at days 80, 100 and 120 after application. However, heat shock protein 70 (HSP70) gene expression was slightly downregulated in these organs. Interestingly, fish fed the diets containing 2 × 105 and 2 × 107 CFU/g E. hirae UPM02 exhibited a significantly lower (P < 0.05) postchallenge mortality rates (32% and 30%, respectively) after 14 days of A. hydrophila challenge than the control fish (58%). In short-term (28 days) application to juvenile catfish, the two concentrations of E. hirae did not affect all growth parameters. Nevertheless, these concentrations markedly elevated all tested immune parameters, similarly to long-term application. Immune-related gene expression was significantly upregulated at day 28 in the head kidney, at day 14 in the liver, and at day 7 in the spleen in fish treated with the two concentrations of the probiotics (P < 0.05). Mortality at 14 days after challenge with A. hydrophila in the groups receiving the two concentrations of the probiotic was significantly lower than that in the control group, at 28, 24, and 48%, respectively (P < 0.05). These results collectively suggest that dietary supplementation with E. hirae UPM02 at 2 × 105 and 2 × 107 CFU/g effectively influenced immune responses, enhanced disease protection, and stimulated immunity-related gene expression in hybrid catfish under both short- and long-term application. However, growth enhancement was significantly evidenced with long-term application only.


Ulnar Collateral Ligament Tear in Elite Baseball Pitchers: Are High School Showcase Exposures Associated With Injury?
Ulnar collateral ligament reconstruction (UCLR) surgeries have increased significantly in amateur and professional baseball pitchers. Although showcase participation has been considered an injury risk factor, limited data are available to corroborate this association. Elite pitchers achieving fastball velocities ≥90, ≥92, and ≥95 mph at younger ages would be more likely to undergo UCLR earlier in their careers compared with pitchers not achieving these velocity thresholds at younger ages. Elite pitchers participating in high showcase volumes would be more likely to undergo UCLR compared with elite pitchers participating in fewer showcases. Cohort study; Level of evidence, 3. Descriptive, showcase performance, and injury data from pitchers selected in the first 5 rounds of the Major League Baseball draft (2011-2020) were gathered from publicly available databases. Continuous and categorical variables for pitchers undergoing UCLR and those not undergoing UCLR were compared, and multivariable analysis was performed using logistic regression. We used standard deviations (SDs) of ±1 SD of mean age at first UCLR to define early-career versus late-career UCLR subgroups after normal distribution was confirmed (Shapiro-Wilk test; P = .183). The "early" UCLR group was defined as ≤-1 SD (19.09 years), whereas the "late" UCLR group was defined as ≥+1 SD (24.79 years). Trends in time were evaluated using linear regression. Of the 845 pitchers selected, 659 pitchers (78.0%) had retrievable showcase performance data. Of the 845 pitchers, 229 (27.1%) underwent UCLR. Peak fastball velocity recorded at showcases was the strongest predictor of UCLR (adjusted odds ratio, 1.19; 95% CI, 1.02 to 1.39; P = .03). Peak fastball velocity in high school (HS) was significantly higher among pitchers who underwent UCLR compared with pitchers in the no-UCLR group (91.57 vs 90.71 mph, respectively; 95% CI, -1.43 to -0.29; P < .01). Age at which pitchers participated in their first HS showcase was significantly younger for the early versus the late UCLR group (15.53 vs 16.51 years, respectively; 95% CI, -1.53 to -0.41; P < .01). Elite pitchers with early UCLR participated in nearly twice as many showcases compared with the late UCLR group (5.38 vs 2.89, respectively; 95% CI, 0.43 to 4.54; P = .02). The mean number of HS showcases that elite pitchers attended more than doubled during the 2011-2020 study period (from 2.88 to 6.00 total showcases; P < .001). Mean age at which pitchers attended their first HS showcase steadily declined as well over the 10-year period (from 16.52 to 15.63 years; P < .001). Peak fastball velocity was the strongest predictor of UCLR in elite pitchers before initiating professional careers. Elite amateur pitchers attended more showcases at younger ages in a decade-long trend. Overall, the variables included in this multivariable analysis were weak predictors, explaining only 3.8% of the variance in UCLR rates.


The significance of coronary reserve in clinical heart disease.
The clinical syndrome "coronary insufficiency with normal coronary arteriogram" is found in approximately 10% to 20% of patients with exercise-induced coronary insufficiency. In most of these cases, disturbances of the coronary microcirculation are present. They can appear in vascular diseases (arterial hypertension, systemic immunopathies, immune complex vasculitis), in rheologic diseases (paraproteinemia, hyperlipoproteinemia, polyglobulia) and in disturbances of transport and diffusion of oxygen (carbon monoxide intoxication, methemoglobinemia). The clinical diagnosis is based on the usual diagnostic procedures (electrocardiogram, exercise electrocardiogram, responsiveness to nitroglycerin), as well as on newer functionally oriented diagnostic procedures (determinations of coronary blood flow and coronary vascular reserve, production of lactate, serologic findings, histology and immune histology of peripheral arteries, measurements of viscosities in both plasma and blood). Many clinically relevant disturbances in the coronary microcirculation can thus be detected and treated on a rational basis by management of the underlying main disease, that is, by treatment of the vascular, rheologic and metabolic disorders. Persistent angina pectoris in the presence of a normal coronary arteriogram does not represent an end to coronary diagnostic procedures, but introduces the clinical task of using all diagnostic possibilities to enable functional and therapeutic assessment of the coronary microcirculation.


Signaling through the neuropeptide GPCR PAC₁ induces neuritogenesis via a single linear cAMP- and ERK-dependent pathway using a novel cAMP sensor.
Both cAMP and ERK are necessary for neuroendocrine cell neuritogenesis, and pituitary adenylate cyclase-activating polypeptide (PACAP) activates each. It is important to know whether cAMP and ERK are arranged in a novel, linear pathway or in two parallel pathways using known signaling mechanisms. Native cellular responses [cAMP elevation, ERK phosphorylation, cAMP responsive element binding (CREB) phosphorylation, and neuritogenesis] and promoter-reporter gene activation after treatment with forskolin, cAMP analogs, and PACAP were measured in Neuroscreen-1 (NS-1) cells, a PC12 variant enabling simultaneous morphological, molecular biological, and biochemical analysis. Forskolin (25 μM) and cAMP analogs (8-bromo-cAMP, dibutyryl-cAMP, and 8-chlorophenylthio-cAMP) stimulated ERK phosphorylation and neuritogenesis in NS-1 cells. Both ERK phosphorylation and neuritogenesis were MEK dependent (blocked by 10 μM U0126) and PKA independent (insensitive to 30 μM H-89 or 100 nM myristoylated protein kinase A inhibitor). CREB phosphorylation induced by PACAP was blocked by H-89. The exchange protein activated by cAMP (Epac)-selective 8-(4-chlorophenylthio)-2'-O-Me-cAMP (100-500 μM) activated Rap1 without affecting the other cAMP-dependent processes. Thus, PACAP-38 potently stimulated two distinct and independent cAMP pathways leading to CREB or ERK activation in NS-1 cells. Drug concentrations for appropriate effect were derived from control data for all compounds. In summary, a novel PKA- and Epac-independent signaling pathway: PACAP → adenylate cyclase → cAMP → ERK → neuritogenesis has been identified.


Protuberant fibro-osseous lesion of the temporal bone: report of four cases and review of the literature.
'Bullough lesions', also referred to as protuberant fibro-osseous lesions (PFOL), are rare temporal bone lesions initially described in 1999. Since only 12 cases have been reported, several key issues, such as their origin and recommended management strategies, remain unresolved. This article reports the largest cohort included in the literature to date, comprising four patients with PFOL. PFOL appears to be characterized by female and right-side predominance. These lesions were consistently located regarding the mastoid, generally diagnosed in early adulthood, without functional symptoms, and were always fibro-osseous. Invasive/malignant features were not found on imaging or histology. The main differential diagnosis was malignant low-grade parosteal osteosarcoma. Clinical examination and computed tomography images provided strong elements supporting the diagnosis of PFOL. Biopsy allowed molecular biology investigations (MDM2 and CDK4 amplification), in order to rule out low-grade parosteal osteosarcoma.


Metabolism of 26,26,26,27,27,27-F6-1alpha,25-dihydroxyvitamin D3 by CYP24: species-based difference between humans and rats.
The compound 26,26,26,27,27,27-F(6)-1alpha,25(OH)(2)D(3) is a hexafluorinated analog of the active form of Vitamin D(3). The enhanced biological activity of F(6)-1alpha,25(OH)(2)D(3) is considered to be related to a decreased metabolic inactivation of the compound in target tissues such as the kidneys, small intestine, and bones. Our previous study demonstrated that CYP24 is responsible for the metabolism of F(6)-1alpha,25(OH)(2)D(3) in the target tissues. In this study, we compared the human and rat CYP24-dependent metabolism of F(6)-1alpha,25(OH)(2)D(3) by using the Escherichia coli expression system. In the recombinant E. coli cells expressing human CYP24, bovine adrenodoxin and NADPH-adrenodoxin reductase, F(6)-1alpha,25(OH)(2)D(3) was successively converted to F(6)-1alpha,23S,25(OH)(3)D(3), F(6)-23-oxo-1alpha,25(OH)(2)D(3), and the putative ether compound with the same molecular mass as F(6)-1alpha,25(OH)(2)D(3). The putative ether was not observed in the recombinant E. coli cells expressing rat CYP24. These results indicate species-based difference between human and rat CYP24 in the metabolism of F(6)-1alpha,25(OH)(2)D(3). In addition, the metabolite with a cleavage at the C(24)z.sbnd;C(25) bond of F(6)-1alpha,25(OH)(2)D(3) was detected as a minor metabolite in both human and rat CYP24. Although F(6)-1alpha,23S,25(OH)(3)D(3) and F(6)-23-oxo-1alpha,25(OH)(2)D(3) had a high affinity for Vitamin D receptor, the side-chain cleaved metabolite and the putative ether showed extremely low affinity for Vitamin D receptor. These findings indicate that human CYP24 has a dual pathway for metabolic inactivation of F(6)-1alpha,25(OH)(2)D(3) while rat CYP24 has only one pathway. Judging from the fact that metabolism of F(6)-1alpha,25(OH)(2)D(3) in rat CYP24-harboring E. coli cells is quite similar to that in the target tissues of rat, the metabolism seen in human CYP24-harboring E. coli cells appear to exhibit the same metabolism as in human target tissues. Thus, this recombinant system harboring human CYP24 appears quite useful for predicting the metabolism and efficacy of Vitamin D analogs in human target tissues before clinical trials.


A microfluidic hollow fiber membrane extractor for arsenic(V) detection.
Microfluidic membrane extraction using a conventional hollow fiber membrane is presented for continuous, on-line extraction of arsenic. Previously reported micro-scale devices used flat membranes. These modules were relatively complex, difficult to seal, and high pressure drops made them prone to leaks. The present design is simpler, has higher active surface area per unit volume, and allows faster flow rates leading to enhanced mass transfer. On-line membrane extraction of As(V) via chelation through a supported liquid membrane was followed by conventional colorimetric detection with a UV-vis spectrophotometer. Enrichment factors were close to 30, and the detection limit was 27 microg L(-1). The extraction was linear and reproducible. The relative standard deviation of six repeat extractions was less than 3%.


ENAA studies of pollution in anoxic Black Sea sediments.
The vertical distributions of five potential pollutants - Zn, As, Br, Sn, and Sb - were determined via epithermal neutron activation in the upper 50cm of unconsolidated sediments from the Black Sea, which were collected 600m below sea surface. This analysis demonstrated increasing concentrations towards the upper limits of sediments, which were greater than alert concentrations in the case of As and Br, and in accordance with Romanian Environment Regulations. The utilization of Chernobyl (137)Cs as a time marker allowed for dating of this region to the last 100 years.


Endovascular stroke treatment in orally anticoagulated patients: an analysis from the German Stroke Registry-Endovascular Treatment.
Endovascular treatment (ET) in orally anticoagulated (OAC) patients has not been evaluated in randomized clinical trials and data regarding this issue are sparse. We analyzed data from the German Stroke Registry-Endovascular Treatment (GSR-ET; NCT03356392, date of registration: 22 Nov 2017). The primary outcomes were successful reperfusion defined as modified thrombolysis in cerebral infarction (mTICI 2b-3), good outcome at 3 months (modified Rankin scale [mRS] 0-2 or back to baseline), and intracranial hemorrhage (ICH) on follow-up imaging at 24 h analyzed by unadjusted univariate and adjusted binary logistic regression analysis. Additionally, we analyzed mortality at 3 months with adjusted binary logistic regression analysis. Out of 6173 patients, there were 1306 (21.2%) OAC patients, 479 (7.8%) with vitamin K antagonists (VKA) and 827 (13.4%) with non-vitamin K antagonist oral anticoagulation (NOAC). The control group consisted of 4867 (78.8%) non-OAC patients. ET efficacy with the rates of mTICI 2b-3 was similar among the three groups (85.6%, 85.3% vs 84.3%, p = 0.93 and 1). On day 90, good outcome was less frequent in OAC patients (27.8%, 27.9% vs 39.5%, p < 0.005 and < 0.005). OAC status was not associated with ICH at 24 h (NOAC: odd's ratio [OR] 0.89, 95% confidence interval [CI] 0.67-1.20; VKA: OR 1.04, CI 0.75-1.46). Binary logistic regression analysis revealed no influence of OAC status on good outcome at 3 months (NOAC: OR 1.25, CI 0.99-1.59; VKA: OR 1.18, CI 0.89-1.56) and mortality at 3 months (NOAC: OR 1.03, CI 0.81-1.30; VKA: OR 1.04, CI 0.78-1.1.37). ET can be performed safely and successfully in LVO stroke patients treated with OAC. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov . Unique identifier: NCT03356392.


Bordetella Pertussis Toxin does not induce the release of pro-inflammatory cytokines in human whole blood.
Pertussis Toxin (PTx) is one of the most important virulence factors of Bordetella pertussis, the cause of whooping cough. Therefore, the inactivated toxin is an obligatory constituent of acellular pertussis vaccines. It is described in the literature that both native PTx and recombinant Pertussis Toxin (PTg) activate human monocytes whereas others report an inhibition of mammalian monocytes during pertussis infection. B. pertussis, as a Gram-negative bacterium, harbours naturally lipopolysaccharide (LPS, also known as endotoxin), one of the strongest stimulators of monocytes. The latter is triggered via the interaction of endotoxin with inter alia the surface receptor CD14. Consequently, it is necessary to consider a potential contamination of Pertussis Toxin preparations with LPS. First, we determined the LPS content in different preparations of PTx and PTg. All preparations examined were contaminated with LPS; therefore, possible PTx- and PTg-driven monocyte activation independently of LPS was investigated. To meet these aims, we examined monocyte response to PTx and PTg while blocking the LPS receptor CD14 with a specific monoclonal antibody (anti-CD14 mAb). In addition, all toxin preparations examined underwent an LPS depletion. Our results show that it is contaminating LPS, not Pertussis Toxin, which activates human monocytes. Blocking the CD14 receptor prevents Pertussis Toxin-mediated induction of pro-inflammatory cytokines in human monocytes. The depletion of LPS from Pertussis Toxin leads to the same effect. Additionally, the PTx toxicity after LPS depletion procedure was confirmed by animal tests. In contrast, the original Pertussis Toxin preparations not treated as mentioned above generate strong monocyte activation. The results in this publication allow the conclusion that purified Pertussis Toxin preparations do not induce the release of pro-inflammatory cytokines in human whole blood.


Yucca fern shaped CuO nanowires on Cu foam for remitting capacity fading of Li-ion battery anodes.
To remit capacity fading of lithium ion battery (LIB) anodes, freestanding yucca fern shaped CuO nanowires (NWs) on Cu foams are fabricated as anodes by combining facile and scalable anodization of copper foams followed by calcination. The porous and radial configuration of the hierarchical CuO NWs on the Cu foam substrate guarantees the remarkably improved electrochemical performance with durable cycle stability and excellent rate capability compared with CuO NWs on Cu foils. The reversible capacity remains 461.5 mAh/g after 100 repeated cycles at a current density of 100 mA/g, and a capacity of 150.6 mAh/g even at a high rate of 1000 mA/g. By examining the surface morphology of the cycled samples, possible performance fading route is proposed. The 3D CuO NWs network with a porous architecture simutaneously reduces the ion diffusion distances, promotes the electrolyte permeation and electronic conductivity. This novel strategy might open a new window to develop durable CuO based composite anodes for LIBs.


The impact of socio-demographic and clinical factors on the quality of life and disease acceptance in patients with Crohn's disease.
Introduction: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract characterized by periodsof remission and exacerbations of varying severity. The symptoms include: abdominal pain, diarrhea, flatulence, nausea, lossof appetite, weight loss, weakness, and changes in body temperature. Treatment is based on a combination of nutritional treatment and pharmacotherapy. Sometimes surgery can be necessary. The quality of life and disease acceptance are essential elements of the functioning of people with CD.

 Aim: The aim of the study is to analyze the factors affecting the quality of life and the level of disease acceptance in patients suffering from Crohn's disease

  Material and methods: The study was conducted in a group of 46 patients diagnosed with Crohn's disease. The study was carried out using the proprietary questionnaire, AIS, and WHOQOL-BREF.

 Results: The study group was dominated by young people. The average age of respondents was 34.28. The quality of life and the level of CD patients' disease acceptance were at an average level. The average score obtained by respondents in the Acceptanceof Illness Scale (AIS) was 28.37. The study revealed a significant impact of disease acceptance level on the respondents' assessment of quality of life.

  Conclusions: Patients' quality of life and level of disease acceptance are influenced by demographic factors and the clinical course of disease. Older patients after several surgeries for CD should receive more intensive psychological care. Health educationof patients with CD regarding disease, self-care, and skillful support are key in increasing the assessment of quality of life and the level of disease acceptance. Further research is required in a larger group of patients with CD subject to surgical treatment.


Can MRI diffusion-weighted imaging identify postoperative residual/recurrent soft-tissue sarcomas?
The aim of this study was to evaluate contrast-enhanced magnetic resonance imaging (CE-MRI) and quantitative diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping in the detection of recurrent/residual postoperative soft tissue sarcomas. This study included 36 patients; 27 patients had postoperative recurrent/residual soft tissue sarcomas and 9 patients had postoperative and treatment-related changes (inflammation/fibrosis). The DWI was obtained with 3 b values including 0, 400, and 800 s/mm2. Calculation of the ADC value of the lesion was done via placing the region of interest (ROI) to include the largest area of the lesion. ADC values were compared to histopathology. Our results showed that including CE-MRI improved the diagnostic accuracy and sensitivity in recurrence detection compared to conventional non-enhanced sequences. However, it showed low specificity (55.56%) with a high false-positive rate that may lead to an unnecessary biopsy of a mass such as region of postoperative scar tissue. The joint use of gadolinium-enhanced MRI and quantitative DWI with ADC mapping offer added value in the detection of recurrent/residual postoperative soft tissue sarcoma. This combined use increased both the diagnostic sensitivity and specificity with a cut-off average ADC value for detecting nonmyxoid recurrent/residual lesions ≤1.3 × 10-3 mm2/s (100% specificity and 90.48% sensitivity). Our results showed limited value of DWI with ADC mapping in assessing myxoid sarcomatous tumor recurrences.


Theory of optical spectra involving charge transfer states: dynamic localization predicts a temperature dependent optical band shift.
The influence of charge transfer states on the optical line shape of chromophore complexes is investigated in a minimal model that includes a coupling between an excited state and an optically dark charge transfer state. In the calculations of the absorption spectrum, an intensity borrowing by the charge transfer state, strong vibrational sidebands, and a temperature dependent shift of optical transitions are obtained. The theory is applied to the bacterial photosynthetic reaction center to explain a 30 nm blueshift of the low-energy absorption band with increasing temperature.


Knock-out of the critical nitric oxide synthase regulator DDAH1 in mice impacts amphetamine sensitivity and dopamine metabolism.
The enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) plays a pivotal role in the regulation of nitric oxide levels by degrading the main endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). Growing evidence highlight the potential implication of DDAH/ADMA axis in the etiopathogenesis of several neuropsychiatric and neurological disorders, yet the underlying molecular mechanisms remain elusive. In this study, we sought to investigate the role of DDAH1 in behavioral endophenotypes with neuropsychiatric relevance. To achieve this, a global DDAH1 knock-out (DDAH1-ko) mouse strain was employed. Behavioral testing and brain region-specific neurotransmitter profiling have been conducted to assess the effect of both genotype and sex. DDAH1-ko mice exhibited increased exploratory behavior toward novel objects, altered amphetamine response kinetics and decreased dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) level in the piriform cortex and striatum. Females of both genotypes showed the most robust amphetamine response. These results support the potential implication of the DDAH/ADMA pathway in central nervous system processes shaping the behavioral outcome. Yet, further experiments are required to complement the picture and define the specific brain-regions and mechanisms involved.


Distribution of the neuronal specific protein, 14-3-2, in central nervous system lesions of tuberous sclerosis.
The distribution of a neuronal specific enolase (14-3-2) in the central nervous system (CNS) lesions of tuberous sclerosis (TS) was examined using antiserum to 14-3-2 and the peroxidase antiperoxidase (PAP) method of Sternberger. In cortical tubers all the giant cells had intense cytoplasmic staining. Only occasional cells in the subependymal nodules were stained. All cells in the subependymal giant cell tumors were intensely stained. This indicates that the cortical giant cells and the giant cell subependymal tumors are of neuronal rather than astrocytic origin.


Inactivation of Id-1 in prostate cancer cells: A potential therapeutic target in inducing chemosensitization to taxol through activation of JNK pathway.
Resistance to anticancer drugs is the major problem in the treatment of many advanced cancers, including androgen-independent prostate cancer. Recently, increased expression of Id-1, a basic helix-loop-helix protein, is reported in several types of advanced cancer. It is suggested that high expression of Id-1 may provide an advantage for cancer cell survival and inactivation of Id-1 may be able to increase cancer cells' susceptibility to apoptosis. To test this hypothesis, in this study, by using RNA interfering technology, we inactivated the Id-1 gene in 2 androgen-independent prostate cancer cell lines, DU145 and PC3, and investigated whether downregulation of Id-1 could lead to increased sensitivity to a commonly used anticancer drug, taxol. By using colony forming assay and MTT assay, we found that inactivation of Id-1 resulted in both decreased colony forming ability and cell viability in prostate cancer cells, after taxol treatment. In addition, the si-Id-1-induced sensitization to taxol was associated with activation of apoptosis pathway, which is demonstrated by increased apoptotic index, DNA laddering, sub-G1 phase of the cell cycle, as well as cleaved-PARP and Caspase 3. Furthermore, c-Jun N-terminal kinase (JNK), one of the common pathways responsible for taxol-induced apoptosis, was also activated in the si-Id-1 transfected cells. Inhibition of JNK activity by a specific inhibitor, SP600125, blocked the si-Id-1-induced sensitivity to taxol. These results indicate that increased Id-1 expression in prostate cancer cells may play a protective role against apoptosis, and downregulation of Id-1 may be a potential target to increase sensitivity of taxol-induced apoptosis in prostate cancer cells.


Influence of ageing on the sympathetic nervous system and adrenal medulla at rest and during stress.
The influence of ageing on the sympathetic nervous system and adrenal medulla was studied neurochemically in humans, using isotopic dilution measurement of regional and whole body catecholamine release to plasma in humans. With ageing, sympathetic activation was evident in the heart, and the gut and liver at rest. The mechanism appeared to be by activation of sympathoexcitatory noradrenergic suprabulbar projections from the brainstem. Sympathetic nervous responses with stressors were augmented. Conversely, adrenal medullary release of epinephrine was subnormal in the elderly, at rest and during stress.


A cooperative nano-CRISPR scaffold potentiates immunotherapy via activation of tumour-intrinsic pyroptosis.
Efficient cancer immunotherapy depends on selective targeting of high bioactivity therapeutic agents to the tumours. However, delivering exogenous medication might prove difficult in clinical practice. Here we report a cooperative Nano-CRISPR scaffold (Nano-CD) that utilizes a specific sgRNA, selected from a functional screen for triggering endogenous GDSME expression, while releasing cisplatin to initiate immunologic cell death. Mechanistically, cascade-amplification of the antitumor immune response is prompted by the adjuvantic properties of the lytic intracellular content and enhanced by the heightened GDSME expression, resulting in pyroptosis and the release of tumor associated antigens. Neither of the single components provide efficient tumour control, while tumor growth is efficiently inhibited in primary and recurrent melanomas due to the combinatorial effect of cisplatin and self-supplied GSDME. Moreover, Nano-CD in combination with checkpoint blockade creates durable immune memory and strong systemic anti-tumor immune response, leading to disease relapse prevention, lung metastasis inhibition and increased survival in mouse melanomas. Taken together, our therapeutic approach utilizes CRISPR-technology to enable cell-intrinsic protein expression for immunotherapy, using GDSME as prototypic immune modulator. This nanoplatform thus can be applied to modulate further immunological processes for therapeutic benefit.


Use of WhatsApp®, for distance teaching during COVID-19 pandemic: Experience and perception from a sub-Saharan African setting.
In the midst of the COVID-19 pandemic, to palliate to the lockdown and cover academic programs, the faculty of medicine and pharmaceutical sciences (FMPS) of the university of Dschang (UDs) in Cameroon has implemented e-learning using WhatsApp®. Describe the opinion of students and lecturers after its implementation of e-learning at the FMPS of UDs. We designed a uniform teaching scheme using WhatsApp® during the university lockdown. Students and members of the teaching staff of the FMPS of UDs were enrolled after receiving clear information on the study implementation. At the end of the online-teaching period of two and a half months, we surveyed our students and teaching staff. Sociodemographic characteristics and opinions about e-learning were collected using a standard questionnaire. We enrolled 229 students and 40 lecturers of the FMPS. Students reported a decremented quality of internet connection (p < 0.001, p-homogeneity < 0.001) despite an increased expenditure related to internet use. Electronic devices were broadly used before the implementation of mobile learning. The use of course materials was significantly more challenging among students because of the size/format of lecture notes and internet connection/cost (all p < 0.05). Perception of discipline compared to classroom-based lessons was not significantly different among students compared to lecturers (all p > 0.05). While lecturers were mainly more comfortable conveying the contents of their lectures, students tended to be less prone to actively participate. The motivation and satisfaction of the latter group toward e-learning were modest compared to classroom-based lectures while their feedback about the organization was positive. E-learning using WhatsApp® could be an effective alternative to conventional classroom-based lessons in the context of COVID-19 pandemic. The use of a blended-learning program including classroom-based sessions could help improve its limitations.


Knowledge, attitude, and practices of grassroot health workers about early childhood caries.
This study examines the knowledge levels pertaining to early childhood caries (ECC) among grassroot workers of rural India. A questionnaire study assessing the awareness levels of various ECC aspects was carried out among 88 auxiliary nurse midwives (ANMs), 140 Anganwadi workers (AWWs), and 210 Accredited Social Health Activist (ASHA) workers in a district of Southern India. A 24-item pretested, structured, and close-ended, self-administered questionnaire was used to collect information on the knowledge of early childhood oral health-related factors. Descriptive statistics and multivariate ANOVA were used to summarize the results. Overall, only 59% of ANMs, 49% of AWWs, and 47% of ASHA workers were found to have adequate knowledge about ECC. The current study clearly highlighted the discrepancy in the awareness levels among grassroot health care workers. A deficit was found to exist in the knowledge of the tested health care workers regarding infant oral care and ECC transmissibility.


Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naïve patients with advanced non-small-cell lung cancer: results of a west Japan oncology group study.
The primary goal of this open-label, multicenter, randomized phase III trial was to determine whether treatment with carboplatin plus the oral fluoropyrimidine derivative S-1 was noninferior versus that with carboplatin plus paclitaxel with regard to overall survival (OS) in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). A total of 564 patients were randomly assigned to receive either carboplatin (area under the curve, 5) on day 1 plus oral S-1 (40 mg/m2 twice per day) on days 1 to 14 or carboplatin (area under the curve, 6) plus paclitaxel (200 mg/m2) on day 1 every 21 days. At the planned interim analysis, with a total of 268 death events available, the study passed the O'Brien-Fleming boundary of 0.0080 for a positive result and noninferiority of carboplatin and S-1 compared with carboplatin and paclitaxel was confirmed for OS (hazard ratio, 0.928; 99.2% CI, 0.671 to 1.283). Median OS was 15.2 months in the carboplatin and S-1 arm and 13.3 months in the carboplatin and paclitaxel arm, with 1-year survival rates of 57.3% and 55.5%, respectively. Rates of leukopenia or neutropenia of grade 3/4, febrile neutropenia, alopecia, and neuropathy were more frequent in the carboplatin and paclitaxel arm, whereas thrombocytopenia, nausea, vomiting, and diarrhea were more common in the carboplatin and S-1 arm. The carboplatin and S-1 arm had significantly more dose delays than the carboplatin and paclitaxel arm. Oral S-1 with carboplatin was noninferior in terms of OS compared with carboplatin and paclitaxel in patients with advanced NSCLC, and is thus a valid treatment option.


Atomically Dispersed Pd Atoms on a Simple MgO Support with an Ultralow Loading for Selective Hydrogenation of Acetylene to Ethylene.
We report a simple and efficient Pd/MgO catalyst loaded with ppm level of Pd (7.8 ppm) for semi-hydrogenation of acetylene to ethylene. The catalyst showed excellent performance with high acetylene conversion (97%), high ethylene selectivity (89%) and good stability. Moreover, the atomically dispersed Pd atoms are inactive for ethylene hydrogenation. Isotopic and FTIR results suggest that H2 dissociates at isolated Pd atoms in a heterolytic manner forming O-H bond, which may account for the high selectivity.


Climate change resiliency choices of small-scale farmers in Cameroon: determinants and policy implications.
Climate variability and change has continued to wreak havoc on the agricultural sector, with small-scale farmers being the most hard-hit. The limited adaptive capacity of small-scale farmers faced with the impacts of climate variability and change principally explains their high level of vulnerability. It is within this framework that this study sought to examine the specific resiliency choices of small-scale farmers faced with climate variability and change in Cameroon, and the plausible policy implications. Data was collected through a survey of 300 small-scale farmer household heads as well as climate data collected from meteorological stations. Data analysis was run on Microsoft Excel 2007 and SPSS 20, employing descriptive and inferential statistics. Findings showed significant fluctuations in climate parameters in recent years. The main resiliency choices of small-scale farmers faced with climate variability and change were on-farm practices (23%), off-farm practices (19%), and agroforestry practices (28%); with 30% of the sampled farmers taking to the no resiliency option. A statistically significant (p < 0.01; p < 0.05; and p < 0.10) causal and non-causal relationship was found to exist between independent variables (household size, age of household head, number of farms, farm size, household income, farm experience, gender, experience of extreme weather events, access to weather information, access to extension services, access to credit, distance to market, access to land, and membership in farming group) and small-scale farmers' practice of different resiliency options faced with climate variability and change. This shows that small-scale farmers' practice of different resiliency options faced with climate variability and change is determined by past experience of extreme weather/climate events as well as socio-economic and institutional factors. On the basis of these findings, it is recommended that policy makers factor in these determinants when taking actions geared towards enhancing small-scale farmers' resilience to climate variability and change.


Cognitive Behavioral Therapy for Late-Life Depression (CBTlate): Results of a Multicenter, Randomized, Observer-Blinded, Controlled Trial.
Different psychotherapeutic interventions for late-life depression (LLD) have been proposed, but their evaluation in large, multicenter trials is rare. The present study evaluated the efficacy of a specific cognitive behavioral therapy (CBT) for LLD (LLD-CBT) in comparison with a supportive unspecific intervention (SUI), both administered in a specialist psychiatric outpatient setting. In this randomized, controlled, parallel group trial, we recruited participants (≥60 years) with moderate to severe depression at 7 trial sites in Germany. Participants were randomly assigned to the LLD-CBT or SUI group. The primary outcome was depression severity at the end of treatment measured by change on the Geriatric Depression Scale (GDS). Secondary outcomes included change in observer-rated depression, anxiety, sleep ratings, and quality of life throughout the treatment phase and at 6-month follow-up. Between October 1, 2018, and November 11, 2020, we randomly assigned 251 patients to either LLD-CBT (n = 126) or SUI (n = 125), of whom 229 provided primary-outcome data. There was no significant between-group difference in the change in GDS scores at the end of treatment (estimated marginal mean difference: -1.01 [95% CI: -2.88 to 0.86]; p = 0.287). Secondary analyses showed significant improvements in several outcomes after 8 weeks and at follow-up in both treatment arms. Our data suggest that LLD-specific CBT and a supportive unspecific treatment both provide clinical benefit in patients with moderate to severe LLD without evidence for superiority of LLD-CBT.


Induction of mouse c-src in RAW264 cells is dependent on AP-1 and NF-kappaB and important for progression to multinucleated cell formation.
C-src is known to play an essential role in osteoclastogenesis. We studied the regulatory mechanism as well as the significance of c-src induction in RANKL-induced differentiation of mouse monocytic RAW264 cells to TRAP-positive-multinucleated cells. We determined the genomic organization of the 5'-terminal region of mouse c-src. Mutational and biochemical analyses in the region 0.9 kb upstream of the transcription start site revealed that c-Fos and JNK pathways, in addition to NF-kappaB, participate in c-src induction in response to RANKL. On the other hand, when the expression of c-src was suppressed by introducing antisense src, the number of multinucleated cells formed was significantly reduced. Together, these findings show that the expression of c-src is under the control of AP-1 and NF-kappaB in the differentiation of RAW264 cells and that c-src plays an essential role at the stage of progression to multinucleated cell formation.


Wavelet and deep learning-based detection of SARS-nCoV from thoracic X-ray images for rapid and efficient testing.
This paper proposes a wavelet and artificial intelligence-enabled rapid and efficient testing procedure for patients with Severe Acute Respiratory Coronavirus Syndrome (SARS-nCoV) through a deep learning approach from thoracic X-ray images. Presently, the virus infection is diagnosed primarily by a process called the real-time Reverse Transcriptase-Polymerase Chain Reaction (rRT-PCR) based on its genetic prints. This whole procedure takes a substantial amount of time to identify and diagnose the patients infected by the virus. The proposed research uses a wavelet-based convolution neural network architectures to detect SARS-nCoV. CNN is pre-trained on the ImageNet and trained end-to-end using thoracic X-ray images. To execute Discrete Wavelet Transforms (DWT), the available mother wavelet functions from different families, namely Haar, Daubechies, Symlet, Biorthogonal, Coiflet, and Discrete Meyer, were considered. Two-level decomposition via DWT is adopted to extract prominent features peripheral and subpleural ground-glass opacities, often in the lower lobes explicitly from thoracic X-ray images to suppress noise effect, further enhancing the signal to noise ratio. The proposed wavelet-based deep learning models of both, two-class instances (COVID vs. Normal) and four-class instances (COVID-19 vs. PNA bacterial vs. PNA viral vs. Normal) were validated from publicly available databases using k-Fold Cross Validation (k-Fold CV) technique. In addition to these X-ray images, images of recent COVID-19 patients were further used to examine the model's practicality and real-time feasibility in combating the current pandemic situation. It was observed that the Symlet 7 approximation component with two-level manifested the highest test accuracy of 98.87%, followed by Biorthogonal 2.6 with an efficiency of 98.73%. While the test accuracy for Symlet 7 and Biorthogonal 2.6 is high, Haar and Daubechies with two levels have demonstrated excellent validation accuracy on unseen data. It was also observed that the precision, the recall rate, and the dice similarity coefficient for four-class instances were 98%, 98%, and 99%, respectively, using the proposed algorithm.


Supercritical Carbon Dioxide Impregnation of Gold Nanoparticles Demonstrates a New Route for the Fabrication of Hybrid Silk Materials.
How many nanoparticles can we load in a fiber? How much will leak? Underlying is the relatively new question of the "space available" in fibers for nanoparticle loading. Here, using supercritical carbon dioxide (scCO2) as a carrier fluid, we explored the impregnation in four Indian silks (Mulberry, Eri, Muga, and Tasar) with five standard sizes of gold nanoparticles (5, 20, 50, 100 and 150 nm in diameter). All silks could be permanently impregnated with nanoparticles up to 150 nm in size under scCO2 impregnation. Accompanying structural changes indicated that the amorphous silk domains reorganized to accommodate the gold NPs. The mechanism was studied in detail in degummed Mulberry silk fibers (i.e., without the sericin coating) with the 5 nm nanoparticle. The combined effects of concentration, time of impregnation, scCO2 pressure, and temperature showed that only a narrow set of conditions allowed for permanent impregnation without deterioration of the properties of the silk fibers.


abeo-abietanes from Teucrium polium roots as protective factors against oxidative stress.
Six new 17(15→16)-abeo-abietanes, along with seven known compounds, were isolated and characterized from ethyl acetate root extract of Teucrium polium L., a medicinal plant belonging to the Labiatae family reported to have hypolipidemic, hypoglycaemic, anti-nociceptive and anti-inflammatory effects. Their structures were elucidated by 1D ((1)H, (13)C and DEPT) and 2D (COSY, TOCSY, HSQC, HMBC, and NOESY) NMR and mass spectral data. The antioxidative properties of pure metabolites were analyzed on the basis of their DPPH radical scavenging capability. The antioxidant capacity in cell-free systems of the isolated metabolites was carried out by measuring their capabilities to inhibit the synthesis of thiobarbituric acid reactive species in assay media using as oxidable substrates a vegetable fat and the pentose sugar 2-deoxyribose and to prevent oxidative damage of the bovine serum albumin (BSA) hydrosoluble protein. All of the compounds showed a significant and dose-response efficacy although weaker than that exercised by the standard Trolox®.


Arbekacin is actively secreted in the rat intestine via a different efflux system from P-glycoprotein.
This study was undertaken to examine the secretory transport of arbekacin, an aminoglycoside antibiotic, in the rat small intestine and to compare it with those in Caco-2 and LLC-PK1 cells. In vitro permeation of arbekacin was examined using an Ussing chamber technique. Serosal-to-mucosal (secretory)/mucosal-to-serosal (absorptive) permeation ratios of 0.5 mM arbekacin were 2.8 in the jejunum and 7.0 in the ileum, respectively, indicating that arbekacin permeation was highly secretory-oriented. In the ileum, the ratios became smaller with increase in arbekacin concentration applied. When D-glucose was replaced with 3-o-methyl-D-glucose in the experimental medium, the directionality of the arbekacin permeation disappeared almost completely. Absorptive permeation of arbekacin was not significantly influenced by verapamil, cyclosporin A, or probenecid. On the other hand, when gentamicin sulfate was added to the serosal medium, secretory transport of arbekacin was significantly inhibited. The results of this study strongly suggest that a specialized efflux system other than P-glycoprotein and multidrug resistance proteins was involved in the secretory transport of arbekacin in the rat intestine. There was no directionality in arbekacin permeation across Caco-2 cell monolayers, suggesting the absence or very slight expression of the secretory system for arbekacin in this cell line.


Vascular and interstitial effect of University of Wisconsin solution on canine lung.
Belzer's University of Wisconsin cold storage solution (UWCSS) has proved useful in extending the shelf life of organs in extrathoracic transplantation and more recently has also been shown to be useful in heart transplantation. I investigated the effect of 4 degrees C UWCSS on the vascular and interstitial properties of the lung to see whether it affected the pulmonary microcirculation or caused pulmonary edema. Infusion of UWCSS was associated with a slight decrease in oxygen tension, but the final oxygen tension was no different from that previously demonstrated with Euro-Collins solution. Vascular conductance was not affected by UWCSS, but average vascular closure increased slightly, indicating that increased vascular tone occurs. This effect is similar to but less than that previously observed with Euro-Collins solution. Based on comparisons of wet to dry weight ratios, estimates of interstitial compliance, transvascular fluid flux, and microvascular filtration coefficient, it does not appear that UWCSS causes pulmonary edema. Further investigation into the usefulness of UWCSS in lung transplantation is therefore warranted.


Natural killer (NK) cells with HNK-1 phenotype in the cervical biopsies of women followed-up for human papillomavirus (HPV) lesions.
Local immunocompetent cell infiltrates in 263 cervical punch biopsies of women followed-up since 1981 (16 +/- 14 months, M +/- SD) for an established Human papillomavirus (HPV) lesion with or without concomitant cervical intra-epithelial neoplasia (CIN) were analysed for presence of human natural killer (NK) cells, defined by the monoclonal antibody HNK-1 (Leu-7) using the avidin-biotin peroxidase complex (ABC) technique. HNK-1+ cells remained at a constant low level (1.8 to 3.0% of the cells) in the different types of HPV lesions (flat, inverted, or papillomatous condylomas), their percentages (range 1.3 to 2.5% of cells) remaining similarly unaffected by the severity of associated CIN. As shown to be the case with human NK cell function in the peripheral blood, the percentages of local HNK-1+ cells did not evidence any age-dependence. Furthermore, the intensity of the infiltrate did not correlate with the relative levels of HNK-1+ cells in the biopsies. Slightly (but not significantly) higher levels (2.5%) of HNK-1+ cells were found in the first biopsies of the HPV lesions found to regress during the follow-up period (28.8% of cases), when compared with those (1.7% and 1.8%, respectively) in persisting lesions (52.1% of cases) or progressing lesions (19.1% of lesions). The results are discussed in terms of the proposed immune surveillance function of human NK cells in malignant growths, and the conclusion is drawn that the present study does not provide any firm evidence to suggest that local NK cell function would contribute significantly to the clinical behavior of the cervical HPV lesions.


Intranasal immunization with poly(γ-glutamic acid) nanoparticles entrapping antigenic proteins can induce potent tumor immunity.
We previously reported strong induction of ovalbumin (OVA)-specific tumor immunity in mice injected subcutaneously with OVA-entrapping nanoparticles comprising amphiphilic poly(γ-glutamic acid) (OVA/γ-PGA NPs). In the present study we investigated antitumor efficacy and associated immune responses in mice vaccinated with OVA/γ-PGA NPs via the nasal cavity. Mice vaccinated intranasally with OVA/γ-PGA NPs resisted challenge by E.G7-OVA tumor cells, and lung metastasis of B16-OVA cells were significantly suppressed by three intranasal doses of OVA/γ-PGA NPs. Although the total serum anti-OVA IgG titer was equivalent between the OVA/γ-PGA NP- and OVA solution-immunized groups, intranasal vaccination with OVA/γ-PGA NPs efficiently induced cytotoxic T lymphocytes (CTLs) and interferon-γ-secreting cells specific for OVA in the spleen and lymph nodes. The antitumor activity induced by intranasal vaccination of OVA/γ-PGA NPs mainly required CD8(+) CTLs, and the development of long-term specific immunity was confirmed in rechallenge experiments. OVA/γ-PGA NPs administered via the nasal cavity were rapidly taken up by nasopharyngeal-associated lymphoid tissue and delivered to the cervical lymph nodes. Thus, nasal vaccination with antigen-entrapping γ-PGA NPs evokes tumor immunity by eliciting antigen-specific CTLs. γ-PGA NPs are a promising antigen delivery carrier for the development of non-invasive cancer vaccines.


Next generation sequencing exome data analysis aids in the discovery of SNP and INDEL patterns in Parkinson's disease.
Whole exome sequencing is an adept method to reveal novel and disease-related SNPs and INDELs as it screen the actionable areas of the genome. We evaluated the exome sequenced datasets of patients with Parkinson's disease (PD) in South African ethnic origin. The primary focus of this study was to discover the SNPs and INDELs patterns responsible for PD. The variant discovery was performed with genome analysis tool kit best practices variant detection pipelines. The SNPs were linked to the genes and categorized based on the filter-based annotation from ANNOVAR. We identified a total of 7955 SNPs and 9952 INDELs in all seven datasets together. A total of 130 missense nsSNPs were prioritized based on its damaging effect predicted from SIFT and Polyphen2 annotation. We noticed a novel nsSNP rs111655870 in gene LRRK2 that shows the mutation of a Leucine to Phenylalanine at position 208 which can alter the protein function. The study also filtered seven nsSNPs in genes NAGA, SULT4A1, MYH8, FLNA, TPM3, ATP13A1, CLN8 that have potentially deleterious effects predicted by various computational tools. This analysis suggested that the above filtered nsSNPs and INDELs have a functional impact and provide the footing for genetic studies related to PD. Further screening of these variations provides deeper insight for molecular mechanism of disease progression.


Emergence of oligodendrocytes from human neural spheres.
To study the development of human oligodendrocyte precursors (OP), we expanded human embryonic brain-derived neural precursors into spheres with basic fibroblast growth factor (FGF2). Over 90% of the cells in the expanded spheres were precursors coexpressing nestin and the polysialylated (PSA) form of NCAM. The remaining cells were mostly astrocytes and neuronal cells located at the periphery of the floating spheres. When spheres were allowed to adhere on fibronectin-coated substrate in the absence of FGF2, neural precursors migrated in the outgrowth and often formed chains of cells expressing high levels of PSA-NCAM. Many migrating cells also expressed beta-3 tubulin while only scattered elongated cells radiating from the spheres were GFAP+ astrocytes. Spindle-shaped cells not associated with the chains were labeled for the PDGF-alpha receptor and often coexpressed MAP2 neuronal isoforms. Neuronal cells in the outgrowth rapidly established a rich neuritic network where OP expressing O4 and DM20/proteolipid antigens appeared. T3 treatment of neural spheres increased the rate of OP formation and the complexity of their shape. Thus, the generation of human oligodendrocytes from neural precursors is tightly correlated with growth of neuronal processes and enhanced by hormonal signals.


Recovery of motor performance deterioration induced by a demanding finger motor task does not follow cortical excitability dynamics.
The performance of a demanding exercise can result in motor performance deterioration and depression of primary motor cortex excitability. In the present work we defined a motor task that requires measurable skilled performance to unveil motor performance changes during the execution of a demanding task and to investigate the dynamics of motor performance and cortical excitability changes in absence of overt peripheral fatigue. Twenty-one normal subjects, divided into three groups were asked to perform a sequence of finger opposition movements (SEQ) paced at 2 Hz for 5 min, quantitatively evaluated by means of a sensor-engineered glove able to perform a spatio-temporal analysis of motor performance. Maximal voluntary contraction (MVC) was evaluated before and after the motor task in group 1 while motor evoked potentials (MEP) were evaluated before and after the motor task in group 2 and 3. Group 1 and 2 performed the 5 min-SEQ while group 3 was asked to perform the 5 min-SEQ twice to assess the dynamics of motor performance and cortical excitability. As a result, we found that the execution of 5 min-SEQ induced motor performance deterioration associated with no change in MVC but a decrease in cortical excitability. We further found that the dynamics of cortical excitability and motor performance were different. In fact, a short rest period (i.e., period necessary to collect MEP) between the execution of two 5 min-SEQs was able to recover the motor performance but not the cortical excitability. Finally, no change in spinal excitability was observed. These findings suggest that although primary motor cortex seems to be mainly involved in motor performance deterioration during the execution of a demanding finger motor task, the recovery of motor performance does not follow cortical excitability dynamics.


Cyclothymic temperament: Associations with ADHD, other psychopathology, and medical morbidity in the general population.
Cyclothymic temperament (CT) is an affective disposition often preceding bipolar disorder (BD), and is the most common affective temperament in patients with BD. In depressed patients, CT is a predictor for developing a bipolar course. In a clinical sample of adults with BD and attention deficit hyperactivity disorder (ADHD), CT was associated with higher loads of psychiatric symptoms, somatic comorbidity, impairment, and higher morbidity among first-degree relatives. We aimed to investigate the morbidity and occupational functioning of persons with CT in the general population. Randomly recruited Norwegian adults (n = 721) were assessed with a 21-item cyclothymic subscale from the TEMPS Autoquestionnaire. Self-reported data were collected on psychiatric symptoms, comorbidity, educational and occupational level, and known family morbidity. Thirteen percent had CT associated with an increased prevalence of ADHD, BD, high scores on the Mood Disorder Questionnaire (MDQ), and childhood and adulthood ADHD symptoms. CT was found in 75% (p < .001) of the bipolar participants, and in 68% (p < .001) of those with a positive MDQ score. CT was associated with more anxiety/depression, substance and alcohol problems, lower educational and occupational levels, and having a first-degree relative with anxiety/depression, alcohol problems, ADHD, and BD. The CT subscale alone might include overlapping features with cyclothymic, anxious, irritable, and depressed temperaments, thus increasing the prevalence estimate of CT. CT is a strong predictor of occupational failure and associated with more psychiatric impairment in the participants and their families. CT should be assessed in both mood disorder and ADHD patients.


Case series of ovarian neuroendocrine carcinoma: overview of clinicopathological features.
Ovarian neuroendocrine carcinoma (O-NEC) is a relatively uncommon neoplasm, and the current knowledge regarding its diagnosis and management is limited. In this series, our objective was to provide an overview of the clinicopathological characteristics of the disease by analyzing clinical case data to establish a theoretical foundation for the diagnosis and management of O-NEC. We included three patients in the present case series, all of whom were diagnosed with primary O-NEC based on pathomorphological observation and immunohistochemistry. Patient 1 was a 62-year-old patient diagnosed with small cell carcinoma (SCC) of the pulmonary type. Post-surgery, the patient was diagnosed with stage II SCC of the ovary and underwent standardized chemotherapy; however, imaging examinations conducted at the 16-month follow-up revealed the existence of lymph node metastasis. Unfortunately, she passed away 21 months after the surgery. The other two patients were diagnosed with carcinoid tumors, one at age 39 and the other at age 71. Post-surgery, patient 2 was diagnosed with a carcinoid in the left ovary, whereas patient 3 was diagnosed with a carcinoid in her right ovary based on clinical evaluation. Neither of the cases received adjuvant therapy following surgery; however, they have both survived for 9 and 10 years, respectively, as of date. Primary O-NECs are rare and of diverse histological types, each of which has its own unique biological features and prognosis. SCC is a neoplasm characterized by high malignancy and a poor prognosis, whereas carcinoid tumors are of lesser malignancy and have a more favorable prognosis.


[Biomarkers collections: the future or a waste of resources?].
Disease biomarkers would aim at a more specific definition of diagnosis or subtype of a certain disease, as well as prognosis definition, including efficacy and side effects of certain therapeutics. Biomarkers could lead to a prognostically optimized definition of remission in the individual patient and thus to a more objective definition of therapeutic efficacy. Is this possible and does it make sense? Or would an extensive analysis of biomarkers to date lead to a costly overestimation of as yet not well established biologic parameters? Although we are currently unable to answer this question, many colleagues argue in favour of more in depth research for a better evaluation of biomarkers in many diseases. This could save money if we were able to predict the efficacy of expensive drugs such as immunobiologics. Biomarkers comprise cytometric information, data on protein expression and secretion, mRNA, microRNA or DNA, including epigenetic variants. Although much of these data already exist in the scientific literature, it is associated with problems in terms of feasibility (for cytometry and RNA analysis only on-site analysis is possible, while for DNA analysis central testing is also possible), costs and reproducibility (ethnic variability!). To date all biomarkers have only limited value in terms of the above-mentioned aims. The present review compiles "PROs and CONs" in a subjective way in order to provoke a discussion on the meaningfulness of biomarkers, while at the same time supporting and encouraging further research in this field.


Electrocardiographic markers of cardiac metastasis.
Cardiac metastases are often clinically inapparent but have important prognostic significance. A total of 1046 consecutive autopsies performed between 1981 and 1983 were reviewed, and 210 patients with both premortem and autopsy diagnoses of cancer were found, in whom a recent (less than 3 months before death) ECG was available. Of these patients, 47 had cardiac metastases (group I) and 163 did not (group II). In group I, 19 patients had new ECG changes suggestive of myocardial ischemia or injury, including either diffuse T wave inversion (10%), segmental (ECG pattern suggestive of a specific coronary distribution) T wave inversion (80%), or ST elevation (10%). None of these patients had symptoms suggestive of myocardial ischemia. In group II, six patients had ECG changes suggestive of myocardial ischemia or injury: four patients with preterminal sepsis, one with myocardial infarction, and one with aspergillus nodules within the myocardium. New atrial arrhythmias (seven patients) and low voltage (10 patients) were found with greater frequency in group I patients (p less than 0.0005 and p less than 0.00001, respectively, vs group II). Patients with normal ECGs were unlikely to have cardiac metastases; however, the finding of nonspecific ST-T wave changes was not helpful in differentiating the two groups. In clinically stable patients with cancer and no cardiac symptoms suggestive of ischemia, any new ECG change should raise the suspicion of cardiac metastases. The ECG finding of myocardial ischemia or injury has high specificity (96%, p less than 0.000001) for cardiac metastases.


Methyl 1-[(6-meth-oxy-5-methyl-pyrimidin-4-yl)meth-yl]-1H-benzo[d]imidazole-7-carboxyl-ate: a combined X-ray and DFT study.
The title compound, C16H16N4O3, was obtained as a side product during the synthesis of the previously reported anti-tubercular agent N-(2-fluoro-eth-yl)-1-[(6-meth-oxy-5-methyl-pyrimidin-4-yl)meth-yl]-1H-benzo[d]imidazole-4-carboxamide and structurally characterized by X-ray crystallography and computational methods. In the crystal (space group P21/n, Z = 4), the title compound adopts a twisted conformation with a dihedral angle between the benzimidazole and pyrimidine mean planes of 84.11 (3)°. The carboxyl-ate group and the 5-methyl group on the pyrimidine ring exhibit partial disorder. The DFT-optimized mol-ecular structure resembles the structure of the minor component in the crystal.


Formation of dimethylthioarsenicals in red blood cells.
The bladder and skin are the primary targets for arsenic-induced carcinogenicity in mammals. Thioarsenicals dimethylmonothioarsinic (DMMTA(V)) and dimethyldithioarsinic (DMDTA(V)) acids are common urinary metabolites, the former being much more toxic than non-thiolated dimethylarsinic acid (DMA(V)) and comparable to dimethylarsinous acid (DMAIII) in epidermoid cells, suggesting that the metabolic production of thioarsenicals may be a risk factor for the development of cancer in these organs. To reveal their production sites (tissues/body fluids), we examined the uptake and transformation of the four dimethylated arsenicals by incubation with rat and human red blood cells (RBCs). Although DMA(V) and DMDTA(V) were not taken up by either type of RBCs, DMAIII and DMMTA(V) were taken up by both (more efficiently by rat ones), though DMMTA(V) was taken up slowly, and then the arsenic transformed into DMDTA(V) was excreted from both types of animal RBCs. On the other hand, although DMA(III) taken up rapidly by rat RBCs was retained in the RBCs, that taken up by human RBCs was immediately transformed into DMMTA(V) and then excreted into the incubation medium without being retained in the RBCs. In a separate experiment, arsenic remaining in primary rat hepatocytes after incubation with 1.5 microM DMAIII was recovered from the incubation medium in the forms of DMA(V) and DMMTA(V) in the presence of human RBCs, but not in the presence of rat RBCs (in which the arsenic was bound to hemoglobin). Thus, DMMTA(V) was detected in the medium only in the presence of human RBCs and increased with incubation time. It was proposed that arsenic is excreted from hepatocytes into the bloodstream in the form of DMAIII and then taken up by RBCs in humans, where it is transformed into DMMTA(V) and then excreted again into the bloodstream.


Signal peptide and denaturing temperature are critical factors for efficient mammalian expression and immunoblotting of cannabinoid receptors.
Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e., ≥95°C), forming a large molecular weight band when analyzed by immuno-blotting. Only denaturing temperatures ≤75°C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immuno-blot analysis. These findings provide very useful information for efficient mammalian expression and immuno-blotting of membrane receptors.


A novel approach for predicting antidepressant-induced sexual dysfunction in rats.
Sexual dysfunction is associated with antidepressant discontinuation. Therefore, there is a need for models that predict antidepressant-induced sexual dysfunction. To develop a predictive method for evaluating antidepressant-induced sexual dysfunction. Male Sprague-Dawley rats were allowed access to sexually receptive females during a single overnight mating session and then treated with antidepressants known to produce differing levels of sexual dysfunction in the clinic. Two to three weeks later, following either acute, subchronic (7-day), or chronic (14-day) antidepressant treatment, rats were observed for penile erections (PE) in the presence of sexually receptive females that were not accessible for contact but served as visual, auditory, and olfactory stimuli in the testing area. Chronic treatment of fluoxetine (10 mg/kg), desipramine (10 mg/kg), and bupropion (20 mg/kg) reduced the number of PE 71, 53, and 8%, respectively, relative to vehicle-treated rats. This rank order of the compounds' propensity for reducing PE is comparable to the rank order of the compounds' ability to produce sexual dysfunction during antidepressant treatment in the clinic. Additionally, drugs used to treat antidepressant-induced sexual dysfunction in the clinic, such as sildenafil, yohimbine, and dopamine agonists, were also effective in attenuating the deficits in the number of noncontact PE produced by chronic fluoxetine treatment. Taken together, this model represents a novel approach for predicting antidepressant-induced sexual dysfunction in rats, which parallels the pattern of reports of sexual dysfunction in the clinic associated with different antidepressant treatments and the ability of adjunct treatment to reverse the sexual impairments produced by antidepressants.


Where does damage lead to enhanced food aversion: the ventral pallidum/substantia innominata or lateral hypothalamus?
It is well known that lesions of the lateral hypothalamus (LH) produce aphagia. Several previous studies have reported that lateral hypothalamus damage produces food aversion in addition to aphagia. However, damage to other regions near the LH also produce aphagia and enhanced aversion. The purpose of this study was to resolve where the site or sites for aversion-inducing lesions is/are located. Small, bilateral excitotoxin lesions (QUIN, 10 micrograms in 1 microliter or IBO, 15 micrograms in 1 microliter) or bilateral sham injections of vehicle were made into the globus pallidus (GP), the ventral pallidum/substantia innominata (VP/SI) or the lateral hypothalamus (LH). Affective reactions to taste were elicited by infusing sucrose solutions (1 M) into the mouth via chronic oral cannulae. The number of aversive responses (gapes, chin-rubbing, head-shaking and forelimb flails) emitted was tallied. Individual lesions were mapped and a single 'necessary and sufficient' site for damage-induced aversion was identified (the area of overlapping damage common to all rats that showed enhanced aversive reactions). To identify the lesions, two lesion-mapping techniques were used: (1) a conventional neuron-counting procedure in which an attempt is made to count all neurons within a brain region, and (2) a new modified 'fractionator' procedure consisting of exhaustive 400 x magnification counts at point locations within a brain region. Results indicated that aversive reactions to food are enhanced only following bilateral neuron loss (> 70%) from the caudal ventromedial VP/SI alone. This shared site has a lateral diameter of 1.0 mm, a dorsoventral diameter of 0.5 mm and a rostrocaudal diameter of 1.0 mm. Damage restricted to the LH never produced enhanced aversion even when it produced aphagia. The crucial region for aversion is located ventral and medial to the globus pallidus and dorsal and lateral to the lateral hypothalamus.


Analysis of curcumin and piperine in biological samples by reversed-phase liquid chromatography with multi-wavelength detection.
Widely accessible food phytochemicals such as curcumin have been reported to have anti-inflammatory and anticarcinogenic properties. However, curcumin has poor absorption in the gut, and piperine has been of interest as a dietary compound that can enhance curcumin bioavailability. The aim of this study was to develop and optimize a technique using reversed-phase chromatography with multi-wavelength detection for the simultaneous measurement of curcumin and piperine in various biological matrices. Emodin was used as an internal standard. Protein precipitation and liquid-liquid extraction based on acetonitrile provided good recovery of these analytes. A 150 mm × 4.6 mm I.D. Luna C18 column was used under isocratic conditions to separate curcumin, piperine, and emodin with baseline resolution, and with good separation from other sample components, in as little as 4 min. The detection limits for curcumin and piperine were 3 and 7 ng/mL, respectively. This method has been used to quantitate these compounds in samples such as human intestinal epithelial cell lysates and mouse plasma or GI tissues in research aimed at examining the bioavailability of curcumin in the presence of piperine.


Epichlorohydrin crosslinked carboxymethyl cellulose-ethylenediamine imprinted polymer for the selective uptake of Cr(VI).
A new ion-imprinted polymer (IIP) was synthesized from sodium carboxymethyl cellulose and used for the adsorption of hexavalent chromium from aqueous solution. Epichlorohydrin was used to stabilize the polymer before ethylenediamine (EDA) ligand and Cr(VI) were introduced. The obtained IIP was characterized with FTIR, XPS, TGA,13C NMR, SEM, EDX, BET and zeta sizer. The kinetics of adsorption followed a pseudo-second-order model while the Langmuir adsorption isotherm provided the best fit with a maximum adsorption capacity of 177.62mg/g at 25°C. The Langmuir adsorption capacity for the non-imprinted polymer (NIP) at 25°C was 149.93mg/g. Thermodynamic parameters indicated an endothermic process and spontaneous adsorption of Cr (VI) on the polymers. IIP adsorbent was successfully recycled 5 times using 0.1M NaOH as a leachate; 98% Cr(VI) was desorbed during the last adsorption-desorption cycle.


An assessment of oncofertility content on reproductive endocrinology and infertility clinic websites.
To assess oncofertility content on fertility clinic websites as indicated by eight relevant keywords. Additionally, we sought to describe the relationship between oncofertility content and five predetermined clinic characteristics. We examined 381 fertility clinic websites that are members of the Society for Associated Reproductive Technology (SART). Extracted data included clinic location, practice type (private vs academic), size (cycles/year), type of NCI designated center (cancer center vs comprehensive cancer center), and distance from the nearest NCI center. Additionally, we documented whether the clinic was located in a state mandating reproductive and infertility services and/or included fertility preservation for "iatrogenic infertility" as reported by the American Society for Reproductive Medicine (ASRM). Data were summarized using descriptive statistics and compared using chi-squared or t-test as appropriate. Of the 381 fertility clinic websites analyzed, 322 (85%) contained at least one oncofertility-related keyword. Most frequently used terms included cancer (79%) and fertility preservation (78%), while less frequently used terms included suppression (9.4%) and shielding (5.0%). Practices that initiated ≥ 501 cycles per year were more likely to mention one of the oncofertility keywords (OR 1.2; 95% CI 1.1-1.3). The associations of oncofertility website content with practice type, state-mandated fertility insurance coverage, and distance from an NCI-designated cancer center were not statistically significant. Large clinic size was the only predictive factor for inclusion of oncofertility website content. Further studies are required to evaluate whether inclusion of oncofertility content on clinic websites impacts the use of these services by patients with cancer. This is the first study correlating availability of oncofertility content on SART fertility clinic websites with consideration of geographic proximity to NCI designated cancer centers. Large clinic size was the only predictive factor for inclusion of oncofertility website content.


Treatment of Comorbid Anxiety and Epilepsy.
Objective: Anxiety is among the most common psychiatric illnesses, and it commonly co-occurs with epilepsy. This review of the existing literature on anxiety comorbid with epilepsy aims to generate new insights into strategies for assessment and treatment. Methods: The authors conducted a narrative literature review to select key publications that help clarify the phenomenology and management of comorbid anxiety and epilepsy. Results: Anxiety symptoms may be relevant even if the criteria for a diagnosis of an anxiety disorder are not met. Associating specific seizure types or seizure localization with anxiety symptoms remains difficult; however, the amygdala is a brain region commonly associated with seizure foci and panic or fear sensations. The hypothalamic-pituitary-adrenal axis may also be relevant for anxiety symptoms, particularly for the selection of treatments. Nonpharmacological treatment is appropriate for anxiety comorbid with epilepsy, particularly because relaxation techniques may reduce hypersympathetic states, which improve symptoms. Medication options include antidepressants and anticonvulsants that may have efficacy for anxiety symptoms. Benzodiazepines are a good choice to address this comorbid condition, although side effects may limit utility. Conclusions: Ultimately, there are numerous treatment options, and although there is a limited evidence base, quality of life may be improved with appropriate treatment for individuals experiencing comorbid anxiety and epilepsy.


Incorporation of branched-chain fatty acid into cellular lipids and caspase-independent apoptosis in human breast cancer cell line, SKBR-3.
13-Methyltetradecanoic acid (13-MTD), an iso-C15 branched- chain saturated fatty acid, has been shown to induce apoptotic cell death of numerous human cancer cells. However, the mechanism for the induction of apoptosis has not been fully understood. This study described the incorporation of 13-MTD into cellular lipid of SKBR-3 breast cancer cells and apoptosis related event to gain more insight into the mechanism action of this fatty acid. Treatment of SKBR-3 cells with 13-MTD lowered the cell viability and induced apoptosis. Proportion of 13-MTD in the glycerolipids increased to saturation level within 6 hours. Triacylglycerol contained 13-MTD in higher concentration than phospholipid with positional preference to sn-2. 13-MTD caused no changes in the caspase activity and its gene expression. Furthermore, addition of caspase-inhibitor to culture medium did not prevent the cells from the cytotoxicity of 13-MTD. No-increase in the cellular calcium level was also noted with 13-MTD treatment. However, 13-MTD disrupted the mitochondrial integrity in 4 hours, and increased the nuclear translocation of apoptosis inducing factor. These results showed that 13-MTD disrupted the mitochondrial integrity, and induced apoptosis via caspase-independent death pathway.


Cerium oxide nanofiber based electroanalytical sensor for TNF-α detection: Improved interfacial stability with Nafion.
The present work is aimed at improving the adhesion of nanomaterials at the interface of solid state working electrodes. Towards this, herein, an efficient method has been proposed that requires the electrode interface to be decorated with an optimally thin layer of Nafion. This selectively permeable layer ensures the stability of the sensor interface, without hampering the transport of biomolecules and electrons. As a case study, here, electrospun Cerium oxide nanofiber (CeNF) modified Glassy carbon electrodes (GCE) have been used as the sensing interface, and stability and performance of the GCE/CeNF/Nafion interface is evaluated using analytical electrochemistry. The CeNF is synthesized via electrospinning and is characterized using X-ray diffraction spectroscopy, Thermal gravimetry, Fourier transform infrared spectroscopy, and Field emission scanning electron microscopy. Further, detection of sepsis specific biomarker TNF-α from spiked buffer samples is demonstrated, as a case study, towards evaluating the effect of Nafion on the interfacial sensitivity. The achieved LOD of GCE/CeNF and GCE/CeNF/Nafion for TNF-α detection were 2.8 fg/mL and 1.2 fg/mL, respectively. A comparative analysis between the Electrochemical impedance spectroscopic (EIS) results of the GCE/CeNF and the GCE/CeNF/Nafion interfaces confirms the improvement in stability, without affecting the sensitivity and the limiting detection.


Simulating the maintenance of a rare fish morph experiencing negative frequency dependent selection.
Empirical work assessing the maintenance of rare genotypes in natural populations is difficult over very long time scales. Skirting this problematic issue is possible with theory and simulations. Major theoretical constructs, including mutation-selection balance and balancing selection, explain the theoretical maintenance of rare genotypes, and the occurrence of multiple, rare genotypes over time. Additionally, numerical simulations are valuable tools for assessing evolving biological systems because they allow for monitoring systems over long time scales, as well as for controlling model parameters, thus contributing to the exploration of system dynamics that cannot be assessed in nature. Here we employed numerical simulations to explore the importance of several biological factors that contribute to the maintenance of a fish color-pattern polymorphism. We present a numerical model of a two-morph fish polymorphism that allowed us to test the sensitivity of the rare morph's persistence and the population's stability to multiple parameters. Our simulations ran over 10,000 years (where one year is approximately one generation) and demonstrated the maintenance of a stable polymorphism with a rare morph which persisted at a frequency of ~10(-2), which is in-fact the frequency of the rare, mottled black mosquitofish morph in natural populations. This pigmentation polymorphism is stable, independent of changes in population size, but can be destabilized with very high predation when coupled with very low birth rates. Employing models with empirical fitness estimates is a valuable tool for monitoring rare vertebrate morphs in nature, however few studies exist that have accomplished this task. Our approach can be adapted for modeling rare morphs (particularly in additional live-bearing fishes like sailfin mollies) that also harbor rare, pigmentation morphs within large populations.


Rational Design of the Alkali Metal Sn-Based Mixed Halides with Large Birefringence and Wide Transparent Range.
Birefringent materials are widely used in various advanced optical systems, owing to their vital role in creating and controlling polarized light. Currently, Sn2+ -based compounds containing stereochemically active lone-pair (SCALP) cations are extensively investigated and considered as one class of promising birefringent materials. To solve the problem of relatively narrow bandgap of Sn2+ -based compounds, alkali metals and multiple halogens are introduced to widen the bandgap during the research. Based on this strategy, four new Sn2+ -based halides, A2 Sn2 F5 Cl and ASnFCl2 (A = Rb and Cs), with large birefringence, short ultraviolet (UV) cutoff edge, and wide transparent range are successfully found. The birefringences of A2 Sn2 F5 Cl (A = Rb and Cs) are 0.31 and 0.28 at 532 nm, respectively, which are among the largest in Sn-based halide family. Remarkably, A2 Sn2 F5 Cl possess relatively shorter UV cutoff edge (<300 nm) and broad infrared (IR) transparent range (up to 16.6 µm), so they can become promising candidates as birefringent materials applied in both UV and IR regions. In addition, a comprehensive analysis on crystal structures and structure-property relationship of metal Sn2+ -based halides is performed to fully understand this family. Therefore, this work provides insights into designing birefringent materials with balanced optical properties.


Fitness recovery and compensatory evolution in natural mutant lines of C. elegans.
Deleterious mutation accumulation plays a central role in evolutionary genetics, conservation biology, human health, and evolutionary medicine (e.g., methods of viral attenuation for live vaccines). It is therefore important to understand whether and how quickly populations with accumulated deleterious mutational loads can recover fitness through adaptive evolution. We used laboratory experimental evolution with four long-term mutation-accumulation (MA) lines of Caenorhabditis elegans nematodes to study the dynamics of such fitness evolution. We previously showed that when homozygous mutant populations are evolved in large population sizes, they can rapidly achieve wild-type fitness through the accumulation of new beneficial or compensatory epistatic mutations. Here, we expand this approach to demonstrate that when replicate lineages are initiated from the same mutant genotype, phenotypic evolution is only sometimes repeatable. MA genotypes that recovered ancestral fitness in the previous experiment did not always do so here. Further, the pattern of adaptive evolution in independently evolved replicates was contingent upon the MA genotype and varied among fitness-related traits. Our findings suggest that new beneficial mutations can drive rapid fitness evolution, but that the adaptive process is rendered somewhat unpredictable by its susceptibility to chance events and sensitivity to the evolutionary history of the starting population.


Neoadjuvant chemotherapy and surgery for esophageal adenocarcinoma: prognostic value of circumferential resection margin and stratification of N1 category.
In the UK, it is standard practice to treat esophageal adenocarcinoma with neoadjuvant chemotherapy (no radiation) and surgery. We examined the prognostic value of the status of the circumferential resection margin (CRM) and stratification of the N1 category into 1-4 nodes or > or = 5 nodes. Between 2000 and 2006, 105 patients with radiologically staged T3, T4 or N1 esophageal adenocarcinoma had preoperative chemotherapy. One hundred and one patients had an Ivor Lewis operation with two-field lymphadenectomy, three had a transhiatal operation and one had a three-incision operation. CRM was assessed by painting the specimen with India ink and transverse sections at 5-10 mm intervals. The CRM was considered positive (CRM+) if malignant cells were within 1 mm of the inked margin. There were 87 men. The median age was 61 years (range 37-81 years). Median lymph node yield was 28 (4-77); 86 patients (83%) had > or = 18 nodes. Seventy-four patients (70%) had N1 disease, with 1-4 involved nodes in 41 patients (39%) and > or = 5 nodes in 33 patients (31%). The CRM was positive in 38 patients (36%). On multivariate analysis, nodal metastasis [N0 versus N1; hazard ratio (HR) 3.3, 3-year survival 80% versus 40%; P = 0.004], CRM status (CRM- versus CRM+: HR 2.6, 3-year survival 64% versus 26%; P = 0.002) and vascular invasion (V0 versus V1: HR 2.2, 3-year survival 67% versus 39%; P = 0.014) retained independently significant prognostic value. N1 patients with 1-4 nodes had longer survival than those with > or = 5 nodes (56% versus 21%; P < 0.001). CRM involvement and stratification of the N1 category are independent prognostic factors after multimodal therapy for esophageal adenocarcinoma.


Cecocolic intussusception in multiple lymphomatous polyposis of the gastrointestinal tract. Report of a case.
A rare case of recurrent cecocolic intussusception in an adult patient with multiple lymphomatous polyposis of the gastrointestinal tract is presented. Clinical features, especially the difficulty in distinguishing this entity from adenomatous polyposis on colonoscopy, and histopathology are discussed. It is important that surgeons and colonoscopists be aware of this rare form of diffuse gastrointestinal lymphoma because of therapeutic implications.


Photoradiation therapy of 9L-gliosarcoma in rats: hematoporphyrin derivative (types I and II) followed by laser energy.
Suspensions of 9L-gliosarcoma cells were inoculated into the brain or flank of rats and photoradiation therapy (PRT) was applied to the resulting tumors. The PRT consisted of hematoporphyrin derivative (HpD), type I or II, followed by single-fiber laser energy 24, 48, or 72 h later. Necrotic foci in brain tumors were most numerous following laser exposure 24 h after HpD; they were more than twice as common, and with less damage to healthy tissue, after HpD II than after HpD I with the same laser dose. Neither lifespan nor the final weight of brain tumor was affected by the type of HpD or whether PRT was applied once or twice. In rats with flank tumor, multiple PRT (up to X 4) did not delay tumor growth; also, 11 of 12 PRT-treated flank tumors grew after implantation at various sites in healthy rats. We conclude that HpD II is a more effective photosensitizer than HpD I. However, the value of PRT will be limited until a lethal dose of laser energy can be delivered throughout a tumor without destroying vital healthy tissue.


Population changes induced in Candida albicans by nalidixic acid.
Cells of Candida albicans plated on media containing nalidixic acid (Nal) either die, adapt physiologically to Nal-tolerance or mutate ot Nal-resistance. The fraction of a population exhibiting each response depends on the growth phase of cells when plated and their nitrogen and carbon nutrition and growth temperatures before and after plating. Nal induces Nal-resistant mutants in very high frequency but only at 37 C on plates containing i) glucose as primary carbon source and ii) adenine, a sulfur amino acid or a representative of the glutamic acid family of amino acids. Nal does not affect either forward mutation to caffeine-resistance or reverse mutation from histidine auxotrophy to prototrophy. Nal-resistant mutants produce minute colonies on N-ALfree medium, respire oxidatively and are unusually sensitive to inhibitors of oxidative phosphorylation. They revert spontaneously to wild type at very high rates but can be propagated indefinitely in the absence of Nal by serial selection and replating of minute colonies. Cellular inactivation and induction of Nal-resistant mutants are greatly affected by specific inhibitors of mitochondrial macromolecular syntheses. The presence of chloramphenicol or erythromycin during exposure to Nal prevents cell death and mutation but has no effect on adaptation to Nal-tolerance. Growth on acriflavin or ethidium bromide enhances resistance of cells to inactivation when subsequently plated on Nal containing media. It is concluded that Nal-induced cellular inactivation and mutation to Nal-resistance, but not adaptation to Nal-tolerance, result from damages to the mitochondrion which are fixed or promoted by macromolecular syntheses within the mitochondrion. Implications of these findings for the therapeutic use of Nal are discussed.


Reliability and limitations of permanent tooth staging techniques.
Reliability, or repeatability, of permanent tooth staging techniques is usually expressed as Cohen's Kappa. This single value obscures information about the quantity and allocation of disagreements. In this study we assess and compare intra-observer reliability of permanent tooth staging techniques described by Nolla, Moorrees et al. and Demirjian et al. The sample was panoramic radiographs of healthy dental patients made up of 100 males and 100 females aged 6-15 years. All permanent teeth on the left side (excluding third molars) were scored twice. Weighted Kappa and percentage agreement were calculated. Results show Kappa values for all teeth combined as 0.918, 0.922 and 0.938 for Demirjian (number of teeth N = 2682), Nolla (N = 2698) and Moorrees (N = 2674) respectively. A comparison of Kappa values between upper and lower teeth showed marginally higher values for upper incisors and lower molar for all three scoring methods. Small differences in Kappa values were noted between tooth types with the upper first molar having smaller values than other teeth. Percentage agreement ranged from 81 % (Moorrees), 86 % (Nolla) to 87 % (Demirjian). Tooth stage differences between first and second assessments were not more than one stage. Our findings show that Demirjian scoring is marginally more reliable than Nolla or Moorrees. We suggest that (1) data for reliability are tabulated in full to show the quantity and allocation of disagreement between first and second readings, and (2) that the reliability sample is sufficiently large with a wide age range to include multiple different tooth stages.


Efficient degradation of p-nitrophenol by Fe@pomelo peel-derived biochar composites and its mechanism of simultaneous reduction and oxidation process.
In this study, waste pomelo peels (PP) mixed with iron salts was treated successively with hydrothermal and pyrolyzing carbonization processes to obtain Fe(0) containing biochar composites (Fe@PP-Hy-Py) and the catalytic degradation of p-nitrophenol (PNP) using these Fe@PP-Hy-Py composites was studied. The results showed that the hydrothermal pre-treatment of the mixture of iron salts and pomelo peels was favorable for the incorporation of iron precursor within biomass network, which enabled copolymerization during the following pyrolysis. Through the pyrolysis process, the iron precursor was reduced in situ to amorphous Fe(0) dopped into the carbonaceous matrix, which conversely decreased the defect and disorder degree of pseudo-graphitic carbons and catalyzed the formation of environmental persistent free radicals (EPFRs). Degradation tests showed that the composites obtained at 600 °C with the theoretical Fe mass loading of 10% exhibited the greatest PNP degradation efficiency. Over 90% of 10 mg/L PNP was removed in 2 min under both N2 and air conditions with 1.0 g/L of catalyst level. The degradation kinetics of PNP were all well fitted by the pseudo-first-order kinetics model with kobs of Fe@PP-Hy-Py600 being 0.953 min-1. HPLC-QTOF/MS analysis demonstrated that both oxidation and reduction of PNP occurred as indicated by the detection of 4-aminophenol and ring opening compounds. The Fe(0) on the Fe@PP-Hy-Py was responsible for the reduction of PNP, while oxidation was induced by EPFRs. This study highlights the feasibility of synthesizing active heterogeneous Fe(0)-biochar composites by hydrothermal-pyrolysis route and the associated mechanisms of pollutant degradation.


Interaction of alpha-lactalbumin with dimyristoyl phosphatidylcholine vesicles. II. A fluorescence polarization study.
The interaction of alpha-lactalbumin with dimyristoyl phosphatidylcholine vesicles was studied as a function of temperature, pH and the molar ratio of phospholipid to protein. The method consisted of measuring the fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene used as a probe embedded in the vesicles. After incubation of the protein with the phospholipid for 2 h at 23 degrees C, the polarization of the light emitted by this probe shifted to higher values; the shift was greater at acidic pH than at neutral pH. After incubation at 37 degrees C, no shift in polarization was found at pH 7, 6 and 5 while a strong increase occurred at pH 4. Lowering the temperature, after incubation at 37 degrees C, had little effect on the polarization at neutral pH. At pH 5, however, and in the transition range of the phospholipid, the polarization increased greatly. A kinetic study of the interaction carried out around the transition temperature of dimyristoyl phosphatidylcholine as a function of pH shows that the speed of complex formation between alpha-lactalbumin and the lipid increases from neutral to acidic pH. From the present results and in agreement with our earlier calorimetric and fluorescence data (Hanssens, I., Houthuys, C., Herreman, W. and van Cauwelaert, F.H. (1980) Biochim. Biophys, Acta 602, 539--557), it is concluded that at neutral pH the interaction mechanism is probably different from that at acidic pH. At neutral pH and at all temperatures, alpha-lactalbumin is mainly absorbed electrostatically to the outer surface of the vesicle with little or no influence on the transition temperature of the phospholipid. At this pH, only around the transition temperature is penetration possible. At pH 4, however, the protein is able to penetrate the vesicle at all temperatures and to interact hydrophobically with the phospholipid fatty acid chains. As a result of this interaction, the transition temperature is increased by about 4 degrees C. This different behaviour changes progressively upon acidification: at pH 5, penetration seems to be impossible at temperatures far above the transition temperature but occurs rapidly around the transition temperature.


Predicting pathological von Willebrand factor unraveling in elongational flow.
The globular-to-unraveled conformation transition of von Willebrand factor (vWF), a large polymeric glycoprotein in human blood plasma, is a crucial step in the process of clotting at sites of vascular injury. However, unraveling of vWF multimers in uninjured vasculature can lead to pathology (i.e., thrombus formation or degradation of vWF proteins by enzyme ADAMTS13, making them nonfunctional). To identify blood flow conditions that might induce pathological unraveling of vWF multimers, here we have computed the globular-to-unraveled transition rate of vWF multimers subjected to varying strain rate elongational flow by employing an enhanced sampling technique, the weighted ensemble method. Weighted ensemble sampling was employed instead of standard brute-force simulations because pathological blood flow conditions can induce undesired vWF unraveling on timescales potentially inaccessible to standard simulation methods. Results here indicate that brief but periodic exposure of vWF to the elongational flow of strain rate greater than or equal to 2500 s-1 represents a source of possible pathology caused by the undesired unraveling of vWF multimers.


CTAB-intercalated molybdenum disulfide nanosheets for enhanced simultaneous removal of Cr(VI) and Ni(II) from aqueous solutions.
The treatment of heavy metal pollution in aquatic environment, especially the pollution caused by multiple heavy metal ions, has been a growing global concern for decades. To address this problem, it is urgent to explore effective and low cost adsorbents which can remove multiple heavy metal ions simultaneously. Herein, Cr(VI) and Ni(II) removal from water by MoS2 with widened interlayer spacing was systematically investigated in comparison with pure MoS2. A series of techniques, including X-ray powder diffraction (XRD), Transmission electron microscopy (TEM), and Brunauer-Emmett-Teller (BET) surface area and porosimetry analysis were applied to characterize the nanocomposites. The XRD results confirmed the enlarged interlayer spacing of MoS2 by intercalating cetyl trimethyl ammonium bromide (CTAB) into the interlamination. The maximum adsorption capacities of Cr(VI) and Ni(II) for MoS2/CTAB were 79.4 mg g-1 and 88.3 mg g-1, respectively. Moreover, a synergistic effect in the simultaneous removal of Cr(VI) and Ni(II) was observed. A new Cr(VI) removal mechanism involving redox reaction between Cr(VI) and Mo(IV) in MoS2/CTAB was verified. The removal efficiencies of Cr(VI) and Ni(II) still remained high at the end of fifth cycle, indicating that MoS2/CTAB has a great potential to remove heavy metals from wastewater.