Laboratory paradigms of impulsivity and alcohol dependence: a review.
Impulsivity can be defined as choosing a smaller, immediate reward over a larger, delayed reward. From this perspective, addictive behaviors such as substance abuse and pathological gambling reflect a series of impulsive choices. However, impulsivity is not a homogeneous construct. Laboratory measures of impulsivity reflect two types of processes. The first is related to behavioral inhibition and refers to an individual's ability to appropriately inhibit thoughts or actions. The second is the delay of reward dimension, namely the degree to which immediate (rewarding) consequences have more control over an individual's behavior than consequences that are delayed. In this review, we describe how alcohol is associated with significant impairments in these paradigms. We also suggest that they may have a role in the development of alcohol dependence. These results are in agreement with a model in which delay of gratification might be a marker for early use and/or abuse of alcohol, whereas impairment in behavioral inhibition might be a marker for maintained use in time and, therefore, for progression towards alcohol dependence.


Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer's disease and other tauopathies.
The largest part of tau secreted from AD nerve terminals and released in cerebral spinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting potential extracellular role(s) of NH2 -derived fragments of protein on synaptic dysfunction underlying neurodegenerative tauopathies, including Alzheimer's disease (AD). Here we show that sub-toxic doses of extracellular-applied human NH2 tau 26-44 (aka NH 2 htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide accumulating in vivo at AD synapses and secreted into parenchyma- acutely provokes presynaptic deficit in K+ -evoked glutamate release on hippocampal synaptosomes along with alteration in local Ca2+ dynamics. Neuritic dystrophy, microtubules breakdown, deregulation in presynaptic proteins and loss of mitochondria located at nerve endings are detected in hippocampal cultures only after prolonged exposure to NH 2 htau. The specificity of these biological effects is supported by the lack of any significant change, either on neuronal activity or on cellular integrity, shown by administration of its reverse sequence counterpart which behaves as an inactive control, likely due to a poor conformational flexibility which makes it unable to dynamically perturb biomembrane-like environments. Our results demonstrate that one of the AD-relevant, soluble and secreted N-terminally truncated tau forms can early contribute to pathology outside of neurons causing alterations in synaptic activity at presynaptic level, independently of overt neurodegeneration.


Primary giant aggressive amelanotic duodenal melanoma.
Primary malignant melanoma of the gastrointestinal tract is extremely rare. A 35-year-old man presented with complaints of abdominal pain and weight loss. Contrast enhanced computed tomography showed a large mass involving the duodenum and the superior mesenteric vessels. Upper gastrointestinal endoscopy demonstrated a large, friable mass along the duodenal wall and biopsy was suggestive of malignant melanoma. A detailed physical examination and whole body imaging (positron emission tomography and computed tomography) did not reveal any other lesion. The patient underwent a pancreaticoduodenectomy with segmental resection and anastomosis of the superior mesenteric vein as well as a segmental colectomy. His postoperative recovery was uneventful. The histopathology of the operative specimen showed a malignant amelanotic melanoma arising from the duodenum with lymph nodal involvement. He received oral temozolomide. However, he developed liver metastasis at six months and again at ten months, which was managed with radiofrequency ablation both times. He is doing well at 32 months of follow-up review. Multimodality treatment including surgery, adjuvant chemotherapy and salvage therapy appears to be a promising tool for achieving long-term survival in such patients.


Enhancement of the antituberculosis activity of weak acids by inhibitors of energy metabolism but not by anaerobiosis suggests that weak acids act differently from the front-line tuberculosis drug pyrazinamide.
Mycobacterium tuberculosis is uniquely susceptible to weak acids compared with other mycobacteria or bacteria. The antituberculosis activity of the front-line drug pyrazinamide (PZA), a weak acid (pyrazinoic acid) precursor, can be enhanced by inhibitors of energy metabolism and anaerobiosis. Here, we investigated the effect of inhibitors of energy metabolism and anaerobiosis on weak acid activity against M. tuberculosis in general. The susceptibility of M. tuberculosis to benzoic acid (BA) esters and amides was determined alone and in the presence of inhibitors of energy metabolism such as N,N'-dicyclohexylcarbodiimide (DCCD) and azide and also under anaerobic conditions in the form of MIC and drug exposure followed by colony count. Some BA esters such as propyl hydroxybenzoic acid and 4-dodecyloxylbenzoic acid had significant activity whereas amides of BA had no activity. As for PZA, inhibitors of energy metabolism DCCD and azide enhanced the antituberculosis activity of weak acids under normal atmospheric oxygen tension. However, unlike PZA, weak acids did not show antituberculosis activity and the inhibitors of energy metabolism did not enhance the weak acid activity under anaerobic conditions. The enhancement of weak acid activity by inhibitors of energy metabolism for M. tuberculosis was not seen in other bacterial species such as Helicobacter pylori. These results suggest that while the antituberculosis activity of weak acids can be enhanced by inhibitors of energy metabolism as for PZA, weak acids act differently from PZA in that they were inactive against M. tuberculosis under anaerobic conditions. The significance of these findings is discussed in the context of the unique physiology of M. tuberculosis and the development of new tuberculosis drugs.


Divergence of group a rotavirus with genetic variations before and after introduction of rotavirus vaccines in northern Taiwan.
Despite the development of vaccines in 2006, rotavirus is still a major cause of acute gastroenteritis worldwide. This study was performed to analyze the presence of circulating rotaviruses before and after the introduction of rotavirus vaccines to allow phylogenetic comparisons of vaccine strains in northern Taiwan.Rotavirus genotyping and sequencing of rotavirus VP7 and VP4 PCR products were performed by Reverse Transcriptase Polymerase Chain Reaction and DNA autosequencing. Phylogenies were constructed by the neighbor-joining and maximum-likelihood methods using CLUSTAL W software included in the MEGA software package (version 6.0).Between April 2004 and December 2012, a total of 101 rotavirus specimens from pediatric patients with acute gastroenteritis hospitalized in Chang Gung Children's Hospital were amplified, and their VP4 and VP7 sequences were determined. These 101 specimens consisted of 55 pre-vaccine strains (G1 [13, 23.6%], G2 [12, 21.8%], G3 [16, 29.1%], and G9 [14, 25.5%]) and 46 post-vaccine strains (G1 [25, 54.3%], G2 [12, 26.1%], G3 [5, 10.9%], and G9 [4, 8.7%]). The most common combination of the G and P types was G2P[4], accounting for 36% cases, followed by G9P[8] (25%), G1P[8] (20%), G3P[4] (15%), G3P[8] (10%), G1P[4] (5%), and G2P[8] (5%). Phylogenetic analysis showed that only the G1 and P[8] genotypes clustered in the same lineages with the rotavirus vaccine strains.Based on our results, the inclusion of G9, modified G2 and G3 with target lineages, and the combination G2P[4] and G9P[8] in the rotavirus vaccines in Taiwan is warranted as a vaccination strategy.


Resonance Frequency Analysis to Evaluate the Effect of Different Drilling Techniques on Implant Stability at Different Time Intervals: A Randomized Clinical Trial.
To evaluate the effect of different drilling techniques on implant stability at different time intervals. Patients were randomly allotted into three groups based on drilling technique for osteotomy: conventional drilling technique; simplified drilling technique; or modified conventional drilling technique. In 30 patients (n = 10 each group), a total of 44 implants were placed. In the conventional drilling technique, drills with increasing diameters were used. In the simplified drilling technique, only pilot and final-diameter drills were used. In the modified conventional drilling technique, all the drills were used in sequential order in the clockwise direction except the last drill, which was used in the counterclockwise direction. Implant stability quotient was recorded immediately after placing implants and at 1 and 3 months. Statistical analysis was performed with two-way analysis of variance (ANOVA) and Student t test. Two-way ANOVA showed that drilling technique (P < .001) and time (P = .002) did have a statistically significant effect on implant stability quotient. The modified conventional drilling technique showed a drop in secondary implant stability at 1 month that was negligible compared to the other techniques. After 1 month, there was a significant increase in implant stability quotient with the modified conventional drilling technique compared to the conventional drilling technique (P = .001). The least crestal bone loss during 3 months of follow-up was with the modified conventional drilling technique (0.37 ± 0.06). Secondary stability increased with the modified conventional drilling technique in 3 months and showed a negligible drop at 1 month. This novel drilling technique had an early shift from a decrease to an increase in stability pattern, along with the least crestal bone loss at 3 months.


Berberine and total base from rhizoma coptis chinensis attenuate brain injury in an aluminum-induced rat model of neurodegenerative disease.
To investigate the protective effects of the total base from rhizoma coptis chinensis (CTB) and berberine (Ber) on neurodegeneration induced by aluminum overload in rats. The study took place in the Department of Pharmacology, Chongqing Medical University, Chongqing, China, between February 2005 and May 2007. Wistar rats were divided into control group, model group, Ber-treated group, CTB (55 mg/kg and 110 mg/kg)-treated group, and nimodipine-treated group (n=20). A rat brain damage model was established via intragastric administration of 400 mg/kg element aluminum once a day, 5 days a week for 12 weeks. The CTB, Ber, and nimodipine were intragastrically administered 4 hours after each aluminum administration for 12 weeks. The morphological changes of the neurons of the rat hippocampus and the changes of rat learning and memory functions were observed. The superoxide dismutase (SOD), choline acetyltransferase (ChAT), acetylcholinesterase (AchE), and monoamine oxidase-B (MAO-B) activities and malondialdehyde (MDA) content, as well as the MAO-B expression in the rat brain were examined. The CTB, Ber, and nimodipine significantly improved the learning and memory ability impairment and hippocampal neuronal death. The CTB, Ber, and nimodipine also significantly blunted the decrease of SOD and ChAT activities, and the increase of MDA content, AchE activities, and MAO-B expressions and activity in the aluminum-overload rats. The CTB and Ber have protective effects on neurodegeneration induced by aluminum overload. The CTB (110 mg/kg) has more powerful neuroprotection than Ber.


Scanning Ion Conductance Microscopy.
Scanning ion conductance microscopy (SICM) has emerged as a versatile tool for studies of interfaces in biology and materials science with notable utility in biophysical and electrochemical measurements. The heart of the SICM is a nanometer-scale electrolyte filled glass pipette that serves as a scanning probe. In the initial conception, manipulations of ion currents through the tip of the pipette and appropriate positioning hardware provided a route to recording micro- and nanoscopic mapping of the topography of surfaces. Subsequent advances in instrumentation, probe design, and methods significantly increased opportunities for SICM beyond recording topography. Hybridization of SICM with coincident characterization techniques such as optical microscopy and faradaic electrodes have brought SICM to the forefront as a tool for nanoscale chemical measurement for a wide range of applications. Modern approaches to SICM realize an important tool in analytical, bioanalytical, biophysical, and materials measurements, where significant opportunities remain for further exploration. In this review, we chronicle the development of SICM from the perspective of both the development of instrumentation and methods and the breadth of measurements performed.


Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis.
The B-cell activation markers CXCL13, sCD23, sCD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of marker-disease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lymphoma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope = 28, Ptrend = 7.279 × 10-10). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. Cancer Res; 77(6); 1408-15. ©2017 AACR.


The role of participatory music making in supporting people with dementia in hospital environments.
Background Improving the quality of care for people with dementia in general hospitals is a key priority. Creative activities including music have been examined for their potential role in enhancing quality of life for people with dementia, although relatively few studies have evaluated their use in acute hospital settings. Methods A mixed methods study examined the effects of a ten week period of weekly music sessions on the wellbeing of patients with dementia and on the ward environment in an acute elderly care service in a UK hospital. Potential effects of the music project on the ward environment were examined by comparing descriptive quantitative ward level data for two equivalent time periods, one with music and one with no music. The impact of the activity on participants' wellbeing was assessed using observational data as well as semi-structured interviews and focus groups with patients, visitors, the musician and staff. Results Ward level data were available for 85 patients with a dementia diagnosis who had stayed on the wards during the study periods. Comparison between the two periods showed a number of differences between the music and the non-music time periods, including a reduction in prescription of antipsychotic drugs. However, many factors could have contributed to the differences in the ward environment. Observational data revealed nuanced responses to music and suggested that participants generally enjoyed the activity. The impacts of music making were mediated strongly by staff responses and hospital organisation. Conclusion Data from this limited pilot study suggest that music is a useful intervention for enhancing patient and staff experiences and improving care in acute dementia care environments. The suggestion that use of anti-psychotic drugs may be reduced when music is present warrants further research.


Biochemical Characterization of a Novel Exo-Type PL7 Alginate Lyase VsAly7D from Marine Vibrio sp. QY108.
Brown algae is a kind of renewable resource for biofuels production. As the major component of carbohydrate in the cell walls of brown algae, alginate can be degraded into unsaturated monosaccharide by exo-type alginate lyases, then converted into 4-deoxy-L-erythro-5-hexoseulose uronate (DEH) by a non-enzyme reaction, which is an important raw material for the preparation of bioethanol. In our research, a novel exo-type alginate lyase, VsAly7D, belonging to the PL7 family was isolated from marine bacterium Vibrio sp. QY108 and recombinantly expressed in Escherichia coli. The purified VsAly7D demonstrated the highest activity at 35 °C, whereas it still maintained 46.5% and 83.1% of its initial activity at 20 °C and 30 °C, respectively. In addition, VsAly7D exhibited the maximum activity under alkaline conditions (pH 8.0), with the simultaneously remaining stability between pH 8.0 and 10.0. Compared with other reported exo-type enzymes, VsAly7D could efficiently degrade alginate, poly-β-D-mannuronate (polyM) and poly-α-L-guluronate (polyG) with highest specific activities (663.0 U/mg, 913.6 U/mg and 894.4 U/mg, respectively). These results showed that recombinant VsAly7D is a suitable tool enzyme for unsaturated alginate monosaccharide preparation and holds great promise for producing bioethanol from brown algae.


Solifenacin significantly improves all symptoms of overactive bladder syndrome.
Overactive bladder syndrome (OAB) is a chronic condition characterised by urgency, with or without associated urge incontinence. Solifenacin succinate is a once daily, bladder selective antimuscarinic available in two doses (5 and 10 mg). The recommended dose is 5 mg once daily and can be increased to 10 mg once daily if 5 mg is well tolerated. This article presents pooled efficacy and safety data from four large, placebo-controlled, multinational phase III trials of solifenacin succinate with a total enrolment of over 2800 patients. Data from these trials show that solifenacin 5 and 10 mg once daily is significantly more effective than placebo at reducing urgency, incontinence, micturition frequency and nocturia and at increasing volume voided per micturition. Adverse events were mainly mild-to-moderate in all treatment groups. The results of these phase III trials support the use of solifenacin in the treatment of OAB.


Associated Pulmonary Hypertension Is an Independent Contributor to Exercise Intolerance in Chronic Fibrosing Interstitial Pneumonias.
Associated pulmonary hypertension (APH) is frequently observed in fibrosing interstitial pneumonias (FIP), such as idiopathic pulmonary fibrosis (IPF). APH is associated with worse prognosis, but it remains unclear whether it is associated with greater functional impairment. Six-minute walk distance (6MWD) is widely used to assess functional capacity in pulmonary hypertension and FIP. To investigate if APH independently contributes to exercise intolerance in FIP, irrespective of the extent of underlying fibrosis. Patients diagnosed with FIP (September 2009 to June 2017) were included in the study if they underwent right heart catheterization, high-resolution chest computed tomography (HRCT), and 6MWD within 3 months. Recruitment was not limited only to patients undergoing lung transplant assessment. APH was defined as mean pulmonary artery pressure (mPAP) ≥25 mm Hg. The extent of fibrosis was quantified on HRCT using a visual fibrosis score by 2 separate observers. Seventy-two patients (60 with IPF) were identified. Fifty-five patients had APH. mPAP was not significantly different in subgroups stratified according to the extent of fibrosis on HRCT. Pulmonary vascular resistance (PVR) was the strongest predictor of 6MWD on both univariate and stepwise regression analyses, and remained so considering only patients with normal wedge pressure (< 15 mm Hg) (n = 61). HRCT fibrosis score and pulmonary function tests did not significantly correlate with 6MWD. In patients with FIP, PVR is a significant contributor of 6MWD, independently from the extent of fibrosis on HRCT. These results strengthen both the rationale to use 6MWD as endpoint in FIP and to target APH with specific therapies.


Women's education and the timing of marriage and childbearing in the next generation: evidence from rural Bangladesh.
In traditional settings where early marriage and early childbearing persist, decisions about age at marriage are often made by parents, and mothers-in-law tend to have considerable influence in hastening the initiation of childbearing. This study analyzes data from a 2002 survey in six villages in rural Bangladesh to test the hypothesis that daughters of women with more education marry later and that daughters-in-law of more educated women initiate childbearing at a slower rate. Using Cox proportional hazard models, we find significant associations between the educational level of mothers and the age at marriage of their daughters and between the educational level of mothers-in-law and the timing offirst birth among their daughters-in-law, although the association between the former attenuates when controlling for other variables. We also find that these associations do not appear to be mediated by the senior women's level of empowerment. We conclude that in rural Bangladesh there is a significant relationship between female education in one generation and the timing of marriage and childbearing in the next.


A comparison of first-responder automated external defibrillator (AED) application rates and characteristics of AED training.
To determine whether there were associations between the characteristics of first-responder automated external defibrillator (AED) training and AED application rates. This multicenter retrospective cohort study analyzed data from ten emergency medical services systems where first responders were trained and equipped with AEDs. Data were provided for all out-of-hospital cardiac arrests (OHCAs) occurring over two years, including whether the first-responder AED was applied (pads attached to patient). Systems were surveyed to determine the characteristics of their initial and continuing AED training. Data were analyzed using odds ratios (ORs) with 95% confidence intervals (95% CIs). Overall, the first-responder AED was applied to 53% of 2,181 OHCAs. First responders applied AEDs to 60% of OHCAs when a national AED training curriculum was used and to 49% of OHCAs when a locally created curriculum was used (OR=1.58; 95% CI=1.32-1.88). First responders applied AEDs to 61% of OHCAs when they were trained to the level of Certified First Responder or higher and to 28% of OHCAs when they were trained only in cardiopulmonary resuscitation (OR=3.97; 95% CI=3.20-4.93). First responders applied AEDs to 66% of OHCAs when they each had an opportunity to apply the AED during continuing training and to 17% of OHCAs when they did not have this opportunity (OR=9.04; 95% CI=7.15-11.42). First responders applied AEDs to 59% of OHCAs when they had not received continuing training within one year of their initial training and to 42% of OHCAs when they had received continuing training in the first year (OR=2.00; 95% CI=1.67-2.40). Use of a national AED training curriculum, training to the level of Certified First Responder or higher, and the ability for each first responder to apply the AED during continuing training were associated with higher AED application rates. Continuing training within the first year did not appear to be as important as actually using the AED during the training.


Successful triple combination therapy of disseminated absidia corymbifera infection in an adolescent with osteosarcoma.
Mucormycosis are opportunistic infections mostly observed in immunocompromised patients. We report the case of a 13-year-old girl who suffered a systemic mucormycosis without presenting the usual risk factors. She was undergoing antineoplastic chemotherapy for advanced osteosarcoma of the femur with an uncommunicative pathologic fracture and pulmonary metastasis. Absidia corymbifera was isolated from skin lesions at the primary tumor site. She subsequently developed fungal pulmonary localizations and blood vessel thrombosis. Surgical treatment together with systemic, high doses of liposomal amphotericin B, posaconazole, and caspofungin cured the local infection and controlled systemic lesions. Unfortunately, the break in chemotherapy led to pulmonary metastasis progression.


Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants.
Effective control of body weight and energy homeostasis requires stringent regulation of caloric intake and energy expenditure. Gut-brain interactions comprise a central axis for the control of energy homeostasis by integrating the intake of nutrients with an effective utilization of ingested calories either by storage or by expenditure as cellular fuel. Ghrelin, a stomach-derived peptide, is the only known circulating orexigenic hormone. It is acylated with a medium-chain fatty acid by the enzyme ghrelin O-acetyltransferase (GOAT) and displays a broad range of activity, from central control of food intake to peripheral functions such as gastric emptying and insulin secretion. PYY, a peptide produced by L cells of the small intestine and rectum, has been shown to inhibit gut motility and is proposed to stimulate a powerful central satiety response. In recent years, pharmacological studies in animals and clinical studies in humans have contributed to our knowledge of principal ghrelin and PYY actions. However, valuable findings from studies using ghrelin-deficient mice, ghrelin receptor [growth hormone secretagogue receptor-1a (GHSR1a)]-deficient mice, double-knockout mice (for ghrelin and GHSR), and GOAT-deficient or -overexpressor mice, as well as mice deficient for PYY or neuropeptide Y receptors have allowed better definition of the actual physiological functions of ghrelin and PYY. This review summarizes findings from mutant mouse studies with emphasis on respective gene knockout and transgenic animals and describes how these studies contribute to the current understanding of how endogenous ghrelin and PYY as two major representatives of endocrine gut-brain communications may regulate energy and glucose homeostasis.


Content validation of a Critical Appraisal Tool for Reviewing Analgesia Studies (CATRAS) involving subjects incapable of self-reporting pain.
This article reports the content validation of a Critical Appraisal Tool designed to Review the quality of Analgesia Studies (CATRAS) involving subjects incapable of self-reporting pain and provide guidance as to the strengths and weakness of findings. The CATRAS quality items encompass 3 domains: level of evidence, methodological soundness, and grading of the pain assessment tool. To validate a critical appraisal tool for reviewing analgesia studies involving subjects incapable of self-reporting pain. Content validation was achieved using Delphi methodology through panel consensus. A panel of 6 experts reviewed the CATRAS in 3 rounds and quantitatively rated the relevance of the instrument and each of its quality items to their respective domains. Content validation was achieved for each item of the CATRAS and the tool as a whole. Item-level content validity index and kappa coefficient were at least greater than 0.83 and 0.81, respectively, for all items except for one item in domain 2 that was later removed. Scale-level content validity index was 97% (excellent content validity). This 67-item critical appraisal tool may enable critical and quantitative assessment of the quality of individual analgesia trials involving subjects incapable of self-reporting pain for use in systematic reviews and meta-analysis studies.


Engineering core-shell hollow-sphere Fe3O4@FeP@nitrogen-doped-carbon as an advanced bi-functional electrocatalyst for highly-efficient water splitting.
Given the rapidly increasing energy demand and environmental pollution, to achieve energy conservation and emission reduction, hydrogen production has emerged as a promising alternative to traditional fossil fuels because of its high gravimetric energy density, and renewable and environmentally friendly characteristics. Herein, a core-shell hollow-sphere Fe3O4@FeP@nitrogen-doped-carbon (labeled as H-Fe3O4@FeP@NC) with a dual-interface, novel morphology, and superior conductivity is prepared as an advanced bi-functional electrocatalyst for electrochemical overall water splitting using a collaborative strategy comprising of facile self-assembly and phosphating. The prepared catalyst exhibits superior electrocatalytic activity compared to H-Fe3O4@NC and H-Fe3O4 for oxygen evolution reaction (OER) and hydrogen evolution reaction (HER). Additionally, the overpotential of H-Fe3O4@FeP@NC for OER/HER (258/165 mV at 10 mA/cm2) is significantly lower than those of H-Fe3O4@NC (274/209 mV) and H-Fe3O4 (287/213 mV) at 10 mA/cm2. Meanwhile, the as-synthesized H-Fe3O4@FeP@NC, as an electrode pair, displays a low cell voltage of 1.69 V at 10 mA/cm2 and excellent stability after 100 h, indicating its practical application for overall water splitting. This work presents a practical and economical strategy toward the fabrication of catalyst for efficient water splitting and fuel cell.


The prognostic value of KRAS mutated plasma DNA in advanced non-small cell lung cancer.
Lung cancer is one of the most common malignant diseases worldwide and associated with considerable morbidity and mortality. New agents targeting the epidermal growth factor system are emerging, but only a subgroup of the patients will benefit from the therapy. Cell free DNA (cfDNA) in the blood allows for tumour specific analyses, including KRAS-mutations, and the aim of the study was to investigate the possible prognostic value of plasma mutated KRAS (pmKRAS) in patients with non-small cell lung cancer (NSCLC). Patients with newly diagnosed, advanced NSCLC eligible for chemotherapy were enrolled in a prospective biomarker trial. A pre-treatment blood sample was drawn and subsequently DNA was extracted and pmKRAS analysed. The patients received carboplatin (AUC5) i.v. day 1 and vinorelbine (30mg/m(2) i.v. day 1 and 60mg/m(2) p.o. day 8) for a maximum of six cycles. Response to chemotherapy was evaluated according to RECIST v.1.0 by CT scans of the chest and upper abdomen. The presence of pmKRAS at baseline was assessed by an in-house qPCR method. The primary endpoint was overall survival (OS). Secondary end-points were progression free survival (PFS) and overall response rate. The study included 246 patients receiving a minimum of 1 treatment cycle, and all but four were evaluable for response according to RECIST. Forty-three patients (17.5%) presented with a KRAS mutation. OS was 8.9 months and PFS by intention to treat 5.4 months. Patients with a detectable plasma-KRAS mutation had a significantly shorter OS and PFS compared to the wild type (WT) patients (median OS 4.8 months versus 9.5 months, HR 1.87, 95% CI 1.23-2.84, p=0.0002 and median PFS 3.0 months versus 5.6 months, HR 1.60, 95% CI 1.09-2.37, p=0.0043). A multivariate Cox regression analysis confirmed the independent prognostic value of pmKRAS in OS but not in PFS. The response rate to chemotherapy was significantly lower in the group of patients with a mutation compared to WT (p<0.0001). The presence of KRAS mutations in plasma may be a marker of poor prognosis and may also hold predictive value. Further validation in an independent cohort is highly needed.


The effect of climate on the presence of Culicoides imicola in Italy.
A model was developed to classify the Italian territories in relation to their suitability to harbour populations of Culicoides imicola and, as a consequence, also able to sustain a bluetongue (BT) epidemic. Italy was subdivided into 3507 10 x 10 km cells. In 546 cells at least one collection was made. The cell was considered the unit for all subsequent analyses. Culicoides were collected using Onderstepoort-type blacklight traps. Some traps were operated weekly at chosen sites; the remainder were moved almost daily to new sites. Only the results obtained during the peak August-November period were used, to exclude bias caused by the seasonality of C. imicola. Climate data for the period 1999-2001 were obtained from 80 weather stations. Multiple logistic regression was performed using the presence or absence of C. imicola in a specific cell as the dependent variable. Annual means of daily values for minimum temperature and minimum relative humidity, and the mean altitude above sea level, were the independent variables. The probability of occurrence of C. imicola in each grid cell was used to create a prediction map for Italy. The model was able to correctly classify 77.5% of the 546 grid cells in which at least one collection had been made. Culicoides imicola was found frequently through much of Sardinia, in parts of southern Italy, and further north along the Tyrrhenian coast, but was absent from along most of the Adriatic coast, and the internal mainland, and from most of Sicily. Six detailed maps are provided. Also mapped are areas where the probability of the occurrence of C. imicola is lower than 5%. This identification of possible mountainous C. imicola-free areas in central Italy could facilitate safer animal trade and transhumance, even if BT infections in traded animals or moving stock, were to go undetected. Needless to say this depends upon no cool-adapted species of Culicoides being involved in the transmission of BT disease.


Hepatitis C infection among injection drug users in Stockholm Sweden: prevalence and gender.
Hepatitis C virus (HCV) infection is widespread among injection drug users. Young women seem to be at higher risk of acquiring HCV. To optimize future intervention and prevention measures, we studied the epidemiology of human immunodeficiency virus (HIV), hepatitis B (HBV), and HCV infection among men and women. Inclusion criteria for this cross-sectional multicentre study were: history of ever injecting drugs, age > 18 y, and no previous HIV diagnosis. In 310 participants, plasma/serum samples were analysed for HBV, HIV and HCV (anti-HCV, HCV-RNA, and HCV genotype). HCV antibodies were noted in 268 (86.5%) participants, of whom 207 (77.0%) also had detectable HCV-RNA. Genotypes 1 and 3 dominated, at 35.9% and 33.0%, respectively. Women acquired HCV (but not HBV) to a significantly higher degree (RR 2.97, 95% confidence interval 1.11-7.93) during the first y of injecting drugs. They also recovered spontaneously from HCV infection more frequently (RR 2.49, 95% CI 1.28-4.53). The HCV prevalence of about 50% within 2 y after initiation of injection drug use underlines the need for early intervention efforts. Possible causes for higher HCV prevalence and the implications of favourable spontaneous recovery rates among women should be considered when designing intervention and prevention measures.


EEG Dominant Frequency Peak Differentiates Between Alzheimer's Disease and Frontotemporal Lobar Degeneration.
We investigated the power of EEG as biomarker in differential diagnosis of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). EEG was recorded from 106 patients with AD or FTLD, of which 37 had a definite diagnosis, and 40 controls. Dominant frequency peaks were extracted for all 19 channels, for each subject. The average frequency of the largest dominant frequency peaks (maxpeak) was significantly lower in AD than FTLD patients and controls. Based on ROC analysis, classification could be made with diagnostic accuracy of 78.9%. Our findings show that quantitative analysis of EEG maxpeak frequency is an easy and useful measure for differential dementia diagnosis.


Effect of Changes in MS Diagnostic Criteria Over 25 Years on Time to Treatment and Prognosis in Patients With Clinically Isolated Syndrome.
To explore whether time to diagnosis, time to treatment initiation, and age to reach disability milestones have changed in patients with clinically isolated syndrome (CIS) according to different multiple sclerosis (MS) diagnostic criteria periods. This retrospective study was based on data collected prospectively from the Barcelona-CIS cohort between 1994 and 2020. Patients were classified into 5 periods according to different MS criteria, and the times to MS diagnosis and treatment initiation were evaluated. The age at which patients with MS reached an Expanded Disability Status Scale (EDSS) score ≥3.0 was assessed by Cox regression analysis according to diagnostic criteria periods. Last, to remove the classic Will Rogers phenomenon by which the use of different MS criteria over time might result in a changes of prognosis, the 2017 McDonald criteria were applied, and age at EDSS score ≥3.0 was assessed by Cox regression. In total, 1,174 patients were included. The median time from CIS to MS diagnosis and from CIS to treatment initiation showed a 77% and 82% reduction from the Poser to the McDonald 2017 diagnostic criteria periods, respectively. Patients of a given age diagnosed in more recent diagnostic criteria periods had a lower risk of reaching an EDSS score ≥3.0 than patients of the same age diagnosed in earlier diagnostic periods (reference category Poser period): adjusted hazard ratio (aHR) 0.47 (95% confidence interval 0.24-0.90) for McDonald 2001, aHR 0.25 (0.12-0.54) for McDonald 2005, aHR 0.30 (0.12-0.75) for McDonald 2010, and aHR 0.07 (0.01-0.45) for McDonald 2017. Patients in the early-treatment group displayed an aHR of 0.53 (0.33-0.85) of reaching age at EDSS score ≥3.0 compared to those in the late-treatment group. Changes in prognosis together with early-treatment effect were maintained after the exclusion of possible bias derived from the use of different diagnostic criteria over time (Will Rogers phenomenon). A continuous decrease in the time to MS diagnosis and treatment initiation was observed across diagnostic criteria periods. Overall, patients diagnosed in more recent diagnostic criteria periods displayed a lower risk of reaching disability. The prognostic improvement is maintained after the Will Rogers phenomenon is discarded, and early treatment appears to be the most likely contributing factor.


Effective utilization of incinerated municipal solid waste incineration ash: zeolitic material synthesis and silica extraction.
In this study the effective utilization of two types of municipal solid waste incinerator (MSWI) ashes, namely air-cooled ash (ACS) and water-cooled ash (WCS) samples obtained from a municipal solid waste incineration plant, was examined by applying zeolitic material synthesis and silica extraction. The influence of the experimental conditions including the ratio of sample : NaOH solution, the reaction temperature and time, and the concentration of NaOH solution were investigated. The results for the 25 experimental trials can be summarized as: (1) the formation of tobermorite and/or pectolite-1A as a major component in most conditions; (2) the synthesis of hydroxycancrinite as a major phase at 200 degrees C; (3) a dramatic increase in the extracted SiO(2) yield at 1 : 30 value of sample : NaOH ratio and 200 degrees C, even at short reaction times; and (4) relatively high SiO(2) yields for WCS ashes rather than ACS ashes. An increase in the reaction time improved the quantity of synthesized zeolitic materials. The reaction temperature determined the type of zeolite. An increase in the NaOH concentration can be an essential factor to improve zeolitic material synthesis, but it significantly reduced the yield of SiO(2) extraction. In conclusion, suitable conditions for obtaining both SiO(2) extraction and synthesized zeolites from the ashes of the incinerated solid waste materials should be: 200 degrees C reaction temperature; a 1 : 30 (g : mL) value for the sample : NaOH ratio; 2 mol L(-1) NaOH concentration; and a reaction time of more than 24 h.


Salmonella induces macrophage death by caspase-1-dependent necrosis.
We provide evidence that Salmonella typhimurium kills phagocytes by an unusual proinflammatory mechanism of necrosis that is distinguishable from apoptosis. Infection stimulated a distinctly diffuse pattern of DNA fragmentation in macrophages, which contrasted with the marked nuclear condensation displayed by control cells undergoing chemically induced apoptosis. In apoptotic cells, DNA fragmentation and nuclear condensation result from caspase-3-mediated proteolysis; caspases also subvert necrotic cell death by cleaving and inactivating poly ADP-ribose polymerase (PARP). Caspase-3 was not activated during Salmonella infection, and PARP remained in its active, uncleaved state. Another hallmark of apoptosis is sustained membrane integrity during cell death; yet, infected macrophages rapidly lost membrane integrity, as indicated by simultaneous exposure of phosphatidylserine with the uptake of vital dye and the release of the cytoplasmic enzyme lactate dehydrogenase. During experimentally induced necrosis, lethal ion fluxes through the plasma membrane can be prevented by exogenous glycine; similarly, glycine completely blocked Salmonella-induced cytotoxicity. Finally, inhibition of the interleukin (IL)-1-converting enzyme caspase-1 blocked the death of infected macrophages, but not control cells induced to undergo apoptosis or necrosis. Thus, Salmonella-infected macrophages are killed by an unusual caspase-1-dependent mechanism of necrosis.


Organogenic responses in tissue culture of srd mutants of Arabidopsis thaliana.
In Arabidopsis thaliana, shoot redifferentiation and root redifferentiation can be induced at high frequency from hypocotyl and root explants by a two-step culture method. Tissues are precultured on callus-inducing medium and then transferred onto shoot-inducing medium for shoot redifferentiation or onto root-inducing medium for root redifferentiation. In an attempt to dissect these organogenic processes genetically, we characterized the responses in tissue culture of srd1, srd2 and srd3 mutants that were originally isolated as temperature-sensitive strains with defects in shoot redifferentiation (Yasutani, I., Ozawa, S., Nishida, T., Sugiyama, M. and Komamine, A. (1994) Plant Physiol. 105, 815-822). These mutants exhibited temperature sensitivity at different steps of organogenesis, which allowed the identification of three states associated with organogenic competence: IC (incompetent); CR (competent with respect to root redifferentiation); and CSR (competent with respect to shoot and root redifferentiation). Hypocotyl explants were shown to be in the IC state at the initiation of culture and to enter the CSR state, via the CR state, during preculture on callus-inducing medium, whereas root explants seemed to be in the CR state at the initiation of culture. The transition from IC to CR and that from CR to CSR appeared to require the functions of SRD2 and SRD3, respectively. It appears that explants in the CSR state redifferentiate shoots with the aid of the products of SRD1 and SRD2 when transplanted onto shoot-inducing medium. Histological examination of the srd mutants revealed that the function of SRD2 is required not only for organogenesis but also for the reinitiation of cell proliferation in hypocotyl explants during culture on callus-inducing medium. Linkage analysis using RFLP markers indicated that SRD1, SRD2, and SRD3 are located at the lower region, the central region, and the upper region of chromosome 1, respectively.


The NCI Alliance for Nanotechnology in Cancer: achievement and path forward.
Nanotechnology is a 'disruptive technology', which can lead to a generation of new diagnostic and therapeutic products, resulting in dramatically improved cancer outcomes. The National Cancer Institute (NCI) of National Institutes of Health explores innovative approaches to multidisciplinary research allowing for a convergence of molecular biology, oncology, physics, chemistry, and engineering and leading to the development of clinically worthy technological approaches. These initiatives include programmatic efforts to enable nanotechnology as a driver of advances in clinical oncology and cancer research, known collectively as the NCI Alliance for Nanotechnology in Cancer (ANC). Over the last 5 years, ANC has demonstrated that multidisciplinary approach catalyzes scientific developments and advances clinical translation in cancer nanotechnology. The research conducted by ANC members has improved diagnostic assays and imaging agents, leading to the development of point-of-care diagnostics, identification and validation of numerous biomarkers for novel diagnostic assays, and the development of multifunctional agents for imaging and therapy. Numerous nanotechnology-based technologies developed by ANC researchers are entering clinical trials. NCI has re-issued ANC program for next 5 years signaling that it continues to have high expectations for cancer nanotechnology's impact on clinical practice. The goals of the next phase will be to broaden access to cancer nanotechnology research through greater clinical translation and outreach to the patient and clinical communities and to support development of entirely new models of cancer care.


Longitudinal Analysis of the Intestinal Microbiota in Liver Transplantation.
Increasing evidence suggests that the intestinal microbiota plays an important role in liver diseases. However, the dynamics of the intestinal microbiota during liver transplantation (LT) and its potential role in clinical course remain unknown. We prospectively analyzed the intestinal microbiota of 38 patients who underwent LT in Kyoto University Hospital. We characterized the microbial compositions of fecal specimens from LT patients using a metagenomics approach by an Illumina MiSeq platform. We analyzed the diversity of microbiota sequentially from pretransplantation until 2 months after LT and also compared the microbiota during an episode of acute cellular rejection (ACR) and bloodstream infections (BSI) to the microbial composition of time-matched fecal specimens obtained from patients who did not experience ACR or BSI, respectively. Three hundred twenty fecal specimens were analyzed. Dynamic changes were observed in the microbial composition of LT recipients during the perioperative period. Over the course of LT, the mean diversity index decreased during the first 3 weeks after LT and gradually increased during our observation period. The loss of intestinal microbiota diversity was associated with high Child-Pugh scores, high model for end-stage liver disease scores, ACR, and BSI. At the family level, Bacteroides, Enterobacteriaceae, Streptococcaceae, and Bifidobacteriaceae were increased whereas Enterococcaceae, Lactobacillaceae, Clostridiaceae, Ruminococcaceae, and Peptostreptococcaceae were decreased in ACR patients. The microbiota of LT patients was associated with the severity of liver diseases and the presence of ACR and BSI. These results lay the groundwork for more comprehensive investigations of microbiota characteristics to identify diagnostic markers for transplant health and to guide intervention strategies to improve transplant outcomes.


A Predictive Risk Index for 30-day Readmissions Following Surgical Treatment of Pediatric Scoliosis.
Pediatric scoliosis often requires operative treatment, yet few studies have examined readmission rates in this patient population. The purpose of this study is to examine the incidence, reasons, and independent risk factors for 30-day unplanned readmissions following scoliosis surgery. A retrospective analysis of the American College of Surgeons National Surgical Quality Improvement-Pediatric database from 2012 to 2013 was performed. Patients undergoing spinal arthrodesis for progressive infantile scoliosis, idiopathic scoliosis, or scoliosis due to other medical conditions were identified and divided between 2 groups: patients with unplanned 30-day readmissions (Readmitted) and patients with no unplanned readmissions (Non-Readmitted). Multivariate logistic regression models were created to determine independent risk factors for readmissions. A total of 3482 children were identified, of which 120 (3.4%) had an unplanned readmission. A majority of patients had a readmission due to a surgical site complication regardless of scoliosis etiology. Risk factors for readmission included obesity (P<0.001) and posterior fusion of 13 or more vertebrae (P=0.029) for idiopathic scoliosis, impaired cognition (P=0.009) for progressive infantile scoliosis, and pelvic fixation (P=0.025) and American Society of Anesthesiologist ≥3 (P=0.048) for scoliosis due to other conditions. We present 30-day readmissions risk factors based on independent patient and procedural risk factors. This may be useful in the clinical management of patients following scoliosis surgery, specifically for the role of preoperative and predischarge risk stratification.


Plasma proteomic analysis of simian immunodeficiency virus infection of rhesus macaques.
Lentiviral replication in its target cells affects a delicate balance between cellular cofactors required for virus propagation and immunoregulation for host defense. To better elucidate cellular proteins linked to viral infection, we tested plasma from rhesus macaques infected with the simian immunodeficiency viral strain SIVsmm9, prior to, 10 days (acute), and 49 weeks (chronic) after viral infection. Changes in plasma protein content were measured by quantitative mass spectrometry by isobaric tags for absolute and relative quantitation (iTRAQ) methods. An 81 and 232% increase in SERPINA1 was seen during acute and chronic infection, respectively. Interestingly, gelsolin, vitamin D binding protein and histidine rich glycoprotein were decreased by 45% in acute conditions but returned to baseline during chronic infection. When compared to uninfected controls, a 48-103% increase in leucine rich alpha 2-glycoprotein, vitronectin, and ceruloplasmin was observed during chronic viral infection. Observed changes in plasma proteins expression likely represent a compensatory host response to persistent viral infection.


Outcome of investigation of patients with presenile dementia.
Of 106 patients admitted for investigation to a neurological hospital with a presumptive diagnosis of dementia, 84 were confirmed to have intellectual impairment or loss of learning and memory function or both. A possible aetiology for the dementia was found in 36 of these 84 patients; the commonest causes discovered were intracranial mass lesions, arterial disease, and alcoholism. Fifteen of the 106 patients were found not to be demented but to have some other illness, most commonly depression. Of the whole series some 15% of the patients suffered from conditions that were amenable to treatment.


Impact of podoplanin expression in oral squamous cell carcinoma: clinical and histopathologic correlations.
Cervical lymph node metastases reduce the overall survival of patients with oral squamous cell carcinoma (OSCC) and require a neck dissection. However, elective management of a clinical N0 neck remains a controversial topic, as there are no reliable factors available predicting cervical lymph node metastases. Recent studies suggest an impact of podoplanin expression on metastatic spread to the cervical lymph nodes. Our aim was to investigate the influence of podoplanin expression on prognosis and metastatic lymphatic spread. In our retrospective study, podoplanin expression was examined in a set of 80 patients with OSCC by immunohistochemistry. We analysed associations between the level of podoplanin expression and various clinicopathologic parameters. In 67 patients (84%), podoplanin was expressed on the tumour cells. Nineteen patients (24%) showed high levels of expression. The 5-year overall survival (31%) for patients with high levels of podoplanin expression was significantly lower (p < 0.001) than for patients with low and moderate expression of podoplanin (93% and 65%, respectively). There was an association between podoplanin expression and the frequency of cervical lymph node metastases. Cervical lymph node metastases were found in 79% of the patients with high podoplanin expression, while patients with weak podoplanin expression had metastases in only 22% (p < 0.001). None of the 13 patients without podoplanin expression had cervical lymph node metastases. We concluded that podoplanin is expressed frequently in OSCC and that podoplanin expression correlates with cervical lymph node metastases and clinical outcome.


Systems analysis of the effects of the 2014-16 Ebola crisis on WHO-reporting nations' policy adaptations and 2020-21 COVID-19 response: a systematized review.
Recent case studies indicate that the 2014-2016 Ebola outbreak, one of the worst pre-2020 global biological catastrophes in modern history, helped some nations to better prepared their responses for the COVID-19 pandemic. While such national case studies explore how specific nations applied EVD-related policies in their domestic battle against the COVID-19 pandemic, there is no known study that assesses how many WHO nations learned from the West African crisis and to what scale. Applying the policy legacies analytical framework and a systematized literature review, this research examines how prior policy experiences with the 2014-16 EVD crisis as a large-scale emergent outbreak helped to inform and to condition WHO nations to proactively prepare their national policies and health systems for future threats, including ultimately COVID-19. A systematized literature review of 803 evaluated sources assesses to what extent Ebola-affected and non-affected nations directly modified governmental health systems in relation to this warning. The study further evaluates how nations with documented Ebola-related changes fared during COVID-19 compared to nations that did not. We present a categorical theoretical framework that allows for classifying different types of national response activities (termed conditioned learning). Ten (90.9%) of 11 nations that were affected by 2014-16 Ebola crisis have documented evidence of repurposing their EVD-related policies to fight COVID-19. 164 (70.0%) of 234 non-EVD-affected nations had documented evidence of specifically adapting national systems to incorporate policy recommendations developed from the 2014-16 crisis, which informed their COVID-19 responses in 2020. The shock of 2014-16 EVD outbreak affected most nations around the world, whether they experienced Ebola cases. We further develop a categorical framework that helps characterised nations previous experiences with this biological catastrophe, providing a means to analyse to what extent that individual nations learned and how these EVD-related changes helped inform their COVID-19 response. Nations that demonstrated EVD-related conditioned learning nations tended to have more stringent COVID-19 responses before April 2020 and utilized documented response mechanisms developed out of the West African crisis.


Calcium Dobesilate Restores Autophagy by Inhibiting the VEGF/PI3K/AKT/mTOR Signaling Pathway.
Objective: Calcium dobesilate (CaD), an effective drug for the treatment of diabetic microvascular complications, especially diabetic retinopathy, is widely used in the clinic. Interestingly, several studies have indicated that CaD is therapeutic for diabetic kidney disease (DKD). Recently, evidence has indicated that altered vascular endothelial growth factor (VEGF) expression and decreased autophagy are the main pathological mechanisms of proteinuria. Thus, this study was conducted to explore the effect of CaD on restoring autophagy in DKD and the possible signaling pathway between VEGF and autophagy. Methods: Obese mice with spontaneous diabetes (KK-Ay) and high-fat diet- and streptozotocin-induced diabetic mice (HFD/STZ) were used in this study. Biochemical staining, western blotting, and immunohistochemistry were conducted to determine the angioprotective effect of CaD and the underlying mechanism between autophagy and VEGF/VEGFR. Results: Our results showed that CaD was capable of reducing albuminuria and restoring renal histological changes in KK-Ay and HFD/STZ-induced diabetic mice. CaD restored autophagy by decreasing the protein expression of LC3 II, Atg5, and beclin 1 and increasing the expression of P62. Moreover, CaD reduced the activation of the autophagy-related PI3K/AKT/mTOR pathway possibly via decreasing VEGF and downregulating VEGF receptor 2. Conclusion: Overall, CaD, as a novel potential therapeutic drug for DKD, plays a key role in protecting renal function and restoring autophagy by blocking VEGF/VEGFR2 and inhibiting the PI3K/AKT/mTOR signaling pathway.


Cellular uptake behaviour, photothermal therapy performance, and cytotoxicity of gold nanorods with various coatings.
With the development of Au nanorods for a number of biomedical applications, understanding their cellular responses has become increasingly important. In this study, we systematically evaluated the cellular uptake behaviour and cytotoxicity of Au nanorods with various surface coatings, including organic cetyltrimethylammonium bromide (CTAB), poly(sodium 4-styrenesulfonate) (PSS), and poly(ethylene glycol) (PEG), and inorganic mesoporous silica (mSiO2), dense silica (dSiO2), and titanium dioxide (TiO2). The cellular behaviour of Au nanorods was found to be highly dependent on both the surface coating and the cell type. CTAB-, PSS-, and mSiO2-coated Au nanorods exhibit notable cytotoxicity, while PEG-, dSiO2-, and TiO2-coated Au nanorods do not induce cell injury. Optical imaging studies indicated that the cell type plays a preferential role in Au nanorod cellular uptake. Higher cellular uptake of Au nanorods was seen in U-87 MG, PC-3, MDA-MB-231, and RAW 264.7 cells, as opposed to HepG2 and HT-29 cells. In addition, Au nanorod cellular uptake is also highly affected by serum protein binding to the surface coating. mSiO2-, dSiO2-, and TiO2-coated Au nanorods show significantly higher cellular uptake than PSS- and PEG-coated ones, which results in a better photothermal ablation effect for Au nanorods with the inorganic surface coatings. Our study provides valuable insights into the effects of the surface modification on the biocompatibility, cellular uptake, as well as biomedical functions of Au nanorods.


The effect of PEG-coated gold nanoparticles on the anti-proliferative potential of Specific Nutrient Synergy.
The role of PEG-coated gold nanoparticles (Au NPs) on the anti-proliferative effect of Specific Nutrient Synergy (SNS) on HTLV-1 infected (C91-PL and HuT-102) and non-infected (CEM and Jurkat) malignant T-lymphocytes cells, was investigated. When PEG-coated Au NPs (of different molecular weights) were added alone, there was no effect on either viability or proliferation of the leukemic cell lines studied. Treatment of cells with SNS and PEG (5 or 10 kDa) coated Au NP reduced significantly the proliferation in all cell lines tested; this reached more than 50% reduction as compared to the control for cells treated for 96 h. Data showed that the best anti-proliferative effect was obtained using SNS and Au NP coated with PEG of molecular weights of 5 and 10 kDa with almost no effect of PEG of lower molecular weights (0.75 and 2 kDa) or higher ones (20 kDa). This was true as well for HTLV-1 infected as for non-infected malignant T-lymphocytes. Electron microscopy results showed uptake of the gold particles to Jurkat cells. All described effects are specific to leukemia cell lines, and no effects were observed with freshly activated human mononuclear lymphocytes as control.


International consensus on natural orifice specimen extraction surgery (NOSES) for gastric cancer (2019).
At present, natural orifice specimen extraction surgery (NOSES) has attracted more and more attention worldwide, because of its great advantages including minimal cutaneous trauma and post-operative pain, fast post-operative recovery, short hospital stay, and positive psychological impact. However, NOSES for the treatment of gastric cancer (GC) is still in its infancy, and there is great potential to improve its theoretical system and clinical practice. Especially, several key points including oncological outcomes, bacteriological concerns, indication selection, and standardized surgical procedures are raised with this innovative technique. Therefore, it is necessary to achieve an international consensus to regulate the implementation of GC-NOSES, which is of great significance for healthy and orderly development of NOSES worldwide.


A glycan-based approach to therapeutic angiogenesis.
Angiogenesis, the sprouting of new blood vessels from existing vasculature, involves multiple complex biological processes, and it is an essential step for hemostasis, tissue healing and regeneration. Angiogenesis stimulants can ameliorate human disease conditions including limb ischemia, chronic wounds, heart disease, and stroke. The current strategies to improve the bioavailability of pro-angiogenic growth factors, including VEGF and FGF2, have remained largely unsuccessful. This study demonstrates that small molecules, termed click-xylosides, can promote angiogenesis in the in vitro matrigel tube formation assay and the ex ovo chick chorioallantoic membrane assay, depending on their aglycone moieties. Xyloside treatment enhances network connectivity and cell survivability, thereby, maintaining the network structures on matrigel culture for an extended period of time. These effects were achieved via the secreted xyloside-primed glycosaminoglycans (GAG) chains that in part, act through an ERK1/2 mediated signaling pathway. Through the remodeling of GAGs in the extracellular matrix of endothelial cells, the glycan approach, involving xylosides, offers great potential to effectively promote therapeutic angiogenesis.


Bags and blogs: creating an ostomy experience for nursing students.
There are well over three-quarters of a million people living in the United States with an ostomy. These individuals experience many physical and emotional challenges which nurses should address during the in-patient hospitalization experience. The purpose of this educational activity was to provide undergraduate nursing students with a simulated laboratory experience which allowed the student to discuss and experience some of the challenges of living with an ostomy. Small group work, an experiential learning activity, and blogging were used to foster the cognitive, psychomotor, and affective development of the nursing students. All 134 students participated in the small group work and blogging experience and over 100 students participated in the experiential learning activity of wearing an ostomy bag overnight with the bag containing a small amount of simulated fecal material. The impact of the simulated experience is evident in the depth of awareness and emotion expressed in the blogs. The students collectively acknowledged the value of the activity and the impact the gained awareness had on their careers as nurses. The use of social technology and the provision of learning activities, not available on the clinical unit, can have a significant impact on the cognitive, psychomotor, and affective development of nursing students.


A Brief Report on an 8-Week Course of Mindfulness-based Care for Chronic Pain in the Treatment of Veterans With Back Pain: Barriers Encountered to Treatment Engagement and Lessons Learned.
Chronic pain and associated symptoms are debilitating for veterans. Medical costs of treatments are high and current treatment options, most notably with opioid medications, have been associated with significant risk. Mindfulness-based interventions appear promising for chronic pain, but require additional testing in veteran care settings. This project was designed to test the feasibility of engaging and retaining veterans with chronic lower back pain in a new mindfulness protocol tailored for veterans, mindfulness-based care for chronic pain (MBCP). Clinical outcomes were also assessed. An open pilot trial of an 8-week MBCP course that included meditation, gentle yoga, and psychoeducation. Twenty-two veterans (mean age=49.77; 18% women) were recruited from a VA Medical Center in the Northeastern US. After screening for inclusion/exclusion criteria, 20 were eligible at baseline. Veterans were assessed at baseline and postintervention for functional impairment, pain intensity and bothersomeness, depression, and mindfulness. The average number of sessions completed was 5; only 4 (20%) attended all sessions. Eleven of the 20 participants (55%) attended 5 or more sessions and had complete preintervention and postintervention visits. Five of the 11 had a clinically meaningful decrease in pain intensity and in depressive symptoms, while 6 of 11 had a meaningful decrease in pain bothersomeness and functional impairment. It was challenging to enroll and retain participants in this study, even with our intervention designed for veterans. We discuss possible adaptations and refinements in MBCP for veterans with chronic pain to enhance feasibility and improve upon these interventions.


Characterisation of chondrocyte activation in response to cytokines synthesised by a synovial cell line.
The lapine, synovial cell line, HIG-82, secretes 'chondrocyte activating factors' (CAF) which induce the synthesis of collagenase (EC 188.8.131.52), gelatinase, caseinase and prostaglandin E2 (PGE2) by confluent, monolayer cultures of lapine, articular chondrocytes. Partially purified CAF increased the production of PGE2 by chondrocytes within 3 h; in certain cultures this occurred in as little as 1 h. Increased levels of the three neutral metalloproteinases, in contrast, were only measurable in the conditioned medium after a delay of 9-18 h. After removal of the CAF, the synthesis of PGE2 reverted to basal levels within 1-4 h, but synthesis of the three proteinases remained high for an additional 4 days. Indomethacin, at concentrations which completely inhibited PGE2 synthesis, had no effect upon the coordinate induction of collagenase, gelatinase and caseinase. However, cycloheximide, alpha-amanitin and 5,6-dichlororibosylbenzimidazole (DRB) suppressed induction of these proteinases suggesting that CAF derepressed the genes coding for these enzymes. Once the chondrocytes had been activated by CAF, the inhibitors of transcription had a much weaker effect on the production of the neutral proteinases, indicating that their mRNAs may be relatively stable. In the presence of CAF, inhibition under these conditions was weaker still, possibly due to stabilisation of these mRNA molecules. Experiments with a number of compounds which modulate cellular Ca2+, cAMP or cGMP failed to support a straightforward role for these mediators in the induction of neutral metalloproteinases in chondrocytes. High concentrations of phorbol myristate acetate (PMA) provoked only a slight synthesis of these enzymes.


Use of a novel penetrating, sutureless anastomotic device in arterial microvascular anastomoses.
The advent of microsurgery and microvascular anastomosis has helped to alter the treatment of many traumatic defects as well as revolutionize the reconstructive options after extirpative surgery. These procedures, however, continue to be technically demanding and intensive. In addition, increased ischemia and operative times are known to raise complications in microsurgery, particularly in older patients. The nitinol U-clip (Medtronic, Inc., Minneapolis, MN) is a new penetrating clip applied in an interrupted fashion that eliminates knot tying and decreases operative time. This technology holds the potential for rapid, reproducible sutureless microvascular anastomoses. In addition, the surgical technique is very similar to conventional suture microanastomosis, lending itself to comparatively decreased learning curves and suitability for training programs. We present three consecutive cases of successful microsurgical anastomoses using this technology.


Nanoparticulate Quillaja saponin induces apoptosis in human leukemia cell lines with a high therapeutic index.
Saponin fractions of Quillaja saponaria Molina (QS) have cytotoxic activity against cancer cells in vitro, but are too toxic to be useful in the clinic. The toxic effect was abolished by converting QS fractions into stable nanoparticles through the binding of QS to cholesterol. Two fractions of QS were selected for particle formation, one with an acyl-chain (ASAP) was used to form killing and growth-inhibiting (KGI) particles, and the other without the acyl-chain (DSAP) was used to formulate blocking and balancing effect (BBE) particles. KGI showed significant growth inhibiting and cancer cell-killing activities in nine of 10 cell lines while BBE showed that on one cell line. The monoblastoid lymphoma cell line U937 was selected for analyzing the mode of action. Low concentrations of KGI (0.5 and 2 microg/mL) induced irreversible exit from the cell cycle, differentiation measured by cytokine production, and eventually programmed cell death (apoptosis). Compared to normal human monocytes, the U937 cells were 30-fold more sensitive to KGI. The nontoxic BBE blocked the cell killing effect of KGI in a concentration-dependent manner. In conclusion, the formulation of QS into nanoparticles has the potential of becoming a new class of anticancer agents.


A Surface-Integrated Sensor Network for Personalized Multifunctional Catheters.
Augmenting the sensing/actuating capabilities of multifunctional catheters used for minimally invasive interventions has been fostered by the reduction of transducers' sizes. However, increasing the number of transducers to benefit from the entire catheter surface is challenging due to the number of connections and/or the required integrated circuits dedicated for multiplexing the transducer signals. Modular concepts enabling personalized catheters are lacking, at all. In this work, we investigated the feasibility of a simple and daisy-chainable transducer node network for active catheters, which overcomes these limitations. Sequentially accessible nodes enabling analog interaction (including signal buffering) with transducers were designed and fabricated using miniature components suited for catheter integration. The effective sampling rate (ESR) per node for acquiring bio-signals from 10 nodes was examined for various signal-to-noise ratios. Thanks to the low circuit complexity, an ESR up to 20 kHz was achieved, which is high enough for many bio-signals.Clinical relevance- Typical daisy-chaining features, namely theoretically indefinite node extension and simple reconfiguration facilitates modularization of the catheter design. The proposed network consequently ensures application and patient-specific requirements while incorporating transducer functions over the entire catheter surface, both may improve minimally invasive interventions.


Composite THz materials using aligned metallic and semiconductor microwires, experiments and interpretation.
We report fabrication method and THz characterization of composite films containing either aligned metallic (tin alloy) microwires or chalcogenide As2Se3 microwires. The microwire arrays are made by stack-and-draw fiber fabrication technique using multi-step co-drawing of low-melting-temperature metals or semiconductor glasses together with polymers. Fibers are then stacked together and pressed into composite films. Transmission through metamaterial films is studied in the whole THz range (0.1-20 THz) using a combination of FTIR and TDS. Metal containing metamaterials are found to have strong polarizing properties, while semiconductor containing materials are polarization independent and could have a designable high refractive index. Using the transfer matrix theory, we show how to retrieve the complex polarization dependent refractive index of the composite films. Finally, we study challenges in the fabrication of metamaterials with sub-micrometer metallic wires by repeated stack-and-draw process by comparing samples made using 2, 3 and 4 consecutive drawings. When using metallic alloys we observe phase separation effects and nano-grids formation on small metallic wires.


BMAL1 and CLOCK proteins in regulating UVB-induced apoptosis and DNA damage responses in human keratinocytes.
A diverse array of biological processes are under circadian controls. In mouse skin, ultraviolet ray (UVR)-induced apoptosis and DNA damage responses are time-of-day dependent, which are controlled by core clock proteins. This study investigates the roles of clock proteins in regulating UVB responses in human keratinocytes (HKCs). We found that the messenger RNA expression of brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) genes is altered by low doses (5 mJ/cm2 ) of UVB in the immortalized HaCat HKCs cell line. Although depletion of BMAL1 or CLOCK has no effect on the activation of Rad3-related protein kinases-checkpoint kinase 1-p53 mediated DNA damage checkpoints, it leads to suppression of UVB-stimulated apoptotic responses, and downregulation of UVB-elevated expression of DNA damage marker γ-H2AX and cell cycle inhibitor p21. Diminished apoptotic responses are also observed in primary HKCs depleted of BMAL1 or CLOCK after UVB irradiation. While CLOCK depletion shows a suppressive effect on UVB-induced p53 protein accumulation, depletion of either clock gene triggers early keratinocyte differentiation of HKCs at their steady state. These results suggest that UVB-induced apoptosis and DNA damage responses are controlled by clock proteins, but via different mechanisms in the immortalized human adult low calcium temperature and primary HKCs. Given the implication of UVB in photoaging and photocarcinogenesis, mechanistic elucidation of circadian controls on UVB effects in human skin will be critical and beneficial for prevention and treatment of skin cancers and other skin-related diseases.


Microcrystalline Tyrosine (MCT®): A Depot Adjuvant in Licensed Allergy Immunotherapy Offers New Opportunities in Malaria.
Microcrystalline Tyrosine (MCT®) is a widely used proprietary depot excipient in specific immunotherapy for allergy. In the current study we assessed the potential of MCT to serve as an adjuvant in the development of a vaccine against malaria. To this end, we formulated the circumsporozoite protein (CSP) of P. vivax in MCT and compared the induced immune responses to CSP formulated in PBS or Alum. Both MCT and Alum strongly increased immunogenicity of CSP compared to PBS in both C57BL/6 and BALB/c mice. Challenge studies in mice using a chimeric P. bergei expressing CSP of P. vivax demonstrated clinically improved symptoms of malaria with CSP formulated in both MCT and Alum; protection was, however, more pronounced if CSP was formulated in MCT. Hence, MCT may be an attractive biodegradable adjuvant useful for the development of novel prophylactic vaccines.


Comparative validation of an epigenetic mortality risk score with three aging biomarkers for predicting mortality risks among older adult males.
A 'mortality risk score' (MS) based on ten prominent mortality-related cytosine-phosphate-guanine (CpG) sites was previously associated with all-cause mortality, but has not been verified externally. We aimed to validate the association of MS with mortality and to compare MS with three aging biomarkers: telomere length (TL), DNA methylation age (DNAmAge) and phenotypic age (DNAmPhenoAge) to explore whether MS can serve as a reliable measure of biological aging and mortality. Among 534 males aged 55-85 years from the US Normative Aging Study, the MS, DNAmAge and DNAmPhenoAge were derived from blood DNA methylation profiles from the Illumina HumanMethylation450 BeadChip, and TL was measured by quantitative real-time polymerase chain reaction (qRT-PCR). A total of 147 participants died during a median follow-up of 9.4 years. The MS showed strong associations with all-cause, cardiovascular disease (CVD) and cancer mortality. After controlling for all potential covariates, participants with high MS (>5 CpG sites with aberrant methylation) had almost 4-fold all-cause mortality (hazard ratio: 3.84, 95% confidence interval: 1.92-7.67) compared with participants with a low MS (0-1 CpG site with aberrant methylation). Similar patterns were observed with respect to CVD and cancer mortality. MS was associated with TL and DNAmPhenoAge acceleration but not with DNAmAge acceleration. Although the MS and DNAmPhenoAge acceleration were independently associated with all-cause mortality, the former exhibited a higher predictive accuracy of mortality than the latter. MS has the potential to be a prominent predictor of mortality that could enhance survival prediction in clinical settings.


Chimeric Antigen Receptor T Cells Targeting CD79b Show Efficacy in Lymphoma with or without Cotargeting CD19.
T cells engineered to express a chimeric antigen receptor (CAR) against CD19 have recently been FDA approved for the treatment of relapsed or refractory large B-cell lymphoma. Despite the success and curative potential of CD19 CAR T cells, several reports describing disease relapse due to antigen loss are now emerging. We developed a novel CAR construct directed against CD79b, a critical receptor for successful B-cell development that remains highly expressed in several subtypes of B-cell lymphoma, including mantle cell lymphoma (MCL). We tested CAR T cells directed against CD79b alone or in combination with CD19 targeting in a single construct, against cell line- and patient-derived xenograft models. We demonstrate CAR79b antigen-specific recognition and cytotoxicity against a panel of cell lines and patient-derived xenograft models of MCL. Importantly, we show that downregulation of CD19 does not influence surface expression of CD79b and that anti-CD79b CAR T cells alone or arranged in a dual-targeting format with a CD19 single-chain variable fragment (scFv) are able to recognize and eliminate CD19+, CD19-, and mixed CD19+/CD19-B-cell lymphoma. Our findings demonstrate that CAR T cells targeting CD79b alone or in combination have promise for treating and preventing CD19 antigen escape in B-cell lymphomas.


Effects of transmural field stimulation in isolated smooth muscle of human rectum and internal anal sphincter.
Smooth muscle preparations from the circular muscle layer of the most distal rectum and the proximal and distal human internal anal sphincter (IAS) mounted in organ baths to record isometric tension developed spontaneous tension. Transmural electrical field stimulation (TMS) induced frequency- and impulse duration-dependent relaxations sensitive to tetrodotoxin in the stimulation range of 0.5-40 Hz and 0.04-0.6 ms. Poststimulus contractions were most frequent and prominent in rectal preparations. Maximal relaxations were comparable in the three locations and were achieved at 10 Hz and 0.4 ms. The frequency inducing half-maximal response was lower in rectal strips compared with IAS. Phentolamine (10-(6) M) enhanced relaxations and diminished off-contractions at 40 Hz in distal IAS. N omega-nitro-L-arginine (L-NNA) concentration dependently inhibited both relaxations and off-contractions (10 Hz, 0.4 ms). The pD2 values (-log EC50) of L-NNA were lower in rectal muscle compared with those in IAS. L-Arginine (10-(4) M) inhibited the blocking effect of L-NNA. In one-half of the preparations, L-NNA reversed the relaxations to duration contractions (15-40 Hz), which were inhibited by atropine in rectal preparations and by phentolamine in IAS. In conclusion, excitatory innervation of the IAS is alpha-adrenergic and cholinergic in the rectum. A product of the L-arginine-nitric oxide pathway mediates the TMS-induced inhibition of the muscle and is also involved in poststimulus contractions.


Bridging gaps: a qualitative inquiry on improving paediatric rheumatology care among healthcare workers in Kenya.
Due to the paucity of paediatric rheumatologists in Kenya, it is paramount that we explore strategies to bridge clinical care gaps for paediatric rheumatology patients in order to promote early diagnosis, prompt referral, and optimal management. To identify proposed interventions which can improve the ability of non-specialist healthcare workers to care for paediatric rheumatology patients across Kenya. We conducted 12 focus group discussions with clinical officers (community physician assistants), nurses, general practitioners and paediatricians across six regions in Kenya. Interviews were conducted, audio-recorded, transcribed verbatim, and analysed using MAXQDA 2022.2 software. A total of 68 individuals participated in the study; 11 clinical officers, 12 nurses, 10 general practitioners, 27 paediatricians and eight other healthcare workers. Proposed patient interventions included patient education and psychosocial support. Community interventions were outreach awareness campaigns, mobilising financial support for patients' care, mobilising patients to access diagnostic and therapeutic interventions. Healthcare worker interventions include diagnostic, management, and referral guidelines, as well as research and educational interventions related to symptom identification, therapeutic strategies, and effective patient communication skills. In addition, it was highlighted that healthcare systems should be bolstered to improve insurance coverage and access to integrated multi-disciplinary clinical care. Study participants were able to identify potential initiatives to improve paediatric rheumatology care in Kenya. Additional efforts are underway to design, implement and monitor the impact of some of these potential interventions.


Infection with the human immunodeficiency virus: clinical manifestations and their relationship to immune deficiency. A report from the Multicenter AIDS Cohort Study.
In 1984 a large prospective study of gay and bisexual men was begun to elucidate the natural history of the human immunodeficiency virus (HIV) infection. At two successive semiannual examinations, clinical or hematologic abnormalities were found up to 13 times more often among HIV-seropositive men (n = 1611) than HIV-seronegative men (n = 2646). More than 30% of the seropositive participants had persistent generalized lymphadenopathy, independent of T-helper lymphocyte (CD4) counts and most other signs and symptoms. Other clinical manifestations such as thrush, anemia, thrombocytopenia, neutropenia, fever, and fatigue occurred with only slightly reduced CD4 counts (400 to 700/mm3) and appeared to increase exponentially with progressively lower counts. A simple systematically derived clinical index using these manifestations identified more than 70% of the seropositive men with significant T-helper cell depletion. This kind of clinical index may be useful for assessing groups of HIV-infected persons, especially those whose T-lymphocyte numbers and function cannot be readily measured.


A review of epidemiological studies on cancer in relation to the use of anti-ulcer drugs.
H2-receptor antagonists have been widely used since the late 1970s for the treatment of gastrointestinal ulcers and other benign conditions of the stomach, oesophagus and duodenum. Several case reports suggested that long-term therapy with H2-receptor antagonists, mainly cimetidine and ranitidine, might increase the risk of gastric cancer. After early case reports, at least six analytical epidemiological studies (two cohort and four case-control) were published, including a total of about 1000 cases of gastric cancer. The relative risks (RR) were systematically and substantially elevated in the first year since starting H2-receptor antagonist use, and levelled off in the following years. Some excess risk was still apparent during the first 5 years of drug use, probably due to incorrect diagnosis and treatment of pre-existing neoplastic gastric lesions, but the estimated RR was not above unity for > or = 10 years since starting drug treatment in the two studies including information on long-term use. The findings of analytical epidemiological studies are thus consistent with the absence of a causal association between H2-receptor antagonist use and gastric cancer risk. Data on oesophageal and colorectal cancer do not support a relevant relation between cimetidine use and the risk of these neoplasms. With reference to total cancer mortality, in a Danish cohort study, for males the RR was 1.9 in the first year, and 1.4 in the first 5 years; corresponding values for females were 1.7 and 1.5. In a British cohort study, the RR was 3.4 in the first year, and 1.3 in the years 2-10. The excess risk in the first year was essentially due to gastric cancer. Post-marketing surveillance data for omeprazole and other proton pump inhibitors are much scantier than for H2-receptor antagonists, particularly on long-term use.


Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M.
Protection of the endothelium is provided by circulating sphingosine-1-phosphate (S1P), which maintains vascular integrity. We show that HDL-associated S1P is bound specifically to both human and murine apolipoprotein M (apoM). Thus, isolated human ApoM(+) HDL contained S1P, whereas ApoM(-) HDL did not. Moreover, HDL in Apom(-/-) mice contains no S1P, whereas HDL in transgenic mice overexpressing human apoM has an increased S1P content. The 1.7-Å structure of the S1P-human apoM complex reveals that S1P interacts specifically with an amphiphilic pocket in the lipocalin fold of apoM. Human ApoM(+) HDL induced S1P(1) receptor internalization, downstream MAPK and Akt activation, endothelial cell migration, and formation of endothelial adherens junctions, whereas apoM(-) HDL did not. Importantly, lack of S1P in the HDL fraction of Apom(-/-) mice decreased basal endothelial barrier function in lung tissue. Our results demonstrate that apoM, by delivering S1P to the S1P(1) receptor on endothelial cells, is a vasculoprotective constituent of HDL.


Effects of chronic administration of vanadate on blood pressure, heart rate and Na+/K+-ATPase activity in adult male wistar rats.
Cardiovascular effects of chronic vanadate consumption were investigated in this study. Male wistar rats were divided into five groups and each group was allowed to drink one of the following fluids: I) water; II) water containing 0.02 mg/ml sodium orthovanadate (Na3VO4, vanadate), III) 1% saline, IV) 1% saline containing 0.02 mg/ml vanadate, and V) water containing 0.2 mg/ml vanadate, for a period of six weeks. Changes in arterial pressure and heart rate were essentially similar in all the groups during the treatment period. At the end of six weeks, studies conducted under urethane anesthesia showed that pressor responses to norepinephrine (NE) were potentiated in saline, saline + low vanadate, and water + high vanadate groups when compared to that of water + low vanadate or water drinking groups. In all these three groups in which NE responses were altered, renal Na+/K+-ATPase activity was found to be significantly suppressed (25 to 35%). In contrast, pressor responses to angiotensin II (A-II) were significantly enhanced in all the groups receiving vanadate or saline when compared to that of the water group, and these changes occurred whether or not there was any change in renal Na+/K+-ATPase activity. The data suggest that the changes noted in cardiovascular responses to vasoconstrictor agents, are conducive to the development of high blood pressure; however, failure to note sustained increase in arterial pressure during the treatment period may be due to the fact that in these rats renal compensation was not compromised.


Nivolumab in Heavily Pretreated Metastatic Gastric Cancer Patients: Real-Life Data from a Western Population.
ATTRACTION-2 trial assessed the role of Nivolumab as a new standard treatment for Asian patients with pretreated metastatic gastric cancer (mGC). The aim of this analysis was to evaluate the safety and efficacy of Nivolumab in a real-life Western population, considering the lack of evidence to date. Patients progressed after ≥2 chemotherapy regimens and able to receive Nivolumab (3 mg/kg q14) were eligible for the analysis. 16 patients received Nivolumab as third (81.3%) or fourth line (18.7%) from September 2017 to July 2019. The safety was in line with the literature and only one patient discontinued treatment due to persistent hematological toxicity. Overall response rate and disease control rate were 18.7% and 31.2%, respectively. Median duration of response was 5 months. With a median follow-up of 21 months, median OS was 6 months (7, 21 and 22 months in the responders) and median PFS 3 months. PD-L1 and microsatellite status were retrospectively collected in 12 patients. All the major responders were MSI, although no statistically significant difference in OS or PFS was observed according to molecular analysis. Nivolumab is feasible and effective in Western patients with mGC. Further investigation is urgently needed also in non-Asians.


Effects of nutrients and serotonin 5-HT3 antagonism on symptoms evoked by distal gastric distension in humans.
Distal gastric distension may contribute to meal-related dyspeptic symptoms. This study's aims were to determine the effects of distinct nutrient classes on symptoms induced by distal gastric distension and their dependence on 5-hydroxytryptamine(3) (5-HT3) receptors. Nine healthy subjects rated pain, nausea, and bloating induced by isobaric distal gastric distensions (6-24 mmHg) during duodenal lipid, carbohydrate, protein, or saline perfusion after treatment with placebo or the 5-HT3 receptor antagonist granisetron (10 microg/kg iv). Distensions produced greater pain, nausea, and bloating with lipid at 1.5 kcal/min compared with saline (P < or = 0.02), primarily because of greater distal gastric volumes at each distending pressure. In contrast, carbohydrate and protein had no significant effect. At 3 kcal/min, lipid increased symptoms through a volume-independent as well as a volume-dependent effect. Granisetron did not affect symptom perception or gastric pressure-volume relationships. In conclusion, isobaric distal gastric distension produces more intense symptoms during duodenal lipid compared with saline perfusion. Symptom perception during distal gastric distension is unaffected by 5-HT3 receptor antagonism.


Interleukin-6 induces secretion of tissue inhibitors of etalloproteinases by breast carcinoma cells.
Interleukin (IL)-6 can induce matrix metalloproteinases (MMPs) expression, which may be critical factors involved in tumor metastasis. Tissue inhibitors of metalloproteinases (TIMPs) are important inhibitory enzymes of MMP. This study was designed to investigate the effect of recombinant IL-6 on the MMP/TIMP expression in MDA-MB-231 breast cancer cell line in a dose dependent manner (10, 25 and 50ng/ml) in comparison to non-treated breast cancer cells (control). The data demonstrated that low dose (10 ng/ml) of IL-6 failed to induce TIMP-1 and -2 production by breast cancer cells compared to control cells whereas moderate (25 ng/ml) and high (50ng/ml) exposure levels promoted a significant expression of TIMP-1 (P<0.01 and P<0.0001) respectively as compared to control cells. TIMP-2 was significantly released (P<0.0001) from breast cancer cells higher than in control cells at moderate and high exposure levels of IL-6. This up-regulation of TIMP-1 and -2 was accompanied with undetectable levels of MMP-1, -2, -3, -8, -9, -10, and -13. Furthermore, IL-6 potentially increased the invasion potency of cancer cells significantly (P<0.05 and P<0.01) at moderate and high exposure levels respectively. These findings suggest that IL-6 could promote the invasion potency of breast cancer cells by inducing secretion of TIMP-1 and -2, causing a disturbance in TIMP/MMP balance.


Frequent fires prime plant developmental responses to burning.
Coping with temporal variation in fire requires plants to have plasticity in traits that promote persistence, but how plastic responses to current conditions are affected by past fire exposure remains unknown. We investigate phenotypic divergence between populations of four resprouting grasses exposed to differing experimental fire regimes (annually burnt or unburnt for greater than 35 years) and test whether divergence persists after plants are grown in a common environment for 1 year. Traits relating to flowering and biomass allocation were measured before plants were experimentally burnt, and their regrowth was tracked. Genetic differentiation between populations was investigated for a subset of individuals. Historic fire frequency influenced traits relating to flowering and below-ground investment. Previously burnt plants produced more inflorescences and invested proportionally more biomass below ground, suggesting a greater capacity for recruitment and resprouting than unburnt individuals. Tiller-scale regrowth rate did not differ between treatments, but prior fire exposure enhanced total regrown biomass in two species. We found no consistent genetic differences between populations suggesting trait differences arose from developmental plasticity. Grass development is influenced by prior fire exposure, independent of current environmental conditions. This priming response to fire, resulting in adaptive trait changes, may produce communities more resistant to future fire regime changes.


alpha-Conotoxin ImI exhibits subtype-specific nicotinic acetylcholine receptor blockade: preferential inhibition of homomeric alpha 7 and alpha 9 receptors.
Through a study of cloned nicotinic receptors expressed in Xenopus oocytes, we provide evidence that alpha-conotoxin ImI, a peptide marine snail toxin that induces seizures in rodents, selectively blocks subtypes of nicotinic acetylcholine receptors. alpha-Conotoxin ImI blocks homomeric alpha 7 nicotinic receptors with the highest apparent affinity and homomeric alpha 9 receptors with 8-fold lower affinity. This toxin has no effect on receptors composed of alpha 2 beta 2, alpha 3 beta 2, alpha 4 beta 2, alpha 2 beta 4, alpha 3 beta 4, or alpha 4 beta 4 subunit combinations. In contrast to alpha-bungarotoxin, which has high affinity for alpha 7, alpha 9, and alpha 1 beta 1 gamma delta receptors, alpha-conotoxin ImI has low affinity for the muscle nAChR. Related Conus peptides, alpha-conotoxins MI and GI, exhibit a distinct specificity, strictly targeting the muscle subtype receptor but not alpha 7 or alpha 9 receptors. alpha-Conotoxins thus represent selective tools for the study of neuronal nicotinic acetylcholine receptors.


Musical functioning, speech lateralization and the amusias.
Amusia is a condition in which musical capacity is impaired by organic brain disease. Music is in a sense a language and closely resembles speech, both executively and receptively. For musical functioning, rhythmic sense and sense of sounds are essential. Musical ability resides largely in the right (non-dominant) hemisphere. Tests have been devised for the assessment of musical capabilities by Dorgeuille, Grison and Wertheim. Classification of amusia includes vocal amusia, instrumental amnesia, musical agraphia, musical amnesia, disorders of rhythm, and receptive amusia. Amusia like aphasia has clinical significance, and the two show remarkable similarities and often co-exist. Usually executive amusia occurs with executive aphasia and receptive amusia with receptive aphasia, but amusias can exist without aphasia. Severely executive aphasics can sometimes sing with text (words), and this ability is used in the treatment of aphasia. As with aphasia, there is correlation between type of amusia and site of lesion. Thus in executive amusia, the lesion generally occurs in the frontal lobe. In receptive amusia, the lesion is mainly in the temporal lobe. If aphasia is also present the lesion will be in the left (dominant) hemisphere.


Experimentally elevated testosterone shortens telomeres across years in a free-living songbird.
Reproductive investment often comes at a cost to longevity, but the mechanisms that underlie these long-term effects are not well understood. In male vertebrates, elevated testosterone has been shown to increase reproductive success, but simultaneously to decrease survival. One factor that may contribute to or serve as a biomarker of these long-term effects of testosterone on longevity is telomeres, which are often positively related to lifespan and have been shown to shorten in response to reproduction. In this longitudinal study, we measured the effects of experimentally elevated testosterone on telomere shortening in free-living, male dark-eyed juncos (Junco hyemalis carolinensis), a system in which the experimental elevation of testosterone has previously been shown to increase reproductive success and reduce survival. We found a small, significant effect of testosterone treatment on telomeres, with testosterone-treated males exhibiting significantly greater telomere shortening with age than controls. These results are consistent with the hypothesis that increased telomere shortening may be a long-term cost of elevated testosterone exposure. As both testosterone and telomeres are conserved physiological mechanisms, our results suggest that their interaction may apply broadly to the long-term costs of reproduction in male vertebrates.