MALAT1 Fusions and Basal Cells Contribute to Primary Resistance against Androgen Receptor Inhibition in TRAMP Mice.
Targeting testosterone signaling through androgen deprivation therapy (ADT) or antiandrogen treatment is the standard of care for advanced prostate cancer (PCa). Although the large majority of patients initially respond to ADT and/or androgen receptor (AR) blockade, most patients suffering from advanced PCa will experience disease progression. We sought to investigate drivers of primary resistance against antiandrogen treatment in the TRAMP mouse model, an SV-40 t-antigen driven model exhibiting aggressive variants of prostate cancer, castration resistance, and neuroendocrine differentiation upon antihormonal treatment. We isolated primary tumor cell suspensions from adult male TRAMP mice and subjected them to organoid culture. Basal and non-basal cell populations were characterized by RNA sequencing, Western blotting, and quantitative real-time PCR. Furthermore, effects of androgen withdrawal and enzalutamide treatment were studied. Basal and luminal TRAMP cells exhibited distinct molecular signatures and gave rise to organoids with distinct phenotypes. TRAMP cells exhibited primary resistance against antiandrogen treatment. This was more pronounced in basal cell-derived TRAMP organoids when compared to luminal cell-derived organoids. Furthermore, we found MALAT1 gene fusions to be drivers of antiandrogen resistance in TRAMP mice through regulation of AR. Summarizing, TRAMP tumor cells exhibited primary resistance towards androgen inhibition enhanced through basal cell function and MALAT1 gene fusions.


Enzymatically activated microencapsulated liposomes can provide pulsatile drug release.
A system for the delayed or pulsed release of biologically active substances was achieved by encapsulating liposomes containing the substance of interest inside microcapsules. The microcapsules retain the liposomes but allow controlled diffusion of the active substance when it is released from the liposomes. Furthermore, by coating the liposomes with phospholipase A2 (an enzyme that removes an acyl group from the 2 position of phospholipids) before placing them within the microcapsule, a pulsatile release pattern was achieved both in vitro and in vivo. The time of onset of the pulse as well as the release rate can be controlled by the amount of phospholipase A2, the molecular weight of the poly(L-lysine) that is used to coat the microencapsulated liposomes, and the composition of the phospholipid bilayer membrane. Even at 37 degrees C the system would protect a model enzyme (horseradish peroxidase). When not placed inside the microencapsulated liposomes, the enzyme lost its activity in solution at 37 degrees C in a few days, whereas it retained 40% of the initial activity after 30 days of incubation at 37 degrees C inside the microencapsulated liposomes.


Correlations of plasma renin activity and aldosterone concentration with ambulatory blood pressure responses to nebivolol and valsartan, alone and in combination, in hypertension.
After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%-73%) and decreased with nebivolol (51%-65%) and the combination treatment (17%-39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%-22%; nebivolol, 20%-26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P < .001) and nebivolol (both, P < .001), but not with valsartan. Baseline ln(aldosterone) correlated with 24-hour systolic and diastolic BP reductions following combination treatment only (P < .001 and P = .005). The implications of the renin-angiotensin-aldosterone system effects of this beta blocker-angiotensin receptor blocker combination should be explored further.


Contrasting effects of age of acquisition and word frequency on auditory and visual lexical decision.
In four experiments, we examined the effects of frequency and age of acquisition on auditory and visual lexical decision. Word frequency affected visual, but not auditory, lexical decision speed (Experiments 1 and 3). Age of acquisition affected lexical decision speed in both modalities (Experiments 2 and 4). We suggest that previous reports of effects of frequency on auditory lexical decision may be due to a confounding of frequency with age of acquisition, and we discuss the implications of these findings for theories of auditory and visual word recognition.


Metallothionein induction prevents toxic side effects of cisplatin and adriamycin used in combination.
The protective effects of metallothionein (MT) preinduction by bismuth subnitrate (BSN) against the renal toxicity of cis-diamminedichloroplatinum (cis-DDP), the cardiotoxicity of adriamycin (ADR), and the lethal and bone marrow toxicities of these drugs were observed in mice receiving cis-DDP and ADR simultaneously. Preinduction of MT biosynthesis by BSN, which is currently used as an antidiarrheal drug, did not affect the antitumor activities of the two drugs, suggesting that the beneficial effects of the preinduction of MT biosynthesis by BSN may be applicable for therapy involving cis-DDP and ADR, either alone or in combination.


B-cell receptor profiling before and after IVIG monotherapy in newly diagnosed idiopathic inflammatory myopathies.
To unravel B-cell receptor (BcR) characteristics in muscle tissues and peripheral blood and gain more insight into BcR repertoire changes in peripheral blood in idiopathic inflammatory myopathies (IIMs), and study how this correlates to the clinical response to IVIG. Nineteen treatment-naive patients with newly diagnosed IIM were prospectively treated with IVIG monotherapy. RNA-based BcR repertoire sequencing was performed in muscle biopsies collected before, and in peripheral blood (PB) collected before and nine weeks after IVIG treatment. Results were correlated to patients' clinical improvement based on the total improvement score (TIS). Prior to IVIG treatment, BcR clones found in muscle tissue could be retrieved in peripheral blood. Nine weeks after IVIG treatment, new patient-specific dominant BcR clones appeared in peripheral blood while pre-treatment dominant BcR clones disappeared. The cumulative frequency of all dominant BcR clones before treatment was significantly higher in individuals who responded to IVIG compared with those who did not respond to IVIG, and correlated with a higher CK. During follow-up, a decrease in the cumulative frequency of all dominant clones correlated with a higher TIS. In treatment-naive patients with newly diagnosed IIM, muscle tissue and peripheral blood share expanded BcR clones. In our study a higher cumulative frequency of dominant BcR clones in blood before treatment was associated with a higher CK and better treatment response, suggesting that response to IVIG may depend on the composition of the pre-treatment BcR repertoire.


Performance of regional water purification plants during extreme weather events: three case studies from New South Wales, Australia.
Climate change is altering weather patterns, which affects water supply systems globally. More frequent extreme weather events like floods, droughts, and heatwaves are impacting the availability of raw water sources that supply cities. These events can lead to less water, higher demand, and potential infrastructure damage. Water agencies and utilities must develop resilient and adaptable systems to withstand shocks and stresses. Case studies demonstrating the impact of extreme weather on water quality are important for developing resilient water supply systems. This paper documents the challenges faced by regional New South Wales (NSW) in managing water quality and supply during extreme weather events. Effective treatment processes, such as ozone treatment and adsorption, are used to maintain drinking water standards during extreme weather. Water-efficient alternatives are provided, and critical water networks are inspected to identify leaks and reduce system demand. Local government areas must collaborate and share resources to ensure that towns can cope with future extreme weather events. Systematic investigation is needed to understand system capacity and identify surplus resources to be shared when demand cannot be met. Pooling resources could benefit regional towns experiencing both floods and droughts. With expected population growth in the area, regional NSW councils will require a significant increase in water filtration infrastructure to handle increased system loading. Continuous research, regular strategy reviews, and innovative approaches are essential to ensure a secure and reliable water supply during future extreme weather events.


Characterisation of the non-5-HT3 high-affinity 'R' binding site for (R)-zacopride in brain and other tissues.
Previous studies showed that whereas the potent 5-HT3 receptor antagonist (S)-[3H]zacopride only labels 5-HT3 receptor binding sites, the (R)-enantiomer, (R)-[3H]zacopride, labels these receptors and another class of high-affinity binding sites, named the R sites, in membranes from the rat cerebral cortex and NG 108-15 clonal cells (Kidd et al., Eur. J. Pharmacol. 211, 133, 1992). Further studies of R sites revealed that they existed not only in the cerebral cortex but also in various other areas of the rat brain and spinal cord. In addition, R sites were also found in post-mortem human brain tissues. Both in the rat and in man, the regional distribution of central R sites was markedly different from that of 5-HT3 receptors specifically labelled with (S)-[3H]zacopride. Under appropriate conditions for the specific labelling of R sites (with (R)-[3H]zacopride in the presence of 1.0 microM ondansetron to saturate 5-HT3 receptor binding sites--and 0.1 mM mianserin for the determination of non-specific binding), these R sites were also found in rat peripheral tissues (intestine > spleen > kidney > testicles = liver > adrenals > lung > heart). At least in the kidney and the liver, the pharmacological profile of R sites corresponded exactly to that found in NG 108-15 cells. R sites were also detected in membranes from C6 glioma cells and glial cells cultured from the whole cortex of new born rats. In contrast, no specific binding of (R)-[3H]zacopride to R sites could be found in membranes from N1E-115 neuroblastoma cells. Conversely, 5-HT3 receptors could be labelled by (S)-[3H]zacopride in the latter cells but not in C6 glioma and cultured glial cells. As expected from their glial location, the density of R sites increased in the rat hippocampus lesioned with kainic or ibotenic acid to induce local gliosis. In contrast, the density of hippocampal 5-HT3 receptors was unchanged in lesioned rats. Finally, the determination of the apparent molecular size of R sites by radiation inactivation gave a value (approximately 30 kDa) which was significantly lower than that of 5-HT3 receptor binding sites in the rat entorhinal cortex (40 kDa) and NG 108-15 cells (57 kDa). All these data clearly showed that R sites and 5-HT3 receptors are different molecular species. Whether R sites mediate the 5-HT3 receptor-unrelated actions of (R)-zacopride deserves further investigations.


Phagocytes and oxidative stress.
Neutrophils and other phagocytes manufacture O(2)(-) (superoxide) by the one-electron reduction of oxygen at the expense of NADPH. Most of the O(2)(-) reacts with itself to form H(2)O(2) (hydrogen peroxide). From these agents a large number of highly reactive microbicidal oxidants are formed, including HOCl (hypochlorous acid), which is produced by the myeloperoxidase-catalyzed oxidation of Cl(-) by H(2)O(2); OH(*) (hydroxyl radical), produced by the reduction of H(2)O(2) by Fe(++) or Cu(+); ONOO(-) (peroxynitrite), formed by the reaction between O(2)(-) and NO(*); and many others. These reactive oxidants are manufactured for the purpose of killing invading microorganisms, but they also inflict damage on nearby tissues, and are thought to be of pathogenic significance in a large number of diseases. Included among these are emphysema, acute respiratory distress syndrome, atherosclerosis, reperfusion injury, malignancy and rheumatoid arthritis.


Substantia nigra damage induced by ischemia in hyperglycemic rats. A light and electron microscopic study.
Preischemic hyperglycemia induced by feeding or glucose infusion worsens the brain damage and the clinical outcome following ischemia of a given duration and density, and characteristically causes postischemic seizure activity. Light microscopy has previously showed that, in the rat, transient hyperglycemia ischemia induced by bilateral carotid occlusion in combination with arterial hypotension causes a uni- or bilateral lesion in the pars reticulata of the substantia nigra. Since this region has a central role in preventing seizure discharges the present study was carried out to determine the ultrastructural characteristics of this lesion. In rats with 10 min of transient hyperglycemic ischemia followed by recirculation for 1 to 18 h, the pars reticulata of the substantia nigra showed signs of status spongiosus, as well as extensive nerve cell alterations. These changes were observed after all recovery periods studied. The spongiotic appearance was mainly caused by swelling of dendrites and, to a lesser degree, by astrocytic swelling. The dendrites were expanded at all recovery times but the severity increased during the later periods of recirculation. These swollen dendrites contained severely expanded mitochondrias and endoplasmic reticulum. The cytoskeletal elements showed disordered lining of microtubules. Two major types of nerve cell alterations were present: a "pale" and a "dark" variety. The pale type was the most frequent cell alteration. It occurred in all experimental groups and at all time points. Redistribution of the nuclear chromatin and of cytoplasmic organelles as well as swelling of the same type as in the dendrites were the essential changes.(ABSTRACT TRUNCATED AT 250 WORDS)


Stress impairs retrieval of extinguished and unextinguished associations in a predictive learning task.
Recovery effects which can frequently be observed after a seemingly successful extinction procedure indicate that extinction does not lead to an erasure of the memory trace. Investigating factors which modulate the retrieval of extinction memory is highly relevant for basic science and clinical applications alike. This study investigated the effect of stress on the retrieval of extinguished and unextinguished stimulus-outcome associations in a predictive learning task. In this task, participants had to imagine being the doctor of a patient who sometimes suffers from stomach trouble after meals in his favorite restaurants. They were presented with different food stimuli while having to predict the occurrence or non-occurrence of stomach trouble. As extinction memory is modulated by context, we manipulated contextual cues so that initial acquisition of critical associations occurred in context (restaurant frame) A on day one, whereas associations were reversed in context B (extinction, day two). On the third day, participants were either stressed (exposed to the socially evaluated cold pressor task (SECPT); n=21) or subjected to a control condition (n=21) shortly before extinction memory retrieval was tested (in contexts A and B). Salivary cortisol and blood pressure measures as well as subjective ratings indicated that stress induction was successful. When retrieval of extinguished associations was tested on day three, participants' predictions reflected a renewal effect, as indicated by stronger recovery of responding in the acquisition context compared to the extinction context. Compared to controls, stressed participants showed impaired retrieval of extinguished and unextinguished associations. Contextual cues abolished the stress-induced memory impairment for unextinguished but not for extinguished associations. These findings might help to explain why stress leads to the reoccurrence of symptoms in affective disorders.


Mass spectrometry-based cortisol profiling during adrenal venous sampling reveals misdiagnosis for subtyping primary aldosteronism.
Primary aldosteronism (PA) is a common form of secondary hypertension. Adrenal venous sampling (AVS) is the gold standard for subtyping PA. This study aimed to determine whether there is a difference between immunoassays and liquid chromatography-mass spectrometry (LC-MS/MS) methods for measuring cortisol levels that affect the judgement of AVS. This was a retrospective study. Included 72 patients who were diagnosed with PA and had undergone AVS. Patients were grouped according to whether they received adrenocorticotropic hormone (ACTH) stimulation during AVS, and the cortisol results were measured using immunoassay and LC-MS/MS. There were 48 patients in the without ACTH stimulation group and 24 in the post-ACTH stimulation group during AVS (bilateral adrenal vein cannulation success rate, 56.25% vs. 83.33%). ACTH stimulation was beneficial for increasing the success rate of AVS (p < .001). Immunoassays were linearly correlated with LC-MS/MS when cortisol concentrations were <1750 nmol/L (r = .959, p < .001). When cortisol concentrations were >17,500 nmol/L, no correlation was found between the two methods (p = .093). The two methods were consistent for the detection of cortisol for evaluating the success of cannulation for AVS. Five percent of patients showed discordant lateralization of aldosterone production according to the cortisol LC-MS/MS and immunoassay results in the without ACTH group, and 15% showed discordant lateralization in the post-ACTH group. The immunoassay method can be used to determine whether cannulation is successful. The final decision for lateralization may be more appropriate based on LC-MS/MS results.


[Characteristics of ischemic stroke according to hospital register data: a role of neuroreparative therapy].
To study characteristics of the acute stage of ischemic stroke (IS) basing on the data of a hospital register of the Perm Regional vascular center and to assess the efficacy and safety of the drug cellex in patients with IS. Authors have analyzed the group of 128 patients with MRI-confirmed acute ischemic lesion. The subgroup of 40 patients, which beside the basic therapy received cellex in dose of 0.1 mg during 10 days, was randomized. The following data were analyzed: gender and age, prevalence of risk factors, primary prevention, time before admission, clinical presentations, results of instrumental diagnostic methods, pathogenic structure of stroke, use of intravenous thrombolysis, regimens of secondary prevention, functional outcome and its predictors. The group of patients was characterized by the high prevalence of risk factors, insufficient primary prevention, prolonged time before the admission, low rate of thrombolysis use and significant prevalence of large artery disease associated with stroke. The main independent predictors of low mobility level at discharge were severe neurological deficit on admission, cognitive impairment and age. Patients treated with cellex were characterized by the lower level of neurologic deficit, higher mobility and better global cognitive status in comparison with controls.


Alcohol intake and risk of rheumatoid arthritis: a Mendelian randomization study.
To examine whether alcohol intake is causally associated with rheumatoid arthritis (RA). We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics of alcohol intake frequency from the UK Biobank genome-wide association studies (GWASs; n = 336,965) as the exposure and a GWAS meta-analysis of 5539 autoantibody-positive RA patients and 20,169 controls as the outcome. We selected 24 single nucleotide polymorphisms (SNPs) associated with alcohol intake frequency at genome-wide significance as instrumental variables (IVs) to improve inference, 16 of which were inversely associated with RA. The IVW method showed no evidence of a causal association between alcohol intake and RA (beta = 0.218, SE = 0.213, p = 0.306). The MR-Egger regression revealed that directional pleiotropy was unlikely to bias the result (intercept = 0.027, p = 0.292). The MR-Egger analysis and the weighted median approach showed no causal association between alcohol intake and RA (beta = -0.778, SE = 0.947, p = 0.420 and beta = -0.286, SE = 0.302, p = 0.344, respectively). Cochran's Q test did not indicate heterogeneity between IV estimates based on the individual variants, and results from a "leave-one-out" analysis demonstrated that no single SNP was driving the IVW point estimate. The MR analysis does not support a causal inverse association between alcohol intake and RA occurrence.


Imaging light-modulated release of synaptic vesicles in the intact retina: retinal physiology at the dawn of the post-electrode era.
Here, we illustrate an optical method for directly measuring the light-regulated synaptic output of neurons in the retina. The method allows simultaneous recording from many retinal neurons in intact flat-mount preparations of the vertebrate retina. These recordings depend on the use of FM1-43, an activity-dependent fluorescent dye that selectively labels synaptic vesicles. Release of the dye, which occurs upon vesicle exocytosis, is detected with 2-photon microscopy. This utilizes an infrared laser to trigger fluorescence excitation of the dye, while minimally perturbing retinal activity by activating phototransduction in rods and cones. Using this approach, one can measure activity of single neurons in the intact retinal network and populations of neurons in different layers of the retina, providing a new way to examine the function of retinal synapses and how visual information is processed.


The adjunctive use of a centralised database in the monitoring of clozapine-related neutropenia.
To assess the effectiveness of centralised routine monitoring of blood counts in subjects receiving clozapine. A cohort study based on a prospective drug exposure database. Patients with schizophrenia in 38 specialised centres across Australia. The time from detection of neutropenia to the interruption of therapy, the time to recovery of the absolute neutrophil count, the eventual outcome of subjects developing neutropenia. A total of 1500 subjects were registered on the database. Seven subjects developed severe neutropenia (a neutrophil count < 1.5 x 10(9)/L) whilst on therapy. Mean time to cessation of therapy was 1.6 days (range < 1-6 days). Neutrophil counts recovered to normal levels in all subjects after 6.4 days (range < 1-13). In the population investigated, the addition of a centralised database to clinical monitoring resulted in very rapid detection of severe neutropenia and an equally rapid cessation of therapy. In the sample investigated, this led to very low morbidity and zero mortality.


Helper and cytotoxic T cell precursor frequencies are not predictive for development of acute graft-versus-host disease after partially T cell-depleted HLA-identical sibling BMT.
Despite the use of partially T cell-depleted grafts, 20% of the recipients of an HLA-identical sibling marrow graft develop aGVHD > or = II. This indicates that the current method for selecting a sibling donor, ie serological typing for HLA-A, B and DR, and a mixed lymphocyte culture (MLC) or molecular typing for HLA-DRB/DQB, is not predictive for aGVHD. In order to optimise our selection procedure, we retrospectively analysed patients who developed aGVHD > or = II by means of sequencing based typing for HLA-DPB and frequency analysis of alloreactive helper and cytotoxic T lymphocyte precursors (HTLp-f and CTLp-f). Patients who did not develop aGVHD or developed aGVHD grade I served as controls. Retrospective typing for HLA-DPB revealed only a single disparity in the group with aGVHD > or = II, indicating that mismatches for antigens other than HLA are the major cause of aGVHD in these patients. Furthermore, in our patient group, neither HTLp-f nor CTLp-f were predictive for development of aGVHD indicating that these assays in their current set-up are insufficiently sensitive to predict aGVHD in BMT with a partially T cell-depleted graft. We conclude, that HLA-identical siblings can be identified by means of serological typing for HLA-A and B and intermediate resolution molecular typing for DRB and DQB, but that for the prediction of aGVHD cellular tests with higher sensitivity and specificity as compared to the currently used HTLp-f and CTLp-f assays need to be developed.


Glucose oxidation-dependent survival of activated B cells provides a putative novel therapeutic target for lupus treatment.
Aberrant metabolic demand is observed in immune/inflammatory disorders, yet the role in pathogenesis remains unclear. Here, we discover that in lupus, activated B cells, including germinal center B (GCB) cells, have remarkably high glycolytic requirement for survival over T cell populations, as demonstrated by increased metabolic activity in lupus-activated B cells compared to immunization-induced cells. The augmented reliance on glucose oxidation makes GCB cells vulnerable to mitochondrial ROS-induced oxidative stress and apoptosis. Short-term glycolysis inhibition selectively reduces pathogenic activated B in lupus-prone mice, extending their lifespan, without affecting T follicular helper cells. Particularly, BCMA-expressing GCB cells rely heavily on glucose oxidation. Depleting BCMA-expressing activated B cells with APRIL-based CAR-T cells significantly prolongs the lifespan of mice with severe autoimmune disease. These results reveal that glycolysis-dependent activated B and GCB cells, especially those expressing BCMA, are potentially key lupus mediators, and could be targeted to improve disease outcomes.


Antihypertensive, antiproteinuric therapy and myocardial infarction and stroke prevention.
Proteinuria is a graded marker for kidney damage, as well as the risk for future cardiovascular events. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) reduce urinary protein excretion and slow progression of renal impairment, independent of blood pressure lowering. Both the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction in Endpoints in NIDDM with the Angiotensin Antagonist Losartan (RENAAL) study were large, randomized, prospective studies in type 2 diabetic patients with proteinuria. There was no reduction in the incidence of myocardial infarction or stroke with the ARBs compared to placebo in either trial. A broader overview of clinical trials comparing ACEIs and ARBs with other antihypertensive drugs fails to show any substantive blood pressure-independent effects on stroke or myocardial infarction with these classes of drugs. Therefore, for cardiovascular end points (as opposed to renal end points), it may be more important that the blood pressure is reduced, rather than how the process is started.


Emergence and predominance of a new serotype of Vibrio parahaemolyticus in Huzhou, China.
During our surveillance period, we found a new type of Vibrio parahaemolyticus (V. parahaemolyticus) with serotype O10:K4, which had increased over the past 2 years in Huzhou and became the second most common serotype after O3:K6. Strains were isolated from stool samples of diarrhea patients in the First People's Hospital in Huzhou. The serotypes, virulence-associated genes, antimicrobial susceptibility, and pulsed field gel electrophoresis (PFGE) of these strains were analyzed. Between January 2017 and December 2021, there were 598 (5.36%) V. parahaemolyticus-positive samples of 11,166 stool specimens. The V. parahaemolyticus detection rate was high in summer months. The O3:K6 was the dominant serotype in 2017-2020 and a new serotype, O10:K4, was the predominant serotype in 2021. The majority of isolates tested were resistant to ampicillin (86.8%). We randomly chose the strains with serotype O3:K6 and O10:K4 for PFGE to compare the genetic relationship between these two serotypes. The results showed that the PFGE profiles of V. parahaemolyticus O3:K6 and O10:K4 were genetically similar. The strains showed a tendency to cluster on the basis of their serotype profiles. However, some O3:K6 strains showed 100% similarity with O10:K4 strains. A new serotype with pandemic potential of V. parahaemolyticus, O10:K4, was detected in 2020 and became dominant in 2021 in Huzhou.


Assessment of the residual tumour of colorectal liver metastases after chemotherapy: diffusion-weighted MR magnetic resonance imaging in the peripheral and entire tumour.
To evaluate the value of diffusion-weighted imaging (DWI) in detecting residual tumours (RTs) in colorectal liver metastases (CLMs) following chemotherapy, with a focus on tumour periphery. From January 2009-January 2012, 57 patients who underwent liver resection for CLMs with preoperative MRI (<3 months) including DWI were retrospectively included. CLMs were classified into three response groups on pathology: (1) major histological (MHR, RTs ≤ 10 %), (2) partial histological (PHR, RT = 10-49 %), and (3) no histological (NHR, RT ≥ 50 %). On DWI, regions of interest (ROIs) were drawn around the entire tumour and tumour periphery. Apparent diffusion (ADC) and pure diffusion (D) coefficients were calculated using a monoexponential fit, and compared using Kruskal-Wallis test on a lesion-per-lesion analysis. 111 CLMs were included. Fourteen (12.5 %), 42 (38 %) and 55 (49.5 %) CLMs presented a MHR, PHR and NHR, respectively. ADC and D of the peripheral ROIs were significantly higher in the MHR group (P = 0.013/P = 0.013). ADC and D from the entire tumour were not significantly different among the groups (P = 0.220/P = 0.103). In CLM treated with chemotherapy, ADC and D values from the entire tumour are not related to the degree of RT, while peripheral zone diffusion parameters could help identify metastases with MHR. Peripheral ADC and D of CLMs were higher with major pathological responses. Global ADC and D of CLMs were not different according to residual tumour. Diffusion-weighted images of CLM periphery could be an interesting biomarker of MHR. Diffusion-weighted images could be used to help tailor treatment.


Contralateral transvenous left ventricular lead placement of implantable devices with pre-sternal tunnelling in chronically obstructed subclavian veins.
Cardiac resynchronisation therapy (CRT) is a recognised therapy for the management of severe left ventricular dysfunction, advanced congestive cardiac failure (NYHA III or IV), ventricular dyssynchrony (either broad LBBB or mechanical dyssynchrony on echocardiography) and failure of optimal medical therapy to achieve improvement in clinical status. Upgrading right ventricular pacemakers or defibrillators to biventricular devices is common and we describe here, 2 such cases of biventricular upgrade with blocked venous access on the ipsilateral side and successful placement of left ventricular leads following pre-sternal tunnelling from the contralateral side.


Rationally engineered nanosensors: A novel strategy for the detection of heavy metal ions in the environment.
Heavy metal ions (HMIs) have been mainly originated from natural and anthropogenic agents. It has become one of biggest societal issues due to their recognised accumulative and toxic effects in the environment as well as biological media. Key measures are required to reduce the risks posed by toxic metal pollutants existing in the environment. The increased research activities of HMIs detection, and use of technologies based on electrochemical detection that combine with engineered nanomaterials, is a key promising and innovative strategy that can potentially confine heavy metal poisoning. Deep understanding of the characteristics of the physicochemical properties of nanomaterials is highly required. It is also important to interpret the parameters at the nano-bio interface level that merely affect cross-interactions between nanomaterials and HMIs. Therefore, the authors outlined the state-of-the-art techniques that used engineeringly developed nanomaterials to detect HMIs in the environment. The possible novel applications of extensive and relatively low-cost HMIs monitoring and detection are discussed on the basis of these strengths. Finally, it is concluded by providing gist on acquaintance with facts in the present-day scenario along with highlighting areas to explore the strategies to overcome the current limitations for practical applications is useful in further generations of nano-world.


Evolution of the properties of semen immediately following vasectomy.
Semen parameters were analyzed in a series of 76 men pre- and postvasectomy. The mean volume decrease was 0.66 ml but it was 0.5 ml or more for only 53% of subjects. A decrease in the number of spermatozoa was correlated primarily with the number of ejaculations. In nearly all cases the total number of spermatozoa contained in all semen samples examined after vasectomy was clearly lower than the average number contained in only one ejaculation prior to vasectomy. Motile spermatozoa were never observed after the 15th day following vasectomy. The reappearance of motile spermatozoa after that time was an almost certain sign of a defect in the vas block or of recanalization of the vas deferens.


Production of high-octane gasoline via hydrodeoxygenation of sorbitol over palladium-based bimetallic catalysts.
A methodology for the synthesis of gasoline-range fuels from carbon neutral resources is introduced. Sorbitol, a sugar-based compound, was employed as a raw material because the compound is readily obtained from cellulose. Gasoline-range hydrocarbons were produced via hydrodeoxygenation (HDO) on zirconium phosphate-supported Pd-bimetallic (Pt-Pd, Ru-Pd, Ni-Pd, Fe-Pd, Co-Pd, W-Pd) catalysts. Among the tested catalysts, the bimetallic W-Pd/ZrP catalyst exhibited the highest yield of gasoline products, peaking at ∼70%. However, with the bimetallic Fe-Pd and Co-Pd catalysts, high-octane gasoline products were made (research octane number (RON) of the products was higher than 100). The Fe-Pd catalyst also showed the highest initial activity for the HDO of sorbitol. This study demonstrates that HDO in the Pd-system is a promising option to produce high-quality gasoline-range hydrocarbons from lignocellulosic biomass.


The effect of elaidic acid incorporation upon the lipid composition of Ehrlich Ascites tumor cells and of the host's liver.
The incorporation of elaidic acid into Ehrlich ascites tumor cells (EATC) upon feeding the host an elaidic acid-rich diet has been investigated in the present study. The EATC lipids contained only one-half the concentration of elaidic acid found in the lipids of either the host livers or of livers from normal mice. On the other hand, elaidic acid incorporation into tumor cells was close to that of ascites fluid. This incorporation was mainly into phospholipids; the highest into choline phospholipids and ethanolamine phospholipids. Some changes in the EATC fatty acid composition were noted due to this incorporation. EATC phospholipids had reduced polyunsaturated fatty acids as compared with oleic acid-grown cells. The same was true with respect to ascites fluid phospholipids, but neutral lipids were not altered. Tumor development was accompanied by an increase in elaidic acid of the host's liver. Elaidic acid incorporation into tumor cells resulted in a reduction in the amount of all major lipids in the tumor. In contrast, elaidic acid had no effect on lipid composition of livers from normal mice and and-tumor bearing mice, and also had no effect upon the lipids of the ascites fluid that bathes the tumor cells. The incorporation of elaidic acid into the lipids of EATC, normal liver and host liver did not affect the relative composition of phospholipids in these tissues. The development of the tumor did result in decreases in triacylglycerols and esterified cholesterol, and increases in phospholipids and free cholesterol in the livers of host animals.


[Efficiency of a pharmaceutical care program for long-acting parenteral antipsychotics in the health area of Santiago de Compostela].
In the healthcare area of Santiago de Compostela (Spain), the therapeutic subgroup "other antipsychotics" represented the fifth largest outpatient expenditure in 2013. More than half of this expenditure corresponded to long-acting parenteral forms of paliperidone and risperidone. Over a 12-month period, the implementation of a pharmaceutical care program based on process management and coordination of actions between health professionals in both levels of care represented savings of € 636,391.01 for the organization and a direct saving of € 16,767.36 and 9,008 trips to the pharmacy for patients. This study shows the efficiency of the program, which was facilitated by its situation in an area of integrated management and the use the unified medical records and electronic prescription, elements that will enable the future implementation of similar programmes. The new registries and healthcare interventions will allow reliable evaluation of their effectiveness in terms of treatment adherence, relapses and hospitalisations.


Increasing adherence to substance abuse aftercare group therapy.
Adherence to aftercare therapy in substance abuse treatment is associated with improved outcomes. Although previous research has established that adherence contracts and orientation to aftercare are an effective method of increasing aftercare attendance, participation levels are often low. We examined whether feedback and prompts are an effective means of further increasing adherence to substance abuse aftercare group therapy beyond that found when orientation and adherence contracts are completed. We randomly assigned 41 substance dependent individuals completing inpatient or intensive outpatient treatment to receive either attendance feedback and prompts to attend aftercare, or no feedback and no prompts. participants who received the feedback and prompts were more likely to begin aftercare, and to attended more weekly aftercare groups, and they were less likely to be readmitted to the hospital. The clinical utility of prompts and feedback are discussed.


Light chain deposition disease neuropathy resembling amyloid neuropathy in a multiple myeloma patient.
A 65-year-old man with IgG lambda multiple myeloma developed severe polyneuropathy with prominent thermal-pain sensory impairment and autonomic failure. Although the clinical presentation suggested amyloid neuropathy, nerve biopsy showed the immunohistochemical and ultrastructural features typical of light chain deposition disease (LCDD). A precise morphologic and clinical description of LCDD neuropathy is given for the first time in the present report.


Neoadjuvant tyrosine kinase inhibitor therapy for patients with gastrointestinal stromal tumor: A propensity-matched analysis.
Tyrosine kinase inhibitor (TKI) neoadjuvant therapy (NAT) is often given in gastrointestinal stromal tumors (GISTs) with the goal to facilitate less morbid resections and improve oncologic outcomes; however, the use of NAT for GIST is poorly studied. We reviewed patients with resected nonmetastatic GIST from 2003 to 2019. Overall (OS) and recurrence-free survival (RFS) were assessed with Kaplan-Meier modeling. We performed 1:1 propensity-matching for relevant clinicopathologic variables for receipt of NAT. We identified 254 patients. Propensity 1:1 matching resulted in 33 patients per group. The median follow-up was 77 months with no difference in 10-year OS (68% vs. 73%), 5-year RFS (13% vs. 10%), or median RFS (24 vs. 27 months) for patients treated with NAT versus upfront resection (all P > 0.9). Hospital length-of-stay (both median 7 days) and Clavien-Dindo ≥ III complications (12% vs. 3%) were not different between groups (both P ≥ 0.35). TKI NAT can be used to facilitate resection in select patients with surgically higher-risk GIST, however it does not result in an independent oncologic benefit.


Hypoxia-induced snail expression through transcriptional regulation by HIF-1α in pancreatic cancer cells.
Intratumoral hypoxia and epithelial-mesenchymal transition are involved in tumor invasion and metastasis. This study investigated the molecular mechanisms that relay the hypoxia signal into the epithelial-mesenchymal transition and metastasis. Morphology analysis and tumor cell migration and invasion assays were performed to detect phenotypic changes of pancreatic cancer cells under normoxic and hypoxic conditions after lentiviral HIF-1α shRNA transfection. Quantitative reverse transcription polymerase chain reaction, western blot, and immunohistochemistry were used to detect gene expression in pancreatic cancer cell lines and tissues or normal pancreatic tissues. Luciferase, gel shift, and ChIP assays were used to assess gene regulation. Under hypoxic conditions, these tumor cells underwent typical morphological and molecular changes to epithelial-mesenchymal transition. Moreover, Snail expression was induced by hypoxic conditions and was regulated by HIF-1α expression at the transcriptional level through HIF-1α-binding to the second site of hypoxia-responsive elements of the Snail gene promoter. In addition, Snail expression was associated with HIF-1α expression in pancreatic cancer tissues, and expression of both was associated with tumor metastasis and poor patient survival. Our study provides key evidence that HIF-1α and Snail are responsible for hypoxia-induced metastasis phenotypes in pancreatic cancer and that HIF-1α and Snail expression can be used as biomarkers to predict tumor metastasis and patient survival.


Identification of adenylate cyclase-coupled beta-adrenergic receptors in frog erythrocytes with (minus)-[3-H] alprenolol.
(minus)-Alprenolol, a potent, competitive beta-adrenergic antagonist labeled to high specific activity with tritium (17 Ci per mmol), has been used to identify binding sites in frog erythrocyte membranes having many of the characteristics to be expected of the beta-adrenergic receptors which are linked to adenylate cyclase in these membranes. The chromatographic behavior and biological activity of the labeled and native drug were essentially identical. (minus)-Alprenolol and (minus)-[3-H]alprenolol both competitively antagonize isoproterenol stimulation of frog erythrocyte membrane adenylate cyclase with a KD OF 5 TO 10 NM. (minus)-[3-H]Alprenolol binding to sites in the frog erythrocyte membranes was studied by a centrifugal assay. At 37 degrees, equilibrium binding was established within 5 min and the half-time for dissociation of bound (minus)-[3-H]alprenolol was approximately 30 s. This rapid onset and dissociation of (minus)-[3-H]alprenolol binding was in good agreement with the rapid onset of action of beta-adrenergic agonists and antagonists on the frog erythrocyte adenylate cyclase. (minus)-[3-H]Alprenolol binding was saturable. There were 0.25 to 0.35 pmol of (minus)-[3-H]alprenolol binding sites per mg of protein corresponding to 1300 to 1800 binding sites per intact frog erythrocyte. The binding sites showed half-maximal saturation at 5.0 to 10 nM (minus)-[3-H]alprenolol, which is in good agreement with the KD for alprenolol antagonism of isoproterenol stimulation of adenylate cyclase. The (minus)-[3-H]alprenolol binding sites exhibited strict stereospecificity. (minus)-Stereoisomers of beta-adrenergic antagonists or agonists were approximately 2 orders of magnitude more potent than the (+)-stereoisomers in competing for the binding sites. Comparable stereospecificity was apparent when agonists and antagonists were tested for their ability to interact with the adenylate cyclase-coupled beta-adrenergic receptors in the membranes. Potency series of 11 agonists and 13 antagonists for inhibition of binding and interaction with adenylate cyclase were identical and were characteristic of a beta2-adrenergic receptor. A variety of nonphysiologically active compounds containing a catechol moiety as well as several metabolites and cholinergic agents did not inhibit (minus)-[3-H]alprenolol binding or interact significantly as agonists or antagonists with the adenylate cyclase. The (minus)-[3-H]alprenolol binding sites studied appear to be equivalent to the beta-adrenergic receptor binding sites in the frog erythrocyte membranes.


Clinical investigation of the menstrual cycle. II. Neuroendocrine investigation and therapy of the inadequate luteal phase.
Nonhormonal drugs--diphenylhydantoin and nialamide, which act on the central nervous system and have no known endocrine activity--were given to two groups of women with distinct types of electroencephalographic patterns in an effort to regulate menstrual disorders. Equalization of the lengths of both the follicular phase and the luteal phase to the normal range was observed during the drug therapy. Forty-five per cent of the pregnancy rate was achieved in 36 of the 80 infecund patients within 4 months of treatment. The mode of action of these drugs is still unknown.


Two Synthetic Approaches to Coinage Metal(I) Mesocates: Electrochemical versus Chemical Synthesis.
We report two different approaches to isolate neutral and cationic mesocate-type metallosupramolecular architectures derived from coinage monovalent ions. For this purpose, we use a thiocarbohydrazone ligand, H2L (1), conveniently tuned with bulky phosphine groups to stabilize the MI ions and prevent ligand crossing to achieve the selective formation of mesocates. The neutral complexes [Cu2(HL)2] (2), [Ag2(HL)2] (3), and [Au2(HL)2] (4) were prepared by an electrochemical method, while the cationic complexes [Cu2(H2L)2](PF6)2 (5), [Cu2(H2L)2](BF4)2 (6), [Ag2(H2L)2](PF6)2 (7), [Ag4(HL)2](NO3)2 (8), and [Au2(H2L)2]Cl2 (9) were obtained by using a metal salt as the precursor. All of the complexes are neutral or cationic dinuclear mesocates, except the silver nitrate derivative, which exhibits a tetranuclear cluster mesocate architecture. The crystal structures of the neutral and cationic copper(I), silver(I), and gold(I) complexes allow us to analyze the influence of synthetic methodology or the counterion role on both the micro- and macrostructures of the mesocates.


A comparison of capillary-scale LC-NMR with alternative techniques: spectroscopic and practical considerations.
Experimental and practical details for the use of capillary LC (CapLC)-NMR are reported. The capillary NMR probe has high sensitivity and excellent flow characteristics and we found CapLC-NMR to be best suited to samples that are truly mass limited. CapLC-NMR relies on good capillary-scale chromatography where highly concentrated peaks with a volume closely matched to the NMR flow cell are achievable. Provided that the loading capacity of the capillary column is not limiting, the combination of high sensitivity and high solvent suppression quality makes CapLC-NMR an excellent choice. For many real samples, however, the loading is limiting and we found the combination of LC-SPE-MS-NMR with a cryoprobe enables more material to be purified for NMR analysis, while retaining sensitivity.


Nilemycin, an intercalating agent for deoxyribonucleic acid.
1. Nilemycin (NM) is found to exert an inhibitory effect on the mouse tumor Sarcoma 180 near toxic doses but not with Leukemia 1210. 2. In Yoshida rat sarcoma cells NM inhibits cellular de novo nucleic acid synthesis and protein to a much lesser extent. 3. More than 50% inhibition by NM to de novo synthesis of RNA, in a system using calf thymus DNA as a template, could be observed. 4. Suitable levels of NM reduce the S values of DNA. 5. The antibiotic induced metachromatic changes in the u.v. spectrum of DNA solutions. 6. NM markedly inhibited the polynucleotide ligase repairing action on DNase-1-nicked DNA. 7. It is presumed that NM intercalates nicked DNA into such a configuration that the reactive sites of the polynucleotides are inaccessible to the ligase activities.


Saturation behavior of ascites tumor cell chloride exchange in the presence of gluconate.
Steady state Cl- flux across the Ehrlich mouse ascites cell membrane was studied when gluconate replaced Cl- in the external medium. Saturation behavior was observed; K 1/2 was 23.9 mM Cl- and V was 758 micromol.g-1 dry weight.h-1. The cells lost K+, Cl- and H2O, consistent with relative impermeability to gluconate, and the Cl- efflux rate coefficient was elevated. The results indicate that a major portion of Cl- exchange occurs as a membrane transport process and suggest that the process is sensitive to intracellular Cl- levels.


Numerical study of variable-density flow and transport in unsaturated-saturated porous media.
Dense contaminant or solute transport in the unsaturated-saturated aquifer commonly exists in the natural environment. However, the influence of hydraulic properties of the unsaturated soil on penetration process of variable density flow in an unsaturated-saturated aquifer system is rarely investigated. In this study, a variable density, variably saturated flow and transport model based on FEFLOW is used to systematically investigate the penetration process of the solute through the unsaturated-saturated aquifer system, with a focus on the influence of the hydraulic parameters of the unsaturated soil on the penetration process. Vertical center of mass, and its speed and acceleration, are used to identify different stages of the penetration process through the unsaturated-saturated aquifer. The hydraulic parameters in the van Genuchten-Mualem model (VGM) affect the water content distribution in the unsaturated zone, subsequently the penetration time through the unsaturated zone. Through influencing the thickness of the transition zone (0.1-0.9 maximum concentration of the plume) when the plume reaches the water table, the hydraulic parameters affect the accumulation time of the solute at the boundary layer in the saturated zone. Thus, the process in not only the unsaturated but also the saturated zones is influenced by the change of the hydraulic properties of the unsaturated zone. Furthermore, the results show that the instabilities start to occur at the zone with high water content (90% of maximum saturation) in the capillary fringe. Freshwater intrudes into the zone with high water content when fingers are completely developed at the entire system. The length of freshwater intrusion above the water table has a negative correlation with the fitting parameter alpha in the VGM model. The influence of the density difference of the solute on the penetration processes is insignificant in the unsaturated zone but significant in the saturated zone. Sensitive analysis for the hydraulic properties of the unsaturated soil on the penetration process shows that pore size distribution index is the main factor influencing the penetration time through the unsaturated zone, the penetration time through the entire aquifer, the accumulation time at the boundary layer, and the development time of the fingers. Two other parameters, fitting parameter alpha and residual saturation, have minor effects.


Systematic review: benefits and harms of transarterial embolisation for treating hepatocellular adenoma.
Transarterial embolisation (TAE) is a standard treatment for bleeding hepatocellular adenoma (HCA) and, occasionally, symptomatic HCA involving large tumours. Whether TAE is similarly safe and effective as an elective treatment for bleeding and nonbleeding HCA remains unclear. To investigate the benefits and harms of TAE for bleeding and nonbleeding HCA. PubMed, Scopus, Embase and Cochrane Library databases were systematically searched for studies that examined post-TAE tumour reduction in patients with bleeding or nonbleeding HCA and that were published between January 2000 and January 2017. Systematic review of 21 case series involving 1468 patients with HCA in the systematic review identified 140 (9.5%) patients with 189 lesions who received TAE. Of these 140 patients, 66.4% had bleeding HCA and 33.6% had nonbleeding HCA. Intended elective TAE was performed in 27.1% of patients (38.6% of HCA lesions). Adenomatosis was observed in 6.1% of patients, and the rate of β-catenin expression was 4.5%. No malignant transformation was observed among the 189 tumours during a median follow-up time of 40 months. The complete response rate among 70 patients was 10.6%, and the partial response rate was 71.7%. No mortality or severe adverse side effects were reported during the hospitalisation period. The available evidence suggests that TAE can be considered safe for elective managment of HCA as well as for management of bleeding HCA. Elective TAE can be regarded as a reasonable alternative to surgery. High-quality prospective studies with long-term follow-up are needed to corroborate and strengthen available evidence.


Subclavian subtleties.
Several helpful technical features are presented that reduce the morbidity associated with subclavian vein catheterization. These techniques include percutaneous insertion through an indwelling catheter, repositioning the catheter without a second puncture, and securing the catheter without kinking or dislodgment. Use of these techniques will spare the patient the risks attendant to multiple subclavian punctures.


Complex III deficiency due to an in-frame MT-CYB deletion presenting as ketotic hypoglycemia and lactic acidosis.
Complex III deficiency due to a MT-CYB mutation has been reported in patients with myopathy. Here, we describe a 15-year-old boy who presented with metabolic acidosis, ketotic hypoglycemia and carnitine deficiency. Electron transport chain analysis and mitochondrial DNA sequencing on muscle tissue lead to the eventual diagnosis of complex III deficiency. This case demonstrates the critical role of muscle biopsies in a myopathy work-up, and the clinical efficacy of supplement therapy.


Splenic artery aneurysm as a rare cause of an upper GIT bleed.
Upper gastrointestinal bleeding (UGIB) is a common life-threatening presentation in the emergency department. Causes are typically divided into variceal and non-variceal bleeds. Non-variceal pathologies typically include bleeding peptic ulcers, haemorrhagic gastritis and Mallory Weiss Tears. Occassionally, less common pathologies are encountered such as Dieulafoy's lesions, haemosuccus pancreas, haemobilia or aorto-enteric fistula. The following report documents the case of a 49-year-old man who presented with an UGIB. His risk factors included a history of nonsteroidal anti-inflammatory drug, smoking and ethanol abuse. Despite his typical presentation and risk factors, investigation revealed an unusual and rare pathology. He was found to have a giant splenic artery aneurysm, abutting and eroding the gastric mucosa. Diagnosis was made using a combination of gastro-oesophagoscopy and CT scan. Successful treatment consisted of angio-embolisation of the aneurysm.


Cesium tolerance is enhanced by a chemical which binds to BETA-GLUCOSIDASE 23 in Arabidopsis thaliana.
Cesium (Cs) is found at low levels in nature but does not confer any known benefit to plants. Cs and K compete in cells due to the chemical similarity of Cs to potassium (K), and can induce K deficiency in cells. In previous studies, we identified chemicals that increase Cs tolerance in plants. Among them, a small chemical compound (C17H19F3N2O2), named CsToAcE1, was confirmed to enhance Cs tolerance while increasing Cs accumulation in plants. Treatment of plants with CsToAcE1 resulted in greater Cs and K accumulation and also alleviated Cs-induced growth retardation in Arabidopsis. In the present study, potential target proteins of CsToAcE1 were isolated from Arabidopsis to determine the mechanism by which CsToAcE1 alleviates Cs stress, while enhancing Cs accumulation. Our analysis identified one of the interacting target proteins of CsToAcE1 to be BETA-GLUCOSIDASE 23 (AtβGLU23). Interestingly, Arabidopsis atβglu23 mutants exhibited enhanced tolerance to Cs stress but did not respond to the application of CsToAcE1. Notably, application of CsToAcE1 resulted in a reduction of Cs-induced AtβGLU23 expression in wild-type plants, while this was not observed in a high affinity transporter mutant, athak5. Our data indicate that AtβGLU23 regulates plant response to Cs stress and that CsToAcE1 enhances Cs tolerance by repressing AtβGLU23. In addition, AtHAK5 also appears to be involved in this response.


Malignant fibrous histiocytoma of the mandible: the importance of an accurate histopathological diagnosis.
A case is presented of a malignant fibrous histiocytoma arising in the mandible and oral cavity of a 62-year old woman. The histopathological features were typical and the diagnosis was confirmed on immunohistochemistry. The exact nature of this usually soft tissue sarcoma is uncertain, but it is a well defined clinicopathological tumour entity which only rarely arises in the jaws. Microscopically, it may resemble other neoplasms, such as sarcomatoid squamous carcinoma, and an accurate diagnosis requires the use of immunohistochemistry or electron microscopy. Treatment is primarily surgical, but because of the difficulties at this site of complete removal with adequate margins, recurrence, metastasis and death due to disease are a likely outcome.


Culture conditions and sample preparation methods affect spectrum quality and reproducibility during profiling of Staphylococcus aureus with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has emerged as a promising tool to rapidly characterize Staphylococcus aureus. Different protocols have been employed, but effects of experimental factors, such as culture condition and sample preparation, on spectrum quality and reproducibility have not been rigorously examined. We applied MALDI-TOF MS to characterize a model system consisting of five methicillin-sensitive (MSSA) and five methicillin-resistant S. aureus isolates (MRSA) under two culture conditions (agar and broth) and using two sample preparation methods [intact cell method and protein extraction method (PEM)]. The effects of these treatments on spectrum quality and reproducibility were quantified. PEM facilitated increases in the number of peaks and mass range width. Broth cultures further improved spectrum quality in terms of increasing the number of peaks. In addition, PEM increased reproducibility in samples prepared using identical culture conditions. MALDI imaging data suggested that the improvement in reproducibility may result from a more homogeneous distribution of sample associated with the broth/PEM treatment. Broth/PEM treatment also yielded the highest rate (96%) of correct classification for MRSA. Taken together, these results suggest that broth/PEM maximizes the performance of MALDI-TOF MS to characterize S. aureus. Two culture conditions (agar or broth) and two sample preparation methods (intact cell or protein extraction) were evaluated for their effects on profiling of Staphylococcus aureus using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Results indicated that MALDI-enabled profiling of S. aureus is most effective when cultures are grown in broth and processed using a protein extraction-based approach. These findings should enhance future efforts to maximize the performance of this approach to characterize strains of S. aureus.


Role of parathyroid hormone in anorexia on maintenance hemodialysis patients.
Anorexia, which is a common condition in patients on hemodialysis (HD), is characterized by impaired appetite, a subjective condition that hinders anorexia diagnosis. Anorexia is frequently associated with protein energy wasting and inflammation, increasing morbidity and mortality risk. The aim of the study was to evaluate the association between appetite and nutritional, inflammatory, hormonal, and dietary intake parameters in patients on maintenance HD. Cross-sectional study with clinical, laboratory, and anthropometric parameters, body composition, muscle function, and dietary intake assessment. To evaluate appetite, a three simple questions questionnaire previously validated was used. After appetite classification, the sample was dichotomized in "normal appetite" and "impaired appetite" and compared. Multiple logistic regression was used to identify association between variables and outcome. 125 patients on HD were included, aged 60.6 ± 14.12 years old, median HD vintage 35.5 months. In dichotomized sample, 78.4% patients showed "normal appetite", and 21.6% "impaired appetite". "Impaired appetite" was independently associated with increased serum PTH (OR 1.001; 95% CI 1.000-1.002; p = 0.03), low zinc intake (OR 0.860; 95% CI 0.746-0.991; p = 0.03) and lower urea serum (OR 0.982; 95% CI 0.965-0.999; p = 0.04). Both groups showed insufficient dietary intake. Appetite was independently associated with increased serum of PTH, low serum concentration of urea, and low zinc intake which may infer association of appetite with mineral bone disease, protein intake and zinc deficiency.


Electrodiagnostic assessment of the brachial plexus.
The brachial plexus is one of the largest and most complex structures of the peripheral nervous system and, as such, cannot be studied by a single nerve conduction study (NCS) or muscle sampled by needle electrode examination (NEE). Typically, the screening sensory NCS is used and expanded to identify the region of involvement, the motor NCS is applied to determine the severity of the process, and the NEE is used to further characterize the lesion. Our approach to the electrodiagnostic assessment of the brachial plexus is the focus of this article; 3 electrodiagnostic cases with discussion follow this article.


Monoclonal antibodies to hog thyroglobulin recognizing disulfide-dependent conformational structures.
Monoclonal antibodies (MAbs) to hog thyroglobulin (Tg) were obtained by fusion of myeloma cells with B-lymphocytes from mice immunized with the protein. The five MAbs were classified into three groups which recognized different determinants; (1) MAb 4, (2) MAbs 6 and 10, and (3) MAbs 16 and 18. MAb 16 was IgG2b and the others IgG1. The immunoreactivity of Tg to the five MAbs was lost after reduction of the protein under denaturing conditions but remained after limited digestion by proteolytic enzymes. Tryptic fragments were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, electrophoretically blotted and stained by a peroxidase-linked second antibody. Various sized tryptic fragments reacted similarly with the three MAbs which had different determinant specificities. All the MAb-reactable fragments in the tryptic digest completely lost their immunoreactivity after reduction of their disulfide linkages.


Radial Neck-to-Humerus Transposition for Elbow Reconstruction Following Oncologic Resection of the Proximal Ulna: A Report of Two Cases.
Two young adult (aged 25 and 21 years) patients presented with sarcomas of the proximal ulna. To achieve an oncological margin, the proximal ulna required resection. Owing to the complex biomechanics of the elbow joint, reconstructive options are limited and have a high complication rate. The elbow was reconstructed with a transposition of the radial neck to the trochlea of the humerus in both patients. At over 2 years of follow-up, both patients have a stable and functional elbow. Transposition of the radial neck to the trochlea of the humerus provides a biological reconstruction in this complex problem.


Metastatic breast cancer is the second most common cause of brain metastasis (BM), and this problem is particularly marked for the amplified HER2 subtype (HER2+), with a cumulative incidence reaching up to 49 % in the ER-/HER2+ subgroup. Literature review shows that therapeutic progress has been major since the marketing of systemic anti-HER2+ treatments, with life expectancies now relatively unaffected by brain development. The recommended treatments are, on the one hand, specific treatment for brain development and, on the other hand, appropriate systemic treatment. Regarding local treatments, we will always favor surgery when possible, especially for large metastases, and stereotaxic radiotherapy, possibly iterative. One should be wary of whole brain irradiation which has never been shown to improve overall survival, but which is clearly associated with more cognitive toxicities. All the systemic anti-HER2 treatments currently on the market have shown efficacy on BM from HER2+ breast cancer and must therefore be chosen above all on the basis of their potential activity on the systemic disease at the time of cerebral evolution. If BM evolution happen without concomitant systemic progression, and local treatment can control it, it is not recommended to change the current medical treatment. Finally, randomized clinical studies opened to patients with active brain disease are starting to be published. The first of them showed the benefit of the triple combination tucatinib-trastuzumab-capecitabine in this context.


Anthropological reflections on youth drug use research in Australia: what we don't know and how we should find out.
This paper outlines an anthropological/sociological view of youth drug use which complements the existing research paradigm. The limitations of the existing paradigm are identified and an argument is presented for the inclusion of ethnography as a fruitful research method and for a greater focus on the social context of drug use by youth. Finally, the implications of this re-direction for future research and prevention are outlined.


Imatinib therapy for a patient with metastasis of colonic gastrointestinal stromal tumor: report of a case.
Gastrointestinal stromal tumors (GISTs) developing in the colon are rare, accounting for <5 % of all GISTs. There are few data on the clinical efficacy of tyrosine kinase inhibitors in colonic GISTs. We report here on an 80-year-old male patient with advanced GIST of the transverse colon. The patient underwent palliative resection of the primary tumor because the disease was associated with multiple liver metastases and peritoneal dissemination. Immunohistochemical analysis of the surgical specimens showed KIT and CD34 expression. Sequence analysis revealed that the tumor harbored deletion mutation at codons 557-558 in exon 11 of the c-kit gene. A diagnosis of colonic GIST was made. The patient postoperatively underwent imatinib therapy for the remaining metastatic tumors. Imatinib therapy induced a cyst-like appearance of the liver metastases and stabilized the disease. In the present case, c-kit gene analysis was found to be clinically helpful for validating the diagnosis and therapeutic decision making for this rare disease.


[The pathogenesis of oral contraceptive hypertension (author's transl)].
Simultaneous administration of estrogen and progestogen accelerates Goldblatt-type hypertension in rats. Neither estrogen nor progestogen alone alters arterial blood pressure. In the hormonal combination the hypertensive effect of estrogen can be replaced by epsilon-amino-capronic acid and the hypertensive effect of progestogen by desoxycorticosterone acetate. Estrogen is the only substance increasing plasma renin activity. There exists no correlation between the increase of the blood pressure and the plasma renin activity in the various groups of experimental animals receiving the different hypertensive preparations. Because of this, oral contraceptive hypertension may be supposed not to result from a stimulation of the renin-angiotensin system but may easily be seen in a combination of endothelial lesions and sodium retention, the former being caused by the estrogen's effect on blood coagulation, the latter produced by the synthetic progestogen.


Unhealthy smokers: scopes for prophylactic intervention and clinical treatment.
Globally, tobacco use causes approximately 6 million deaths per year, and predictions report that with current trends; more than 8 million deaths are expected annually by 2030. Cigarette smokings is currently accountable for more than 480,000 deaths each year in United States (US) and is the leading cause of preventable death in the US. On average, smokers die 10 years earlier than nonsmokers and if smoking continues at its current proportion among adolescents, one in every 13 Americans aged 17 years or younger is expected to die prematurely from a smoking-related illness. Even though there has been a marginal smoking decline of around 5% in recent years (2005 vs 2015), smokers still account for 15% of the US adult population. What is also concerning is that 41,000 out of 480,000 deaths results from secondhand smoke (SHS) exposure. Herein, we provide a detailed review of health complications and major pathological mechanisms including mutation, inflammation, oxidative stress, and hemodynamic and plasma protein changes associated with chronic smoking. Further, we discuss prophylactic interventions and associated benefits and provide a rationale for the scope of clinical treatment. Considering these premises, it is evident that much detailed translational and clinical studies are needed. Factors such as the length of smoking cessation for ex-smokers, the level of smoke exposure in case of SHS, pre-established health conditions, genetics (and epigenetics modification caused by chronic smoking) are few of the criteria that need to be evaluated to begin assessing the prophylactic and/or therapeutic impact of treatments aimed at chronic and former smokers (especially early stage ex-smokers) including those frequently subjected to second hand tobacco smoke exposure. Herein, we provide a detailed review of health complications and major pathological mechanisms including mutation, inflammation, oxidative stress, and hemodynamic and plasma protein changes associated with chronic smoking. Further, we discuss about prophylactic interventions and associated benefits and provide a rationale and scope for clinical treatment.


Expression of the intestinal T-lymphocyte-associated-molecule recognized by the HML-1 antibody on mononuclear cells from HTLV-I-infected subjects.
We investigated the expression of a monoclonal antibody (HML-1) defined antigen that appears on human intestinal T-lymphocytes in HTLV-I-related disease. We studied 25 ATL, and 24 healthy HTLV-I carriers. Patients with acute ATL showed a variety of the expression of the HML-1 antigen (range 0.4-74.8%). HML-1 expression on mononuclear cells (MNCs) in blood from patients with chronic ATL ranged from 1.7-43.6% (mean 13.5%). This level of expression was less than that of patients with acute ATL, but not significantly. In patients with smoldering ATL, the degree of patients with acute ATL, but not significantly. In patients with smoldering ATL, the degree of expression ranged from 1.6-13.3% (mean 8.0%). In contrast to patients with acute ATL, MNCs from patients with acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and B-cell type chronic lymphocytic leukemia (B-CLL) did not express the HML-1 antigen, except for the 2 patients with ALL. Healthy HTLV-I carriers and healthy controls also were negative for HML-1 reactivity. In acute ATL, patients with gastrointestinal tract infiltration tended to have high expression of the HML-1 epitope. After stimulation with phytohemagglutinin (PHA), healthy HTLV-I carriers showed significantly increased expression of the HML-1 epitope (P < 0.05). Recently, the beta 7 integrin family has been found to play a specific role in mucosal localization or adhesion, and HML-1 protein was found to match the deduced beta 7 N-terminal sequence. We propose that the cellular gene responsible for HML-1 epitope expression may, like IL-2, IL-2R, etc., be transactivated by infection with HTLV-I, and HML-1 antigen gene expression by HTLV-I infection may lead to infiltration of ATL cells with highly expressed HML-1 epitope into the gut mucosa.


Evaluation of a centrifugal blood cell processor for washing platelet concentrates.
A semiautomated saline wash procedure using a blood cell processor was evaluated as a technique for removing plasma from platelet concentrates. In vitro studies demonstrated 92 to 99.6 percent (mean, 96%) removal of total plasma protein (n = 30) with 84 to 97 percent (mean, 90.8%) platelet recovery (n = 28) in post-wash units. Post-wash pH values changed by +0.2 to -0.86 (mean, -0.47) (n = 30); the level of recovery from hypotonic shock was 69 to 97 percent (mean, 86%) (n = 11) of pre-wash units; weighted morphology scores decreased from a mean of 248 to 223 (n = 9). Aggregation response to arachidonic acid, collagen, and adenosine diphosphate plus epinephrine showed essentially no change following the wash procedure, and electron microscopy demonstrated slight morphologic alteration. Autologous platelets labeled with indium-111 demonstrated 43 +/- 20 percent recovery (n = 11) for washed units, compared to 41 +/- 10 percent for control unwashed units (n = 5); mean survivals were 140 +/- 41 hours (n = 11) for washed platelets and 185 +/- 28 hours for unwashed units (n = 5). Thirteen alloimmunized patients receiving 55 washed platelet concentrates demonstrated a mean 1- to 4-hour corrected count increment of 3.99 X 10(3) per microliter, compared to 3.02 X 10(3) per microliter for 77 unwashed platelet units given to the same patients. This study documents that platelet concentrates maintain viability and efficacy following a semiautomated saline wash method using the Cobe 2991 Blood Cell Processor, a technique that may be helpful for patients who require plasma-depleted platelet transfusions.


Thermophilic nucleoside phosphorylases: Their properties, characteristics and applications.
Nucleoside phosphorylases catalyze the reversible phosphorolysis of pyrimidine and purine nucleosides in the presence of phosphate. They are valuable catalysts in the synthesis of nucleosides and their analogues, which are often used as pharmaceuticals or their precursors. Thermostable nucleoside phosphorylases are promising biocatalysts, as they withstand harsh reaction conditions such as high pH or the addition of organic solvents. In this review, the characteristics and properties of thermostable nucleoside phosphorylases are described. Differences in amino acid content and protein structure were compared to their mesophilic homologues to identify features involved in thermostability. Substrate spectra of thermostable nucleoside phosphorylases were analyzed, and it is shown that thermostable nucleoside phosphorylases have a wider substrate spectrum than their mesophilic counterparts. Thus, thermostable nucleoside phosphorylases are interesting biocatalysts for industrial applications.


Probiotic supplementation attenuates increases in body mass and fat mass during high-fat diet in healthy young adults.
The objective was to determine the effects of the probiotic, VSL#3, on body and fat mass, insulin sensitivity, and skeletal muscle substrate oxidation following 4 weeks of a high-fat diet. Twenty non-obese males (18-30 years) participated in the study. Following a 2-week eucaloric control diet, participants underwent dual X-ray absorptiometry to determine body composition, an intravenous glucose tolerance test to determine insulin sensitivity, and a skeletal muscle biopsy for measurement of in vitro substrate oxidation. Subsequently, participants were randomized to receive either VSL#3 or placebo daily during 4 weeks of consuming a High-fat (55% fat), hypercaloric diet (+1,000 kcal day(-1) ). Participants repeated all measurements following the intervention. Body mass (1.42 ± 0.42 kg vs. 2.30 ± 0.28 kg) and fat mass (0.63 ± 0.09 kg vs. 1.29 ± 0.27 kg) increased less following the High-fat diet in the VSL#3 group compared with placebo. However, there were no significant changes in insulin sensitivity or in vitro skeletal muscle pyruvate and fat oxidation with the High-fat diet or VSL#3. VSL#3 supplementation appears to have provided some protection from body mass gain and fat accumulation in healthy young men consuming a High-fat and high-energy diet.


Synthesis of 6-phosphofructose aspartic acid and some related Amadori compounds.
We describe the synthesis and characterization of 6-phosphofructose-aspartic acid, an intermediate in the metabolism of fructose-asparagine by Salmonella. We also report improved syntheses of fructose-asparagine itself and of fructose-aspartic acid.


Alexander Ogston and the Army Medical Services formation of the Royal Army Medical Corps 1 July 1898.
The Royal Army Medical Corps came into existence on 1st July 1898, in response to dissatisfaction with the organisation and efficiency of the Army Medical Service. Although much of the pressure for change came from officers within the service, a significant factor was the campaign conducted by a civilian, Alexander Ogston, Professor of Surgery at Aberdeen.


Results after colectomy for colonic inertia: a sixteen-year experience.
Colonic inertia (CI) is a disturbance of colonic motility characterized by severe constipation and abdominal pain. This study was conducted to assess the results of total abdominal colectomy (TAC) in the management of CI. A retrospective chart review of 55 patients who underwent TAC for CI was conducted. Forty-eight patients (87%) were female with an average age of 40; severe constipation existed 2 years prior to surgery. Symptoms included severe constipation (100%) and abdominal pain (84%); diagnostic workup included sitz marker study, anal manometry, and Gastrografin enema. In all cases, sitz marker studies were abnormal and anal manometry was normal. Histologically, no patient had absence of neuroenteric plexuses. Complications included prolonged ileus (24%) and small bowel obstruction (8%). Some 49 patients (89%) had "good" or "excellent" results and 6 patients (11%) had "poor" results. Postoperative stool frequency was 5, 4, and 3 per day at 1, 2, and 12 months, respectively. TAC results in resolution of constipation in most patients. We conclude that TAC is effective treatment in patients with CI.


The effect of halothane on the action of alcuronium in the dog.
The effect of halothane on the action of alcuronium on neuromuscular transmission was studied in the intact dog. Electrical and mechanical evoked responses from stimulation of the ulnar nerve were recorded. The administration of 0.5% halothane prolonged the duration of action of alcuronium by about 50%.


Gastric bypass versus sleeve gastrectomy in patients with type 2 diabetes (Oseberg): a single-centre, triple-blind, randomised controlled trial.
For patients with obesity and type 2 diabetes, weight loss improves insulin sensitivity and β-cell function, and can induce remission of diabetes. The comparative efficacy of various bariatric procedures for the remission of type 2 diabetes has not been fully elucidated. We aimed to compare the effects of the two most common bariatric procedures, gastric bypass and sleeve gastrectomy, on remission of diabetes and β-cell function. We conducted a single-centre, triple-blind, randomised trial at Vestfold Hospital Trust (Tønsberg, Norway), in which patients (aged ≥18 years) with type 2 diabetes and obesity were randomly assigned (1:1) to receive gastric bypass or sleeve gastrectomy (the Oseberg study). Randomisation was performed with a computerised random number generator and a block size of 10. Treatment allocation was masked from participants, study personnel, and outcome assessors and was concealed with sealed opaque envelopes. Surgeons used identical skin incisions during both surgeries and were not involved in patient follow-up. The primary clinical outcome was the proportion of participants with complete remission of type 2 diabetes (HbA1c of ≤6·0% [42 mmol/mol] without the use of glucose-lowering medication) at 1 year after surgery. The primary physiological outcome was disposition index (a measure of β-cell function) at 1 year after surgery, as assessed by an intravenous glucose tolerance test. Primary outcomes were analysed in the intention-to-treat and per-protocol populations. This trial is ongoing and closed to recruitment, and is registered with ClinicalTrials.gov, NCT01778738. Between Oct 15, 2012, and Sept 1, 2017, 1305 patients who were preparing for bariatric surgery were screened, of whom 319 consecutive patients with type 2 diabetes were assessed for eligibility. 109 patients were enrolled and randomly assigned to gastric bypass (n=54) or sleeve gastrectomy (n=55). 107 (98%) of 109 patients completed 1-year follow-up, with one patient in each group withdrawing after surgery (per-protocol population). In the intention-to-treat population, diabetes remission rates were higher in the gastric bypass group than in the sleeve gastrectomy group (risk difference 27% [95% CI 10 to 44]; relative risk [RR] 1·57 [1·14 to 2·16], p=0·0054); results were similar in the per-protocol population (risk difference 27% [95% CI 10 to 45]; RR 1·57 [1·14 to 2·15], p=0·0036). In the intention-to-treat population, disposition index increased in both groups (between-group difference 55 [-111 to 220], p=0·52); results were similar in the per-protocol population (between-group difference 21 [-214 to 256], p=0.86). In the gastric bypass group, ten of 54 participants had early complications and 17 of 53 had late side-effects. In the sleeve gastrectomy group, eight of 55 participants had early complications and 22 of 54 had late side-effects. No deaths occurred in either group. Gastric bypass was found to be superior to sleeve gastrectomy for remission of type 2 diabetes at 1 year after surgery, and the two procedures had a similar beneficial effect on β-cell function. The use of gastric bypass as the preferred bariatric procedure for patients with obesity and type 2 diabetes could improve diabetes care and reduce related societal costs. Morbid Obesity Centre, Vestfold Hospital Trust.


Complex-forming organic ligands in cloud-point extraction of metal ions: a review.
Cloud-point extraction (CPE), an easy, safe, environmentally friendly, rapid and inexpensive methodology for preconcentration and separation of trace metals from aqueous solutions has recently become an attractive area of research and an alternative to liquid-liquid extraction. Moreover, it provides results comparable to those obtained with other separation techniques and has a greater potential to be explored in improving detection limits and other analytical characteristics over other methods. A few reviews have been published covering different aspects of the CPE procedure and its relevant applications, such as the phenomenon of clouding, the application in the extraction of trace inorganic and organic materials, as well as pesticides and protein substrates from different sources, or incorporation of CPE into an FIA system. This review focuses on general properties of the most frequently used organic ligands in cloud-point extraction and on literature data (from 2000 to 2012) concerning the use of modern techniques in determination of metal ions' content in various materials. The article is divided according to the class of organic ligands to be used in CPE.


Endocrine, metabolic, and cranial computed tomographic findings in anorexia nervosa.
Computerized tomographic brain scans were completed in 50 inpatients with anorexia nervosa and were compared with an age- and sex-matched control group. Seventy percent of the anorectic patients displayed enlarged lateral ventricles. There was a close link between ventricular size and low weight, but not between ventricular size and duration of the eating disorder. In addition, sulcal widening was observed more frequently in patients with enlarged ventricles than in patients without these structural changes. After weight gain, a statistically significant decrease in ventricular dilatation could be observed even when mean ventricular size still far exceeded that of the control subjects. The analysis of the endocrine and metabolic parameters, known to be indicators for the process of starvation, revealed a significant inverse correlation between triiodothyronine and ventricular size. Various possible pathogenetic mechanisms for the morphological brain alterations in patients with eating disorders are discussed.


Po-210 activity concentrations in wild and farmed fish from the Aegean Sea and Sea of Marmara and dose assessment to consumers.
Polonium (210Po) is the major contributor (with approximately 90%) to the radiation dose from radionuclides contained in the human diet, and it is mostly associated with seafood. This study presents 210Po activity concentrations in the tissues of 16 fish species from the Aegean Sea and Sea of Marmara. Among all species investigated, the highest 210Po activity concentration was 4450 ± 33 Bq kg-1 dry weight (dw) in the digestive tract of anchovy (Engraulis encrasicolus), and the lowest 210Po activity concentration was 1.3 ± 0.6 Bq kg-1 (dw) in the muscle tissue of the thornback ray (Raja clavata). Significant differences in 210Po concentrations were consistently found among the tissues of fish (P < 0.05). In general, the prominent accumulation of 210Po was observed in the digestive tract and liver while the muscle tissue generally displayed the lower concentrations. Polonium concentrations in the internal organs, such as muscle and liver, were related to the feeding ecology of fish and thus are a consequence of 210Po transfer in the food chain rather than 210Po uptake from water. The average 210Po concentration in fish filet was 54.1 Bq kg-1 dw and to attain the recommended limit for the annual committed effective dose (1 mSv year-1) would require the consumption of 1024 kg of mixed fish filet in 1 year, which is unlikely to happen. The highest 210Po activity concentration in the edible part of fish (filet) was determined in the anchovy (E. encrasicolus) but to reach the 1 mSv year-1 limit would require still the consumption of 7.1 kg year-1 of anchovy filet. Similar size specimens of wild and farmed fish, Dicentrarchus labrax and Sparus aurata, were analyzed to assess the differences in 210Po concentrations. Polonium concentrations in the wild fish were several-fold higher than in farmed specimens, these ones fed with fish feed with 210Po content lower than natural food in the sea. Therefore, the current trend of increasing the consumption of seafood from aquaculture seems to be reducing the radiation exposure to 210Po in the human diet that is considered beneficial to public health.


Decoding covert spatial attention using electrocorticographic (ECoG) signals in humans.
This study shows that electrocorticographic (ECoG) signals recorded from the surface of the brain provide detailed information about shifting of visual attention and its directional orientation in humans. ECoG allows for the identification of the cortical areas and time periods that hold the most information about covert attentional shifts. Our results suggest a transient distributed fronto-parietal mechanism for orienting of attention that is represented by different physiological processes. This neural mechanism encodes not only whether or not a subject shifts their attention to a location, but also the locus of attention. This work contributes to our understanding of the electrophysiological representation of attention in humans. It may also eventually lead to brain-computer interfaces (BCIs) that optimize user interaction with their surroundings or that allow people to communicate choices simply by shifting attention to them.


Excretion of mercapturic acids of acrylamide and glycidamide in human urine after single oral administration of deuterium-labelled acrylamide.
We investigated the human metabolism of AA to the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) and N-(R/S)-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L: -cysteine (GAMA) which are derived from AA itself and from its oxidative genotoxic metabolite glycidamide (GA), respectively. A healthy male volunteer received a single dose of about 1 mg deuterium-labelled acrylamide (d(3)-AA), representing 13 microg/kg body weight, in drinking water. Urine samples before dosing and within 46 h after the dose were analysed for d(3)-AAMA and d(3)-GAMA by LC-ESI-MS/MS. A first phase of increase in urinary concentration was found to last 18 h with a broad plateau between 8 and 18 h for AAMA, and 22 h for GAMA. Elimination half-lives of both AAMA and GAMA were estimated to be approximately 3.5 h for the first phase and more than 10 h up to few days for the second phase. Total recovery in urine after 24 h was about 51% as the sum of AAMA and GAMA and hereby well in accordance with former studies in rats. After 2 days AAMA, accounting for altogether 52% of the total AA dose, was the major metabolite of AA in humans. GAMA, accounting for 5%, appeared as a minor metabolite of AA. In humans we found a urinary ratio of 0.1 for GAMA/AAMA compared to previously reported values of 0.2 for rats and 0.5 for mice. Therefore, the metabolic fate of AA in humans was more similar to that in rats than in mice as already demonstrated in terms of the haemoglobin adducts. Consequently a genotoxic potency of AA mediated by GA could be supposed to be comparable in rats and humans.


Immunoradiometric assay for human thyroglobulin and variations in thyroid pathology.
A specific and sensitive double antibody radioimmunoassay for measuring human serum thyroglobulin (Tg) has been developed. Serum Tg levels are reported for patients with differentiated and undifferentiated thyroid carcinomas, post-treated and untreated hyperthyroidism, thyroiditis, and cold nodular goiters. We have studied results of serum Tg levels in the follow-up and care of patients who have undergone total thyroidectomy for differentiated thyroid carcinomas. Tg has no diagnostic value in the detection of thyroid cancer, but is a reliable index of metastatic growth in the follow-up of patients with differentiated carcinomas. In addition, serum Tg determination might be helpful in the aetiological diagnosis of bone or lung metastases of unknown origin.


Definition of colorectal anastomotic leakage: A consensus survey among Dutch and Chinese colorectal surgeons.
To determine the level of consensus on the definition of colorectal anastomotic leakage (CAL) among Dutch and Chinese colorectal surgeons. Dutch and Chinese colorectal surgeons were asked to partake in an online questionnaire. Consensus in the online questionnaire was defined as > 80% agreement between respondents on various statements regarding a general definition of CAL, and regarding clinical and radiological diagnosis of the complication. Fifty-nine Dutch and 202 Chinese dedicated colorectal surgeons participated in the online survey. Consensus was found on only one of the proposed elements of a general definition of CAL in both countries: 'extravasation of contrast medium after rectal enema on a CT scan'. Another two were found relevant according to Dutch surgeons: 'necrosis of the anastomosis found during reoperation', and 'a radiological collection treated with percutaneous drainage'. No consensus was found for all other proposed elements that may be included in a general definition. There is no universally accepted definition of CAL in the Netherlands and China. Diagnosis of CAL based on clinical manifestations remains a point of discussion in both countries. Dutch surgeons are more likely to report 'subclinical' leaks as CAL, which partly explains the higher reported Dutch CAL rates.


Expression and Clinical Significance of Metalloproteases and Their Inhibitors by Endothelial Cells From Invasive Breast Carcinomas.
Given that tumor blood vessels are important in tumor progression and metastasis, tumor endothelial cells (ECs) are the main targets of antiangiogenic therapy. The aim of the present work was to evaluate the phenotype of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) from ECs at the tumor center and its relationship to MMP/TIMP global expression and its relationship to the occurrence of distant metastasis. An immunohistochemical study was performed using tissue arrays and specific antibodies against MMPs (MMP-2, -7, -9, -11, -13, and -14) and TIMPs (TIMP-1, -2, and -3) at the tumor center in 104 patients with primary ductal invasive breast tumors. MMP-11 expression by ECs was related to shorter relapse-free survival, whereas TIMP-3 expression was related to low occurrence of distant metastasis. In addition, MMP-11 and TIMP-2 expression by ECs was associated with shorter overall survival, whereas TIMP-3 expression by ECs was associated with longer overall survival. Our findings indicate significant relationships between the expression of MMPs/TIMPs by ECs and the global expression of these factors at the tumor scene. High MMP/TIMP expression by ECs from breast carcinomas, which may be consequence of the cross-talk between tumor cells and their surrounding microenvironment.


MiR-26a-5p inhibits GSK3β expression and promotes cardiac hypertrophy in vitro.
The role of miR-26a-5p expression in cardiac hypertrophy remains unclear. Herein, the effect of miR-26a-5p on cardiac hypertrophy was investigated using phenylephrine (PE)-induced cardiac hypertrophy in vitro and in a rat model of hypertension-induced hypertrophy in vivo. The PE-induced cardiac hypertrophy models in vitro and vivo were established. To investigate the effect of miR-26a-5p activation on autophagy, the protein expression of autophagosome marker (LC3) and p62 was detected by western blot analysis. To explore the effect of miR-26a-5p activation on cardiac hypertrophy, the relative mRNA expression of cardiac hypertrophy related mark GSK3β was detected by qRT-PCR in vitro and vivo. In addition, immunofluorescence staining was used to detect cardiac hypertrophy related mark α-actinin. The cell surface area was measured by immunofluorescence staining. The direct target relationship between miR-26a-5p and GSK3β was confirmed by dual luciferase report. MiR-26a-5p was highly expressed in PE-induced cardiac hypertrophy. MiR-26a-5p promoted LC3II and decreased p62 expression in PE-induced cardiac hypertrophy in the presence or absence of lysosomal inhibitor. Furthermore, miR-26a-5p significantly inhibited GSK3β expression in vitro and in vivo. Dual luciferase report results confirmed that miR-26a-5p could directly target GSK3β. GSK3β overexpression significantly reversed the expression of cardiac hypertrophy-related markers including ANP, ACTA1 and MYH7. Immunofluorescence staining results demonstrated that miR-26a-5p promoted cardiac hypertrophy related protein α-actinin expression, and increased cell surface area in vitro and in vivo. Our study revealed that miR-26a-5p promotes myocardial cell autophagy activation and cardiac hypertrophy by regulating GSK3β, which needs further research.


The Second Anesthetists' Travel Club Meeting: Bootleggers, Madison and Ralph Waters!
The second annual meeting of any organization is almost as critical as the first. A second meeting begins to assure the viability and importance of the organization. After the very successful first meeting of the Anesthetists' Travel Club in Rochester, Minnesota, in December of 1929, Ralph Waters (1883-1979) was charged with hosting the 1930 meeting at the University of Wisconsin in Madison. The meeting was held Thursday December 18th through Saturday December 20th. Dr. Waters started the meeting at 8:00 am with a tour of the operating rooms of the Wisconsin General Hospital. Lunch followed at the Memorial Union with the afternoon split between experimental surgery, and the anatomy, and physiology laboratories. There was an early dinner before the group took in the basketball game between the University of Pennsylvania and the University of Wisconsin. Friday's meeting was very similar; starting in the operating rooms at 8:00 am followed by a Union Club lunch. The afternoon was spent in the Pharmacology laboratory with a 4:00 pm lecture entitled "Demonstration Clinical Effects of Barbiturates in Neuropsychiatry". Dinner was held at the University Club. Saturday's program followed the same lines, but with an afternoon tea and a dinner at the Waters' home. In February1931, almost a year to the date from his first note, Waters wrote to those who had attended the meeting. He followed up on the clinical cases the group had seen, and commented upon the Guedel-Waters balloons for endotracheal tubes and the spinal he had performed. He even commented upon the use of cyclopropane in obstetrics. Thus, the Anesthetists' Travel Club meeting in 1930 successfully concluded.


Long-term role of nitric oxide in the enteric nervous system of the transplanted rat intestine.
We investigated the long-term changes of the nitric oxide (NO)-related neural component after syngeneic total small bowel transplantation in rats. In the present study, the NO-related neural component was examined using the electrophysiological and NADPH-diaphorase histochemical technique. The rats were divided into four groups: an untreated young adult control group, an untreated 2-year-old control group, a group killed 1 month after transplantation, and a group killed 2 years after transplantation. A superfusion apparatus was used to evaluate the response of jejunal strips to electrical transmural stimulation. In the presence of adrenergic and cholinergic blockade, the inhibitory effect of L-N(G)-nitro arginine (L-NNA; a nitric oxide synthesis inhibitor) on nonadrenergic, noncholinergic (NANC) relaxation was expressed as a L-NNA-sensitive component. The L-NNA-sensitive component accounted for 41.6 +/- 4.6% (mean +/- SE), 43.1 +/- 3.5%,54.6 +/- 4.1%, and 55.8 +/- 3.5% in the young control group, 2-year control group, 1-month transplant group, and 2-year transplant group, respectively, being significantly higher in the transplant groups (p < 0.05). The actual strength of the L-NNA-sensitive component was 0.24 +/- 0.03 (mean +/- SE), 0.26 +/- 0.02, 0.44 +/- 0.04, and 0.46 +/- 0.04 mg of tension per mg of wet weight, respectively, also being significantly higher in the transplant groups (p < 0.001). In addition, the percentage of NADPH-diaphorase-positive fibers was 24.1 +/- 1.1% (mean +/- SE), 25.5 +/- 1.4%, 31.0 +/- 1.6%, and 30.9 +/- 2.0%, respectively, being significantly higher in the transplant groups (p < 0.05). These results suggest that NO neurons in the intrinsic jejunal nervous system have an adaptive role in maintaining intestinal graft motility.