Intraoperative Frozen Section for Margin Evaluation During Radical Prostatectomy: A Systematic Review.
Surgical margin status and preservation of the neurovascular bundles (NVB) are important prognostic indicators for oncological and functional outcomes of patients undergoing radical prostatectomy (RP). Intraoperative frozen section (IFS) has been used to evaluate margin status during surgery with the intention of reducing positive surgical margins (PSMs) and guiding safe preservation of the NVBs during RP, but its value is controversial. To evaluate current literature comparing outcomes of men undergoing RP with IFS versus RP without IFS. Medline, Embase, and Cochrane Library searches for all relevant publications (PROSPERO ID CRD42019125940), including comparative studies reporting on men undergoing RP with and without IFS, were performed. Outcomes of interest were surgical margin status, long-term oncological outcomes, NVB status, and erectile function (EF) recovery. Data were narratively synthesised in light of methodological and clinical heterogeneity of included studies. After screening 834 publications, 10 nonrandomised retrospective comparative studies (including 16 897 patients) were retrieved. The technique of IFS differed considerably between studies. Eight studies reported a reduction in PSM rates (-1.4% to -14.5%) with IFS, though two studies report higher PSM rates (+0.4% and +10%) with IFS. Three studies reported on long-term oncological outcomes, and no difference was seen with IFS. Three studies reported on the performance of IFS systematically at the posterolateral margin of the prostate (neurovascular structure-adjacent frozen-section examination [NeuroSAFE] technique). In all these three studies, either NVB preservation or EF recovery was improved. All studies were deemed to be at either a serious or a moderate risk of bias. No randomised controlled trials were identified, and significant heterogeneity existed with regard to many features of the studies included. Within the limitations of this review, the evidence suggests that IFS during RP can facilitate a modest reduction in PSM rates. There is evidence that IFS performed systematically at the posterolateral margin of the prostate can facilitate more NVB preservation. However, in the main, the lack of prospective, randomised, standardised research with long-term oncological and functional outcomes precludes strong conclusions and highlights the need for such studies. The data of this review suggest that frozen section sampling of the prostate (ie, whilst the patient is still asleep) during prostate cancer surgery can reduce the likelihood of cancer being detected at the edge of the removed prostate. It also finds that a type of frozen section analysis (neurovascular structure-adjacent frozen-section examination [NeuroSAFE] technique) can help allow the nerves around the prostate to be left intact safely during surgery. However, the studies in this review are very different from one another and generally at a high risk of errors. Therefore, comparisons and conclusions must be made carefully.


Circulating Tumor DNA Markers for Early Progression on Fulvestrant With or Without Palbociclib in ER+ Advanced Breast Cancer.
There are no established molecular biomarkers for patients with breast cancer receiving combination endocrine and CDK4/6 inhibitor (CDK4/6i). We aimed to determine whether genomic markers in circulating tumor DNA (ctDNA) can identify patients at higher risk of early progression on fulvestrant therapy with or without palbociclib, a CDK4/6i. PALOMA-3 was a phase III, multicenter, double-blind randomized controlled trial of palbociclib plus fulvestrant (n = 347) vs placebo plus fulvestrant (n = 174) in patients with endocrine-pretreated estrogen receptor-positive (ER+) breast cancer. Pretreatment plasma samples from 459 patients were analyzed for mutations in 17 genes, copy number in 14 genes, and circulating tumor fraction. Progression-free survival (PFS) was compared in patients with circulating tumor fraction above or below a prespecified cutoff of 10% and with or without a specific genomic alteration. All statistical tests were 2-sided. Patients with high ctDNA fraction had worse PFS on both palbociclib plus fulvestrant (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.17 to 2.24; P = .004) and placebo plus fulvestrant (HR = 1.77, 95% CI = 1.21 to 2.59; P = .004). In multivariable analysis, high-circulating tumor fraction was associated with worse PFS (HR = 1.20 per 10% increase in tumor fraction, 95% CI = 1.09 to 1.32; P < .001), as was TP53 mutation (HR = 1.84, 95% CI = 1.27 to 2.65; P = .001) and FGFR1 amplification (HR = 2.91, 95% CI = 1.61 to 5.25; P < .001). No interaction with treatment randomization was observed. Pretreatment ctDNA identified a group of high-risk patients with poor clinical outcome despite the addition of CDK4/6 inhibition. These patients might benefit from inclusion in future trials of escalating treatment, with therapies that may be active in these genomic contexts.


Should elderly non-small-cell lung cancer patients be offered elderly-specific trials? Results of a pooled analysis from the North Central Cancer Treatment Group.
To answer the question, "should elderly non-small-cell lung cancer patients be offered elderly-specific trials?" The North Central Cancer Treatment Group (NCCTG) performed a pooled analysis of elderly patients who participated in elderly-specific trials (required age > or = 65 years) and age-unspecified trials (required age > or = 18 years). Between 1998 and 2000, all NCCTG non-small-cell lung cancer (NSCLC) patients with incurable cancer, age > or = 65 years, and receiving first-line chemotherapy were included. A total of 118 elderly patients participated in elderly-specific trials, and 108, in age-unspecified trials. Demographics and outcomes were compared based on trial type. The median age of elderly patients in elderly-specific trials was greater: median (range): 73 years (65 to 87) and 70 years (65 to 85), respectively (P < .001), as was the percentage older than 80 years: 17% and 3%, respectively (P = .0008). Median survival times were 232 and 302 days, respectively (P = .08). After adjustment for baseline age, Eastern Cooperative Oncology Group performance score, cancer stage, and body mass index, this survival difference was not statistically significant (hazard ratio = 1.25; P = .16). Grade 3 or worse nonhematologic adverse event rates were greater in age-unspecified trials (81% v 57%, respectively; P < .001), as were grade 3 or worse hematologic events (68% v 10%, respectively; P < .001). Elderly patients in NSCLC elderly-specific trials suffered lower rates of severe adverse events with no statistically significant differences in survival. It seems that elderly-specific trials are providing quality care and helping to define optimal cancer therapy in the elderly, particularly among the "oldest of the old."


Interaction between cyclic adenosine monophosphate and cyclic gunaosine monophosphate in guinea pig ventricular myocardium.
The purpose of this study was to examine the mechanisms underlying adrenergic-cholinergic antagonism in ventricular myocardium. Myocardial contractility, cyclic adenosine monophosphate (AMP) levels, and cyclic guanosine monophosphate (GMP) levels were measure in isolated guinea pig ventricles after treatment with various inotropic agents given alone and simultaneously with acetylcholine. Acetylcholine alone markedly elevated cyclic GMP levels but did not substantially change myocardial contractility. However, the same concentration of acetylcholine significantly attenuated the inotropic effect of isoproterenol and histamine, two drugs that may act by increasing myocardial levels of cyclic AMP. The decrease in the inotropic response to isoproterenol did not appear to be due to a decrease in the generation of cyclic AMP, because cyclic AMP levels were similar in hearts receiving isoproterenol alone and those receiving isoproterenol with acetylcholine. Dibutyryl cyclic GMP also antagonized the intropic action of isoproterenol. Acetylcholine did not alter the inotropic effects of ouabain, an agent that increases myocardial contractility without changing cyclic AMP levels. These results suggest that cyclic GMP mediates the antiadrenergic effects of acetylcholine by specifically antagonizing the inotropic actions of cyclic AMP.


Fluctuation-driven directional flow in biochemical cycle: further study of electric activation of Na,K pumps.
Directional flow of information and energies is characteristic of many types of biochemical reactions, for instance, ion transport, energy coupling during ATP synthesis, and muscle contraction. Can a fluctuating force field, or a noise, induce such a directional flux? Previous work has shown that Na,K-ATPase of human erythrocyte can absorb free energy from an externally applied random-telegraph-noise (RTN) electric field to pump Rb+ up its concentration gradient. However, the RTN field used in these experiments was constant in amplitude and would not mimic fluctuating electric fields of a cell membrane. Here we show that electric fields which fluctuate both in life time and in amplitude, and thus, better mimicking the transmembrane electric fields of a cell, can also induce Rb+ pumping by Na,K-ATPase. A Gaussian-RTN-electric field, or a field with amplitude fluctuating according to the Gaussian distribution, with varied standard deviation (sigma), induced active pumping of Rb+ in human erythrocyte, which was completely inhibited by ouabain. Increased values for sigma led to a nonmonotonic reduction in pumping efficiency. A general formula for calculating the ion transport in a biochemical cycle induced by fluctuating electric field has been derived and applied to a simple four-state electroconformational coupling (ECC) model. It was found that the calculated efficiency in the energy coupling decreased with increasing sigma value, and this effect was relatively small and monotonic, whereas experimental data were more complex: monotonic under certain sets of conditions but nonmonotonic under different sets. The agreement in general features but disagreement in some fine features suggest that there are other properties of the electric activation process for Na,K-ATPase that cannot be adequately described by the simple ECC model, and further refinement of the ECC model is required.


In vitro susceptibility to pyrimethamine of DHFR I164L single mutant Plasmodium falciparum.
Recently, Plasmodium falciparum parasites bearing Pfdhfr I164L single mutation were found in Madagascar. These new mutants may challenge the use of antifolates for the intermittent preventive treatment of malaria during pregnancy (IPTp). Assays with transgenic bacteria suggested that I164L parasites have a wild-type phenotype for pyrimethamine but it had to be confirmed by testing the parasites themselves. Thirty Plasmodium falciparum clinical isolates were collected in 2008 in the south-east of Madagascar. A part of Pfdhfr gene encompassing codons 6 to 206 was amplified by PCR and the determination of the presence of single nucleotide polymorphisms was performed by DNA sequencing. The multiplicity of infection was estimated by using an allelic family-specific nested PCR. Isolates that appeared monoclonal were submitted to culture adaptation. Determination of IC(50s) to pyrimethamine was performed on adapted isolates. Four different Pfdhfr alleles were found: the 164L single mutant-type (N = 13), the wild-type (N = 7), the triple mutant-type 51I/59R/108N (N = 9) and the double mutant-type 108N/164L (N = 1). Eleven out 30 (36.7%) of P. falciparum isolates were considered as monoclonal infection. Among them, five isolates were successfully adapted in culture and tested for pyrimethamine in vitro susceptibility. The wild-type allele was the most susceptible with a 50% inhibitory concentration (IC(50)) < 10 nM. The geometric mean of IC(50) of the three I164L mutant isolates was 6-fold higher than the wild-type with 61.3 nM (SD = 3.2 nM, CI95%: 53.9-69.7 nM). These values remained largely below the IC(50) of the triple mutant parasite (13,804 nM). The IC(50)s of the I164L mutant isolates were significantly higher than those of the wild-type (6-fold higher) and close from those usually reported for simple mutants S108N (roughly10-fold higher than wild type). Given the observed values, the determination of IC(50)s directly on parasites did not confirm what has been found on transgenic bacteria. The prevalence increase of the Pfdhfr I164L single mutant parasite since 2006 could be explained by the selective advantage of this allele under sulphadoxine-pyrimethamine pressure. The emergence of highly resistant alleles should be considered in the future, in particular because an unexpected double mutant-type allele S108N/I164L has been already detected.


Visualising and controlling the flow in biomolecular systems at and between multiple scales: from atoms to hydrodynamics at different locations in time and space.
A novel framework for modelling biomolecular systems at multiple scales in space and time simultaneously is described. The atomistic molecular dynamics representation is smoothly connected with a statistical continuum hydrodynamics description. The system behaves correctly at the limits of pure molecular dynamics (hydrodynamics) and at the intermediate regimes when the atoms move partly as atomistic particles, and at the same time follow the hydrodynamic flows. The corresponding contributions are controlled by a parameter, which is defined as an arbitrary function of space and time, thus, allowing an effective separation of the atomistic 'core' and continuum 'environment'. To fill the scale gap between the atomistic and the continuum representations our special purpose computer for molecular dynamics, MDGRAPE-4, as well as GPU-based computing were used for developing the framework. These hardware developments also include interactive molecular dynamics simulations that allow intervention of the modelling through force-feedback devices.


Antibiotics for clinically diagnosed acute rhinosinusitis in adults.
In primary care settings, the diagnosis of rhinosinusitis is generally based on clinical signs and symptoms. Technical investigations are not routinely performed, nor recommended. Individual trials show a trend in favour of antibiotics, but the balance of benefit versus harm is unclear. To assess the effect of antibiotics in adults with clinically diagnosed rhinosinusitis in primary care settings. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2012), MEDLINE (January 1950 to February week 4, 2012) and EMBASE (January 1974 to February 2012). Randomised controlled trials (RCTs) of antibiotics versus placebo in participants with rhinosinusitis-like signs or symptoms. Two authors independently extracted data and assessed the risk of bias. We contacted trial authors for additional information. We collected information on adverse effects from the trials. We included 10 trials involving 2450 participants. Overall, the risk of bias in these studies was low. Irrespective of the treatment group, 47% of participants were cured after one week and 71% after 14 days. Antibiotics can shorten the time to cure, but only five more participants per 100 will cure faster at any time point between 7 and 14 days if they receive antibiotics instead of placebo (number needed to treat to benefit (NNTB)) 18 (95% confidence interval (CI) 10 to 115, I(2) statistic 0%, eight trials). Purulent secretion resolves faster with antibiotics (odds ratio (OR) 1.58 (95% CI 1.13 to 2.22)), (NNTB 11, 95% CI 6 to 51, I(2) statistic 0%, three trials). However, 27% of the participants who received antibiotics and 15% of those who received placebo experienced adverse events (OR 2.10, 95% CI 1.60 to 2.77) (number needed to treat to harm (NNTH)) 8 (95% CI 6 to 13, I(2) statistic 13%, seven trials). More participants in the placebo group needed to start antibiotic therapy because of an abnormal course of rhinosinusitis (OR 0.49, 95% CI 0.36 to 0.66), NNTH 20 (95% CI 14 to 35, I(2) statistic 0%, eight trials). Only one disease-related complication (brain abscess) occurred in a patient treated with antibiotics. The potential benefit of antibiotics in the treatment of clinically diagnosed acute rhinosinusitis needs to be seen in the context of a high prevalence of adverse events. Taking into account antibiotic resistance and the very low incidence of serious complications, we conclude that there is no place for antibiotics for the patient with clinically diagnosed, uncomplicated acute rhinosinusitis. This review cannot make recommendations for children, patients with a suppressed immune system and patients with severe disease, as these populations were not included in the available trials.


Early-onset peripheral arterial occlusive disease: clinical features and determinants of disease severity and location.
Early-onset peripheral lower extremity arterial occlusive disease (PAD) is an uncommon, poorly characterized manifestation of atherosclerotic vascular disease. We studied the clinical presentation and correlates of disease severity and location in patients with early-onset PAD identified at non-invasive arterial evaluation. We identified a series of 159 patients who were younger than 50 years and had an abnormal resting or postexercise ankle brachial index (ABI) (< 0.9) or, if arteries were noncompressible, monophasic arterial Doppler signals. Disease severity and location were determined based on results of noninvasive vascular laboratory testing. Presence of coexisting atherosclerosis in other arterial beds was ascertained by review of patient records. Multivariable logistic regression analyses were used to identify risk factors associated with disease severity and location. Mean age of the patients was 42.7 +/- 4.2 years and 55% were women. Prevalence of risk factors was 76% for current or past smoking; 71%, dyslipidemia; 53%, hypertension; 35%, diabetes; and 53%, family history. Claudication was present in 50%, rest pain in 3%, ulceration in 31% and the remaining 16% did not have symptoms from PAD. Low high-density lipoprotein (HDL)-cholesterol and female sex were associated with severity. Of 102 patients in whom disease location could be determined noninvasively, 65% had aortoiliac disease. Female sex, low HDL-cholesterol, and absence of diabetes were associated with aortoiliac disease. Atherosclerosis in other arterial beds was identified in 53% of the patients. In this study population of early-onset atherosclerotic PAD, men and women were equally represented. The disease involved predominantly the aortoiliac location. Low HDL-cholesterol and female sex were associated with disease severity. An aggressive approach to diagnosis and treatment may be warranted as atherosclerosis in other arterial beds was prevalent in half of the patients.


Black carbon accrual during 2000 years of paddy-rice and non-paddy cropping in the Yangtze River Delta, China.
Rice straw burning has accompanied paddy management for millennia, introducing black carbon (BC) into soil as the residue of incomplete combustion. This study examined the contribution of BC to soil organic matter and the rate at which it accumulates in paddy soils as a result of prolonged paddy management. Soil depth profiles were sampled along a chronosequence of 0-2000 years of rice-wheat rotation systems and adjacent non-paddy systems (50-700 years) in the Bay of Hangzhou (Zhejiang province, China). The soil BC content and its degree of condensation were assessed using benzene-polycarboxylic acids (BPCAs) as geochemical markers. The results showed that despite regular long term BC input, BC only contributed 7-11% of total soil organic carbon (SOC) in the topsoil horizons. Nevertheless, along with SOC, paddy soils accumulated BC with increasing duration of management until 297 years to reach a steady-state of 13 t BC ha(-1). This was 1.8 times more than in non-paddy soils. The fate of BC in paddy soils (0-1 m) could be modeled revealing an average annual input of 44 kg ha(-1) yr(-1), and a mean residence time of 303 years. The subsoils contributed at least 50% to overall BC stocks, which likely derived from periods prior to land embankment and episodic burial of ancient topsoil, as also indicated by BPCA pattern changes. We conclude that there is a significant but limited accumulation of C in charred forms upon prolonged paddy management. The final contribution of BC to total SOC in paddy soils was similar to that in other aerobic ecosystems of the world.


Area security unit in a psychiatric hospital.
Since 1974 a psychiatric hospital security unit, designed to serve the whole catchment area, has cared for mentally ill (mostly psychotic) patients with disturbed behaviour that cannot be managed in open wards. There are a few long-term dangerous patients but most stay only briefly. The admission of women to the unit was not followed by the expected reduction in violence. The unit has facilities for occupational therapy, physical recreation, work, and study, which are particularly important for those who are too dangerous to leave it. The unit's calming influence depends as much on the supportive effect of the high staff ratio as on the use of tranquillisers. This type of unit is not suitable for patients with personality disturbances who "act out" or for mentally abnormal offenders; but it functions well as a crisis centre for the disturbed mentally ill, and there is an increasing demand for its services.


Alpha-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats.
Impaired glucose uptake and metabolism by peripheral tissues is a common feature in both type I and type II diabetes mellitus. This phenomenon was examined in the context of oxidative stress and the early events within the insulin signalling pathway using soleus muscles derived from non-obese, insulin-resistant type II diabetic Goto-Kakizaki (GK) rats, a well-known genetic rat model for human type II diabetes. Insulin-stimulated glucose transport was impaired in soleus muscle from GK rats. Oxidative and non-oxidative glucose disposal pathways represented by glucose oxidation and glycogen synthesis in soleus muscles of GK rats appear to be resistant to the action of insulin when compared to their corresponding control values. These diabetes-related abnormalities in glucose disposal were associated with a marked diminution in the insulin-mediated enhancement of protein kinase B (Akt/PKB) and insulin receptor substrate-1 (IRS-1)-associated phosphatidylinostol 3-kinase (PI 3-kinase) activities; these two kinases are key elements in the insulin signalling pathway. Moreover, heightened state of oxidative stress, as indicated by protein bound carbonyl content, was evident in soleus muscle of GK diabetic rats. Chronic administration of the hydrophobic/hydrophilic antioxidant alpha -lipoic-acid (ALA, 100 mg/kg, i.p.) partly ameliorated the diabetes-related deficit in glucose metabolism, protein oxidation as well as the activation by insulin of the various steps of the insulin signalling pathway, including the enzymes Akt/PKB and PI-3 kinase. Overall, the current investigation illuminates the concept that oxidative stress may indeed be involved in the pathogenesis of certain types of insulin resistance. It also harmonizes with the notion of including potent antioxidants such as ALA in the armamentarium of antidiabetic therapy.


Rescue of misrouted GnRHR mutants reveals its constitutive activity.
G protein-coupled receptors (GPCR) play central roles in almost all physiological functions, and mutations in GPCR are responsible for over 30 hereditary diseases associated with loss or gain of receptor function. Gain of function mutants are frequently described as having constitutive activity (CA), that is, they activate effectors in the absence of agonist occupancy. Although many GPCR have mutants with CA, the GnRH receptor (GnRHR) was not, until 2010, associated with any CA mutants. The explanation for the failure to observe CA appears to be that the quality control system of the cell recognizes CA mutants of GnRHR as misfolded and retains them in the endoplasmic reticulum. In the present study, we identified several human (h)GnRHR mutants with substitutions in transmembrane helix 6 (F(272)K, F(272)Q, Y(284)F, C(279)A, and C(279)S) that demonstrate varying levels of CA after being rescued by pharmacoperones from different chemical classes and/or deletion of residue K(191), a modification that increases trafficking to the plasma membrane. The movement of the mutants from the endoplasmic reticulum (unrescued) to the plasma membrane (after rescue) is supported by confocal microscopy. Judging from the receptor-stimulated inositol phosphate production, mutants F(272)K and F(272)Q, after rescue, display the largest level of CA, an amount that is comparable with agonist-stimulated activation. Because mutations in other GPCR are, like the hGnRHR, scrutinized by the quality control system, this general approach may reveal CA in receptor mutants from other systems. A computer model of the hGnRHR and these mutants was used to evaluate the conformation associated with CA.


Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia.
Significant cardiac neural and electrophysiologic remodeling occurs with hypercholesterolemia (HC). Whether simvastatin can reverse HC-induced remodeling is unclear. The purpose of this study was to determine the mechanisms underlying the antiarrhythmic effects of statins. Rabbits (N = 38) were fed HC chow (HC), standard chow (Control), HC chow followed by standard chow (Withdrawal), or HC chow and simvastatin (Statin) for 8 weeks. The hearts then were Langendorff-perfused for electrophysiologic studies. Nerves were identified by immunostaining of growth-associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Action potential duration (APD) restitution in normal hearts with (N = 5) and without (N = 5) simvastatin therapy also was studied. Serum cholesterol levels (mg/dL) were 1,855 +/- 533 in HC, 50 +/- 21 in Control, 570 +/- 115 in Withdrawal, and 873 +/- 112 in Statin groups (P <.001). Compared with HC (16,700 +/- 5,342; 12,200 +/- 3,878 microm(2)/mm(2)), the Statin group had significantly reduced GAP43-positive (10,289 +/- 3,393 microm(2)/mm(2), P = .03) and TH-positive (7,685 +/- 2,959 microm(2)/mm(2), P = .04) nerve density, respectively. APD was longer in HC rabbits than in controls (192 +/- 20 ms vs 174 +/- 17 ms; P <.03). Withdrawal and Statin groups had less APD prolongation than HC group. Statin group has less repolarization heterogeneity than HC group (P <.01). Statin therapy flattened the slope of APD restitution in normal hearts. Ventricular fibrillation was either induced or occurred spontaneously in 79% of hearts in HC, 20% in Control, and 66% in Withdrawal groups. However, there was no VF in hearts of Statin group (P <.001). Simvastatin significantly reduced vulnerability to ventricular fibrillation via the mechanism of reduction of HC-induced neural and electrophysiologic remodeling.


Ibotenate lesions of the diagonal band of broca attenuate baroreceptor sensitivity of rat supraoptic vasopressin neurons.
Previous electrophysiological studies in the rat suggest that neurons in the diagonal band of Broca participate in baroreceptor-induced suppression of the spontaneous activity of vasopressin-secreting neurons in the hypothalamic supraoptic nucleus. In order to test this hypothesis, extracellular recordings were obtained from phasically-active vasopressin neurons in the supraoptic nucleus of anesthetized rats injected at least 3 days previously with ibotenic acid (1.25 μg/250 nl) in the diagonal band of Broca, the medial and lateral septum, or the median preoptic nucleus. In normal rats, brief increases in blood pressure produced by injections of metaraminol (10 μg/10 μl iv) that were sufficient to activate peripheral baroreceptors, suppressed the activity of a majority (21 tested, 19 suppressed) of phasically-active vasopressin-secreting neurons. In rats with ibotenic acid lesions of the diagonal band of Broca, the number of phasically-active neurons that were baroreceptor-sensitive was significantly reduced (21 tested, 8 suppressed) while lesions of the medial and lateral septum (17 tested, 16 suppressed) or the median preoptic nucleus (21 tested, 20 suppressed) had no effect. The results support the hypothesis that diagonal band of Broca neurons participate in a central pathway mediating the inhibitory effects of peripheral baroreceptor stimulation on the activity of vasopressin-secreting neurons in the rat supraoptic nucleus.


Patients' experience of colonoscopy in the English Bowel Cancer Screening Programme.
Understanding patients' experience of screening programs is crucial for service improvement. The English Bowel Cancer Screening Programme (BCSP) aims to achieve this by sending out questionnaires to all patients who undergo a colonoscopy following an abnormal fecal occult blood test result. This study used the questionnaire data to report the experiences of these patients. Data on patients who underwent colonoscopy between 2011 and 2012 were extracted from the BCSP database. Descriptive statistics were used to summarize key questionnaire items relating to informed choice, psychological wellbeing, physical experience, and after-effects. Multilevel logistic regression was used to test for associations with variables of interest: sex, age, socioeconomic status, colonoscopy results, and screening center performance (adenoma detection rate, cecal intubation rate, proportion of colonoscopies involving sedation). Data from 50,858 patients (79.3 % of those eligible) were analyzed. A majority reported a positive experience on items relating to informed choice (e. g. 95.7 % felt they understood the risks) and psychological wellbeing (e. g. 98.3 % felt they were treated with respect). However, an appreciable proportion experienced unexpected test discomfort (21.0 %) or pain at home (14.8 %). There were few notable demographic differences, although women were more likely than men to experience unexpected discomfort (25.1 % vs. 18.0 %; P < 0.01) and pain at home (18.2 % vs. 12.3 %; P < 0.01). No associations with center-level variables were apparent. Colonoscopy experience was generally positive, suggesting high satisfaction with the BCSP. Reported pain and unexpected discomfort were more negative than most other outcomes (particularly for women); measures to improve this should be considered.


Metalinguistic awareness in children: a developmental progression.
The purpose of this study was to determine if a developmental order exists in the metalinguistic ability of children to make judgments about the form of language while simultaneously attending to a meaningful linguistic context. The stimulus material consisted of a short story into which 20 nonsense lexical items had been substituted. The 20 stimuli were comprised of phonotactically illegal and legal sequences of phonemes. In addition, the lexical items had been positioned to replace either structure or content words within the story. The participants were 90 Caucasian children who were divided into nine age groupings from 4;0 to 12;11. Baseline data were obtained from 10 adults. All subjects were required to respond to the audio-recorded stimuli by pressing a button whenever a nonsense item was perceived. The data were analyzed for both number of correct responses and reaction times. Results revealed a major shift in metalanguage ability occurring between 7 and 8 years of age. The 8- to 12-year-olds responded correctly to more items and at significantly faster rates than the 4- to 7-year-olds. The adults outperformed the children on all tasks, showing that metalanguage development continues beyond childhood.


The Diagnostic Value of Routine Papanicolaou Smears for Detecting Endometrial Cancers: An Update.
The presence of degenerative endometrial debris and abnormal endometrial cells is considered to be the hint for endometrial pathology. The purpose of this study was to evaluate the efficacy of Papanicolaou (Pap) smears in detecting endometrial cancers. There were 146 cases of endometrial cancer diagnosed at our institute in 2000-2002 and 271 in 2010-2012. Among them, 57 and 95 relevant reports of Pap smears 6 months prior to the histology diagnosis were retrieved for this study, respectively. In the first time period, new criteria for detecting endometrial lesions had not yet been incorporated into routine screening. Twenty cases (21%) of adenocarcinoma, 12 (13%) of atypical glandular cells, 4 (4%) of endometrial debris and 59 (62%) negative reports were found among the more recent 95 relevant Pap smears. The overall efficacy of the Pap smear for detecting endometrial malignancy was 38%, higher than 10 years previously (30%). Although the Pap smear was originally designed to screen cervical lesions, more effective detection of endometrial lesions could be achieved by adding new criteria to the routine screening.


Reward-period activity in primate dorsolateral prefrontal and orbitofrontal neurons is affected by reward schedules.
Reward-period activity observed in the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex (OFC) is thought to represent the detection of reward delivery. To investigate whether this activity plays the same role in these areas, we examined this activity under different reward schedules and whether the reward schedule has similar effects on this activity in each of these areas. A monkey performed an oculomotor delayed-response (ODR) task under two reward schedules. In the ODR-1 schedule, the monkey received a large amount of reward only after four successful trials, whereas in the ODR-2 schedule, it received a small amount of reward after every successful trial. Although reward-period activity was observed in both areas, more neurons exhibited this activity in the OFC. Reward-period activity was modulated by the proximity to reward delivery in both areas and this feature was observed more frequently in the OFC. The onset time of this activity also gradually advanced depending on the proximity to reward delivery. Moreover, many OFC neurons with this activity responded to free reward delivery. These results indicate that reward-period activity in the OFC represents the detection of reward delivery and that the gradual change in the magnitude and the onset time of this activity represents the expectation of reward delivery. Similar features of reward-period activity were observed in DLPFC neurons, although a significant number of DLPFC neurons did not respond to free reward delivery and no advance was observed in the onset time of this activity. These results suggest that reward-period activity in the DLPFC participates in whether or not correct performance was achieved. Thus, although similar reward-period activity was observed in both areas, the activity in the OFC represents the detection of reward delivery and is affected by the monkey's motivational state, whereas that in the DLPFC seems to participate in monitoring whether or not the necessary performance is achieved.


Social Self-Sorting of Colloidal Families in Co-Assembling Microgel Systems.
Colloids are valuable model systems to understand the structure and dynamics of matter, explore new self-assembly concepts, and realize advanced materials. Herein, we demonstrate social self-sorting of co-assembled families of colloids by orthogonal host/guest recognition using cyclodextrins. We show that mixtures of four partners self-sort into their respective families without mutual interference. Additionally, the self-assemblies and their interactions are switchable using orthogonal triggers. This study goes beyond previous features of molecular self-sorting, and opens the design space for future self-sorting colloidal systems via rationally designed molecular recognition.


Effect of different levels and sources of zinc supplementation on quantitative and qualitative semen attributes and serum testosterone level in crossbred cattle (Bos indicus x Bos taurus) bulls.
An experiment was conducted on 16 crossbred bulls (about 2 years of age, 316.2+/-0.77 kg average body weight), divided into groups I, II, III and IV to study the effect of different levels of Zn supplementation from inorganic and organic sources on semen quality. The animals in the first 3 groups were supplemented with 0, 35 and 70 ppm Zn from Zn sulfate, respectively and the animals in-group IV were supplemented with 35 ppm Zn as Zn propionate. Semen collection and evaluation was done in the first month (to assess semen quality at the start of the experiment) and 7th, 8th and 9th month of experimental feeding to evaluate the effect of supplemental Zn on semen attributes. We gave 6 months for Zn feeding, so that 3 sperm cycles of spermatogenesis had passed and the collected semen reflected the complete effect of Zn supplementation. Six ejaculates from each bull were collected and evaluated for semen quantitative (ejaculate volume, sperm concentration and sperm number per ejaculate) and qualitative characteristics (semen pH, mass motility, individual motility, sperm livability percent and abnormal sperm percent, percent intact acrosome, bovine cervical mucus penetration test, hypo-osmotic sperm swelling test) and activity of seminal plasma enzymes i.e., alkaline phosphatase, acid phosphatase, GOT and GPT. Testosterone level in the blood serum of crossbred bulls was also estimated. Mean values of semen quantitative and qualitative characteristics at the start of the experiment were statistically non significant (P > 0.05) in all the crossbred cattle bulls, however, there were statistically significant differences among the bulls of different groups after 6 months of zinc supplementation. Mean ejaculate volume (mL) was 2.37, 4.70, 5.86 and 6.38, respectively in groups I to IV, indicating a statistically significant (P < 0.05) higher semen volume in Zn-supplemented groups as compared to the control group of bulls. Similarly, sperm concentration (million.mL(-1)), live sperm (%) and motility (%) were significantly (P < 0.01) higher in Zn-supplemented groups as compared to the control group. The results of BCMPT and HOSST revealed a significant improvement in sperm functional ability in all the groups supplemented with Zn as compared to the control group. The activity of alkaline and acid phosphatase in seminal plasma was significantly (P < 0.05) higher in the Zn-supplemented groups, whereas GOT and GPT activities in seminal plasma were significantly (P < 0.05) lower in the Zn propionate supplemented group as compared to the control group. Testosterone concentration (ng.mL(-1)) in blood serum was significantly higher in animals of groups III and IV, as compared to control group. It may be concluded that Zn supplementation either in the inorganic or organic form in the diet of crossbred bulls improved the qualitative and quantitative attributes of semen; however, the number of sperm per ejaculate, mass motility and semen fertility test like bovine cervical mucus penetration was significantly higher in bulls given Zn in an organic form (Zn propionate) as compared to an inorganic form (Zn sulfate).


Synthesis, structure, and condensed-phase reactivity of [Ag3(μ3-H)(μ3-BH4)LPh3](BF4) (LPh = bis(diphenylphosphino)amine) with CS2.
Electrospray ionisation mass spectrometry (ESI-MS) was used to monitor the reaction of AgBF4, bis(diphenylphosphino)amine (dppa = (Ph2P)2NH = LPh) and NaBH4 in acetonitrile and thereby direct the synthesis of the silver nanocluster [Ag3(μ3-H)(μ3-BH4)LPh3](BF4), 3b·BF4, formed via reaction of AgBF4, bis(diphenylphosphino)amine (dppa = (Ph2P)2NH = LPh) and NaBH4 in acetonitrile. The X-ray structure of 3b·BF4 highlights that the cation adopts a planar trinuclear Ag3 geometry surrounded by three dppa ligands and coordinated on the bottom face by a μ3-hydride and on the top face by a μ3-BH4. The solution phase structure of 3b·BF4 was characterised by multinuclear NMR and DOSY NMR, which showed that the borohydride anion remains bound in the [Ag3(μ3-H)(μ3-BH4)LPh3]+ cluster cation in solution. ESI-MS and in situ1H and HSQC NMR spectroscopy reveals that 3b·BF4 reacts with CS2 in solution at the BH4 site to yield [Ag3(H)(S2CH)LPh3]+, 4b, which has to date eluded structural characterisation via X-ray crystallography due to lack of formation of suitable crystals. The gas-phase ion chemistry of [Ag3(H)(S2CH)LPh3]+ was examined under multistage mass spectrometry conditions using collision-induced dissociation (CID) and compared to that of the previously examined copper analogue, [Cu3(H)(S2CH)LPh3]+. While both cluster cations fragment via ligand loss, the CID spectra of the resultant [M3(H)(S2CH)LPh2]+ are different. Unlike [Cu3(H)(S2CH)LPh2]+, which solely undergoes loss of thioformaldehyde to give [Cu3(S)LPh2]+, [Ag3(H)(S2CH)LPh2]+ gives a richer CID spectrum with fragmentation channels that include ligand loss, CH2S loss and reductive elimination of dithioformic acid. DFT calculations exploring rearrangement and fragmentation of the model systems [M3(H)(S2CH)LMe2]+ ((Me2P)2NH = dmpa = LMe) were used to suggest plausible mechanisms and examine the energetics of the three competing channels: ligand loss, CH2S loss and reductive elimination of dithioformic acid.


Alu insertions versus blood group plus protein genetic variability in four Amerindian populations.
Do the population relationships obtained using DNA or blood group plus protein markers remain the same or do they reveal different patterns, indicating that the factors which influence genetic variation at these two levels of analysis are diverse? Can these markers shed light on the biological classification of the Aché, a Paraguayan tribe which only recently established more permanent contacts with non-Indians? To consider these questions we typed 193 individuals from four Amerindian tribes in relation to 12 Alu polymorphisms (five of them never studied in these populations), while 22 blood group plus protein systems were studied among the Aché. These data were then integrated with those previously available (blood groups plus proteins) for the three other populations. DNA extraction and amplification, as well as the other laboratory procedures, were performed using standard methods currently in use in our laboratory. The genetic relationships were obtained using the D(A) distance, and the trees were constructed by the neighbour-joining method, both developed by M. Nei and collaborators. Reliability of the trees was tested by bootstrap replications. Other population variability values were also determined using Nei's methods. Alu polymorphism was observed in all populations and for most of the loci; in the seven systems from which we could compare our results with those of other Amerindian groups agreement was satisfactory. Unusual findings on the blood group plus protein systems of the Aché were a very low (5%) HP*1 frequency and the presence of the C(W) phenotype in the Rh blood group. The intertribal patterns of relationship and other aspects of their variation were remarkably congruent in the two sets (Alu; blood group plus protein) of systems. The answer to the first question posed above is affirmative. However, the problem of whether the Aché derived from a Gê group that preceded the Guarani colonization of Paraguay, or are just a differentiated Guarani group, could not be answered with the genetic information available; the second hypothesis seems more likely at present, but the point to be emphasized is the striking genetic distinctiveness of the Aché as compared to other Amerindians.


Plasmon-plasmon coupling probed by ultrafast, strong-field photoemission with <7 Å sensitivity.
The coupling of propagating surface plasmon waves and localized plasmon oscillations in nanostructures is an essential phenomenon determining electromagnetic field enhancement on the nanoscale. Here, we use our recently developed ultrafast photoemission near-field probing technique to investigate the fundamental question of plasmon-plasmon coupling and its effect on large field enhancement factors. By measuring and analyzing plasmon field enhancement values at different nanostructured surfaces, we can separate the contributions from propagating and localized plasmons. When resonance conditions are met, a significant field enhancement factor can be attributed to the generation of localized plasmons on surface nanostructures, acting as dipole sources resonantly driven by the propagating plasmon field. Our plasmon-plasmon coupling results can contribute directly to applications in surface-enhanced Raman scattering (SERS) and the development of plasmonic sensors and nanostructured photocathodes.


Lack of Accredited Clinical Training in Movement Disorders in Europe, Egypt, and Tunisia.
Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. To survey the accessible MD clinical training in these regions. We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.


Genetic variation in caspase genes and risk of non-Hodgkin lymphoma: a pooled analysis of 3 population-based case-control studies.
Caspases play a critical role in regulation of apoptosis, cell differentiation, inflammation, and innate immunity, and several are mutated or have altered expression in non-Hodgkin lymphoma (NHL). To study the impact of genetic variation in caspases on NHL risk, we analyzed tag single nucleotide polymorphisms (SNPs) in 12 caspase and related genes in 3 population-based case-control studies (1946 cases and 1808 controls). Gene-based analysis, adjusting for the number of tagSNPs genotyped in each gene, showed significant associations for CASP8, CASP9, and CASP1. SNP-based analysis showed that CASP8 rs6736233 (odds ratio (OR) (CG) = 1.21; OR(CC) = 2.13; P trend = .011); CASP9 rs4661636 (OR(CT) = 0.89; OR(TT) = 0.77; P trend = .011); and CASP1 rs1785882 (OR(AT) = 1.12; OR(AA) = 1.30; P trend = .0054) were significantly associated with NHL risk and consistent across studies. It is noteworthy that genetic variants in CASP8 were associated with risk of all major NHL subtypes. Our findings suggest that genetic variation in caspases may play an important role in lymphomagenesis.


Polarity-switching top coats enable orientation of sub-10-nm block copolymer domains.
Block copolymers (BCPs) must necessarily have high interaction parameters (χ), a fundamental measure of block incompatibility, to self-assemble into sub-10-nanometer features. Unfortunately, a high χ often results from blocks that have disparate interfacial energies, which makes the formation of useful thin-film domain orientations challenging. To mitigate interfacial forces, polymers composed of maleic anhydride and two other components have been designed as top coats that can be spin-coated from basic aqueous solution in the ring-opened, acid salt form. When baked, the anhydride reforms and switches polarity to create a neutral layer enabling BCP feature alignment not possible by thermal annealing alone. Top coats were applied to the lamella-forming block copolymers poly(styrene-block-trimethylsilylstyrene-block-styrene) and poly(trimethylsilylstyrene-block-lactide), which were thermally annealed to produce perpendicular features with linewidths of 15 and 9 nanometers, respectively.


Impulsivity and inhibitory control deficits are associated with unhealthy eating in young adults.
Heightened impulsivity and inefficient inhibitory control are increasingly recognized as risk factors for unhealthy eating and obesity but the underlying processes are not fully understood. We used structural equation modeling to investigate the relationships between impulsivity, inhibitory control, eating behavior, and body mass index (BMI) in 210 undergraduates who ranged from underweight to obese. We demonstrate that impulsivity and inhibitory control deficits are positively associated with several facets of unhealthy eating, including overeating in response to external food cues and in response to negative emotional states, and making food choices based on taste preferences without consideration of health value. We further show that such unhealthy eating is, for the most part, associated with increased BMI, with the exception of Restraint Eating, which is negatively associated with BMI. These results add to our understanding of the impact of individual differences in impulsivity and inhibitory control on key aspects of unhealthy eating and may have implications for the treatment and prevention of obesity.


Quantitative Structure Activity Relationship Models for the Antioxidant Activity of Polysaccharides.
In this study, quantitative structure activity relationship (QSAR) models for the antioxidant activity of polysaccharides were developed with 50% effective concentration (EC50) as the dependent variable. To establish optimum QSAR models, multiple linear regressions (MLR), support vector machines (SVM) and artificial neural networks (ANN) were used, and 11 molecular descriptors were selected. The optimum QSAR model for predicting EC50 of DPPH-scavenging activity consisted of four major descriptors. MLR model gave EC50 = 0.033Ara-0.041GalA-0.03GlcA-0.025PC+0.484, and MLR fitted the training set with R = 0.807. ANN model gave the improvement of training set (R = 0.96, RMSE = 0.018) and test set (R = 0.933, RMSE = 0.055) which indicated that it was more accurately than SVM and MLR models for predicting the DPPH-scavenging activity of polysaccharides. 67 compounds were used for predicting EC50 of the hydroxyl radicals scavenging activity of polysaccharides. MLR model gave EC50 = 0.12PC+0.083Fuc+0.013Rha-0.02UA+0.372. A comparison of results from models indicated that ANN model (R = 0.944, RMSE = 0.119) was also the best one for predicting the hydroxyl radicals scavenging activity of polysaccharides. MLR and ANN models showed that Ara and GalA appeared critical in determining EC50 of DPPH-scavenging activity, and Fuc, Rha, uronic acid and protein content had a great effect on the hydroxyl radicals scavenging activity of polysaccharides. The antioxidant activity of polysaccharide usually was high in MW range of 4000-100000, and the antioxidant activity could be affected simultaneously by other polysaccharide properties, such as uronic acid and Ara.


Slit2 involvement in glioma cell migration is mediated by Robo1 receptor.
Slit and Robo proteins are evolutionarily conserved molecules whose interaction underlies axon guidance and neuronal precursor cell migration. During development secreted Slit proteins mediate chemorepulsive signals on cells expressing Robo receptors. Because similar molecular mechanisms may be utilized in glioma cell invasion and neuroblast migration, we studied the expression of Slit2 and its transmembrane receptor Robo1 as well as their functional role in migration in glioma cells. qRT-PCR and immunohistochemistry of human specimens revealed that Slit2 was distinctly expressed by non-neoplastic neurons, but at only very low levels in fibrillary astrocytoma and glioblastoma. Robo1 also was mainly restricted to neurons in the normal brain, whereas astrocytic tumor cells in situ as well as glioblastoma cell lines overexpressed Robo1 at mRNA and protein levels. Recombinant human Slit2 in a concentration of 0.45 nM was repulsive for glioma cell lines in a modified Boyden chamber assay. RNAi-mediated knockdown of Robo1 in glioma cell lines neutralized the repulsive effect of Slit2, demonstrating that Robo1 served as the major Slit2 receptor. Our findings suggest that a chemorepulsive effect mediated by interaction of Slit2 and Robo1 participates in glioma cell guidance in the brain.


Determination of the embedded thermo-optical expansion coefficients of PbTe and ZnSe thin film infrared multilayers.
This paper reports the first derived thermo-optical properties for vacuum deposited infrared thin films embedded in multilayers. These properties were extracted from the temperature-dependence of manufactured narrow bandpass filters across the 4-17 µm mid-infrared wavelength region. Using a repository of spaceflight multi-cavity bandpass filters, the thermo-optical expansion coefficients of PbTe and ZnSe were determined across an elevated temperature range 20-160 °C. Embedded ZnSe films showed thermo-optical properties similar to reported bulk values, whilst the embedded PbTe films of lower optical density, deviate from reference literature sources. Detailed knowledge of derived coefficients is essential to the multilayer design of temperature-invariant narrow bandpass filters for use in non-cooled infrared detection systems. We further present manufacture of the first reported temperature-invariant multi-cavity narrow bandpass filter utilizing PbS chalcogenide layer material.


The role of blood transfusion in the management of upper and lower intestinal tract bleeding.
Patients with gastrointestinal (GI) haemorrhage use 13.8% of all red blood cell transfusions in England. This review addresses the evidence for red blood cell, fresh frozen plasma and platelet transfusions in acute and chronic blood loss, from both the upper and lower intestinal tract. It reviews the indications for transfusion in GI bleeding, the haematological consequences of massive blood loss and massive transfusion, and the importance of managing coagulopathy in bleeding patients. It also looks at the safety and risks of blood transfusion, and provides clinicians with evidence to reduce unnecessary transfusion. Large controlled clinical trials of blood transfusion specifically in GI bleeding are required, along with further research into the use of adjuvant therapies such as recombinant activated factor VIIa. Changing clinician behaviour to reduce inappropriate blood transfusion remains a key target for future transfusion research.


Clinical and Echocardiographic Features Associated With Improved Survival in Patients With Severe Aortic Stenosis Undergoing Balloon Aortic Valvuloplasty (BAV).
Balloon aortic valvuloplasty (BAV) is used in high-risk patients with severe aortic stenosis (AS) when the benefit of transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) is unclear. Our objective was to identify clinical or echocardiographic features that identify patients likely to benefit from BAV. We studied 141 consecutive patients who underwent BAV from July, 2011 to October, 2017. Clinical characteristics, routine echocardiographic parameters, and speckle tracking imaging of global longitudinal strain (GLS) were assessed before and after BAV. The primary outcome was all-cause mortality as ascertained by the National Death Index. There were 141 patients, median age, 80 years (interquartile range [IQR], 74-87 years) with severe AS (median aortic valve area, 0.66 cm²; IQR, 0.53-0.79 cm²) and median mean gradient of 36 mm Hg (IQR, 27-48 mm Hg) who underwent BAV. The 1-year mortality rate was 52%. Characteristics associated with survival were New York Heart Association class I symptoms, lower brain natriuretic peptide level, higher left ventricular ejection fraction (LVEF) >53%, and higher GLS (>13.2%; absolute values were used for GLS). Landmark analysis at 60 days showed the 47 patients who underwent TAVR/SAVR after BAV had significantly better 1-year survival than those who did not (P<.001). A high 1-year mortality rate was observed in severe AS patients selected for BAV. LVEF and left ventricular (LV)-GLS offer similar prognostic value for 1-year mortality; however, LV-GLS may have potentially increased clinical utility, as it provides a clear threshold for predicting poor outcomes compared with LVEF. As patients who undergo TAVR/SAVR have markedly improved mortality, careful consideration should be given to advance definitive valve therapy in carefully selected BAV patients.


Crossing the midline as a function of distance from midline.
This study examined the effect of differential block placement on the frequency of midline crossing during the Space Visualization test (SV) of the Southern California Sensory Integration Tests. The SV test was administered at distances of 0.75, 3.00, and 6.00 inches to a group of 71 normal right-handed boys (ages 5 and 7 years) to obtain the Space Visualization Contralateral Use score (SVCU) and the Space Visualization Contralateral Use Percentage score (SVCU percent). Space Visualization (SV) adjusted scores were also obtained to examine the effect of differential block placement on visual perception scores. The analyses for the SVCU and SVCU percent scores showed that age and distance were significant. Analysis of variance of the SV adjusted standard score indicated that trial, but not distance or age, was significant. There was a significant age-by-trial interaction. The need for a standard protocol for block placement during the administration of the SV test was shown. Future research needs were identified.


The Mechanism of the Osteoprotective Action of a Polyphenol-Rich Aronia melanocarpa Extract during Chronic Exposure to Cadmium is Mediated by the Oxidative Defense System.
Recently, we demonstrated in a rat model that consumption of a polyphenol-rich extract obtained from the berries of Aronia melanocarpa could protect from cadmium-induced disorders in bone turnover and changes in bone mineral status. The aim of this study was to investigate whether the osteoprotective effect of this extract is mediated by the oxidative defense system. Enzymatic and nonenzymatic antioxidants, total antioxidative and oxidative status, hydrogen peroxide, and markers of oxidative protein, lipid, and DNA damage were determined in bone tissue at the distal femoral epiphysis of female Wistar rats receiving 0.1 % aqueous A. melanocarpa extract (prepared from the lyophilized commercial extract containing 65.74 % of polyphenols) as the only drinking fluid and/or cadmium in the diet (1 and 5 mg/kg) for 3, 10, 17, and 24 months. The total oxidative and antioxidative status of the serum was also evaluated. The administration of A. melanocarpa extract provided significant protection from cadmium-induced oxidative stress in the bone and serum, and from lipid peroxidation and oxidative damage to the protein and DNA in the bone tissue. Numerous correlations were noted between indices of the oxidative/antioxidative bone status and markers of bone metabolism previously assayed in the animals receiving A. melanocarpa extract. The results allow the conclusion that the ability of A. melanocarpa extract to mediate the oxidative defense system and prevent oxidative modifications of protein, lipid, and DNA in the bone tissue plays an important role in its osteoprotective action under exposure to cadmium. The findings provide further evidence supporting our suggestion that chokeberry may be a promising natural agent for protection against the toxic action of cadmium in women chronically exposed to this metal.


Complications of a failed Bristow procedure and their management.
The management of patients who have a failed Bristow reconstruction of the shoulder is very complex. In order to determine the complications that occur when a Bristow procedure fails, and how they should be managed, we retrospectively evaluated forty shoulders in thirty-nine patients who had been treated by the senior one of us for a failed Bristow procedure from 1977 to 1987. The complications of the index Bristow procedures included recurrent painful anterior instability, injury to the articular cartilage, failure of the coracoid bone-block to unite with the glenoid, loosening of the screw, neurovascular injury, and posterior instability. The primary etiology of failure of the index Bristow procedure was excessive laxity of the capsule in thirty-two shoulders (80 per cent) that were affected by chronic, painful anterior or posterior instability. An untreated Perthes-Bankart lesion was present in the remaining eight shoulders (20 per cent). The use of anterior reconstruction for the revision of a failed Bristow procedure is a difficult operation that necessitates meticulous technique. As our over-all plan of treatment resulted in a good or excellent outcome in only 50 per cent of the patients, we do not recommend the Bristow procedure for primary treatment of symptomatic anterior instability of the shoulder.


Pulmonary capillaries are smaller in the centre than in the periphery of the guinea-pig lung lobule: possible contributory mechanism for the centrilobular location of emphysema?
We used scanning electron microscopic morphometry of microvascular corrosion casts to compare the capillary structure in the centre and periphery of the lung lobule in the guinea-pig. Capillaries in the centre of the lobule had a lesser diameter than in the periphery (8.6 +/- 1.6 vs 10.4 +/- 1.9 microns respectively, P < 0.001). The polygonal capillary rings differed in structure between the centre and periphery of the lobule, although the number of branches remained constant. Capillary density in the centre of the lung (0.71 +/- 0.05) was significantly less than in its periphery (0.78 +/- 0.06, P < 0.001). We conclude that the capillary structure of the centre of the lung lobule is markedly different from that seen in the periphery. The smaller capillary diameter seen in the centre might be important in trapping polymorphonuclear leucocytes that lose the ability to deform after contact with cigarette smoke components; such an effect could explain why cigarette smoke induced emphysema tends to involve the centre of the lung lobule.


Improved purification and enzymatic properties of a mixture of Sticholysin I and II: isotoxins with hemolytic and phospholipase A(2) activities from the sea anemone Stichodactyla helianthus.
Sticholysin I and Sticholysin II (StI and StII) are two potent hemolysins which form pores in natural and model membranes at nanomolar concentrations. These proteins were purified from the aqueous extract of the sea anemone Stichodactyla helianthus, Ellis 1768, by gel filtration and ionic exchange chromatography. This procedure rendered StI and StII with high purity (purification factors: 36 and 50, respectively) but a low yield of hemolytic activity, HA (<3%). Additionally, these toxins exhibited very low phospholipase activity (10(-3)U/mg of protein). In this work, a mixture StI-StII was obtained (yield >95%, with an increase in specific activity: 14 times) from the animal extract using an oxidized phospholipid-based affinity chromatographic matrix binding phospholipases. Cytolysin identification in the mixture was performed by immunoblotting and N-terminal sequence analyses. Phospholipase A2 (PLA2) activity of StI-StII was relatively high (1.85U/mg) and dependent of Ca(2+). The activity resulted optimum when was measured with the mostly unsaturated soybean phosphatidylcholine (PC), when compared to the less unsaturated egg PC or completely saturated dipalmitoyl PC, in the presence of 40mM Ca(2+) at pH 8.0. This Ca(2+) concentration did not exert any effect on binding of StI-StII with soybean PC monolayers. Then, PLA2 activity seems not be required to binding to membranes.


Transient memory effect in the photoluminescence of InGaN single quantum wells.
The transition to maximum photoluminescence of InGaN single quantum wells is a phenomena that has time constants in the range of few seconds. Using a systematic illumination/darkening procedure we found that these characteristics are related to previous stimulations as if the sample has a memory of past illumination events. Choosing opportune time sequences, time constants were observed to vary more than 100%. These facts suggest the presence of carrier trapping/de-trapping processes that act beyond the single illumination event, accumulating over time in a complex effect.


First Report of Anthracnose Caused by Colletotrichum gloeosporioides on Malus prunifolia in Korea.
In 2010 and 2011, crab apples in Andong Province, Korea were found with dark brown spots on the fruit and mummified fruit on a tree. The fruit surface had red, circular spots that contained smaller, white spots; the color of the inner spots later changed to brown or black. Eventually, the rotten fruit dried and became mummified. Microscopic examination revealed the presence of acervuli and dark brown-to-black, needle-shaped setae. To isolate potential pathogens from infected fruit, small sections (5 to 10 mm2) were excised from the margins of lesions. These sections were surface sterilized with 70% ethanol and 1% NaOCl for 1 min and then rinsed three times with sterile distilled water. The fungus that was isolated produced whitish mycelia when grown on potato dextrose agar (PDA); the mycelia later became gray to dark gray with aerial mycelia in tufts and numerous conidia were produced. The conidia were straight, cylindrical with an obtuse apex and a truncated base, and measured 11.4 to 17.5 × 4.2 to 7.1 μm. The measurements and taxonomic characteristics coincide with those of Colletotrichum gloeosporioides (Penz.) (1). The isolated fungus was tested for pathogenicity on crab apples and cv. Fuji apples by inoculation with a conidial suspension (105 conidia/ml) prepared from 20-day-old PDA cultures. A 20-μl drop of the conidial suspension was placed onto crab apple and apple fruits that had been wounded by piercing them 1 to 2 mm deep with a pin. Small, dark lesions were observed on the artificially inoculated fruit 3 days after inoculation. Nine days after inoculation, dark lesions with salmon-colored masses of conidia were observed on fruit, which were also soft and sunken. Abundant masses of conidia were produced in the decayed tissues. The fungus was reisolated from the parts of the fruits showing the symptoms. The internal transcribed spacer (ITS) rDNA of the isolated fungus was amplified and sequenced by PCR as described by White et al. (2). The resulting 582-bp of ITS rDNA sequence was deposited in GenBank (Accession No. JQ405742). A BLAST analysis for sequence similarity of the ITS region revealed 100% identity with nucleotide sequences for C. gloeosporioides isolates (Accession Nos. HQ645080 and AB458667). The results obtained on morphological characteristics, pathogenicity, and molecular data corresponded with those of C. gloeosporioides described by Sutton (1). To our knowledge, this is the first report of the presence of C. gloeosporioides on crab apple in Korea (3). Crab apple is used as a pollinator for single-cultivar apple orchards and may become a possible source of inoculum for cultivated apple. References: (1) T. B. Sutton. Compendium of Apple and Pear Diseases. The American Phytopathological Society, St. Paul, MN, 1990. (2) T. J. White et al. PCR Protocols: A Guide to Methods and Applications, Academic Press, Inc., New York, 1990. (3) S. H. Yu. List of Plant Diseases in Korea. 5th ed. (in Korean). The Korean Society of Plant Pathology, 2009.


Beyond junctions: nonlocal form constraints on motion interpretation.
Because of the aperture problem, local motion measurements must be combined across space. However, not all motions should be combined. Some arise from distinct objects and should be segregated, and some are due to occlusion and should be discounted because they are spurious. Humans have little difficulty ignoring spurious motions at occlusions and correctly integrating object motion, and are evidently making use of form information to do so. There is a large body of theoretical and empirical evidence supporting the importance of form processes involving junctions in the way motion is integrated. To assess the role of more complex form analysis, we manipulated nonlocal form cues that could be varied independently of local junctions. Using variants on diamond and plaid stimuli used in previous studies, we found that manipulations distant from the junctions themselves could cause large changes in motion interpretation. Nonlocal information often overrides the integration decisions that would be expected from local cues. The mechanisms implicated appear to involve surface segmentation, amodal completion, and depth ordering.


Aqueous shunts with mitomycin C versus aqueous shunts alone for glaucoma.
Glaucoma affects more than 70 million people worldwide, with about 10% being bilaterally blind, making it the leading cause of irreversible blindness globally. In patients with advanced glaucoma or those who have failed medical treatment without achieving adequate intraocular pressure (IOP) control, trabeculectomy (glaucoma filtration surgery where an ostium is created into the anterior chamber from underneath a partial thickness scleral flap to allow for aqueous flow out of the anterior chamber intointo the subconjunctival space forming a filtering bleb) and aqueous shunt surgery for more complex and refractory cases remain the mainstay therapies. Proliferation of fibrous tissue around an implanted aqueous shunt may block the diffusion of aqueous humour. Mitomycin C (MMC) is one of two commonly used adjunct antifibrotic agents used during aqueous shunt surgery to prevent proliferation of fibrous tissue. However, the effectiveness and safety of the use of intraoperative MMC during aqueous shunt surgery has not been established. To evaluate the effectiveness and safety of MMC versus no MMC used during aqueous shunt surgery for reducing IOP in primary and secondary glaucoma. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 13 February 2018. We included randomized controlled trials (RCTs) in which one group of participants received MMC during aqueous shunt surgery and another group did not. We did not exclude studies based on outcomes. Two review authors independently reviewed titles and abstracts from the literature searches. We obtained full-text reports of potentially relevant studies and assessed them for inclusion. Two review authors independently extracted data related to study characteristics, risk of bias, and outcomes. We used standard methodological procedures expected by Cochrane. We included five RCTs, with a total of 333 eyes with glaucoma randomized, and identified two ongoing trials. All included trials examined the effect of MMC versus no MMC when used during aqueous shunt surgery for glaucoma. The trials included participants with different types of uncontrolled glaucoma. One study was conducted in China, one in Saudi Arabia, two in the USA, and one study was a multicenter study conducted in Brazil, Canada, Scotland, and USA. We assessed all trials as having overall unclear risk of bias due to incomplete reporting of study methods and outcomes; two of the five trials were reported only as conference abstracts.None of the included trials reported mean decrease from baseline in IOP; however, all five trials reported mean IOP at 12 months post-surgery. At 12 months, the effect of MMC on mean IOP compared with no MMC was unclear based on a meta-analysis of trials (mean difference -0.12 mmHg, 95% CI -2.16 to 2.41; low-certainty evidence). Two trial did not report sufficient information to include in meta-analysis, but reported that mean IOP was lower in the MMC group compared with the no MMC group at 12 months.None of the included trials reported mean change from baseline in visual acuity; however, one trial reported lower mean LogMAR values (better vision) in the MMC group than in the no MMC group at 12 months post-surgery. None of the included studies reported the proportion of participants with stable best-corrected visual acuity. Three trials reported that loss of vision was not significantly different between groups (no data available for meta-analysis).None of the included studies reported the proportion of participants with a postoperative hypertensive phase, which is defined as IOP > 21 mmHg within 3 months after surgery. Two trials reported adverse events (choroidal effusion, corneal edema, flat anterior chamber, and retinal detachment); however, due to small numbers of events and sample sizes, no clear difference between MMC and placebo groups was observed. We found insufficient evidence in this review to suggest MMC provides any postoperative benefit for glaucoma patients who undergo aqueous shunt surgery. Data across all five included trials were sparse and the reporting of study methods required to assess bias was inadequate. Future RCTs of this intervention should report methods in sufficient detail to permit assessment of potential bias and estimate target sample sizes based on clinically meaningful effect sizes.


The prevalence and severity of fluorosis in children who received toothpaste containing either 440 or 1,450 ppm F from the age of 12 months in deprived and less deprived communities.
This study compared fluorosis in the upper central incisors of children from socially diverse backgrounds who had received either 440- or 1,450-ppm F toothpaste from 12 months of age. The children were resident in non-fluoridated districts in the north-west of England. They received either 440- or 1,450-ppm F toothpaste and advice regarding its use until the age of 5-6 years. Dental fluorosis (TF index) was assessed on digital images of dried teeth when the children (n = 1,268) were 8-10 years old. In the less deprived districts the prevalences of fluorosis (TF >or=0) for the 1,450- and 440-ppm F groups were 34.5 and 23.7% (p = 0.006). In the deprived districts the prevalences of fluorosis were 25.2 and 19.5% (p = 0.2). Overall the prevalences of TF >or=2 were 7 and 2.1% for the 1,450- and 440-ppm F groups and 2.2 and 0.2% for TF >or=3. These differences were statistically significant (p < 0.003). There was a strong association between the deprivation status of wards and fluorosis. Only 1 subject with a TF score of 3 was identified in the two most deprived quintiles of the Townsend score. It is concluded that careful targeting of programmes of this type to children living in high caries risk deprived communities carries only a small risk of aesthetically objectionable fluorosis (TF >2) whether low or high fluoride toothpastes are used. High fluoride (1,450 ppm F) toothpastes should not be provided on a community basis to very young children in less deprived communities.


Do younger men have better biochemical outcomes after radical prostatectomy?
To examine the relationship between age and biochemical failure after radical prostatectomy (RP), controlling for the year of surgery. Prior studies have suggested that younger men have lower prostate-specific antigen recurrence rates after RP, although none of the prior studies had controlled for the year of surgery. We examined the data from 1753 men treated with RP between 1988 and 2002 at five equal access medical centers. We compared age, as a categorical variable according to decade of life (50 years old or younger, 51 to 60, 61 to 70, and older than 70 years), with the clinical and pathologic variables at RP, as well as the time to biochemical recurrence, using a multivariate Cox proportional hazards model. Age was significantly related to the year of surgery, with the more recently treated patients being younger than less recently treated patients (P <0.001). After controlling for the year of surgery, the younger men had smaller prostates, fewer high-grade tumors on biopsy, and less lymph node metastasis, but a greater percentage of cores with cancer. On multivariate analysis, men 50 years old or younger had significantly lower recurrence rates than did the older men. Moreover, men older than 70 years had significantly greater prostate-specific antigen failure rates than men aged 51 to 70 years or men aged 50 years or younger. The average age of men undergoing RP has decreased with time. Independent of this, young men have more favorable outcomes after RP than older men. Continued screening to detect prostate cancer among younger men when it is most curable appears warranted.


An in vivo study comparing the efficacy and complications of diode laser and long-pulsed Nd:YAG laser in hair removal in Chinese patients.
Lasers with long wavelengths are less well absorbed by melanin and are considered to be particularly suitable for hair removal in dark-skinned patients. To compare the efficacy and complications of 800 nm diode and long-pulsed 1064 nm Nd:YAG lasers in laser-assisted hair removal in Chinese patients. Fifteen women had hair removal treatments (13 axillae and 2 legs) with diode laser on one side and Nd:YAG laser on the other. They were followed up for 36 weeks. Subjective assessments included the degree of immediate pain and the degree of hair regrowth. Clinical photographs were taken for evaluation by two independent observers to assess complications and the degree of hair regrowth. Long-pulsed Nd:YAG laser was found to be significantly associated with a greater degree of immediate pain after laser surgery (P =.0001, independent sample t-test) and also had a longer laser time (P =.0001, independent sample t-test). Besides transit adverse effects such as erythema and perifollicular edema, only one patient developed hypopigmentation at week 6 which resolved by week 36. Although regrowth rates were low at week 6 (subjective rates were 23% and 19% for Nd:YAG and diode laser, respectively), most patients had significant regrowth at week 36 (subjective regrowth rate 91% for both long-pulsed Nd:YAG and diode lasers). Diode 800 nm and Nd:YAG 1064 nm lasers are safe in laser-assisted hair removal in Chinese patients, and besides immediate pain, there was no other significant adverse effect. Most patients experienced regrowth 36 weeks after a single treatment. Further study is necessary to determine the long-term clinical efficacy and complications of laser-assisted hair removal with these systems in dark-skinned patients.


Sex Differences and Tumor Blood Flow from Dynamic Susceptibility Contrast MRI Are Associated with Treatment Response after Chemoradiation and Long-term Survival in Rectal Cancer.
Background MRI is the standard tool for rectal cancer staging. However, more precise diagnostic tests that can assess biologic tumor features decisive for treatment outcome are necessary. Tumor perfusion and hypoxia are two important features; however, no reference methods that measure these exist in clinical use. Purpose To assess the potential predictive and prognostic value of MRI-assessed rectal cancer perfusion, as a surrogate measure of hypoxia, for local treatment response and survival. Materials and Methods In this prospective observational cohort study, 94 study participants were enrolled from October 2013 to December 2017 (ClinicalTrials.gov: NCT01816607). Participants had histologically confirmed rectal cancer and underwent routine diagnostic MRI, an extended diffusion-weighted sequence, and a multiecho dynamic contrast agent-based sequence. Predictive and prognostic values of dynamic contrast-enhanced, dynamic susceptibility contrast (DSC), and intravoxel incoherent motion MRI were investigated with response to neoadjuvant treatment, progression-free survival, and overall survival as end points. Secondary objectives investigated potential sex differences in MRI parameters and relationship with lymph node stage. Statistical methods used were Cox regression, Student t test, and Mann-Whitney U test. Results A total of 94 study participants (mean age, 64 years ± 11 [standard deviation]; 61 men) were evaluated. Baseline tumor blood flow from DSC MRI was lower in patients who had poor local tumor response to neoadjuvant treatment (96 mL/min/100 g ± 33 for ypT2-4, 120 mL/min/100 g ± 21 for ypT0-1; P = .01), shorter progression-free survival (hazard ratio = 0.97; 95% confidence interval: 0.96, 0.98; P < .001), and shorter overall survival (hazard ratio = 0.98; 95% confidence interval: 0.98, 0.99; P < .001). Women had higher blood flow (125 mL/min/100 g ± 27) than men (74 mL/min/100 g ± 26, P < .001) at stage 4. Volume transfer constant and plasma volume from dynamic contrast-enhanced MRI as well as ΔR2* peak and area under the curve for 30 and 60 seconds from DSC MRI were associated with local malignant lymph nodes (pN status). Median area under the curve for 30 seconds was 0.09 arbitrary units (au) ± 0.03 for pN1-2 and 0.19 au ± 0.12 for pN0 (P = .001). Conclusion Low tumor blood flow from dynamic susceptibility contrast MRI was associated with poor treatment response in study participants with rectal cancer. © RSNA, 2020 Online supplemental material is available for this article.


The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains.
Ubiquitin chain complexity in cells is likely regulated by a diverse set of deubiquitinating enzymes (DUBs) with distinct ubiquitin chain preferences. Here we show that the polyglutamine disease protein, ataxin-3, binds and cleaves ubiquitin chains in a manner suggesting that it functions as a mixed linkage, chain-editing enzyme. Ataxin-3 cleaves ubiquitin chains through its amino-terminal Josephin domain and binds ubiquitin chains through a carboxyl-terminal cluster of ubiquitin interaction motifs neighboring the pathogenic polyglutamine tract. Ataxin-3 binds both Lys(48)- or Lys(63)-linked chains yet preferentially cleaves Lys(63) linkages. Ataxin-3 shows even greater activity toward mixed linkage polyubiquitin, cleaving Lys(63) linkages in chains that contain both Lys(48) and Lys(63) linkages. The ubiquitin interaction motifs regulate the specificity of this activity by restricting what can be cleaved by the protease domain, demonstrating that linkage specificity can be determined by elements outside the catalytic domain of a DUB. These findings establish ataxin-3 as a novel DUB that edits topologically complex chains.


Activated v-myc and v-ras oncogenes do not transform normal human lymphocytes.
Activated v-myc (pSV v-myc) and v-Ha-ras (GT10) oncogenes were introduced into normal human lymphocytes, NIH 3T3 fibroblasts, B-lymphoblastoid cells, and human epithelial cells, using a reconstituted Sendai virus envelope-mediated gene transfer technique. Efficient transfer of the plasmid in each cell type was demonstrable within 1.5 h of transfection by Southern blotting of extrachromosomal DNA extracts, which unexpectedly revealed that v-myc plasmid DNA was unstable in normal lymphocytes but not in the other cell types. The v-myc plasmid was stabilized when cotransfected into lymphocytes together with v-Ha-ras. The transfected v-Ha-ras plasmid was stable in all the cell types tested. v-myc plasmid expression was clearly detectable by 5 h in all cell types except human lymphocytes. Lymphocytes expressed v-myc when transfected together with v-Ha-ras. Transfected ras oncogene was efficiently expressed in all the cell types tested. Expression of the transfected genes increased at 24 and 48 h after transfection. Even though plasmid stability and expression were achieved in myc-ras-cotransfected lymphocytes, no effects on cellular DNA synthesis or immortalization were observed, in contrast to efficient transformation of NIH 3T3 fibroblasts by the same procedure. Our data suggest that efficient expression of transfected myc and ras oncogenes in normal quiescent human lymphocytes is not sufficient for the induction of cell growth and immortalization.


Increased mitochondrial fission and neuronal dysfunction in Huntington's disease: implications for molecular inhibitors of excessive mitochondrial fission.
Huntington's disease (HD) is a fatal, progressive neurodegenerative disease with an autosomal dominant inheritance, characterized by chorea, involuntary movements of the limbs and cognitive impairments. Since identification of the HD gene in 1993, tremendous progress has been made in identifying underlying mechanisms involved in HD pathogenesis and progression, and in developing and testing molecular therapeutic targets, using cell and animal models of HD. Recent studies have found that mutant Huntingtin (mHtt) interacts with Dynamin-related protein 1 (Drp1), causing excessive fragmentation of mitochondria, leading to abnormal mitochondrial dynamics and neuronal damage in HD-affected neurons. Some progress has been made in developing molecules that can reduce excessive mitochondrial fission while maintaining both the normal balance between mitochondrial fusion and fission, and normal mitochondrial function in diseases in which excessive mitochondrial fission has been implicated. In this article, we highlight investigations that are determining the involvement of excessive mitochondrial fission in HD pathogenesis, and that are developing inhibitors of excessive mitochondrial fission for potential therapeutic applications.


12-Month prevalence of allergies in Germany.
The prevalence of allergies has increased dramatically during recent decades, and thus, got into the focus of public health. As part of the 2014 German Health Update (GEDA 2014/2015-EHIS), 28.1% of respondents reported that they were affected by an allergic disease other than asthma. Reports of allergies are more common among women than men and among younger and middle-aged adults than people over the age of 65. Adults with higher levels of education stated more frequently that they are affected by allergies than adults with lower levels of education. Allergic reactions occur in various organ systems, but the skin, mucous membranes, respiratory tract and the intestines are most commonly affected. As allergic reactions often significantly restrict people's quality of life, early diagnosis and appropriate care for sufferers is essential.


Cross-linking exogenous bifunctional peptides into fibrin gels with factor XIIIa.
Bi-domain peptides with a factor XIIIa substrate in one domain and a bioactive peptide in another domain were covalently incorporated into fibrin gels during coagulation through the action of the transglutaminase factor XIIIa. The cross-linking characteristics were determined for two bi-domain peptides with factor XIIIa substrates based on fibrinogen, dYRGDTIGEGQQHHLGG-NH2, and dLRGDGAKDV-NH2, as well as one bi-domain peptide with a substrate sequence based on alpha2-plasmin inhibitor, dLNQEQVSPLRGD-NH2, and another with a nonbiological, oligolysine substrate, dLRGDKKKKG-NH2 (substrate domains in italic). Each of these peptides was able to cross-link into the fibrin gels during coagulation, with the peptide containing the factor XIIIa substrate based on alpha2-plasmin inhibitor being incorporated at levels in excess of 8 mol/mol fibrinogen. The structural characteristics of these peptide-modified gels proved to be the same as those for a native fibrin gel. The bioactivity of the incorporated active factors was tested in a neuronal culture model with day 8 chicken dorsal root ganglia using two bioactive sequences, RGD and DGEA, and one inactive control sequence, RDG. Each of these peptides influenced the extension of neurites from the ganglia as expected, indicating that the incorporated factors retained their activity. With the use of soluble competitive inhibitors, it was shown that this effect was due to the covalently incorporated peptides. Through exploiting the role of factor XIIIa in coagulation, we have developed a method by which to impart the character of nonfibrin proteins, such as extracellular matrix proteins, to fibrin, a biological material with many potential therapeutic and academic applications.


A portrait of district nursing: its contribution to primary health care.
This paper explores the role and contribution of district nursing within primary health care. Examples of how this service is organised within different health care systems are used to discuss the context-dependent nature and challenges of the work. By drawing on UK policy change, health priorities and recent research into district nursing, the paper concludes that, in attempting to deal with the challenges of health care in the 21st century, the significance and potential of district nursing services are frequently overlooked. It is recommended that a research strategy for district nursing should build on the profession's comprehensive understanding of the needs of families and communities and should aim to provide evidence for practice that will further improve patient and client outcomes.


Excitatory effects of parvalbumin-expressing interneurons maintain hippocampal epileptiform activity via synchronous afterdischarges.
Epileptic seizures are characterized by periods of hypersynchronous, hyperexcitability within brain networks. Most seizures involve two stages: an initial tonic phase, followed by a longer clonic phase that is characterized by rhythmic bouts of synchronized network activity called afterdischarges (ADs). Here we investigate the cellular and network mechanisms underlying hippocampal ADs in an effort to understand how they maintain seizure activity. Using in vitro hippocampal slice models from rats and mice, we performed electrophysiological recordings from CA3 pyramidal neurons to monitor network activity and changes in GABAergic signaling during epileptiform activity. First, we show that the highest synchrony occurs during clonic ADs, consistent with the idea that specific circuit dynamics underlie this phase of the epileptiform activity. We then show that ADs require intact GABAergic synaptic transmission, which becomes excitatory as a result of a transient collapse in the chloride (Cl(-)) reversal potential. The depolarizing effects of GABA are strongest at the soma of pyramidal neurons, which implicates somatic-targeting interneurons in AD activity. To test this, we used optogenetic techniques to selectively control the activity of somatic-targeting parvalbumin-expressing (PV(+)) interneurons. Channelrhodopsin-2-mediated activation of PV(+) interneurons during the clonic phase generated excitatory GABAergic responses in pyramidal neurons, which were sufficient to elicit and entrain synchronous AD activity across the network. Finally, archaerhodopsin-mediated selective silencing of PV(+) interneurons reduced the occurrence of ADs during the clonic phase. Therefore, we propose that activity-dependent Cl(-) accumulation subverts the actions of PV(+) interneurons to perpetuate rather than terminate pathological network hyperexcitability during the clonic phase of seizures.


Noradrenergic and dopaminergic modulation of thyrotropin secretion in the rat.
Noradrenergic and dopaminergic regulation of thyrotropin (TSH) secretion was investigated in adult male Wistar rats. TSH secretion displayed a circadian variation with peak serum TSH levels at 10.00 h. The alpha 2-adrenoceptor agonist, clonidine (250 micrograms/kg, i.p.), was found to cause an enhancement of serum TSH levels at 10.00 h (160 +/- 10% of control values, P less than 0.001) which was antagonized by prior administration of the alpha 2-adrenoceptor antagonist, yohimbine (3 mg/kg, i.p.). The alpha-adrenoceptor antagonist phentolamine caused a significant decrease in serum TSH levels at 10.00 h (62 +/- 15% of control values, P less than 0.05) at a dosage of 2 mg/kg, i.p. The alpha 1-adrenoceptor agonist, phenylephrine (0.2 or 2 mg/kg, i.p.), was without effect as were the dopaminergic receptor agonist, apomorphine (1 or 5 mg/kg, i.p.), and the antagonist, sulpiride (20 mg/kg, i.p.). The beta-adrenoceptor agonist, isoproterenol (1 mg/kg, i.p.) was found to cause a decrease in serum TSH levels at 10.00 h (70 +/- 16% of control levels, P less than 0.01), which was completely antagonized by prior administration of the beta-adrenoceptor antagonist, propranolol (10 mg/kg, i.p.). TSH-releasing hormone (TRH, 5 micrograms/kg, i.v.) caused a significant stimulation of TSH secretion (470 +/- 63% of basal levels, P less than 0.001), which was not affected by prior treatment of the rats with yohimbine (0.1 mg/kg, i.p.), phentolamine (2 mg/kg, i.p.), propranolol (10 mg/kg, i.p.) or sulpiride (20 mg/kg, i.p.). There was, however, a tendency towards a decrease in the TRH-stimulated release of TSH in rats pretreated with phentolamine or propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)


Population-based trends in treatment rates in psychiatry in Oxfordshire, 1975-1986.
Routinely collected abstracts of medical records for patients in Oxfordshire were used to identify each individual's first contact with specialist psychiatric in-patient, out-patient or community care services over a 12-year period (1975-1986). During this period first-contact rates for people under 65 years of age declined by 3.3 per cent. The decline was observed for contacts with specialist care outside hospital as well as for in-patient care. It is therefore not attributable simply to a shift away from in-patient care. The decline was seen in most major diagnostic groups including schizophrenia, affective psychosis and the neuroses, and it is therefore not attributable to changing diagnostic practices between these groups. Increases in first-contact rates in this age group were found for alcohol-related disorders in women and self-harm in men. First-contact rates for people aged 65 years and over increased by 3 per cent per year. The condition that mainly accounted for the increase over time was dementia, which was by far the commonest recorded psychiatric diagnosis in this age group. Although the increase was seen in all modes of care, it was the domiciliary visiting service that contributed most to the upward trend. The implications of these trends for service planning and their limitations as measures of changes in morbidity are discussed.


The chemical forms of mercury in aged and fresh dental amalgam surfaces.
Mercury-containing dental amalgam is known to be a source of human exposure to mercury. We have explored the use of electron yield Hg L(III) X-ray absorption spectroscopy to characterize the chemical nature of dental amalgam surfaces. We find that the method is practical and that it shows extensive mercury depletion in the surface of the aged amalgam with significant differences between old and fresh amalgam surfaces. Whereas the fresh amalgam gives spectra that are typical of metallic mercury, the aged amalgam is predominantly beta-mercuric sulfide. The toxicological implications of these results are discussed.


Diminished expression of S100A2, a putative tumor suppressor, at early stage of human lung carcinogenesis.
To identify and understand early events in lung carcinogenesis, we used a cDNA array to screen for genes that are expressed differentially in normal human bronchial epithelial (NHBE) cells and a tumorigenic cell line (1170-I) derived from immortalized HBE cells after exposure to cigarette smoke condensate in vivo. Among these genes, we have identified the S100A2 gene, which encodes a nuclear calcium-binding protein, as being down-regulated in the 1170-I cells. Because this gene has been implicated as a tumor suppressor in breast cancer, we examined its potential role as a tumor suppressor in lung carcinogenesis. Levels of S100A2 transcript and protein, which were high in NHBE cells, decreased by up to 50% in immortalized HBE cells (BEAS-2B and 1799) and to low to nearly undetectable levels in transformed (1198) and tumorigenic (1170-I) HBE cells. Furthermore, S100A2 mRNA and protein were undetectable in 8 and expressed at a reduced level in 3 of 11 non-small cell lung cancer (NSCLC) cell lines. Positive immunohistochemical staining of S100A2 was detected in the majority (75-83%) of normal and hyperplastic lung tissues, whereas it was detected in <10% of metaplastic lung tissues, squamous cell carcinoma, and adenocarcinoma. Treatment of 1170-I HBE and NSCLC cells with 5-aza-2'-deoxycytidine resulted in partial restoration of S100A2 expression in seven of eight cell lines. Indeed, CpG methylation was detected in the promoter region of the S100A2 gene. Our results suggest that S100A2 expression is suppressed early during lung carcinogenesis, possibly by hypermethylation of its promoter, and that its loss may be a contributing factor in lung cancer development or a biomarker of early changes in this process.


Diagnosis and treatment in inflammatory neuropathies.
The inflammatory neuropathies are a large diverse group of immune-mediated neuropathies that are amenable to treatment and may be reversible. Their accurate diagnosis is essential for informing the patient of the likely course and prognosis of the disease, informing the treating physician of the appropriate therapy and informing the scientific community of the results of well-targeted, designed and performed clinical trials. With the advent of biological therapies able to manipulate the immune response more specifically, an understanding of the pathogenesis of these conditions is increasingly important. This review presents a broad overview of the pathogenesis, diagnosis and therapy of inflammatory neuropathies, concentrating on the most commonly encountered conditions.