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All statistical (https://foodprocessingtechasia.com/content/uploads/files/download/pasw-statistics-18-crack-for-euro.zip) analysis was performed with PASW Statistics 18 (IBM Analytics). For comparisons of means in samples with normal distributions and homogeneous variances (as indicated by a Levene’s test), an independent samples t test or ANOVA was used for comparisons between two means or two or more means, respectively, followed by Fisher’s Bonferroni adjusted post hoc test when necessary. In cases of a non-normal distribution (as indicated by a Shapiro–Wilk test) or unequal variances (Levene’s test), a nonparametric Mann–Whitney U test or Kruskal–Wallis test was used for comparisons between two means or two or more means, respectively, followed by a median test for post hoc analyses. Significance was ascribed at p < 0/05. A repeated measures analysis was used for change over time within a cell or a slice, when appropriate. Pasw statistics 18 cracks. In the case of a non-normal distribution, a Friedman test followed by post hoc Wilcoxon signed-rank tests with the alpha level Bonferroni adjusted for multiple comparisons was used.

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Similarly, artificial respiration with pure oxygen is unlikely to cause hypoxia but still appeared to cause a decline in auditory sensitivity over time. While no consistent, immediate deterioration associated with the switch to artificial oxygen respiration was found, unexplained drastic threshold losses occurred beyond 4–5 h in adult owls receiving artificial oxygen respiration. This is reminiscent of the significant further deterioration within 1 h reported for mice under isoflurane (but not ketamine) anesthesia, breathing oxygen unaided (Cederholm et al, 2021). Such a time-dependent deterioration could also have been a confounding factor for the auditory nerve single-unit thresholds reported here, as these measurements typically only began with a substantial delay after anesthetic induction, due to prolonged surgery. Together, these observations point to additional, detrimental changes in the long term that would not be observed in short-term experiments such as minimally invasive ABR measurements or most veterinary procedures. Importantly, there were no indications from our EKG monitor that the state of the animals may have been compromised.

SCN (150 μm) slices were prepared on days 10–21 after injection as described above. Successful injections were confirmed by observing expression of the green reporter GCaMP6 or mCherry expression from the Gq DREADD in the SCN.

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Passages, Third Edition, is a two-level, multi-skills course that will quickly and effectively move adult and young-adult learners of English from high-intermediate to the advanced level. The Passages, Third Edition, Student's Books have been updated to offer fresh, contemporary content, relevant speaking and listening activities, comprehensive grammar and vocabulary support, enhanced reading skills development, and a step-by-step academic writing strand. Students will progressively elevate their language ability in both formal and informal communication through a variety of real-world contexts. Frequent communication reviews will systematically consolidate learning, while the popular Grammar Plus and new Vocabulary Plus sections in the back of the Student's Book provide additional skills support.


Men ranked stress, air pollution, and lifting and carrying as greater hazards to reproduction than women (Table 4). Why this should be so is not clear. Air pollution and lifting and carrying have not been linked to adverse male reproductive effects and it may be that women adjust to everyday hazards that they face and “downplay” them. With much recent information and media discussion of stress, it is perhaps easier to explain why younger age groups rank stress highest and older age groups place it lowest although different definitions of stress may be used by different age groups. Findings for which no explanation exist or where sample size may be a factor occur on water pollution which attracts the highest hazard rating for younger age groups but the lowest for the 35–44 group.

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A logistic regression was then carried out with whether or not the pollutant was considered to be harmful or very harmful as the dependent variable. Odds ratios were determined for each covariate, adjusted for all other covariates.


Although insightful, the current study was subject to a number of limitations. Participants were volunteers and therefore there may be some selection bias. However, it is worth noting that respondents were answering questions on a number of health-related topics and are unlikely to have agreed to participate because they feel strongly about the topic area being studied here. Also, only Queensland residents that were contactable by a landline telephone were able to participate. It should be acknowledged that the sample is not representative of the Australian population with over representation of the 45 years and older age group and under representation of the 45 years and younger group. Gaining adequate participation of younger respondents when conducting computer-assisted telephone interviewing surveys using only randomly generated landline telephone samples has become more difficult as increasing numbers of young people use only mobile telephones. Recent studies have shown that exclusion of mobile-phone-only households does not significantly influence survey results . The response rate of 35/2% is representative of general household surveys which have been on the decline in recent years . It has been suggested that with reduced telephone number listings and people's increasing resistance to unwanted phone calls, alternatives to telephone surveys, such as computer and internet-based approaches, should be investigated . Strengths of this study include the use of a large state-wide sample to conduct an analysis of perceived risks of environmental health on human reproduction.

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The aim of this study was to explore aspects of the public’s perceived risks of environmental hazards on human reproduction by (i) gender, (ii) place of residence (city, town or rural), (iii) age, and (iv) presence of children in the household. The specific environmental hazards considered in this study were selected due to the previous work we have conducted in this area and from the literature reviewed. These are also the hazards that are believed to be most familiar to the public.


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Whilst it is commonly accepted that dangers and hazards do exist, they are not necessarily viewed equally by the public. However the public's concerns about risks cannot necessarily be attributed to ignorance or irrationality. It has been maintained that risk has generally been discussed through a “paradigm of rational choice” and to consider risk assessment independent of culture is useless . Research has also shown that much of the public's reactions to risk can be attributed to how they respond to hazards in terms of technical, social, and perceptional elements that are not normally well addressed in risk assessments .


We constructed a generalized linear model, using PASW Statistics 18.0, where the dependent variable (VL) was modeled as a gamma distribution, reflecting the skew in distribution toward lower values, and allowed better fitting of the model to the data than a normal distribution, while still permitting the identification of any linear associations with VL (unlike log transforming VL data). Statistical analyzes were performed using PASW Statistics version 18 (SPSS Inc, Chicago, IL, USA). All the data were de-identified. Out of these patients, 27.3% showed no underlying disorder and 18.2% (no = 8) showed chronic renal failure; 25% were immunodepressed patients; 31% underwent urinary instrumentation in the previous 15 days, yet only three of them had undergone permanent urine catheterization. CEA, other studies reported contradictory results. Data were normal and homogeneous; therefore, one-tailed t-test were used to compare means of a given soil property of the cultivated and uncultivated sites.

Cannabinoid signaling modulates SCN neuronal activity, although the mechanism remains unclear

Hypertension was defined as a history of antihypertensive treatment or a history of hypertension (systolic blood pressure (BP) >140 mmHg, diastolic BP >90 mmHg, or both) . Dyslipidemia was defined as a history of statin treatment or a history of dyslipidemia (total cholesterol >240 mg/dL and/or high-density lipoprotein cholesterol <40 mg/dL for men and <50 mg/dL for women and/or low-density lipoprotein cholesterol >160 g/dL and/or triglycerides >200 mg/dL) . Diabetes was defined as a history of antidiabetic drug treatment or a history of diabetes (HbA1c >6/5%) .


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In fig 4B, it is hard to see any changes caused by AM251. The authors should choose more representative traces.


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After demonstrating that WIN decreases the frequency of mGPSCs, we next sought to determine whether astrocytes played a role in cannabinoid signaling. Astrocytic metabolic function was inhibited with FC (1 μM), an inhibitor of the Krebs cycle preferentially taken up by astrocytes (Navarrete and Araque, 2008).

This is of some concern for the interpretation of these data, especially because it would appear that there is no CNO only control (No DREADD). Also, in the light of (Gomez et al Science 2021), these are particularly relevant and needed controls.


The anatomical distribution of coronary artery stenoses does not contribute to AF in CAD patients. However, AF is linked to a higher CAD severity, which might predispose individuals to AF by driving ischemic heart disease and changes in left ventricular function.

Statistical tests were carried out using the statistical software PASW Statistics 18 and the SAS Enterprise Guide V. 4.1. The following instructions are for. A recent systematic review found them to have numerous health benefits with virtually no adverse effects. The chi-square test was used for binary variables and the Mann–Whitney U. Research investigating the relationship between neuropsychological test performances and self-reported cognitive functioning in patients with anorexia nervosa (AN) is limited, and existing experimental studies only demonstrate a low-to-moderate relationship between the performance based tests and everyday behaviour. The SPSS Statistics Guide to Data Analysis for PASW Statistics 18 is also in development.


The statistical value of the EUTOS score was validated in an independent dataset

Rigorous colocalization rates showing how many GFAP expressing cells also express the cl Sen and the other relevant rates) should be provided for the reader to evaluate what is claimed here. The morphology of the SCN should be appreciable in the micrographs and insets should clearly show such colocalization, or lack of there of. Moreover, if the NFHC is only localized in a part of the SCN, as the figure 2G might suggest, it may not be an appropriate neuronal marker for the colocalization analysis. If that is indeed the case the authors should comment appropriately. The author should also provide a reference to NFHC as a neuronal marker, which appear to be missing in the text.

The sex of the species studied is not mentioned in the materials and methods section. Please mention “male”, “female”, “x males and x females”, “of either sex”.


Köppl C (2021) Evolution of the octavolateral efferent system. In: Auditory and vestibular efferents (Ryugo D, Fay RR, Popper AN, eds), pp 217–259.

Can the authors comment as to why these respective control groups are different? Could these have biased the results?


The EKG was continuously monitored on an oscilloscope display during the experiments and notes of salient changes were entered into the lab book but we did not obtain permanent records or carry out a quantitative analysis. As stated in the manuscript, the recording also showed muscle potentials, most importantly those associated with breathing. One change that we watch for is a transient increase in heart rate, accompanied by prolonged breathing muscle activity, immediately after a ketamine/xylazine injection.

Bonati LH, Lyrer P, Ederle J, Featherstone R, Brown MM (2021) Percutaneous transluminal balloon angioplasty and stenting for carotid artery stenosis. Cochrane Database Syst Rev 9:CD000515.


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In the present study, the EUTOS score predicted that 34% of high-risk patients will fail to achieve a CCgR in 18 months, and also predicted PFS. Whereas the value of the score should be further validated by other investigators, it will be difficult to improve upon because the therapeutic efficacy of imatinib is high. If it were even higher, no discrimination would be possible. We believe that only progress in assessing molecular response32-38 will support a better prognostic classification. In addition, advances in pharmacogenomics, gene-expression profiling, and whole-genome sequencing studies39-44 will no doubt contribute to identifying the molecular basis of failure, and thus will enable a more patient-tailored and better-targeted form of therapy and treatment evaluation. Until then, however, the EUTOS score is a simple and inexpensive method for determining prognosis. As demonstrated herein, 1 in 3 high-risk patients fails on imatinib. Moreover, although the new and validated EUTOS score requires only 2 variables, its predictive power is better than that of the Sokal and Euro (https://foodprocessingtechasia.com/serial-code/?file=3723) scores. This does not mean that all treatment decisions must be based on prognosis, but that the EUTOS score can identify patients with a significantly higher risk of progression and impaired survival, thus alerting the treating physician to the need for closer patient observation and early therapeutic intervention.


In contrast, four (3/7%) “permanent” complications and 13 (12/1%) “transient” complications were observed in the standard group (Table 3). “Transient” complications included post-operative delirium, transient ischemic attack, renal dysfunction, heart failure, nasal bleeding and pneumonia. There were no statistically (have a peek at this site) significant differences in the rate of “permanent” and “transient” complications in the high age group, compared with the standard group (Table 3).

Endocannabinoids, endogenously generated lipophilic molecules, act as retrograde signals from neurons to regulate presynaptic neurotransmitter release via activation of G-protein-coupled cannabinoid-1 receptors (CB1Rs; Ohno-Shosaku et al, 2001; Wilson et al, 2001; Wilson and Nicoll, 2001; Araque et al, 2021). The production and metabolism of endocannabinoids have diurnal patterns, indicating they may be under circadian clock control (Valenti et al, 2004; Liedhegner et al, 2021; Koch et al, 2021). Cannabinoid receptor activation blocks light-induced phase shifts of circadian behavior (Sanford et al, 2008; Acuna-Goycolea et al, 2021). In addition, cannabinoid signaling increases neuronal firing within the SCN by decreasing presynaptic GABA release (Acuna-Goycolea et al, 2021). Given this evidence of interactions between the circadian and cannabinoid systems, surprisingly little is known about how cannabinoids alter SCN function and circadian clock timing. Endocannabinoids can alter neuronal function by activating astrocyte signaling pathways and the release of gliotransmitters (Navarrete and Araque, 2008). Here, we hypothesize that cannabinoid signaling activates an intracellular Ca2+ signaling pathway in astrocytes and releases neuromodulators to alter SCN neuronal function and ultimately change circadian clock timing.


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Exposure to pesticides is also linked to several other cancers, birth defects, fetal death, and altered growth [9, 12]. Exposure to polychlorinated biphenyls (PCBs) can have a subtle effect on children’s neurodevelopment , and lead and PCBs can affect brain development, behaviour, and reproduction at very low levels . There is also evidence to suggest a causal relationship between air pollution and fetal growth but the association is small and it is difficult to determine which particulates are most harmful [15–18]. However, there is equivocal or conflicting evidence on the associations between effects on the fetus and diagnostic X-rays , nonionizing radiation [20, 21], exposure to hair products , and nitrates in drinking water .

Astrocyte regions were defined as soma or non-soma by shape; somas were identified as more circular with thin processes branching from the center. This distinction was made because astrocytes differentially, spatiotemporally, regulate Ca2+ influxes throughout their somas and processes (Shigetomi et al, 2021; Tong et al, 2021; Bindocci et al, 2021). Increases or decreases of intracellular Ca2+ were defined as events if the amplitude was >2 SD from baseline, with variable responses showing both a significant increase and a significant decrease (Irwin and Allen, 2021). WIN (3 μM) application increased [Ca2+]i in 52/5% of the somas.


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Activation of Gq DREADDs increases intracellular Ca2+ in astrocytes. A, Representative SCN slice of a GFAP-Cre+ mouse injected with Gq DREADD and GCaMP6. Scale bar is 50 μm, images taken at 40× and the inserts magnified 120×. B, Fluorescent intensity over time of the slice shown in A. Black arrow indicates the CNO (10 μM) application. Gray lines are individual regions, the black line is the average response of regions. C, Pie charts depict the percentage of regions that increase (black), decrease (dark gray), have a variable response (light gray), or do not respond (white) to CNO treatment across all experiments. D, Average fluorescent intensity before and after CNO application displayed as mean ± SEM for soma and non-soma regions.


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White scale bar is 50 μm, image taken at 40×. White, numbered ellipses are the ROIs plotted in B. B, Representative traces of intensity 180 s before, during, and after AM251 treatment (indicated by black bar). Numbers 1–4 correspond to numbered regions in A. Note that the event examples were picked to reflect the varying responses to AM251 with traces 2 and 3 showing a clear reduction in frequency. C, Average event numbers across all experiments of regions before, during, and after AM251 treatment depicted as mean ± SEM (*p < 0/05, Friedman test). D, Average percentage of regions responding with a decrease, increase, or no change on treatment with AM251 across all experiments (mean ± SEM). E, Cumulative probability curves of amplitude for both soma (top) and non-soma (bottom) regions before, during, and after treatment with AM251.

Mice were terminally anesthetized between zeitgeber time (ZT)3 and ZT5 (ZT12 defined as lights off) with isoflurane followed by cervical dislocation and decapitation. All recordings were made between projected ZT7– ZT10. Brains were harvested, sectioned, and recorded using the patch clamp technique. Experimental treatments included WIN 55,212-2 (WIN; 3 μM; Sigma-Aldrich), AM251 (5 μM; Tocris), fluorocitrate (FC; 1 μM; Sigma-Aldrich), ACPT-II (200 μM; Tocris), CGS15943 (50 μM; Tocris), DPCPX (0/2 μM; Tocris), clozapine-N-oxide (CNO; 10 μM; Cayman Chemical), thaspsigargin (1 μM; Tocris), and adenosine (100 μM; Sigma-Aldrich). All miniature GABA(A) receptor-mediated postsynaptic currents (mGPSC; for rationale behind terminology, see Chavas and Marty, 2003; Woodin et al, 2003) recordings were performed in the presence of TTX (1 μM; Tocris) and CNQX (10 μM; Tocris) to block action potential driven synaptic transmission. During electrophysiological recordings, cells were voltage-clamped at –60 mV to ensure inward GABA currents. The microelectrode internal solution consisted of the following: 150 mM KCl, 20 mM HEPES, and 5 mM dextrose. Slicing solution consisted of the following: 111 mM NaCl, 6 mM Na(gluconate), 3 mM KCl, 1 mM Na2H2PO4, 4 mM MgCl2/6H2O, 26 mM NaHCO3, 11 mM dextrose, and 0/5 mM CaCl2/2H2O. Recording solution consisted of the following: 114 mM NaCl, 6 mM Na(gluconate), 2/7 mM KCl, 1 mM Na2H2PO4, 1 mM MgCl2/6H2O, 26 mM NaHCO3, 11 mM dextrose, and 2 mM CaCl2/2H2O.


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Circadian rhythms are 24-h cycles in physiology regulated by the suprachiasmatic nucleus (SCN) in the brain, where daily cues act on SCN neurons to alter clock timing. Cannabinoid signaling modulates SCN neuronal activity, although the mechanism remains unclear. We propose that neuronal activity generates endocannabinoid release, activating astrocyte Ca2+ signaling, which releases adenosine and activates adenosine-1 receptors (A1Rs) on the presynaptic axon terminals, decreasing GABA release. We demonstrated, in mice, that activation of cannabinoid-1 receptors (CB1R) with the agonist WIN 55,212-2 (WIN) reduced the miniature GABA receptor-mediated postsynaptic current (mGPSC) frequency by a mechanism that requires astrocytes and A1R. WIN activated an intracellular Ca2+ signaling pathway in astrocytes. Activating this intracellular Ca2+ pathway with designer receptors exclusively activated by designer drugs (DREADDs) also decreased the mGPSC frequency and required A1R activation. The frequency of spontaneous Ca2+ events, including those induced by depolarization of a postsynaptic SCN neuron, was reduced by blocking CB1R activation with AM251, demonstrating neuronal endocannabinoid signaling modulates astrocytic Ca2+ signaling in the SCN. Finally, daytime application of WIN or adenosine phase advanced the molecular circadian clock, indicating that this cannabinoid signaling pathway is vital for the timing of circadian rhythms.

Thapsigargin (1 μM) increased [Ca2+]i by 380/4 ± 165/5% from pre-treatment levels, with Ca2+ levels dropping off significantly after the maximum as internal stores were depleted. WIN (3 μM) was applied after the [Ca2+]i reached a steady state value for at least 300 s. Because thapsigargin depletes intracellular Ca2+ stores, and the intensity of the GCaMP6 signal is dependent on [Ca2+]i, fewer somas were identifiable after Ca2+ depletion (before thapsigargin treatment: 35 visible somas, after: 11 visible somas). Thapsigargin treatment reduced the number and magnitude of WIN-induced [Ca2+]i increases indicating that WIN is activating Ca2+ release from intracellular stores. Of the 11 soma regions, only 4 showed an increase.


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For ABR measurements of adult owls, the beak of the owl was fixed in a custom-built holder. To prevent the buildup of negative middle-ear pressure under anesthesia (Larsen et al, 2021), a sterile 27 gauge cannula was inserted through the skull into the middle-ear cavity for ventilation during ABR measurements.


Page 10: Could the authors comment as to why DMSO alone caused a change in astrocytic calcium levels. Is there a possibility that the DMSO concentration used was too high?

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The reference to ketamine- isoflurane etc - recovery conditions is not clear. The animals were anaesthetized and were not in a phase of recovery from anaesthesia. At some point they had recovered, your data were obtained during anaesthesia. It indeed could be the case that some of anesthetics have longer lasting effects that persist into the recovery phase ]but this does not appear to be the focus of this study.

Traditionally, cannabinoids act as a retrograde signal whereby after a depolarizing event a postsynaptic cell synthesizes and releases endocannabinoids that activate cannabinoid receptors on the presynaptic cell to regulate neuronal excitability (Wilson et al, 2001; Wilson and Nicoll, 2001). Our model supports previous work challenging this model, implicating astrocytes as necessary intermediates to fine tune retrograde responses (Navarrete and Araque, 2008, 2021; Min et al, 2021; Di et al, 2021; Viader et al, 2021). In the SCN, there has been growing evidence that astrocytes actively modulate neuronal function and circadian rhythmicity (Barca-Mayo et al, 2021; Brancaccio et al, 2021; Tso et al, 2021), broadening the role of astrocytes from mediating retrograde responses from neurons to actively integrating time-of-day information to the SCN network. A recent study demonstrated that astrocyte-specific deletion of BMAL1, an essential circadian gene, causes bimodal activity of animals in constant darkness. Blockade of GABA(A) over several days was able to rescue this behavioral phenotype, indicating that astrocytes regulate GABAergic signaling (Barca-Mayo et al, 2021). The current study supports these observations, demonstrating that astrocytes are necessary for modulation of GABAergic tone. Utilizing the circadian tau mutant, where a selective deletion of a mutant form of casein kinase ε in astrocytes causes a circadian period mismatch in neurons and astrocytes of 22 and 24 h, respectively, astrocytes have been shown to influence circadian free-running period, or day length (Tso et al, 2021). Future work will investigate the ability of astrocytes to synchronize SCN neurons, perhaps via cannabinoid signaling.


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By adjusting the dosage if it occurred. Another salient change is a gradual overall increase of muscle potentials without any visible animal movement which signals that the plane of anaesthesia is getting lighter. We did not notice any other systematic changes in heart rate during a given experiment.

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Did the scope of effects of anaesthesia depend on repetition rate? If auditory nerve or other peripheral adaptive phenomena differ for different anesthetics, repetition rate would influence results. It would also be valuable to assess whether evoked spike rates and latencies (response strength at some dB above threshold) differed between anesthesia groups.

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Achieving a CCgR within 18 months has been shown to be a solid early surrogate marker of outcome. The formula of the new EUTOS score could be applied to 1873 registry patients for whom data on spleen size, basophils, and known time to CCgR were available, and to 2021 patients for whom data on follow-up of survival were available. Figure 2C shows the cumulative incidence for CCgR. Figure 3 shows the probabilities of survival free from progression to AP or BP in both EUTOS risk groups.


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Neurons utilize endocannabinoid signaling to activate astrocyte Ca2+ signaling pathways. A, Representative bright field (top) and GCaMP6 (bottom) images from a single slice. White scale bar is 50 μm, images taken at 40×. White arrow indicates the placement of the microelectrode tip. Numbered ellipses correspond to locations of traces in B. B, Representative intensity changes from the regions marked in A before and after depolarization of an SCN neuron (indicated by black bar) before (left) and during (right) AM251 (5 μM) treatment. C, Average number of events pre- and post-depolarization, before, during, and after treatment with AM251 across all experiments (mean ± SEM, *p < 0/05, Friedman test). D, Cumulative percentage of regions per change in event number from depolarization, before, during, and after AM251. E, Boxplot of event amplitudes pre- and post-depolarization, before, during, and after treatment with AM251.


For auditory nerve single units recorded in young owls, the frequency–threshold curves were derived from responses to a matrix of tone bursts of 50 ms duration, presented randomly at different frequencies and levels, three times each, at a rate of five stimuli per second; the threshold criterion was, on average, 20 spikes/s above spontaneous rate. The spontaneous rate was estimated from the same datasets, either by counting spikes in the 50 ms window immediately before each stimulus (ketamine-terminal group) or from randomly inserted silent trials (isoflurane-terminal group). A new measure of relative sensitivity was defined that normalizes for the known threshold changes that occur with age that have been quantified for ketamine/xylazine anesthetized owls (Köppl and Nickel, 2007).

Why is the amplitude in Fig 4F and 5E plotted differently, using cumulative probability graphs and boxplots? Please standardize data plotting for comparisons.


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Very similar results were obtained when the new prognostic score was applied to the validation sample, comprising 271 patients (Table 3 and Figure 2B). As in the learning sample, every third patient in the high-risk prognosis group was not in CCgR at 18 months, with a PPV of 34%. Finally, the new score was applied to all 1197 patients with a known CCgR status at 18 months, for whom data on basophils and spleen size were available (Table 3 and Figure 2C). The PPV in these patients was 34%, the sensitivity 23%, and the specificity 92%.


Work on glial cell activity in the SCN continues to reveal the pivotal roles of glia communication in circadian rhythm generation. In this study, the authors provide evidence suggesting that synaptic communication in the SCN can be regulated by endocannabinoids through glia-neuronal interactions. The mechanism may involve adenosine release from glia which acts on presynaptic adenosine-receptor type 1 to regulate synaptic transmission. For the most part, the manuscript is well and succinctly written and the experiments are well designed, and the results are clearly reported.

Our work identified important, previously unrecognized confounding effects of respiration, in addition to confirming a basic detrimental effect of inhalants. We feel unable to completely resolve all possible new aspects that were raised within the scope of this study but distil interesting questions for future research (see also next question).


With the bioluminescence experiment, the authors implied in the discussion, and stated in the abstract (line 15), that the endocannabinoid system recruits A1R signaling to phase-shift the clock and generate circadian rhythms. Although it is perfectly acceptable to predict and show that WIN and adenosine alone could have similar phase-shifting effects on clock phase, at such integrated molecular level it unfortunately does not confirm their interdependency in shaping clock phase. Other signaling pathways may be involved. To systematically exclude this possibility, it is prudent that the authors also show the effect (or lack of effect) of WIN in the presence of DPCPX on clock-phase.

Of a total of 127 patients, 20 (15/7%) cases were in the high age group and 107 (84/3%) cases in the standard group (Table 2). There was no statistically significant difference at baseline between the two groups. During this study, 27 patients, including two aged >80 years, underwent CAS mainly for anesthesiologic problems or following patient’s request. There was no significant difference in the rate of CEA and CAS performed in the high age group, compared with the standard group.


This study provides a snapshot of risk perceptions. Whilst the scientific evidence of the effects of prenatal exposure to environment hazards and adverse effects on children is on the rise, it is important to investigate what the public believe about the exposure to a range of hazards and reproductive health. To date, little empirical data about the public’s knowledge about environmental hazards and reproduction have been reported. Data such as that collected in this study has been compared with the scientific evidence base, whether that provides strong, weak, or absent links to adverse effects to human health. Comparisons such as these may provide an invaluable contribution to both environmental health policy and practice developments.

The analysis of data took into account the complex design of multi-stage cluster surveys. All participants were informed about the aims of the projects and the confidentiality of the information they would give, and signed the written consent. Results Within the conventional medical research field. This paper is concerned with the identification of these factors and of how their spatial variability influences the spatial variability of the Share of Households in Potential Economic Distress (SHED). Aims To investigate the work incapacity in terms of absence days in patients with AS and to evaluate whether. The effectiveness of a manual of clinical guidelines for smoking cessation during pregnancy and the role of patient education has been previously evaluated, through which the provision of a self-help manual, a videotape and a brief counselling intervention were found to be more effective in promoting cessation in comparison to the provision of "usual care" (17.3% in the experimental group vs.

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As stated above we performed a sensitivity analysis based on the complete sample of 279. All analyses were conducted using PASW Statistics 17.0 and R for Windows. PASW Statistics 18. A third reviewer (SB) was consulted to resolve any disagreements. Horas V 3 1 Patch By Shock. Of the 1223 patients in whom cytogenetic remission status at 18 months had been examined, the Euro and Sokal scores were available for 1165 and 1167 patients, respectively. IBM SPSS version 18 but the book can also be used with older and newer versions.


Of these study groups, we analyzed all 1261 patients who progressed or died within 36 months or had a minimum follow-up of 36 months, and all 1223 patients in whom cytogenetic response status had been evaluated at 18 months (acceptable interval 15-21 months). The latter group was divided into 2 subgroups: a learning sample of 938 patients from the German, GIMEMA, and HOVON groups, and a validation sample of 285 patients from the French and Nordic groups. A patient flow diagram is provided in Figure 1. All clinical and hematologic factors were determined at baseline. Patient demographics were comparable across the national subsets. There were no relevant differences in timing of diagnosis, diagnostic procedures, or monitoring. All patients had been enrolled in prospective studies of treatment with imatinib or imatinib-based regimes.

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Air-dried SCN-containing sections were hydrated in 0/1 M PB. To reduce background autofluorescence, the sections were incubated in an aldehyde-reducing agent 1% NaBH4 in 0/1 M PB for 30 min and rinsed copiously with multiple changes of 0/1 M PB until there were no signs of bubbles. The tissue was permeabilized with 0/3% Triton X-100 in TBS and non-specific binding was blocked by incubation in 5% normal donkey serum for 1 h at room temperature. For GFAP staining, the primary antibody was mouse anti–GFAP (1:1000, Millipore Bioscience Research Reagents MAB 3402, RRID:AB_94844). The secondary antibody was donkey anti-mouse Dy-Light 594 (1:1000, Jackson ImmunoResearch #715-585-151, RRID:AB_2340855). For neurofilament heavy chain (NFHC), primary antibody was chicken polyclonal anti-NFHC (1:500, Aves Labs, catalog #NFH, RRID:AB_2313552). The secondary antibody was donkey anti-chicken/CF 488A (1:500, Sigma SAB4600031, RRID:AB_2721061). For the neural/glial antigen-2 (NG2) staining, the primary antibody was mouse monoclonal anti-NG2 (1:250, Abcam catalog #ab50009, RRID:AB_881569). The secondary antibody was donkey anti-mouse Dy-Light 594 (1:1000, Jackson ImmunoResearch #715-585-151, RRID:AB_2340855).

Finally, there is conflicting evidence regarding the effects of gas anesthetics on the responses of sensory hair cells, specifically the outer hair cells of the mammalian cochlea, measured as otoacoustic emissions. In humans, several studies reported a selectively depressive effect of gas anesthetics on evoked emissions (Ferber-Viart et al, 1998; Ropposch et al, 2021; Gungor et al, 2021). However, it is currently unclear whether this is a truly pharmacological effect on the cochlea or may be a secondary consequence of changes in arterial blood pressure.


Some aspects of the discussion seem somewhat far-fetched: “Perhaps endocannabinoids, which can regulate both sleep and astrocytic responses to the local neuro-environment (Metna- Laurent & Marsicano, 2021), may be critical modulators of the glymphatic system. In addition, we demonstrate daytime application of WIN 55, 212-2 and adenosine phase advances clock timing in the SCN.

In calculating positive predictive values (PPVs), negative predictive values (NPVs), sensitivities, and specificities, the models were compared with each other and with the established scores. PPVs were always calculated for the high-risk group, and NPVs for the remaining patients.


I believe this reduces significantly the relevance of the authors' findings. However, I note that the authors focused their recordings at ZT3-5, which is when astrocytes have low intracellular calcium and are less active (Brancaccio et al. 2021, 2021). I believe that repeating the experiments at peak astrocytic Ca2+ (CT/ZT14-CT/ZT18) may be far more informative and put these findings in a completely different light. This comment actually applies to most of the data presented in this manuscript, as the conditions are consistent throughout.

We have even fought hard to defend your privacy in legal cases; however, we've done it with almost no financial support - paying out of pocket to continue providing the service. Limewirepro 4.18.6 Serial Number. PASW is a powerful statistics software application. ADHD pathophysiology However. Statistics (hop over to here) version 18 (SPSS). Multilevel models were estimated with PASW statistics 18, based on a unique dataset, constructed by merging data from the Belgian Health Interview Surveys from 2020 and 2020 with data from 264 municipalities derived from Statistics Belgium and the General Socio-Economic Survey.


In the present study, the anesthetic regime was changed during an ongoing experimental series on the development of auditory nerve responses in the barn owl (Tyto alba). Previous auditory research in several laboratories had successfully used a combined ketamine/xylazine or ketamine/diazepam injection anesthesia in both adult and young owls (Cohen and Knudsen, 1995; Köppl, 1997; Keller and Takahashi, 2005; Bremen et al, 2007; Köppl and Nickel, 2007). Nevertheless, a change to isoflurane inhalant anesthesia was recommended by the consulting veterinarians, citing animal welfare concerns (Varner et al, 2004).

CAP responses in young owls were recorded to frequencies of 500 Hz and 1 to 10 kHz in 1 kHz steps. At each frequency, responses to a range of randomly presented levels were recorded, generally in 5 dB increments, and decreased to 3 dB near threshold. CAP amplitude was defined as the difference between the first negative peak N1 and the following most prominent positive peak. Thresholds were derived from linear regression fits through the initial segment of the curve (four to six data points collected at the lowest stimulus levels), as the level eliciting a 5 µV response.


The Queensland Social Survey is an annual omnibus survey that addresses a variety of topics of interest to the research community. The survey consists of a standardised introduction, a series of question sets reflecting the specific research interests of the university and community researchers participating in the study, and demographic questions. Questions relating to the public’s opinion of environmental hazards and human reproduction were embedded into the survey. Interviewees were asked to firstly rank five individual environmental hazards from “very harmful” to not “harmful at all” to human reproduction and secondly to choose from a list of five hazards which they perceived to be the hazard most harmful to human reproduction.

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We chose to study cannabinoid signaling in the SCN during the day for several reasons. First, previous work demonstrated that endocannabinoids may act as a nonphotic cue (Acuna-Goycolea et al, 2021), which are more effective during the day. Next, the endogenous CB1 agonist 2-arachidonoyl-glycerol shows a diurnal rhythm, with a peak during the day (Valenti et al, 2004; Liedhegner et al, 2021). Finally, endocannabinoid signaling is different from many transmitter signaling systems in that the endocannabinoids are synthesized on demand in response to increases in neuronal activity (Navarrete and Araque, 2008), and SCN neurons are most active during the day (Green and Gillette, 1982). Astrocytes in the SCN have increased global intracellular calcium at night, with relatively little calcium signaling during the day (Brancaccio et al, 2021; Brancaccio et al, 2021). The current model suggests this increased calcium at night reflects active extracellular glutamate buffering by the astrocytes via NMDAR dependent mechanisms (Brancaccio et al, 2021, 2021). Although providing an explanation to the potential roles of astrocytes in setting periodicity and neuronal activity at night, relatively little is known about astrocytic function during the day. We suggest that decreased [Ca2+]i during the day fits our model, enabling astrocytes to fine-tune neuronal activity locally at synapses compared to broadly buffering glutamate across the SCN. This is supported both by AM251 and FC having no direct effect on neuronal activity and by AM251 decreasing spontaneous, local astrocytic [Ca2+]i, supporting our hypothesis that endogenous cannabinoid signaling in the SCN involves astrocytes. One endogenous, physiologic condition in the SCN that could induce cannabinoid signaling may be a light stimulus that excites neurons broadly over the SCN.


For this purpose, a European registry of CML patients was established by the European LeukemiaNet (ELN). It has been maintained and implemented within the framework of a project supported by Novartis Oncology Europe, the European Treatment and Outcome Study for CML (EUTOS).

The authors claim to observe a phase advance but judging from their (representative) traces they are in presence of a shorter period (to start with) in the WIN treated slices. Moreover, the period of Per2 :Luc seems to lengthen after the WIN treatment. Similar considerations apply to the adenosine data, with the aggravation of a damping oscillation after the treatment, which contaminate any interpretation of circadian parameters. I believe the authors should not only provide better representative traces, but also a proper analysis of circadian parameters (period, amplitude, robustness, phase) and discuss their findings appropriately. Furthermore, and similarly to experiments in acute slices, the authors perform their treatment when SCN astrocytes are less active: repetition of these experiments at other circadian time may be far more informative, especially if corroborated by a PRC.


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Objective: Carotid endarterectomy (CEA) is one of the surgical treatments for carotid artery stenosis. While a large clinical trial showed that advanced age is a risk factor for CEA, other studies reported contradictory results. The aim of this study was to evaluate the outcomes of CEA in patients aged over 80.

There are a multitude of cannabinoids, from plant derived such as cannabidiol or (–)-trans-Δ9-tetrahydrocannabinol found in marijuana, to endocannabinoids produced by the body such as 2-arachidonoylglycerol and anandamide, to pharmacological agents designed to activate specific cannabinoid receptors (Stella, 2021; Le Boisselier et al, 2021). The affinity of these compounds for cannabinoid receptors varies greatly (McPartland et al, 2007) and cannabinoid receptors can have multiple binding sites (Lauckner et al, 2005; McPartland et al, 2007; Khajehali et al, 2021; Hua et al, 2021). To control for these confounds, we not only activated CBRs via the potent agonist WIN, but blocked CB1Rs, specifically, with AM251 to investigate the role of endocannabinoid signaling instead of relying on observations made with exogenous cannabinoids. Conventionally, CB1Rs are identified as Gi-coupled G-protein-coupled receptors, but WIN binds CB1 in such a way that it couples to Gq G-proteins and promotes release of Ca2+ from internal stores (Lauckner et al, 2005). Our data supports these findings such that the effects of WIN in the SCN are dependent on CB1R activation, Gq signaling increases astrocytic intracellular Ca2+ to a similar extent as WIN, and blockade of CB1R decreases Ca2+ events. Further work must be done to identify which endocannabinoid, specifically, is responsible for these Ca2+ events, but given the complexity of CB1R binding and function this may be difficult to discern.


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Greater uncertainty and doubt exist about what could be described as nonpersonal environmental risk factors and their impacts generated not by choices but by activities external to and usually beyond the control of individuals. These are the focus of our paper. They may also often involve complex inter-actions and long-term, low-level exposures and reviews flag both the established risks and new potential hazards during pregnancy that may involve a range of environmental factors.

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A pioneering study which is still relevant to the present analysis of global risks to health concluded that the most highly uncertain risks such as pesticides and nuclear power are deemed the most dreaded, while risks associated with health interventions and clinical procedures are more acceptable . A range of factors have been shown to influence risk perceptions and these are embedded within different economic, social, and cultural environments . Some of these have been explored in the survey such as gender, age, and location. Others like employment, family and peer group, and education may also be factors. The media too plays a part in risk perception and rating—the web as well as radio, TV, and newspapers are of growing significance although evidence-based media sources may not always be accessed.

The mechanisms that produce general anesthesia at the systems level are still poorly understood (Rudolph and Antkowiak, 2004; Ishizawa, 2007). The cellular sites of action commonly involve ion channels and neurotransmitter receptors that are widely expressed in the CNS and should thus act at all levels. Nevertheless, as a general rule, a gradual effect is observed, such that higher-level cognitive functions are impaired at lower anesthetic concentrations than motor functions, early visual processing, or basic homeostatic physiology (Campagna et al, 2003; Rudolph and Antkowiak, 2004; Ishizawa, 2007). This suggests that while the cellular sites of action may be similar, higher centers tend to show the combined result of direct anesthetic action and cumulative effects in neural networks. This also promotes the common assumption that general anesthesia, when appropriately dosed, should not significantly affect primary sensory processes. Therefore, the pronounced effect of isoflurane and sevoflurane at the most peripheral levels of the auditory system, the hair cells and auditory nerve, is surprising.


In the SCN, postsynaptic neurons recruit astrocytes via endocannabinoid signaling to modulate presynaptic GABA release. Activation of CB1Rs with the cannabinoid agonist WIN decreases the frequency but not the amplitude of mGPSCs in the SCN, consistent with a reduction in GABA release. This effect is dependent on astrocyte function, and A1R activation. WIN also induces an astrocytic Ca2+ signaling cascade. Mimicking this increased Ca2+ signal in astrocytes using DREADD technology causes a decrease in mGPSC frequency that is also dependent on A1R activation. Finally, blockade of endogenous CB1R activation with AM251 decreases both spontaneous Ca2+ events, and the number of Ca2+ events induced by depolarization of a postsynaptic neuron indicating neuronal-derived endocannabinoid signaling modulates astrocytic Ca2+ signaling in the SCN. We propose a model whereby postsynaptic neuronal activity generates endocannabinoid release, activating cannabinoid receptors on astrocytes and activating an intracellular Ca2+ signaling pathway, causing the release of adenosine and activation of A1Rs on the presynaptic neuron to decrease GABA release. Adenosine itself decreases mGPSC frequency, supporting this hypothesis. In addition to this novel model of astrocyte recruitment to modulate GABAergic signaling in the SCN, daytime application of either WIN or adenosine phase advanced PER2 :LUC rhythms, indicating a conserved mechanism for modulation of circadian timing.

Gas Anesthesia Impairs Peripheral Auditory Sensitivity in Barn Owls

Anesthesia and analgesia are necessary for most invasive experiments. Their effects are also a concern for studying normal neural and sensory functions. We show a significant deterioration of hearing sensitivity of the auditory nerve under gas anesthesia (isoflurane or sevoflurane), compared with injection anesthesia with ketamine/xylazine, in barn owls. This generalizes similar findings across birds and mammals, and suggests that while inhalants are widely recommended as safe and easy-to-use anesthetics in veterinary contexts, they should only be used with great caution in auditory neurophysiology, even at the most peripheral level. Future important questions are whether the deterioration of sensitivity at the periphery generalizes to other senses and what the precise mechanisms are that determine the species-specific extent of sensitivity loss.


The anesthetic agents were not the only difference between the experimental groups in our initial study with young barn owls. Young owls of the isoflurane-terminal group were artificially respirated with oxygen or carbogen, while the ketamine-terminal group breathed normal air unaided. Therefore, in the follow-up study on adult owls, each individual was tested repeatedly under otherwise identical conditions. This confirmed the specific, detrimental effect of gas anesthesia. However, the threshold difference relative to ketamine anesthesia was smaller for the group of adult owls, opening several possibilities for confounding effects. These were addressed in the terminal experiments with adult owls.

Improvement of the discriminatory power of the 2 established scores was attempted by combining low- and intermediate-risk groups and using the minimal P value approach to define a new cutoff point for the 2 prognostic classes with the greatest differences. However, the discriminatory power did not improve sufficiently. The PPVs of high-risk patients were between 25% and 28% and the relationship between sensitivity and specificity was not well balanced. Specifically, either there were many patients in the high-risk group and thus the sensitivity was high but the specificity was low, or the specificity was high but there were few patients without CCgR who were identified as high-risk.


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The effects of exposure to environmental toxins especially for pregnant women were propelled into the public domain in the 1960s with events such as the poisoning of Minamata Bay by mercury dumped by a plastics company . Infants born to mothers who had consumed contaminated fish from the bay developed a number of problems including cerebral palsy, developmental delays, central nervous system damage, and blindness.


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The original aim of the single-unit experiments on young owls was to study maturation of auditory-nerve responses. The age range of animals was chosen to include a period of significant maturation of auditory thresholds, as previously documented with CAP recordings (Köppl and Nickel, 2007). In contrast, the present manuscript focusses on anaesthesia effects on auditory sensitivity. The normalization of single-unit thresholds to the age-matched CAP audiogram was introduced to eliminate known maturation effects on thresholds and identify those changes that are due to the anaesthetic regime.

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In ABR recordings from adult owls, a standard set of six frequencies was tested, at 1, 2, 4, 6, 8, and 10 kHz. At each frequency, responses to a range of randomly presented levels were recorded, generally in 5 dB increments, and decreased to 3 dB near threshold (with few exceptions).


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ABR thresholds were elevated under gas anesthesia. A, Box plot showing ABR thresholds as a function of frequency, for the same four adult individuals, tested with different anesthetic protocols in successive experiments. B, The same data, with thresholds now normalized to the values at the respective frequency for the ketamine-ABR condition; as a visual reference, the dashed line indicates the reference condition. Note that the minor variation across frequencies was not significant (Table 1, References 27 and 28). Therefore, C then shows an overall comparison between anesthetic conditions. Thresholds for either the isoflurane-ABR or sevoflurane-ABR condition were significantly higher than thresholds for the ketamine-ABR condition (Table 1, References 24 and 25). Thresholds for the ketamine-ABR condition are shown as empty boxes, for the isoflurane-ABR condition as hatched boxes, and for the sevoflurane-ABR condition as gray boxes. Boxes and whiskers indicate the interquartile ranges and 1/5 times the interquartile ranges, respectively. Horizontal lines within boxes indicate medians. There were no outliers beyond 1/5 times the interquartile ranges.

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The paper's impact would be strengthened by considering these results in the broader context of neuronal processing at multiple levels of sensory hierarchies. For instance, what is the predicted impact of these levels of sensitivity loss on downstream regions, and what new insights does this potentially give us into the interpretation of previous data across avian or even mammalian species? Finally, the authors are advised to address the bottom line here: what does the relative impact of gas anesthesia on neural responses say about its use in neurophysiology? Given that it has an observable dose-dependent effect, are there other ways of safely and humanely administering, for example, isoflurane while also mitigating depression of neural responses? One common approach is the combination of isoflurane and nitrous oxide, which allows for a deeper plane of anesthesia with less isoflurane and oxygen toxicity. Comparing this anesthetic regime with the others in this study would be highly valuable to the field.

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