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Root reinforcement, provided by plants in soil, can be exerted by a mechanical effect, increasing soil shear strength for the presence of roots, or by a hydrological effect, induced by plant transpiration. No comparisons have been still carried out between mechanical and hydrological reinforcements on shallow slope stability in typical agroecosystems. This paper aims to compare these effects induced by sowed fields and vineyards and to assess their effects towards the shallow slope staibility. Root mechanical reinforcement has been assessed through Root Bundle Model-Weibull. Root hydrological reinforcement has been evaluated using an empirical relationship with monitored or modelled pore water pressure. Each reinforcement has been inserted in a stability model to quantify their impacts on susceptibility towards shallow landslides. Considering the same environment, corresponding to a typical agroecosystem of northern Italian Apennines, land use has significant effects on saturation degree and pore water pressure, influencing hydrological reinforcement. Root hydrological reinforcement effect is higher in summer, although rainfall-induced shallow landslides rarely occur in this period due to dry soil conditions. Instead, in wet and cold periods, when shallow landslides can develop more frequently, the stabilizing contribution of mechanical reinforcement is on average higher than the hydrological reinforcement. In vineyards, the hydrological reinforcement effect could be observed also during autumn, winter and spring periods, giving a contribution to slope stability also in these conditions. This situation occurs when plants uptake enough water from soil to reduce significantly pore water pressure, guaranteeing values of hydrological reinforcement of 1-3 kPa at 1 m from ground, in agreement with measured mechanical root reinforcement (up to 1.6 kPa). These results suggest that both hydrological and mechanical effects of vegetation deserve high regard in susceptibility towards shallow landslides, helping in selection of the best land uses to reduce probability of occurrence of these failures over large territories., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Multiple studies have demonstrated the efficacy and safety of ibrutinib for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). This first-in-class inhibitor of Bruton's tyrosine kinase has become a standard treatment for patients with CLL and MCL., Patients and Methods: We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with ibrutinib versus comparators. Data were pooled from 4 completed randomized controlled studies that had included 756 ibrutinib-treated and 749 comparator-treated patients with CLL/SLL or relapsed/refractory MCL. Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates., Results: The median treatment duration was 13.3 months (maximum, 28.2 months) for ibrutinib and 5.8 months (maximum, 27.3 months) for comparators. When adjusted for exposure, diarrhea, atrial fibrillation, and hypertension were the only common grade ≥ 3 AEs more often reported with ibrutinib than with the comparators. Dose reductions (7% vs. 14%) and discontinuation (12% vs. 16%) because of AEs occurred less often with ibrutinib, and deaths due to AEs occurred at similar rates (6% vs. 7%). When adjusted for exposure, the corresponding data were all lower with ibrutinib than with the comparators (0.06 vs. 0.22, 0.11 vs. 0.22, and 0.06 vs. 0.09 patient-exposure-years, respectively). The prevalence of common grade 3/4 AEs with ibrutinib generally decreased over time, with the exception of hypertension., Conclusion: These results from an integrated analysis support a favorable benefit/risk profile of ibrutinib in patients with CLL/SLL and MCL., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Women are twice as likely as men to experience stress-related psychiatric disorders. The biological basis of these sex differences is poorly understood. Orexins are altered in anxious and depressed patients. Using a rat model of repeated stress, we examined whether orexins contribute to sex differences in outcomes relevant to stress-related psychiatric diseases., Methods: Behavioral, neural, and endocrine habituation to repeated restraint stress and subsequent cognitive flexibility was examined in adult male and female rats. In parallel, orexin expression and activation were determined in both sexes, and chromatin immunoprecipitation was used to determine transcription factors acting at the orexin promoter. Designer receptors exclusively activated by designer drugs were used to inhibit orexin activation throughout repeated restraint to determine if the stress-related impairments in female rats could be reduced., Results: Female rats exhibited impaired habituation to repeated restraint with subsequent deficits in cognitive flexibility compared with male rats. Increased orexin expression and activation were observed in female rats compared with male rats. The higher expression of orexin messenger RNA in female rats was due to actions of glucocorticoid receptors on the orexin promoter, as determined by chromatin immunoprecipitation. Inhibition of orexins using designer receptors exclusively activated by designer drugs in female rats throughout repeated restraint abolished their heightened hypothalamic-pituitary-adrenal responsivity and reduced stress-induced cognitive impairments., Conclusions: Orexins mediate the impairments in adaptations to repeated stress and in subsequent cognitive flexibility exhibited by female rats and provide evidence for a broader role for orexins in mediating functions relevant to stress-related psychiatric diseases., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: A chikungunya epidemic occurred in 2013-2014 in the Caribbean and Americas. Although the disease is usually benign, some patients required admission to the intensive care unit (ICU). The characteristics and outcomes of patients with chikungunya virus (CHIKV) infection admitted to an ICU during this epidemic are reported., Methods: An observational study of consecutive patients with confirmed CHIKV infection admitted to ICUs in Martinique and Guadeloupe, French West Indies, between January and November 2014, was performed. In addition, patients with CHIKV-related manifestations were compared with those whose manifestations were not specifically related to CHIKV infection., Results: Sixty-five patients were admitted to the ICU with CHIKV infection. Fifty-four (83%) had a pre-existing underlying disease and 27 (41.5%) were admitted due to exacerbation of a comorbidity. Thirty-seven (57%) patients were mechanically ventilated. ICU and hospital mortality rates were 26% and 27%, respectively. CHIKV-related manifestations were observed in 28 (18%) patients and were mainly encephalitis, Guillain-Barré syndrome, and severe sepsis. These patients less frequently had chronic arterial hypertension and diabetes and more frequently had autoimmune diseases compared with patients without CHIKV-related manifestations., Conclusions: Most patients admitted to the ICU with CHIKV infection had a pre-existing comorbidity. However, severe manifestations such as Guillain-Barré syndrome, encephalitis, and severe sepsis could be specifically related to CHIKV., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Trafficking of G protein-coupled receptors (GPCRs) is a critical determinant of cellular sensitivity of neurons. To understand how endogenous or exogenous ligands impact cell surface expression of GPCRs, it is essential to employ approaches that achieve superior anatomical resolution at the synaptic level. In situations in which light and fluorescence microscopy techniques may provide only limited resolution, electron microscopy provides enhanced subcellular precision. Dual labeling immunohistochemistry employing visually distinct immunoperoxidase and immunogold markers has been an effective approach for elucidating complex receptor profiles at the synapse and to definitively establish the localization of individual receptors and neuromodulators to common cellular profiles. The immuno-electron microscopy approach offers the potential for determining membrane versus intracellular protein localization, as well as the association with various identifiable cellular organelles. Corticotropin-releasing factor (CRF) is an important regulator of endocrine, autonomic, immunological, behavioral and cognitive limbs of the stress response. Dysfunction of this neuropeptide system has been associated with several psychiatric disorders. This review summarizes findings from neuroanatomical studies, with superior spatial resolution, that indicate that the distribution of CRF receptors is a highly dynamic process that, in addition to being sexually dimorphic, involves complex regulation of receptor trafficking within extrasynaptic sites that have significant consequences for adaptations to stress, particularly within the locus coeruleus (LC), the major brain norepinephrine-containing nucleus., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The dorsal raphe nucleus (DR) contains serotonin (5-HT) neurons that innervate the cortex and limbic system and through these projections is thought to regulate cognition and behavior. Clinical and pharmacological findings implicate dysfunctions in the DR-5-HT system in affective disorders, including anxiety, depression and suicide. Although the DR is often considered in light of its 5-HT neurons, recent studies underscore the complexity of this nucleus and its heterogeneous nature. Of particular interest, are peptides that are either present within neurons in the DR, innervate DR-5-HT neurons or act upon local circuitry within the DR to indirectly impact on this 5-HT system. These peptides are positioned to fine-tune the activity of selective groups of serotonergic neurons within the DR and thereby 5-HT release in different terminal fields. This review will focus on substance P and corticotropin-releasing factor as two peptides that act independently and interdependently to influence DR-5-HT function. The role of non-serotonergic components of the DR in translating the effect of each of these peptides is discussed. This synthesis refines our views on the regulation of the DR-5-HT system and importantly, gives insight into mechanisms of endogenous control of DR function, the dysregulation of which may contribute to pathophysiology.

Background and Aim: To evaluate the prevalence of goitre by means of urinary iodine excretion, palpatory and ultrasonographic thyroid examinations in a heterogeneous population living by the sea., Methods and Results: We used a special self-administered questionnaire to evaluate thyroid size, iodine intake, eating habits and cardiovascular risk factors in 600 subjects with a mean age of 45 +/- 17 years: 253 men (42.3%) and 347 women (57.7%). Urinary iodine excretion was low (72.1 +/- 15.7 microg/L; median 71.2) and associated with ultrasonographic evidence of an enlarged thyroid (16%) or structural thyroid abnormalities (30%), thus allowing us to define the Salerno Gulf as a mild-moderate area of endemic goitre. All of the subjects ate a Mediterranean diet, with a mean of two portions of fish/week. The cardiovascular risk factors considered were obesity, cigarette smoking, hypertension, hypercholesterolemia, hypertriglyceridemia and diabetes, the prevalences of which were in line with those reported in other studies of similar age-matched populations., Conclusions: The moderate intake of fish and the consumption of a Mediterranean diet did not prevent goitre. Iodine deficiency and subsequent goitre endemia are also present at sea level, probably because of a diet based on local products grown on soil with a low iodine content or possible seawater, soil and air environmental pollution that may interfere with the availability of iodine. The assessment of iodine deficiency should therefore involve the entire population and not only subjects living far from the sea.

Background: Neurochemical and electrophysiological studies indicate that the locus coeruleus (LC)-norepinephrine system is activated by physiological and external stressors. This activation is mediated in part by corticotropin-releasing factor (CRF), the hypothalamic neurohormone that initiates the endocrine response to stress. We have previously shown that the central nucleus of the amygdala (CNA) provides CRF afferents to noradrenergic processes in the peri-LC area that may serve to integrate emotional and cognitive responses to stress. The bed nucleus of the stria terminalis (BNST) shares many anatomical and neurochemical characteristics with the CNA, including a high density of CRF-immunoreactive cells and fibers; however, recent studies have suggested that the CNA and the BNST may differentially regulate responses to conditioned and unconditioned fear, respectively, suggesting divergent neuroanatomical circuits underlying these processes., Methods: In the present study, neuroanatomical substrates subserving regulation of the LC by the BNST were examined. Anterograde tract-tracing was combined with immunoelectron microscopy to test the hypotheses that BNST efferents target noradrenergic neurons of the LC and that these efferents exhibit immunolabeling for CRF., Results: Ultrastructural analysis of sections that were dually labeled for the anterograde tracer biotinylated dextran amine (BDA) injected into the BNST and tyrosine hydroxylase (TH)-immunoreactivity demonstrated that BDA-labeled axon terminals formed synaptic specializations (primarily inhibitory) with TH-labeled dendrites and dendrites that lacked TH immunoreactivity. In contrast to CNA efferents that exhibited substantial immunolabeling for CRF, far fewer BDA-labeled terminals from the BNST in the rostrolateral peri-LC contained CRF., Conclusions: The present results indicate that the BNST may provide distinct neurochemical regulation of the peri-LC as compared to other limbic afferents such as the CNA. These data are interesting in light of behavioral studies showing that the CNA and BNST may be differentially involved in fear versus anxiety, respectively.

Background and Aim: The aim of this study was to determine the validity of our previous hypothesis of adrenal 11 beta-hydroxylase (11-OH) dysregulation in "essential" low-renin hypertension., Methods and Results: A comparison was made between 30 hypertensive patients and 30 age-matched controls (NC) in basal conditions and after ACTH stimulation (ACTH 1-17) test. The 11-deoxycortisol (S) and deoxycorticosterone (DOC) integrated areas under the curve (AUCs) of stimulus were significantly higher in the hypertensives (p < 0.001) and pointed to adrenal 11-OH dysregulation., Conclusions: The ACTH 1-17 test detects impairment of 11-OH activity of probable genetic origin. The relative mineralocorticoid excess thus provoked could be an additional cause of "essential" low-renin hypertension.

An increased frequency of reproductive endocrine diseases has been described in women with epilepsy and a subclinical reproductive dysfunction has been suggested in normally menstruating epileptic women. We assessed the reproductive endocrine function in 11 normally menstruating, drug-free epileptic women, evaluating the basal hormonal profile and LH pulsatile secretion during continuous EEG monitoring. A significant LH hyperpulsatility was observed in epileptic women compared with controls; moreover, a significant increase of gonadotropin basal secretions was observed when inter-ictal paroxysmal activity increased. The derangement of the hypothalamic GnRH pulse generator may represent a subclinical condition associated with epilepsy, not necessarily affecting the regularity of menstrual function. However, it is possible that the alteration of LH pulsatile pattern might eventually cause reproductive endocrine diseases. Paroxysmal activity seems to be an important additional factor in the derangement of gonadotropin secretion.

Neuroendocrine and catecholamine dysfunctions in depression may be linked by corticotropin-releasing factor (CRF) effects on locus coeruleus (LC) neurons. One consequence of CRF hypersecretion in depression would be persistent elevated levels of LC discharge and diminished responses to phasic sensory stimuli. The hypothesis that antidepressants could reverse these changes was tested by characterizing effects of pharmacologically distinct antidepressants on LC sensory-evoked discharge, LC activation by stress, and LC activation by CRF. The most consistent effect of all of the antidepressants tested was a decrease in LC sensory-evoked discharge after acute administration. However, tolerance occurs to these effects after chronic administration. With chronic administration each of the antidepressants produced effects which could potentially interfere with CRF function in the LC. Desmethylimipramine and mianserin attenuated LC activation by a stressor which requires endogenous CRF, suggesting that these antidepressants attenuate stress-elicited release of CRF and perhaps the hypersecretion that occurs in depression. The serotonin reuptake inhibitor, sertraline (SER), enhanced the signal-to-noise ratio of the LC sensory response, an effect opposite to that of CRF. Thus, SER could serve as a functional antagonist of CRF that is hypersecreted in depression. The finding that three pharmacologically distinct antidepressants share the potential to interfere with CRF function in the LC implies that this may be an important common mechanism for antidepressant activity.

In rat hippocampal slices, opioids potentiate the synaptic activation of pyramidal neurons as revealed by the shift to the left in the input-output curve constructed by plotting the population spike as a function of the field EPSP. The peak effect was obtained within 12-25 min with D-Ala2,D-Leu5-enkephalin (DADLE), morphiceptin and morphine. However, the effect of both peptides declined during constant superfusion. About 60% peak effect was lost after 1 hr superfusion with morphiceptin or after 4 hr with DADLE. In contrast, the effect of morphine gradually increased over a 4 hr incubation. Following superfusion of the slices for 4 hr in DADLE or morphine, or 1.5 hr in morphiceptin, the membrane particulate fractions were prepared from the homogenate of slices. Opiate receptor binding activities were measured with 125I-DADLE (delta-receptors) and 125I-FK 33824 (mu-receptors). A significant reduction in delta- but not mu-receptor binding was detected in slices treated with DADLE. This seems to correlate to the development of desensitization to DADLE. Neither mu-receptor nor delta-receptor binding activity was altered by the superfusion of morphine or morphiceptin despite the development of desensitization to morphiceptin. These data suggest that there are differences in the regulation of mu- and delta-receptors in hippocampus. The down-regulation of delta-receptors may result in desensitization to delta-agonists and a different mechanism may be responsible for desensitization to mu-agonists.

A number of opiate antagonists and the dextro isomers of some of these drugs were studied for antagonism of acute opiate effects on ilea isolated from opiate-naive guinea pigs, precipitation of a withdrawal contraction of ilea isolated from morphine-dependent guinea pigs, precipitation of withdrawal in morphine-dependent rhesus monkeys and stereospecific displacement of 3H-etorphine binding to rat-brain membranes. With the exception of d-naloxone, all of the compounds displaced 3H-etorphine. With the exception of d-naloxone, nalorphine, and quaternary nalorphine, all of the antagonists caused a contraction of ilea isolated from morphine-dependent guinea pigs. Moreover, the IC 50 values of the compounds for displacing 3H-etorphine binding were well correlated with both their Ke values for antagonism in the ileum (r = 0.95) and with their EC 50 values for precipitating a contraction in this preparation (r = 0.92). Generally, the concentration of antagonist necessary to precipitate half maximal contracture was 30-fold greater than the Ke value of the antagonist. Most of the opiate antagonists also precipitated withdrawal when administered to morphine-dependent rhesus monkeys and their in vivo potencies were well correlated with their in vitro potencies in ileum (with Ke: r = 0.95; with EC 50: r = 0.99) and in displacing 3H-etorphine (r = 0.95). The quaternary derivative of naltrexone, however, was an effective opiate antagonist only in vitro, and was ineffective in precipitating withdrawal in morphine-dependent rhesus monkeys. These results suggest that the receptor sites labeled by 3H-etorphine are the same as those involved in antagonism of acute opiate actions and in precipitation of withdrawal.

This discriminative effects of cyclorphan were studied in pigeons trained to discriminate 0.32 mg/kg ethylketazocine, 1.8 mg/kg cyclazocine, or 32 mg/kg naltrexone from saline. A fourth group of pigeons was administered 100 mg/kg/day morphine and trained to discriminate 0.1 mg/kg naltrexone from saline. Cyclorphan produced dose-related ethylketazocine-appropriate responding that reached a maximum of 83% of the total session responses at 0.3 mg/kg. Higher cyclorphan doses produced less ethylketazocine-appropriate responding. IN pigeons trained to discriminate cyclazocine from saline, maximum drug-appropriate responding of greater than 90% occurred at 5.6-10.0 mg/kg cyclorphan. In narcotic-naive pigeons trained to discriminate 32 mg/kg naltrexone from saline, cyclorphan produced a maximum of less than 50% drug-appropriate responding. In contrast, in pigeons chronically administered morphine and trained to discriminate 0.1 mg/kg naltrexone from saline, 1.0 mg/kg cyclorphan resulted in 100% drug-appropriate responding. In pigeons responding under a multiple fixed-interval, fixed-ratio schedule of food delivery, cyclorphan produced a complete dose-related reversal of the rate-decreasing effects of 10 mg/kg morphine, the maximally effective antagonist doses being 1.0-3.2 mg/kg. Higher cyclorphan doses (10 mg/kg) resulted in response rate decreases that were not reversed by naloxone (1 mg/kg). Thus, cyclorphan has discriminative effects that are similar to those of both ethylketazocine and at 20 fold higher doses, cyclazocine. In addition, in morphine-treated pigeons, cyclorphan, across the same range of doses that produce ethylketazocine-appropriate responding, has discriminative effects that are similar to those of naltrexone, an effect that is probably related to the antagonist action of the drug.

The effects of dynorphin-A (Dyn) and [Leu5]-enkephalin (Enk) were compared in the vitro hippocampal slice preparation, using extracellular field potential and intracellular voltage recordings. In the CA1 region, Dyn, like Enk, consistently increased the size of the extracellularly recorded population spike (PS) evoked by stratum radiatum (StR) stimulation of the Schaffer collaterals. These responses were naloxone reversible. In contrast, in the CA3 region, Dyn both increased and decreased the PSs evoked by mossy fiber stimulation, whereas Enk slightly enhanced the PS. Intracellular recordings from CA3 pyramidal neurons (HPNs) revealed both excitatory and inhibitory actions of Dyn on spontaneous activity. Associated membrane potential changes were variable. In contrast, Enk had only weak effects on spontaneous activity and no effect on membrane potential. These data suggest regional differences in the effect of Dyn and Enk on hippocampal activity.

The sodium retention associated with liquorice ingestion has been thought to be due to a direct mineralocorticoid effect, despite the fact that it does not seem to occur in patients or animals with severe adrenal insufficiency. This study in seven normal subjects given liquorice showed that sodium retention is associated with a significant change in cortisol metabolism indicating inhibition of 11-beta-hydroxysteroid dehydrogenase (11 beta-OHSD). Congenital deficiency of this enzyme produces a syndrome of apparent mineralocorticoid excess. It is suggested that in both conditions there is a defect in the renal conversion of cortisol to cortisone by 11 beta-OHSD which results in high intrarenal cortisol levels, acting on type 1 mineralocorticoid receptors to cause sodium retention.

The ability of several opioids in potentiating the synaptic activation of CA1 pyramidal cells in the rat hippocampal slice were compared. Morphine and the opioid peptides, (D-ala2, D-leu5)-enkephalin (DADL), morphiceptin, beta-endorphin, and Tyr-D-Ser-Gly-Phe-Leu-Thr (DSThr) caused a concentration-dependent, naloxone-reversible shift to the left in the input-output (IO) curve constructed by plotting the population spike as a function of the field EPSP. These opioids then produced an increase in the size of the population spike while leaving the EPSP unaffected. In contrast, the kappa agonist prototype, ethylketazocine, had no effect on the IO curve when perfused in concentrations up to 10 microM. The rank order of potency for the opioids in the CA1 region of the hippocampus was DADL greater than DSThr greater than beta-endorphin greater than morphiceptin greater than morphine much greater than ethylketazocine. Thus, opioids that are more specific for delta opiate receptors were the most potent and mu receptor agonists, the least potent in this action. Taken together with previous studies suggesting that morphine and DADL may interact with a common opiate receptor in the CA1 region, the results are consistent with the notion that these epileptiform effects may be primarily mediated by delta opiate receptors in this area although the potency of morphiceptin indicates that mu receptors play some role in this effect.