Over 90% of patients who undergo modified radical mastectomy for their locally advanced disease requiring adjuvant chest wall radiotherapy develop radiation dermatitis. Breast cancer patients receiving chest wall radiotherapy develop acute skin toxicity (radiation dermatitis) during the course of radiotherapy or a short period after

the completion of radiotherapy.1,2 Chest Inhibitors,research,lifescience,medical wall radiation dermatitis can decrease tolerance for continuing radiotherapy, negatively influence quality of life, postpone treatment, and cause treatment failure.1 For the all the research hitherto conducted on the management of radiation-induced dermatitis, a consensus has yet to emerge as to what constitutes the optimal care.2 Topical corticosteroids Inhibitors,research,lifescience,medical comprise one group of the suggested agents for the treatment of radiation-induced dermatitis. Corticosteroids have anti-inflammatory effects, which may play a crucial role in alleviating patients’ complaints. Recent evidence Inhibitors,research,lifescience,medical shows the efficacy of topical corticosteroids in this category.2,3 In addition, other local high throughput screening compounds treatments such as Dexpanthenol, Calendula, and honey ointment have been recommended for treating dermatitis.4,5 Another drug which has newly been introduced for the management of burning and infectious wounds is natural Henna (Lawsonia inermis linn),6 with some investigators providing evidence

for its antimicrobial and antioxidant properties in wound healing as well.7-10 The data regarding the efficacy of Henna compounds in the management of burn and infected wounds are, however,

insufficient, and there are no optimal recommendations for skin care in breast cancer patients suffering Inhibitors,research,lifescience,medical radiation dermatitis. This Inhibitors,research,lifescience,medical study aimed to compare topical Alpha ointment and topical hydrocortisone cream (1%) in terms of their efficacy in the healing of radiation-induced dermatitis in breast cancer patients undergoing post-mastectomy chest wall radiotherapy. Patients and Methods This study is an open, randomized, controlled, phase II clinical trial. Eligible patients had newly pathologically proven, locally advanced breast cancer (treated with modified PAK6 radical mastectomy, followed by sequential adjuvant chemotherapy and chest wall radiotherapy [45-50.4 Gy]) and grade 2 and/or 3 radiation-induced dermatitis. Exclusion criteria consisted of any history of collagen vascular diseases, diabetes mellitus, taking any drugs interfering with the wound healing process like systemic steroids, previous history of chest wall radiotherapy, and concurrent use of chemotherapy. All the patients had to sign the consent form before participating in the study. This clinical trial was approved by the local Research Ethics Committee of Shiraz University of Medical Sciences.

1999; Bob et al. 2010), increased TNF-α, IFN-γ, IL-1β, and decreased production of interleukin-8 (IL-8) and interleukin-2 (IL-2). More recently, increases in a number of proinflammatory cytokines and chemokines (IL-6, IL-1α, IL-1β, IL-8, monocyte chemotactic protein-1 [MCP-1], macrophage

inflammatory protein-1 α [MIP-1α], Inhibitors,research,lifescience,medical eotaxin, granulocyte macrophage CSF [GM-CSF], interferon-alpha [IFN-α]) were observed in patients with PD and PTSD (Hoge et al. 2009). A number of factors may help explain the above heterogeneous results, including differences between anxiety disorder subtypes, study design, and confounding factors. Despite these heterogeneous results, other insights suggest increased inflammation contributes to anxiety pathogenesis. For instance, Inhibitors,research,lifescience,medical cytokine-based selleck immunotherapy can lead to increased anxiety symptoms (Maes et al. 2001). Furthermore, depressive and anxiety symptoms induced by administration of cytokines are responsive to selective SSRIs (Gupta et al. 2006; de Knegt et al. 2011). We are not aware of any studies that have assessed the impact of cigarette smoking on inflammatory mediator expression in anxiety disorders. However, there is evidence that smoking and depression act synergistically to increase inflammation (Nunes et al. 2012). Inhibitors,research,lifescience,medical Further, in a study assessing cytokine

levels in the gingival crevicular fluid in patients with periodontal disease, levels of inflammatory cytokines IL-6 and IL-8 were both positively correlated with increasing psychological stress, as measured by the Modified and Perceived Stress Scale (Linn 1986), and cigarette smoking

Inhibitors,research,lifescience,medical (Giannopoulou et al. 2003). Oxidative and nitrosative stress Free radicals are by-products of oxidative Inhibitors,research,lifescience,medical phosphorylation that, at low or moderate concentrations, participate in normal cellular processes such as signaling pathways, mitosis, apoptosis, and responses to injury or infection (Valko et al. 2007). However, damage can occur to cellular components, including proteins, nucleic acid, carbohydrates, and lipids when levels of oxidative free however radicals increase beyond the antioxidant capacity of cells. Increases in free radical concentrations can occur through both increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and/or decreased expression of antioxidants (Hovatta et al. 2010). Damage to these cellular components can alter the structure and function of membrane fatty acids and proteins, and alter or damage DNA and mitochondrial function leading to cell death (Maes et al. 2011b). Increased plasma markers of O&NS have been repeatedly demonstrated in anxiety-disordered populations and animal models of anxiety (for review see Hovatta et al. 2010). In addition, increased hippocampal oxidative stress is anxiogenic (de Oliveira et al. 2007).

Only 1 out of the 758 recipients called to protest about the procedure, and asked to be sent no further questionnaires. However, a year later, this person relented and has since been participating in the study, as well as this person’s family. Many others called to point out that the questionnaire did not include the question that was most important to them, ie, the question of salvaging the ship. It was explained to the relatives that this question should not be asked Inhibitors,research,lifescience,medical by Ersta, as we are a hospital concerned with their health and well-being, and that the government had already made

the decision on December 15, 1994, not to salvage the Estonia. We contacted the Department of Communications, and

tried to explain how important it was to the relatives that they be asked their opinion, Inhibitors,research,lifescience,medical in spite of the fact that the decision had already been made. However, it was clear that the government was not about to consult the relatives regarding the salvaging issue. In the end, it was decided to let the relatives themselves formulate the questions Inhibitors,research,lifescience,medical that they thought were important. So when the second questionnaire was completed, the matter of salvaging was included. In the third questionnaire, the matter of ccwering the Estonia with concrete appeared for the first time. To date, seven questionnaires have been distributed and at least two more are planned. Conclusion We would like to conclude this paper with a poem that a relative, a young man, sent in connection with the questionnaire. We want to show that the

questionnaire study is not just Inhibitors,research,lifescience,medical important in terms of figures and charts, but that it also provided an opportunity for relatives and survivors to give vent to deep-felt emotions. I miss my mother. I wish Inhibitors,research,lifescience,medical she were alive again, If only for a, day. One hour, a few minutes, If only for a day. To say good-bye. To thank her for everything she has given me. She gave me life. Now she has given me her last gifts, Death and great sorrow. Now I have received life in its entirety Notes This study was supported by grants from Stockholm County Council, Folksams, AMF, other companies, private individuals, and from the Swedish government. We thank Sara Gôransson and Sam Sundquist for their skillful crotamiton assistance.
Pomalidomide chemical structure Nosological classification in psychiatry, as it is currently applied, does not facilitate biological and psychopharmacological research. • Syndromal acuity has disappeared. Consequently, it is impossible to determine: (i) vi/hether a particular drug affects a particular symptom configuration; (ii) what exactly the behavioral correlate of a particular biological disturbance is. The problem of unfocused diagnoses is greatly magnified by the phenomenon called comorbidity. • The boundary between distress and disorder is illdefined.

All meta-analyses – JNK inhibitor in vitro analyzing similar data sets – found that amisulpride, clozapine, olanzapine, and risperidone were significantly more efficacious than FGAs. When Leucht and colleagues14 reviewed the head-tohead comparisons of SGAs they reported a similar pattern. Regarding total PANSS score change, olanzapine was

more efficacious than aripiprazole, quetiapine, risperidone, and ziprasidone; risperidone Inhibitors,research,lifescience,medical was more efficacious than quetiapine and ziprasidone, and amisulpride was not statistically different from olanzapine or risperidone. However, regarding dropouts due to inefficacy, olanzapine was only superior to quetiapine and ziprasidone, two Inhibitors,research,lifescience,medical SGAs often dosed inappropriately low in schizophrenia, and amisulpride was more efficacious than ziprasidone. Surprisingly, clozapine only proved to be superior to zotepine and to

risperidone in dropouts due to inefficacy. As the authors suggest, possibly inadequate doses of clozapine used in some studies might have contributed to these findings, which are inconsistent with most of the large individual studies. In comparing Inhibitors,research,lifescience,medical these analyses to the results of CATIE and CUtLASS, there are some consistencies. In CATIE,17 olanzapine was superior in dropout rates due to inefficacy and time on effective treatment (at least when including the 23% of patients who were rerandomized to olanzapine), and clozapine (though given openly) was superior to all other studied SGAs in phase 2.28 In CUtLASS,24

clozapine was superior to other SGAs as well, but in this study, quality of life, and not all-cause discontinuation, was the primary Inhibitors,research,lifescience,medical outcome measure. This difference highlights the importance of the choice of the primary outcome measure, particularly in effectiveness studies, where the outcome is supposed to address elements of efficacy, tolerability, patient acceptability, and functioning. Although the meta-analyses Inhibitors,research,lifescience,medical tended to find more support for risperidone’s superiority than CATIE did, the dose equivalences used in CATIE have been challenged where the modal dose of risperidone was only 3.9 mg/day. However, there were no differences between the individually studied SGAs and the FGA comparator perphenazine in CATIE,17 Tryptophan synthase as well as between the class of clinician’s choice SGAs and FGAs (mainly consisting of sulpiride, which some consider to be an SGA) in CUtLASS.23 The large effectiveness trials have been discussed in great detail elsewhere. Despite the rigorousness with which we try to design trials, there are always compromises in both design and execution that are unavoidable, particularly when multiple outcome measures are included and multiple questions are addressed simultaneously. A particularly important issue which impacts all of the effectiveness trials was stressed by Kraemer et al.

Although no valid data exist regarding the frequency of substance abuse, there is no doubt that many persons suffering from TS show a comorbid substance abuse. Alcohol and sedative drugs such as benzodiazepines have a short-term effect on tics and other symptoms of TS, leading to a high prevalence of alcohol abuse, which is estimated at about 30% in our own sample(Muller, unpublished observation). Due to the early onset of tics, many children affected with

tics are socially withdrawn; they become outsiders in their families and peer groups. This might promote the ZD1839 cost development of personality disorders, which have been described in 60% of TS patients.27 A comorbid depressive Inhibitors,research,lifescience,medical syndrome is found in about Inhibitors,research,lifescience,medical a quarter of affected persons.11 Markedly higher is the rate of comorbidity with ADHD, observed in 55% of the TS patients.28 The comorbidity

with OCD appears to be even higher, having been described in 40% to 90% of the patients.5,29 However, due to the broad overlap of tics, in particular complex tics and OC symptoms, there is some discussion as to whether “specific” compulsions such as symmetry behavior, echophenomena, or touching should be classified as tics or as OC behavior.3,9 Neurobiological characteristics of TS Although TS is a disorder of primarily Inhibitors,research,lifescience,medical the dopaminergic system of the basal ganglia, there is no doubt that cortical structures Inhibitors,research,lifescience,medical are also involved. The hypothesis of Kurlan,30 in particular, focuses on disinhibition within the cortical-striatal-thalamic motor loop, including the limbic system. Similar conclusions were drawn by studies using transcranial magnetic stimulation, which show reduced intracortical inhibition in TS patients.31 We found that disturbed saccadic

eye movements are in Inhibitors,research,lifescience,medical keeping with the hypothesis of a disturbed activation of the frontal cortex by ascending loops from the basal ganglia.32 Moreover, the disturbed inhibition of unwanted orientation reactions revealed by antisaccades, as well as the known attention problems, favor a functional impairment of the frontal cortex in TS. Brain isothipendyl morphology of TS A neuroimaging study in adult TS patients without longterm antipsychotic treatment revealed smaller mean volumes of the caudate, lenticular, and globus pallidus nuclei compared with controls, on both the right and left. Further analyses of basal ganglia asymmetry indices suggest that TS basal ganglia do not have the volumetric asymmetry (left greater than right) seen in normal controls.33 Similar findings were reported by other researchers studying a group of TS children: statistical comparisons between TS patients, with (n=18) or without (n=19) ADHD, and controls showed significant differences in the volume of the left globus pallidus and in lenticular asymmetry.34 Interestingly, caudate volumes in children with TS predict the severity of tic and OC symptoms in early adulthood.

2 A contracted midpelvis is a common cause for the occipito-posterior position or transverse arrest of the fetal head transverse arrest. In most cases these conditions lead to dystocia.1 Before full dilation in prolonged deliveries, a part of fetal head skin located on drug discovery cervix becomes swollen. The incidence

of swelling when the fetal head is located in the lower part of the canal is higher because the outlet provides a source of resistance to the fetal head which most likely occurs in the posterior occipital position and with cephalopelvic Inhibitors,research,lifescience,medical disproportion.1,21 According to the results of the current study, women who have experienced 6.8 times more dystocia had fetuses whose heads were swollen. In the present study women with transverse diagonal of the Michaelis sacral that was ≤9.6 cm experienced 6.1 times more dystocia. The Michaelis sacral is a rhombic space in the sacral bone. The upper angle is located between L5-S1 and the lower angle is consistent with the tip of the coccyx, the lateral Inhibitors,research,lifescience,medical angles are at the level of the superior Inhibitors,research,lifescience,medical posterior spins.22

Initially, Michael proposed the importance of this space for evaluation of pelvic capacity in 1851.8,23 The transverse diameter of this rhombus could be observed between cavities of superior posterior spines on the skin.23 According to a number of studies, an abnormal shape and size of the Michaelis sacral rhomboid area indicates an abnormal shape and size of the mother’s pelvis. The results of the present study have supported these findings. We observed that women with height to fundal height ratings of ≤4.7 experienced 2.6 times more dystocia. Logistic regression

analyses showed that maternal height and neonatal birth Inhibitors,research,lifescience,medical weight were not significant risk factors for dystocia Inhibitors,research,lifescience,medical by themselves. It could be concluded that a normal delivery could be possible despite the shortness of height or macrosomia. If height was in proportion to fetal size, the mother could experience normal delivery; a disproportionate fetal size to the mother’s height was more important in dystocia. Barnhard et al. observed a significantly lower mean height to fundal height ratio in the dystocia group compared to the normal delivery group (P=0.002),14 which was consistent with the result of the others present study. In the present study despite a lower mean for mother’s head circumference and higher rate of head circumference to height in the dystocia group according to logistic regression, these findings were not effective on dystocia. The higher ratio of head circumference to height in the dystocia group could be related to the shorter stature of women in this group. The only study in this field was conducted by Connolly et al. who noted opposite findings. These researchers reported higher mean head circumference in the dystocia group. They concluded that larger head circumference was a risk factor for dystocia.

Study protocol All patients underwent cardiac biomarkers (creatine kinase-MB, troponin I) determinations and 12-lead ECG examinations at initial presentation to the emergency department and then followed-up at 6 and 24 hours LDN-193189 in vivo afterward. The serum level of troponin I was measured by the chemiluminescent assay (CLIA assay), and a value of troponin I >1.5 ng/mL was considered abnormal. The presence of significant ECG change was defined as an ST-segment depression >0.05 mV. After the initial clinical evaluation, MCE was performed and 740 MBq of technetium-99m sestamibi was administered intravenously in the emergency room within 6 hours of

presentation. As described previously,11) single-photon emission computed Inhibitors,research,lifescience,medical tomographic (SPECT) MPI acquisition occurred within 6 hours of tracer injection. The MCE and MPI results were not reported to the attending physicians, who made disposition decisions based on routine Inhibitors,research,lifescience,medical assessment. A diagnosis of acute myocardial infarction (AMI) was confirmed by the presence of more than two of the following criteria: chest

pain consistent with myocardial ischemia, Inhibitors,research,lifescience,medical development of Q wave and an increase of serum cardiac biomarkers (creatine kinase-MB >10 IU/L, 2 times the upper limit of the normal value).12),13) The definition of acute coronary syndrome was based on the development of AMI or documentation of significant coronary artery stenosis that required urgent revascularization Myocardial contrast echocardiography To evaluate Inhibitors,research,lifescience,medical regional wall motion abnormalities and myocardial perfusion, intravenous MCE was performed in apical 4-, 3-, and 2-chamber views with triggered replenishment imaging using Sonos 5500 instrument (Philips Medical Imaging, Andover, Massachusetts, USA). Intermittent harmonic power Doppler imaging was performed with a broadband harmonic transducer that transmitted and received at mean frequencies

of 1.8 and 3.6 MHz, respectively. Emission power was set at the highest level (mechanical index 1.3 to 1.6). Images were obtained by triggering at end-systole. In an attempt to differentiate true perfusion from motion artifact, a dual-frame imaging technique was Inhibitors,research,lifescience,medical used. The 2 frames were displayed side by side. One represented the perfusion frame and the other represented the post-destruction frame which was obtained approximately PD184352 (CI-1040) 50 milliseconds later. In the cases of tissue motion artifact, the post-destruction frame showed nearly the same signal intensity as the actual perfusion frame and the motion artifact could easily be recognized. The contrast agent, perfluorocarbon-exposed sonicated dextrose albumin (PESDA),14) was intravenously administered as a continuous infusion of 0.05 mL/kg in 30 mL of normal saline at a rate of 0.8 to 3 mL/min. The Doppler gain setting and infusion rate of a contrast agent were adjusted to maximize the left ventricular cavity signal without causing attenuation artifacts in the destruction-phase image.

It is generally acknowledged that most Holocaust survivors have succeeded in mobilizing effective skills for coping, manifesting themselves by recreating families and adapting to social roles. However, the click here impact of the Holocaust on ego functions led to the activation of defense mechanisms, mostly of splitting and ensuing encapsulation, numbing, Inhibitors,research,lifescience,medical and avoidance. As in psychosis, the coexistence of psychosis in our patients led to processes of fragmentation of the ego, thus impairing the exercise of these ego functions. Again, this may have been a decisive factor in the occurrence of active PTSD symptomatology. Furthermore,

the primary process (psychosis) may have uncovered the core memories Inhibitors,research,lifescience,medical of the traumatic experience and prevented the possibility of masking. One of our patients only described a cannibalistic experience during extreme starvation in the Theresienstadt concentration camp when in the manic-psychotic phase of his bipolar disorder. While euthymic or depressed, he was unable to recall or recollect this experience. Our sample demonstrates a relative Inhibitors,research,lifescience,medical preponderance of intrusive symptomatology versus avoidant features. This finding may also be related to the disorganizing effect of psychosis on the ego.34 Conclusion

Our findings show that the comorbidity of psychosis and PTSD in Holocaust survivors leads to a lifelong debilitating illness. Nonpsychotic survivors usually succeeded in achieving a sense of integrity through “historicizing” their memories35 (establishing a continuity between early, positive pre-Holocaust memories, through traumatic memories during the Holocaust and memories of reestablishing the fabric of life in the post-Holocaust period). In contrast, the psychotic Inhibitors,research,lifescience,medical survivors were unable to reach this equilibrium and, for them, memory is a lifelong burden. Selected abbreviations and acronyms Inhibitors,research,lifescience,medical IES Impact of Event Scale PTSD posttraumatic stress disorder R-PTSD Revised Posttraumatic Stress Disorder (inventory) SCID Schizophrenia Clinical Montelukast Sodium Interview for Diagnosis WWII World War II
Posttraumatic stress

disorder (PTSD) is a maladaptive response to a traumatic event, which is currently underdiagnosed and undertreatcd. It is probable that several myths that surround PTSD, for example, that it is almost solely related to combat situations and that it is a “normal” response to a traumatic situation, have contributed to poor recognition of this disorder. The misconception regarding combat and PTSD is reflected in the history of the names given to the disorder – “shell shock,” “soldier’s heart,” “combat neurosis,” and “operational fatigue.” However, in the late 1980s, it was realized that PTSD is related to all types of traumatic events, including rape, physical attack, severe automobile accidents, and natural or humanmade disasters.

These articles describe 30 apparently-unique cases of severe envenomation. From this group, five cases did not contain sufficient data about the clinical course after FabAV administration to judge whether the manifestations of severe envenomation responded to therapy, and one case was determined to be included in two different series; these cases were therefore excluded[10,20-24]. The remaining 24 cases from 19 published reports are presented in Table ​Table33[4,10,13,20,22,25-38]. Figure 1 Article identification and selection process. This information is also presented as an attached file. Table 3 Published

cases of Inhibitors,research,lifescience,medical severe envenomation treated with FabAV Five cohort studies and Inhibitors,research,lifescience,medical fourteen non-cohort studies were identified. Two of the cohort studies collected data prospectively, two collected

data retrospectively, and one used both prospective and retrospective data collection. All of the non-cohort studies were of retrospective design. Seven severely envenomated patients were MG-132 supplier reported in the cohort studies, and 17 severely envenomated patients were described in the non-cohort studies. Initial response to FabAV therapy Sixty-five specific severe venom effects were reported in these 24 patients. The initial response to FabAV treatment for these specific severe venom effects was: improved/resolved, 50 Inhibitors,research,lifescience,medical effects (77%); no improvement, 11 effects (17%); not reported, 4 effects (6%). All of the 22 specific venom effects (100%) experienced by the seven patients in the cohort studies improved after FabAV administration. In contrast, of the 43 specific venom effects experienced by the patients in the non-cohort studies, 28 effects improved or resolved (65%), 11 effects did not improve (26%), and the response of 4 effects were not reported (9%). Initial control of the envenomation Inhibitors,research,lifescience,medical syndrome Inhibitors,research,lifescience,medical was achieved in 12 patients (50%), not achieved in 9 patients (38%), and not fully reported in 3 patients (13%). All seven (100%) of the severely envenomated patients in the

cohort studies achieved initial control. Once again, the response to initial therapy was not as good in the patients reported in non-cohort studies. Among these 17 patients, initial control of the envenomation syndrome was achieved in 5 patients (29%), not achieved in 9 patients (53%), and incompletely documented in 3 patients (18%). The median dose of FabAV used to achieve initial control Dipeptidyl peptidase of the envenomation syndrome in these 12 patients was 6 vials (range: 4 – 18 vials). Persistent severe venom effects One or more persistent severe venom effects were reported in 0/7 patients reported in cohort studies (0%), and in 9/17 patients in non-cohort reports (53%). These cases are summarized in Table ​Table44[27-30,34,36,38]. These effects consisted of limb swelling, limb pain, soft tissue bleeding, thrombocytopenia, neurotoxicity, or compartment syndrome. Response to therapy was not reported for four patients, summarized in Table ​Table55[26,27,32,35].

That is, it is a quantification of the rule that determines how a choice is made. When response bias shifted to a relatively more liberal bias, that is, the decision criterion changed, increased activation was observed in the left IFG. This seems to be in line with the aforementioned findings from Crone and colleagues (Crone et al. 2006) who observed an increase in activity in this selleck region when the rule used to make a choice needed to be changed. Previous studies investigating the

neural correlates of perceptual decision-making have implicated the left SFS in the computation Inhibitors,research,lifescience,medical of perceptual decisions (Heekeren et al. 2004, 2006; Pleger Inhibitors,research,lifescience,medical et al. 2006; Philiastides et al. 2011). For example, Heekeren and colleagues (Heekeren et al. 2006) found that activation in

the left superior frontal sulcus reflected the comparison of accumulated evidence needed for the discrimination of perceptual stimuli. When activity in this region was disrupted, the rate of sensory Inhibitors,research,lifescience,medical evidence accumulation decreased and decisions became less accurate (Philiastides et al. 2011). While the left SFS may be involved in comparing sensory evidence, we (Reckless et al. 2013) previously found that a more ventral region of the frontal cortex, the left IFG may be involved in adjusting the decision criterion between different decision environments. Inhibitors,research,lifescience,medical However, the block design of that study limited how this

relationship could be interpreted. The present findings suggest that the left IFG is indeed involved in adapting the decision criterion. This is in keeping with findings from Rahnev and colleagues (Rahnev et al. 2011) who found that individuals who adjusted their response bias more based on information from predictive cues had greater activation in the left IFG. However, Inhibitors,research,lifescience,medical one problem that arises when considering results across perceptual decision-making studies is whether the perceptual decision-making task was one of detection or one of discrimination and what decision-making model was used to evaluate the behavioral Mephenoxalone and imaging findings. This study used a detection task and signal detection theory (SDT). Rahnev and colleagues (Rahnev et al. 2011), who found a similar relationship between response bias and activation in the left IFG, used a discrimination task and SDT. The finding that there is a relationship between response bias and the left IFG in both a discrimination and a detection task suggests that the relationship is independent of the type of perceptual decision-making task performed. A limitation of this study was that it used one theory of decision-making to investigate the neural correlates of the decision criterion.