Recognizing that not all physicians will be intimately familiar with each rare condition, the informed patient may come to view themselves as an “expert consultant on syndrome X.” For their part, the physician faces the challenge of gauging the extent and accuracy of this patient’s medical knowledge and adapting the clinical encounter to the patient’s needs. If the

physician, operating under the Inhibitors,research,lifescience,medical traditional models, refuses to acknowledge the medical information that this patient has acquired, both patient and physician will be frustrated in the encounter. Our model suggests some ways in which the clinical encounter can adapt to this new challenge. The first step is to assess the degree of autonomy, values, and information that that patient possesses. As indicated by the location of point “C” in Figure 3, the example patient has high autonomy, Inhibitors,research,lifescience,medical modest values formation, and moderate medical knowledge. Thus, this patient will benefit from guidance in forming appropriate health-related values, which will be an important part of the clinical encounter. Ponatinib Additionally, the informed layperson will not have the benefit of a comprehensive medical education and will still need general medical care and counseling in the context of a rare condition, for example, the management of high

blood pressure (a common condition) in a patient with Inhibitors,research,lifescience,medical Stiff-person syndrome (a rare condition). The physician can provide guidance about the use of specific websites that convey well-vetted and reliable information. Thus by assessing Inhibitors,research,lifescience,medical the patient for levels of autonomy, values, and medical knowledge, the physician can more accurately calibrate their contributions to the interaction to better meet the needs of the patient. An example of someone entering the medical encounter with an extreme degree of medical knowledge

is the physician-as-patient (D in Figure 3). In the case of a physician seeking medical care, the discussion of medical Inhibitors,research,lifescience,medical information is often brief, revolving around clarifying some points of detail or highlighting the very latest developments within a field. As a rule, the physician-as-patient expects to selleck inhibitor exercise a high degree of autonomy, and this can be quickly confirmed by the treating physician. What may be less certain is the capacity of the physician-as-patient to identify and apply their professionally held health-related Brefeldin_A values to their own medical condition. Sometimes it is especially difficult for a physician to shift into the role of patient. A focused effort on the part of the treating physician to acknowledge this difficulty and explore the extent to which health-related values are being properly applied can reduce feelings of isolation and distress. Minimizing patient distress is always important for genuine patient–physician interaction, because it is often only when a patient feels truly comfortable that the most critical concerns come to the surface.

41 In addition, a recent analysis of 2q23.1 microdeletion syndrome, which also shares similarities to autism, pinpointed MBD5 as the causative locus.42 Further association of MBD5 with autism has been shown via sequencing of autistic individuals with chromosomal abnormalities.43 Interestingly, three recent independent sequencing studies implicated another

gene involved in chromatin remodeling: chromodomain-helicase-DNA-binding protein 8 (CHD8).27,28,43 One study also identified de novo events in CHD3 and CHD7.28 Individuals with mutations in CHD7 develop CHARGE syndrome, 68% of whom exhibit an autistic-like phenotype.44 Inhibitors,research,lifescience,medical Furthermore, the histone methyltransferase EHMT1, which is responsible for another syndromic form of autism called Kleefstra’s syndrome,45 was Inhibitors,research,lifescience,medical identified in two of these studies.28,43 Another recent exome sequencing study of 343 simplex families identified 13 candidate genes involved in either transcription regulation or chromatin remodeling.30 As a whole, these findings suggest

that autism may arise as a result of impaired regulation of the chromatin state. Such selleck chemical dysregulation may result in improper Inhibitors,research,lifescience,medical synaptic wiring of brain circuitry and/or prevent the proper neuronal response from external stimuli necessary for the development of social cognition. Further analyses into the relationship between neuronal activity and chromatin remodeling are necessary to garner clues for how the two may orchestrate Inhibitors,research,lifescience,medical circuit formation. Large recurrent copy number variants (CNVs) have been associated with autism.46 Careful consideration of the molecular effects of such a genetic locus is

warranted. On first consideration, it is likely that the majority of such loci alter the dosage or gene expression level of a number of contiguous genes. Is one gene involved in these loci or is Inhibitors,research,lifescience,medical it a combination of genes? For the majority of CNVs, it seems most likely that the latter model will prevail, that CNVs lead to a complex interaction of the effects of perturbed gene expression from multiple contiguous genes. In some ways, the loss of a gene that modulates gene expression such a chromatin modifying gene may have similar effects, ie perturbation of dosage of a collection of genes. Pre-mRNA splicing Disruption of A2BP1/FOX1, a gene involved in mediating RNA splicing, has been noted in Drug_discovery two autistic individuals.47-48 This is especially intriguing in that another category of genes implicated in autism—cell adhesion molecules (CAMs)—exhibit selleck chemical Tofacitinib numerous alternatively spliced transcripts that appear crucial for cell-cell recognition.49 The aforementioned transcriptome analysis not only revealed A2BP1 to be downregulated in comparison to control tissue but also determined many of the protein’s targets were genes involved in synaptic function.

Complete release of DOX from the vesicles at each time point yields 100% dequenching and was obtained from control ethanol-treated liposome samples. The percentage release of DOX from the vesicles was determined from the fluorescence intensity of each sample relative to 100% dequenching, which can then be expressed in terms of percentage of DOX release. 2.5. Cytotoxicity Assay The cytotoxicity of all liposomal systems used in this study, as well as free DOX, on the cells was determined using the CellTiter-Glo Luminescent Cell Viability Assay. Inhibitors,research,lifescience,medical The M14#5,

M14#11, and BJ cells were plated on 96-well tissue cultured treated plates corning at a density of 5 × 103 cells per well and incubated for 24h at 37°C and 5% CO2. The culture medium was then replaced with 100μL of medium containing various concentrations of each liposomal system or free DOX. The cells were then exposed to Inhibitors,research,lifescience,medical the drug for 3h; the cells were washed twice with sterile PBS following drug exposure. Fresh culture medium was then added, and the incubation was continued for 24h. After the incubation period, 100μL CellTiter Glo reagent was added to each well. The cells were allowed to incubate for an additional 3h at 37°C and 5% CO2. The cytotoxicity assays were done in triplicate and were repeated at least twice in separate selleck chem experiments. 2.6. Tumor Growth In Vivo B16F10 murine Inhibitors,research,lifescience,medical melanoma cells

were prepared at the Washington University [60]. C57BL/6 mice were obtained from the Harlan selleck catalog Laboratories (Indianapolis, IN). Mice were housed under pathogen-free conditions according to the guidelines of the Division of Comparative Medicine, Washington University School of Medicine. The Washington University Animal Studies Committee Inhibitors,research,lifescience,medical approved all experiments. Tumor cells (105 cells/100μL in PBS) were injected subcutaneously in the neck of C57BL/6 anesthetized mice and allowed to grow 7–14d until tumors were ~5 × 5mm. Eight mice per treatment group were inoculated with 105 tumor cells. The number of animals Inhibitors,research,lifescience,medical tested (n) was calculated by power analysis (probability

of type I error α = 0.05; probability of type II error β = 0.20) based on previous data. This was Batimastat the minimum number of animals required to achieve statistical significance. Mice inoculated with tumor cells were divided into a control (saline treated) as well as groups treated with the various DOX-loaded liposomes at doses (5mg/kg with an average mouse weighing ~20g) corresponding to those used previously for DOX-loaded liposomes in melanoma mouse models [22]. Liposomes or saline was injected on days 0, 3, 5, 6, and 8, with day 0 being the first day of the regimen and all animals dosed on the same days. The experiment was terminated at 11d after initiation of treatment regimen. Mice were anesthetized by isoflurane (2% vaporized in O2).

20 A series of studies have reported a better response to clozapine in patients who had the thymine allele of rs6313. The thymine allele of rs6313 has also been associated with a lower risk for the development of extrapyramidal side effects when taking antipsychotic medications.21-23 The serotonin receptor 2C gene (HTR2C) HTR2C is a very large gene that is located on the X chromosome and consists of 326 074 nucleotides. However, it codes for a protein things product that is composed of only 458 amino acids. Variations in the HTR2C gene have been Inhibitors,research,lifescience,medical associated with a better

clinical response to clozapine. Specifically, patients with schizophrenia who have a copy of the cytosine allele of rs6318 have achieved better control of their psychotic symptoms than patients with Inhibitors,research,lifescience,medical the guanine allele.24,25 However, this same variant has been associated with a higher risk for the development of extrapyramidal side effects in patients who are taking typical antipsychotic medications.26 An increased risk for the development

of weight gain has been linked to a different HTR2C variant. Specifically, Inhibitors,research,lifescience,medical the cytosine allele of rs518147 is associated with increased weight gain, while the thymine allele is conceptualized as providing protection against weight gain.27-29 The clinical utility of pharmacogenomic testing in psychiatric practice Assessing the clinical utility of pharmacogenomic testing is an ongoing process, given that the accuracy of genotyping is continually improving, and new research is identifying additional Inhibitors,research,lifescience,medical genetic variants that influence medication responses. Reports of adverse responses to 2D6 substrate medications in patients with decreased 2D6 metabolic capacity support the use of testing at this most basic level. Specifically, poor 2D6 metabolizers have had quite dramatic side effects to 2D6 substrate medications3 and some toxic reactions have been inhibitor U0126 lethal.30,31 However, there have been no large randomized clinical trials to demonstrate the clinical utility of pharmacogenomic

testing. Such trials Inhibitors,research,lifescience,medical would reinforce the use of testing. However, it is unlikely that these trials will ever be conducted because, by definition, they are not designed to concentrate on those patients who are the most likely to benefit from Entinostat pharmacogenomic testing. Trials that screen vulnerable populations and identify patients at risk for suboptimal responses to medications are a more efficient method to address the clinical usefulness of testing patients with decreased metabolic capacity. These screened patients could then be enrolled in protocols designed to provide optimal response for their specific genotypes and predicted pharmacogenomic phenotypes. Ethical considerations for pharmacogenomic testing in psychiatric practice The provision of pharmacogenomic testing involves relatively few risks, but ethical safeguards are still important to consider.

Some people say we should consider such symptoms normal because so many people exposed to this devastating life event experience

them. However, there is another way to look at this. It is normal to break your leg when you fall off a ladder or to develop a bad sore throat and dangerous antibodies when you are exposed to a streptococcus infection. As clinicians, we don’t tell a man with a broken leg not to worry; that his injury is normal. Nor would diagnosis of a strep infection be considered pathologizing a normal reaction. The premise of this paper is that acute grief is a normal reaction to loss that does not require a clinical diagnosis. By contrast, Inhibitors,research,lifescience,medical major depression, post-traumatic stress disorder (PTSD), panic disorder, and CG are mental disorders that should be Inhibitors,research,lifescience,medical diagnosed. Clinicians need to know how to tell the difference. Whichever way we view mood and anxiety in the wake of bereavement, it is clear that the person who died makes a difference to the likelihood

of experiencing these symptoms. The way a person dies can also be difficult for surviving friends and family. Death that is sudden and unexpected, especially if it is violent and untimely, is especially difficult.10 Suicide of a loved one, in Inhibitors,research,lifescience,medical particular, can challenge a bereaved person. 11 Interestingly, though, the framework of grief is remarkably similar across these differences. The more difficult the death, the more potholes in the road, but the direction and destination of mourning is similar. quality control Characteristics of grief

Grief is the usual instinctive psychological response to bereavement. Typical kinds of thoughts, feelings, and behaviors occur, albeit in a pattern and intensity that vary Inhibitors,research,lifescience,medical and evolve over time. Acute grief is a blend of yearning and sadness, with accompanying thoughts, memories, and images of the death and the deceased person, and a tendency to be more interested in this inner world than Inhibitors,research,lifescience,medical in the activities that populate ordinary life. On the other hand, like the love that spawns it, grief’s molecular expression is unique to each relationship. Grief is usually erratic in its manifestations, Carfilzomib intensity, and course. Yet, looked at from a bird’s-eye perspective, most bereaved people make their way along a road, albeit bumpy and strewn with potholes, that leads to acceptance of the inevitability of the loss, integration of its reality into ongoing life, and reimagining a future with the possibility of joy and satisfaction. During this this research journey, acute grief, intensely painful and dominant, becomes integrated, muted, and in the background. CG is the syndrome that occurs when this transformation does not occur. Grief is not a form of depression Some people conflate the terms grief and depression. They are not the same. Both infuse our lives with sadness, and both cause disruption, but the similarity ends there. Depression is a mental disorder. Grief is not.

There has been a decided lack of investigations considering the OCD-related disorders. Expense, difficulty, and time limit the numbers of individuals that can be studied, and thus there are only a very few studies of OCD subgroups, such as one comparing OCD patients with and without hoarding40 and studies comparing the symptom dimensions of OCD.161 A similar situation exists for psychological and physiological

measures or endophenotypes and for animal models, all of which are at the stage of mostly searching for relevant measures for OCD phenotypes.162-164 One rodent model, which documented changes in microneuroanatomical structures in pathways that were associated Inhibitors,research,lifescience,medical with shifts from normal Inhibitors,research,lifescience,medical goal-directed behaviors to more limited, habit -based “compulsive” behaviors following multiple types of chronic stressors would seem of relevance to environmental trauma and stress as discussed above regarding the genesis of an environmental OCD spectrum.128 Conceptually, combinations of stresses (from the environment such as psychological sellckchem traumatic events and from disease-based etiologies such as neurologic disorders or comorbid anxiety, mood, or other neuropsychiatric disorders), plus genetic

vulnerabilities might be envisaged as combining to lead towards temporarily adaptive OCD-related thoughts and behaviors that Inhibitors,research,lifescience,medical limit further nonadaptive disorganization. Their continuation, however, past the times of most marked stress, may become nonadaptive – a sustained reduction in abilities to act towards more adaptive, social, and occupational goal-directed functions. Prior clinical data and Inhibitors,research,lifescience,medical theoretical formulations

have led to some similar suggestions resembling this interpretation and application to OCD of this experimental animal model.128 Inhibitors,research,lifescience,medical selleck compound Conclusions Thus, we are left with a multifaceted array of obsessivecompulsive features that cut across traditional (DSM-IV/TR) as well as draft plans for the DSM-5. Before elaborating what comprises OCSD and OCRD, it seems important to consider “uncomplicated,” OCD, as such individuals may be important to study for many purposes and comparisons.69,70 For example, if our current nosologic distinctions retain some validity, detailed knowledge of uncomplicated OCD may help to clarify which genes are more directly OCD-related when coexisting mood, anxiety, and other groupings of comorbid disorders and their underlying Drug_discovery genes are also present. However, even uncomplicated OCD demonstrates symptom heterogeneity, leading to continuing efforts such as using latent class modeling to go beyond factor and cluster analyses in order to parse the condition into more valid groups. Considering underlying features, stressors and the other environmental contribution to symptoms may be additional factors to consider in these investigations.

The first most prominent products are Doxil (Sequus) and DaunoXome (Gilead, Nexstar). Both are indicated as anticancer drugs, which were successfully tested in clinical studies, followed by the US Food and Drug Administration (FDA) approval in the 1990s. In general, liposomes are defined as spherical vesicles with particle sizes ranging from 30nm to several micrometers. They consist of one or more lipid bilayers surrounding aqueous compartments, where the polar head groups are oriented towards the interior and exterior

aqueous phases. However, self-aggregation of polar lipids is not restricted to conventional bilayer structures which depend on temperature, Inhibitors,research,lifescience,medical molecular shape, and environmental and preparation conditions but may self-assemble into various kinds of colloidal particles [5, 6]. Due to this fact, the liposome

family includes various kinds of colloidal particles and structures Inhibitors,research,lifescience,medical which hamper systematic classification. However, they can be classified by structure, composition, and preparation, as shown in Table 1. Table 1 Classification of commonly known lipid vesicles according to their structures and/or preparation. Technology and application are driven by two major Inhibitors,research,lifescience,medical facts. First, the transfer from academic bench to a highly regulated, high technology industry was difficult for liposome technology because of the lack of appropriate methods Inhibitors,research,lifescience,medical to produce large quantities in a controlled and reproducible manner. Although several methods are suitable for large-scale production, their development, implementation, and sellekchem Quality control needed a certain time. Second, early clinical trials were not as successful as expected because the stability of conventional Inhibitors,research,lifescience,medical liposomes was low, caused by inefficient preparation, physical properties, and unfavorable choice of lipids.

Furthermore, they were to a great extent cleared by liver and spleen very rapidly so that neither a prolonged biological half-life nor specific targeting was achieved. More stable conventional liposomes and second-generation formulations, such as the stealth technology, gave new impulses to the industry as well as to kinase inhibitor Belinostat clinicians with the development of industrial processes in the AV-951 1990s. 1.2. Liposome Technology and Regulatory Requirements In the last decade, the European Agency of the Evaluation of Medical Products (EMA) as well as the FDA has implemented the subject of liposome into their guidelines. Currently, EMA has not yet published any summarizing document or guideline which is dealing exclusively with nanoparticular structures. However, general aspects of liposomes are covered in several guidelines such as “Note of Guidance on the Quality, Preclinical and Clinical Aspects of gene transfer medicinal,” and “Guideline on adjuvant in vaccines for human use”.

2A). At both sides of A3, the primary neurite gave off a large anterior and a smaller posterior dendrite. The ipsilateral and contralateral dendrites branched out bilateral symmetrically in the very dorsal neuropile of A3. In each neuromere

of the three thoracic ganglia, one prominent anterior branch and one or two posterior branches arose from the main axon and projected dorsally toward the midline of the respective ganglion. A3-AO occurred as a bilateral pair of sibling neurons, and in all three neurobiotin-labeled specimen, the Inhibitors,research,lifescience,medical mirror-image sibling neuron was clearly stained as well (Fig. 3). Such dye coupling may indicate electrical coupling between the left and right A3-AO interneuron via gap junctions (cf. Ewadinger et al. 1994; Fan et al. 2005; Anava et al. 2009). Figure 2 Structure and Diabete activity of the

abdominal ascending opener-interneuron A3-AO. (A) Morphology of A3-AO with cell body and dendrites in A3 and axonal projections in thoracic ganglia (ventral view). (B–D) Inhibitors,research,lifescience,medical Singing motor pattern (top trace) and activity … Figure 3 Dye coupling of the two A3-AO sibling neurons with neurobiotin. Extended focus views (maximum intensity projections of confocal image stacks) showing the fluorescence-labeled (neurobiotin-avidinCy3) arborizations of the two bilateral symmetrical A3-AO … During fictive singing, the membrane potential of A3-AO, as recorded in its main dendrite, oscillated with the syllable pattern (Fig. 2B). Inhibitors,research,lifescience,medical In the opener phase of each syllable, it depolarized by 20–25 mV, and in the closer phase, it hyperpolarized 5–10 mV beneath resting potential. The depolarization preceding the first syllable of a chirp was up to 3.5 mV higher than the following. Every depolarization gave rise to a volley Inhibitors,research,lifescience,medical of 4–6 action potentials with a spike frequency of up to 380 Hz during the first syllable and 360 Hz during the following syllables of a chirp. The spike activity Inhibitors,research,lifescience,medical in A3-AO preceded the next opener burst in the wing nerve by 10.1 ± 0.8 msec (mean ± SD; N = 10) and the following closer burst by 29.2 ± 2.2 msec (mean ± SD; N = 10). Therefore, we refer to A3-AO as an opener interneuron. Interestingly, we never observed any

synaptic inputs or spike activity in the A3-AO dendrite before and after singing episodes or during chirp seriously intervals. When a constant depolarizing current of 5 nA was injected into the dendrite of A3-AO, the interneuron responded with consistently repeated depolarization–hyperpolarization oscillations of its membrane potential generating a burst Brefeldin_A of 2–6 action potentials during each depolarization. This rhythmic interneuron activity reliably elicited alternating opener–closer motoneuron activity reflecting the normal syllable pattern in the ipsi- and contralateral wing nerves. Activation of a single A3-AO interneuron is therefore sufficient to continuously drive the motor pattern of the syllable rhythm. Current pulses of 500 msec elicited long chirps with 14–15 syllables (Fig.

The study has advanced knowledge of this population by taking a person-centred, multi-perspective approach to explore the domains of wellbeing stipulated in policy guidance, while going beyond prior single-domain studies to describe the interrelatedness of these domains. Findings highlight the stark reality of living with HIV, confirming that patients experience psychosocial and spiritual suffering, as well as physical pain and other symptoms. The use of multiple perspectives enabled triangulation of findings, contributing to validity. Patients’ everyday lives were characterised Inhibitors,research,lifescience,medical by poverty and stigma: they

were preoccupied with worries about basic needs such as food, employment and transport Inhibitors,research,lifescience,medical to collect medication, and described feelings of isolation and experiences of discrimination which added to the burden of living with HIV. The existential impact of HIV, including hopelessness, fears of the future and feelings

of despair and doubt, was intimately related to psychosocial and physical suffering. The findings elucidate the detrimental effect of stigma on patients and their families. Stigma against those with HIV is highly prevalent in sub-Saharan Africa [34,35]. In collectivist societies in which social relationships are highly important [36], the experience of stigma and Inhibitors,research,lifescience,medical social isolation may be particularly detrimental. Stigma contributes to non-adherence to ART [37,38] and is associated with rejection [39], breakdown of social support [39,40], difficulty finding work [41] and poor mental health [19]. Pain management at the facilities was limited by problems with opioid availability. As in Dekker et al’s study of Inhibitors,research,lifescience,medical a public hospital and its clinics in the Eastern Cape, South Africa, strong pain medicines were often in short supply

or unavailable [42]. Dekker et al. found that health care providers’ misperception of palliative care as end of life care (and hence inappropriate to patients with HIV) constituted a barrier to adequate pain selleckchem Ruxolitinib control in HIV patients. Findings from our study provide further support for the need for staff training in the palliative care approach, Inhibitors,research,lifescience,medical including psychosocial and spiritual support as well as improved pain control. Counselling and limited spiritual support were described, but unmet psychosocial and spiritual needs appeared to contribute to and exacerbate patients’ experience of pain. The findings from this study thus support the notion that pain is a complex phenomenon which can have nonphysical Dacomitinib as well as physiological dimensions and causes, as captured in the concept of ‘total pain’ [42]. The total pain model recognises that pain is multifaceted and that psychological, social and spiritual problems can contribute to the inhibitor manufacture overall phenomenology of pain [42]. While previous research into the experience of total pain has focussed on developed country settings [43-45], this study demonstrates the total pain experienced by HIV patients in sub-Saharan Africa.

3 days (95% CI: 6.2, 6.4). Among all types of strokes, the overall hospital selleck chem mortality was 20.5%. Multiple logistic regression revealed significantly higher in-hospital mortality in women and children (P<0.001) but not in patients with low socioeconomic status or from rural areas. During the study period, the mortality proportions increased from 17.8% to Inhibitors,research,lifescience,medical 22.2%. Conclusion: In comparison to western countries, a larger proportion of

our patients were young adults and the mortality rate was higher. Key Words: Stroke, Cerebrovascular disease, Cerebrovascular accident, Mortality, Sex Introduction There has been a significant decrease in stroke mortality rates in developed countries, but this success story has not been mirrored in developing countries.1 Of 5.7 Inhibitors,research,lifescience,medical million stroke patients who died in 2005, 87% were from low and middle-income countries, where stroke is considered a major disabling health problem.2,3 Iran is a middle-income country according to the World Bank classification.4 Recent reports have shown that the prevalence of stroke in Iran is significantly higher than that in western countries; this is especially true for stroke in the young population.5,6 These

reports have emerged from northern and central provinces of Iran. In southern Iran, however, information on stroke epidemiology is limited. Fars Province is located in southwestern Iran, and Shiraz is its provincial capital. Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical According to a census in 2006, Fars Province had a population of 4.3 million, 60% of them residing in urban areas.7 Nemazee Hospital is a tertiary center in

Shiraz and admits patients from the entire Fars Province. Ethnic history of Iran abounds with successive waves of occupation and migration, with the largest ethnic group being the Persians. Mitochondrial DNA linage analysis has determined the main lineage to be western Eurasian.8 In Iran, life expectancy is about 72 years for women and 69 years for men, which suggests an ageing population perhaps similar to those in developed countries.9 Regarding health plans in Iran, about 90% of the PF-2341066 Iranians are covered by at least one health insurance carrier. Several Inhibitors,research,lifescience,medical types of health organizations are available to provide health coverage and these include social security, medical services, armed forces, private insurances, and charities. The first three organizations cover mainly urban public and private sector employees, as well as members of the armed Dacomitinib forces. In 2000, a rural health insurance system was implemented to provide health coverage to rural inhabitants. The main charity provider is “Imam Khomeini Charity Foundation”, which covers individuals with low or no income that is reflective of a low socioeconomic status.10 Similar to other regions of Iran, the population of Fars Province is covered by the same health insurance carriers, with those in the low socioeconomic status accounting for approximately 7%. This study was performed to provide basic epidemiological data on stroke.