Major depression and bipolar disorder are heterogeneous conditions in which there can be dysregulation of (1) the stress system response, (2) its capacity for counterregulation after danger has ...passed and (3) the phase in which damaging molecules generated by the stress response are effectively neutralized. The response to stress and depressed mood share common circuitries and mediators, and each sets into motion not only similar affective and cognitive changes, but also similar systemic manifestations. We focus here on two highly interrelated processes, parainflammation and endoplasmic reticulum (ER) stress, each of which can potentially interfere with all phases of a normal stress response in affective illness, including adaptive neuroplastic changes and the ability to generate neural stem cells. Parainflammation is an adaptive response of the innate immune system that occurs in the context of stressors to which we were not exposed during our early evolution, including overfeeding, underactivity, aging, artificial lighting and novel foodstuffs and drugs. We postulate that humans were not exposed through evolution to the current level of acute or chronic social stressors, and hence, that major depressive illness is associated with a parainflammatory state. ER stress refers to a complex program set into motion when the ER is challenged by the production or persistence of more proteins than it can effectively fold. If the ER response is overwhelmed, substantial amounts of calcium are released into the cytoplasm, leading to apoptosis. Parainflammation and ER stress generally occur simultaneously. We discuss three highly interrelated mediators that can effectively decrease parainflammation and ER stress, namely the central insulin, klotho and peroxisome proliferator-activated receptor-γ (PPAR-γ) systems and propose that these systems may represent conceptually novel therapeutic targets for the amelioration of the affective, cognitive and systemic manifestations of major depressive disorder.
Klotho is a hormone secreted into human cerebrospinal fluid (CSF), plasma and urine that promotes longevity and influences the onset of several premature senescent phenotypes in mice and humans, ...including atherosclerosis, cardiovascular disease, stroke and osteoporosis. Preliminary studies also suggest that Klotho possesses tumor suppressor properties. Klotho's roles in these phenomena were first suggested by studies demonstrating that a defect in the Klotho gene in mice results in a significant decrease in lifespan. The Klotho-deficient mouse dies prematurely at 8-9 weeks of age. At 4-5 weeks of age, a syndrome resembling human ageing emerges consisting of atherosclerosis, osteoporosis, cognitive disturbances and alterations of hippocampal architecture. Several deficits in Klotho-deficient mice are likely to contribute to these phenomena. These include an inability to defend against oxidative stress in the central nervous system and periphery, decreased capacity to generate nitric oxide to sustain normal endothelial reactivity, defective Klotho-related mediation of glycosylation and ion channel regulation, increased insulin/insulin-like growth factor signaling and a disturbed calcium and phosphate homeostasis accompanied by altered vitamin D levels and ectopic calcification. Identifying the mechanisms by which Klotho influences multiple important pathways is an emerging field in human biology that will contribute significantly to understanding basic physiologic processes and targets for the treatment of complex diseases. Because many of the phenomena seen in Klotho-deficient mice occur in depressive illness, major depression and bipolar disorder represent illnesses potentially associated with Klotho dysregulation. Klotho's presence in CSF, blood and urine should facilitate its study in clinical populations.
Major depression and bipolar disorder are associated with decreased bone mineral density (BMD). Antidepressants such as imipramine (IMIP) and specific serotonin reuptake inhibitors (SSRIs) have been ...implicated in reduced BMD and/or fracture in older depressed patients. Moreover, anticonvulsants such as valproate (VAL) and carbamazepine (CBZ) are also known to increase fracture rates. Although BMD is a predictor of susceptibility to fracture, bone strength is a more sensitive predictor. We measured mechanical and geometrical properties of bone in 68 male Sprague Dawley rats on IMIP, fluoxetine (FLX), VAL, CBZ, CBZ vehicle and saline (SAL), given intraperitoneally daily for 8 weeks. Distinct regions were tested to failure by four-point bending, whereas load displacement was used to determine stiffness. The left femurs were scanned in a MicroCT system to calculate mid-diaphyseal moments of inertia. None of these parameters were affected by antidepressants. However, VAL resulted in a significant decrease in stiffness and a reduction in yield, and CBZ induced a decrease in stiffness. Only CBZ induced alterations in mechanical properties that were accompanied by significant geometrical changes. These data reveal that chronic antidepressant treatment does not reduce bone strength, in contrast to chronic anticonvulsant treatment. Thus, decreased BMD and increased fracture rates in older patients on antidepressants are more likely to represent factors intrinsic to depression that weaken bone rather than antidepressants per se. Patients with affective illness on anticonvulsants may be at particularly high risk for fracture, especially as they grow older, as bone strength falls progressively with age.
Diabetes mellitus type 2 (DM type 2) is associated with depressive symptomatology and intermittent hyperfunction of the hypothalamic-pituitary-adrenal (HPA) axis. DM type 2 is also accompanied by ...increased tissue levels of angiotensin II (Ang II), which stimulates the HPA axis through the Ang II type 1 receptors (AT1). We investigated the effect of candesartan, an angiotensin receptor blocker (ARB) that crosses the blood brain barrier, on the activity of the HPA axis and on the affect of 17 patients with DM type 2, aged 40-65 years, who were treated with 4 mg/day candesartan per os for at least 3 months. Before and after candesartan administration, a corticotropin-releasing hormone (CRH) stimulation test and psychological tests were performed. In response to hCRH, time-integrated secretion of ACTH was not altered by candesartan administration, however, the cortisol response was decreased significantly compared to baseline (mean ± SEM, 2327 ± 148.3 vs. 1943 ± 131.9 μg/dl, P = 0.005) suggesting reduced sensitivity of the adrenals to ACTH. In parallel, there was a significant improvement in interpersonal sensitivity (0.91 ± 0.16 vs. 0.70 ± 0.15, P = 0.027) and depression scores (0.96 ± 0.15 vs. 0.71 ± 0.10, P = 0.026). We suggest that candesartan resets the HPA axis of patients with DM type 2 and improves their affect.
Major depression and bipolar disorder are heterogeneous conditions in which there can be dysregulation of (1) the stress system response, (2) its capacity for counterregulation after danger has ...passed and (3) the phase in which damaging molecules generated by the stress response are effectively neutralized. The response to stress and depressed mood share common circuitries and mediators, and each sets into motion not only similar affective and cognitive changes, but also similar systemic manifestations. We focus here on two highly interrelated processes, parainflammation and endoplasmic reticulum (ER) stress, each of which can potentially interfere with all phases of a normal stress response in affective illness, including adaptive neuroplastic changes and the ability to generate neural stem cells. Parainflammation is an adaptive response of the innate immune system that occurs in the context of stressors to which we were not exposed during our early evolution, including overfeeding, underactivity, aging, artificial lighting and novel foodstuffs and drugs. We postulate that humans were not exposed through evolution to the current level of acute or chronic social stressors, and hence, that major depressive illness is associated with a parainflammatory state. ER stress refers to a complex program set into motion when the ER is challenged by the production or persistence of more proteins than it can effectively fold. If the ER response is overwhelmed, substantial amounts of calcium are released into the cytoplasm, leading to apoptosis. Parainflammation and ER stress generally occur simultaneously. We discuss three highly interrelated mediators that can effectively decrease parainflammation and ER stress, namely the central insulin, klotho and peroxisome proliferator-activated receptor-γ (PPAR-γ) systems and propose that these systems may represent conceptually novel therapeutic targets for the amelioration of the affective, cognitive and systemic manifestations of major depressive disorder.
Exercise represents a physical stress that challenges homeostasis. In response to this stressor, the autonomic nervous system and hypothalamus-pituitary-adrenal axis are known to react and ...participate in the maintenance of homeostasis and the development of physical fitness. This includes elevation of cortisol and catecholamines in plasma. However, physical conditioning is associated with a reduction in pituitary-adrenal activation in response to exercise. On the other hand, highly trained athletes exhibit chronic mild hypercortisolism at baseline that may be an adaptive change to chronic exercise. In addition the proinflammatory cytokine, IL-6 is also activated, probably via catecholamines. On the other hand, the stress of chronic exercise induces certain changes to the thyroid axis. Peripheral thyroid hormone metabolism suppression is observed, and the result is a hormonal status similar to that of euthyroid sick syndrome (ESS), with suppression of T3 and elevation of rT3 plasma levels. One mechanism proposed involves exercise-activated pathways participating in the pathogenesis of ESS. This is realized through norepinephrine's activation of NF-kappaB. Neuroendocrine response to exercise stress involves activation of NF-kappaB resulting in inactivation of T3-dependent 5'-deiodinase gene expression and enzyme activity. Thus, ESS is generated in the periphery. On the other hand, activation and nuclear translocation of NF-kappaB leads to increased transcription of proinflammatory genes responsible for the expression of proinflammatory cytokines such as TNF-alpha and IL-6. These cytokines could activate cortisol, which in turn inhibits NF-kappaB activation through IkappaB and finally shuts down this cycle.
Abstract
Background
although the utilization of left ventricular assist devices (LVADs) in heart failure (HF) patients has been increasing, little is known about the patients’ experience of living ...and managing daily life post LVAD implantation. Knowing more about the patients’ experience would help LVAD nurses establish a less hierarchical and more meaningful therapeutic relationship with their patients, and anticipate the patients’ physical, emotional and social needs post LVAD implantation.
Purpose
to identify the themes and patterns amongst individuals with HF who have opted for LVAD implantation, as very few studies have looked at the needs of this patient group.
Methods
a systematic search of PubMed, Scopus, ScienceDirect and Google Scholar in November 2022 yielded 530 research papers from 2011-2022 with keywords: LVAD, left-assist, patient, qualitative. All studies were imported into Covidence, 24 duplicates were removed, and 506 papers were subjected to abstract, title and full-text screening by three researchers independently. Screening resulted in the inclusion of 15 qualitative studies on the experiences of adult patients with implanted LVAD. All studies that were included had conducted qualitative interviews. Each study was scored according to CASP criteria, and no distinction was made between Bridge-To-Transplantation Therapy and Destination Therapy.
Results
Fifteen n=15 studies in 7 countries involving 296 individuals (232 patients and 64 informal caregivers) were reviewed. The review of the literature revealed a variety of findings. Data analysis identified seven themes pertaining to the experience of living with LVAD: a) physical and functional dimensions of life n=7 studies, b) emotional – psychological dimensions n=10 studies, c) hope and optimism n=5 studies d) social aspects and relations to others n=6 studies, e) adaptation and coping mechanisms n=6 studies, f) receiving support from others as part of holistic care n=3 studies, and g) liminality and ambivalence n=3 studies.
Conclusions
LVAD patients experience a life with functional limitations, fear, lifestyle changes, frustration, with "up and down-ness", that requires them to resort to a repertoire of adaptation and coping mechanisms, hope, and support from family and services. LVAD implantation introduces them to a new embodied experience of living with stigma, but also to a feeling that they have been "saved". Somewhere along their "LVAD trajectory", they experience loss of identity and "liminality", and they go through what is also known as "biographical disruption". Professionals in LVAD and Heart Failure services would be better suited to support patients and their caregivers through this journey of life transformation and ambivalence, if they were more aware of the aforementioned findings. This review sheds light on the experience of a very unique group of patients, who need specialist and needs-specific care in this post-modernism biotechnical era.PRISMA Flow DiagramTable of the included studies
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