Findings from numerous laboratories and across neuroimaging modalities have consistently shown that exogenous administration of cytokines or inflammatory stimuli that induce cytokines disrupts ...circuits and networks involved in motivation and motor activity, threat detection, anxiety, and interoceptive and emotional processing. While inflammatory effects on neural circuits and relevant behaviors may represent adaptive responses promoting conservation of energy and heightened vigilance during immune activation, chronically elevated inflammation may contribute to symptoms of psychiatric illnesses. Indeed, biomarkers of inflammation such as cytokines and acute phase reactants are reliably elevated in a subset of patients with unipolar or bipolar depression, anxiety-related disorders, and schizophrenia and have been associated with differential treatment responses and poor clinical outcomes. A growing body of literature also describes higher levels of endogenous inflammatory markers and altered, typically lower functional or structural connectivity within these circuits in association with transdiagnostic symptoms such as anhedonia and anxiety in psychiatric and at-risk populations. This review presents recent evidence that inflammation and its effects on the brain may serve as one molecular and cellular mechanism of dysconnectivity within anatomically and/or functionally connected cortical and subcortical regions in association with transdiagnostic symptoms. We also discuss the need to establish reproducible methods to assess inflammation-associated dysconnectivity in relation to behavior for use in translational studies or biomarker-driven clinical trials for novel pharmacological or behavioral interventions targeting inflammation or its effects on the brain.
Bone Alkaline Phosphatase in CKD–Mineral Bone Disorder Sardiwal, Sunita, PhD; Magnusson, Per, PhD; Goldsmith, David J.A., FRCP ...
American journal of kidney diseases,
10/2013, Letnik:
62, Številka:
4
Journal Article
Recenzirano
Overall and cardiovascular mortality in patients with chronic kidney disease (CKD) is greatly increased, without obvious current effective treatments. Mineral and bone disorder (MBD) is a common ...manifestation of CKD and contributes to the high risk of fracture and cardiovascular mortality in these patients. Traditionally, clinical management of CKD-MBD focused on attenuation of secondary hyperparathyroidism due to impaired renal activation of vitamin D and phosphate retention, although recently, adynamic forms of renal bone disease have become more prevalent. Definitive diagnosis was based on histologic (histomorphometric) analysis of bone biopsy material supported by radiologic changes and changes in levels of surrogate laboratory markers. Of these various markers, parathyroid hormone (PTH) has been considered to be the most sensitive and currently is the most frequently used; however, the many pitfalls of measuring PTH in patients with CKD increasingly are appreciated. We propose an alternative or complementary approach using bone alkaline phosphatase (ALP), which is directly related to bone turnover, reflects bone histomorphometry, and predicts outcomes in hemodialysis patients. Here, we consider the overall merits of bone ALP as a marker of bone turnover in adults with CKD-MBD, examine published bone histomorphometric data comparing bone ALP to PTH, and discuss possible pathogenic mechanisms by which bone ALP may be linked to outcomes in patients with CKD.
The evidence to date, coupled with advances in immunology and genetics has afforded the field an unparalleled opportunity to investigate the hypothesis that a subset of patients with schizophrenia ...may manifest an immunophenotype, toward new potential diagnostics and therapeutics to reduce risk, alleviate symptoms, and improve quality of life in both at-risk populations and patients with established schizophrenia. In this paper, we will first summarize the findings on immune dysfunction in schizophrenia, including (1) genetic, prenatal, and premorbid immune risk factors and (2) immune markers across the clinical course of the disorder, including cytokines; C-reactive protein; immune cells; antibodies, autoantibodies and comorbid autoimmune disorders; complement; oxidative stress; imaging of neuroinflammation; infections; and clinical trials of anti-inflammatory agents and immunotherapy. We will then discuss a potential mechanistic framework toward increased understanding of a potential schizophrenia immunophenotype. We will then critically appraise the existing literature, and discuss suggestions for the future research agenda in this area that are needed to rigorously evaluate this hypothesis.
Despite renin-angiotensin-aldosterone system blockade, which retards progression of CKD by reducing proteinuria, many patients with CKD have residual proteinuria, an independent risk factor for ...disease progression. We aimed to address whether active vitamin D analogs reduce residual proteinuria. We systematically searched for trials published between 1950 and September of 2012 in the Medline, Embase, and Cochrane Library databases. All randomized controlled trials of vitamin D analogs in patients with CKD that reported an effect on proteinuria with sample size≥50 were selected. Mean differences of proteinuria change over time and odds ratios for reaching ≥15% proteinuria decrease from baseline to last measurement were synthesized under a random effects model. From 907 citations retrieved, six studies (four studies with paricalcitol and two studies with calcitriol) providing data for 688 patients were included in the meta-analysis. Most patients (84%) used an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker throughout the study. Active vitamin D analogs reduced proteinuria (weighted mean difference from baseline to last measurement was -16% 95% CI, -13% to -18%) compared with controls (+6% 95% CI, 0% to +12%; P<0.001). Proteinuria reduction was achieved more commonly in patients treated with an active vitamin D analog (204/390 patients) than control patients (86/298 patients; OR, 2.72 95% CI, 1.82 to 4.07; P<0.001). Thus, active vitamin D analogs may further reduce proteinuria in CKD patients in addition to current regimens. Future studies should address whether vitamin D therapy also retards progressive renal functional decline.
Nephrotic syndrome in adults Hull, Richard P; Goldsmith, David J A
BMJ,
05/2008, Letnik:
336, Številka:
7654
Journal Article, Book Review
Recenzirano
Odprti dostop
Hull and Goldsmith discuss nephrotic syndrome in adults. The nephrotic syndrome is one of the best known presentations of adult or pediatric kidney disease. It can present in diverse ways in multiple ...healthcare settings and has important complications. Investigating and managing the syndrome is made more challenging by the lack of a guiding evidence base, but strategies derived from expert consensus are available for its initial management. All patients presenting with nephrotic syndrome should be discussed with local kidney specialists before embarking on further investigations and management. Large randomized trials in the management of the nephrotic syndrome, and in glomerular disease in general, are urgently needed to achieve further progress.
Abnormalities of cognitive function and high levels of depression incidence are characteristic of hemodialysis patients. Although previously attributed to the humoral effects of uremia, it is ...becoming increasingly appreciated that many elements of the overall disease state in CKD patients contribute to functional disturbances and physical brain injury. These factors range from those associated with the underlying primary diseases (cardiovascular, diabetes etc.) to those specifically associated with the requirement for dialysis (including consequences of the hemodialysis process itself). They are, however, predominantly ischemic threats to the integrity of brain tissue. These evolving insights are starting to allow nephrologists to appreciate the potential biological basis of dependency and depression in our patients, as well as develop and test new therapeutic approaches to this increasingly prevalent and important issue. This review aims to summarize the current understanding of brain injury in this setting, as well as examine recent advances being made in the modification of dialysis-associated brain injury.
Negative symptoms of schizophrenia are debilitating and chronic in nature, are difficult to treat, and contribute to poor functional outcomes. Motivational deficits are a core negative symptom and ...may involve alterations in reward processing, which involve subcortical regions such as the basal ganglia. More specifically, dopamine-rich regions like the ventral striatum, have been implicated in these reward-processing deficits. Inflammation is one mechanism that may underlie negative symptoms, and specifically motivational deficits, via the effects of inflammatory cytokines on the basal ganglia. Previous work has demonstrated that inflammatory stimuli decrease neural activity in the ventral striatum and decrease connectivity in reward-relevant neural circuitry. The immune system has been shown to be involved in the pathophysiology of schizophrenia, and inflammatory cytokines have been shown to be altered in patients with the disorder. This paper reviews the literature on associations between inflammatory markers and negative symptoms of schizophrenia as well as the role of anti-inflammatory drugs to target negative symptoms. We also review the literature on the role of inflammation and reward processing deficits in both healthy controls and individuals with depression. We use the literature on inflammation and depression as a basis for a model that explores potential mechanisms responsible for inflammation modulating certain aspects of negative symptoms in patients with schizophrenia. This approach may offer novel targets to treat these symptoms of the disorder that are significant barriers to functional recovery and do not respond well to available antipsychotic medications.
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