Prevalence of malnutrition and 12-month incidence of mortality in two Sydney teaching hospitals.
AIMS: The objectives of the present study were to determine: (i) the prevalence of malnutrition in two Sydney teaching hospitals using Subjective Global Assessment (SGA), (ii) the effect of malnutrition on 12-month mortality and (iii) the proportion of patients previously identified to be at nutritional risk. METHODS: A prospective study using SGA to assess nutritional status of eligible inpatients, from April to September 1997, with a 12-month follow-up to assess mortality. A total of 819 patients was systematically selected from 2,194 eligible patients. Patients were excluded if they were under the age of 18, had dementia or communication difficulties, or were under obstetric or critical care. The main outcome measures were prevalence of malnutrition, 12-month incidence of mortality, proportion of patients identified with malnutrition, and hospital length of stay (LOS). RESULTS: The prevalence rate of malnutrition was 36%. The proportion of malnourished patients was not significantly different between the two hospitals (P = 0.4). The actuarial incidence of mortality at 12 months after assessment was 29.7% in malnourished subjects compared with 10.1% in well-nourished subjects (P < 0.0005). Malnourished subjects had a significantly longer median LOS (17 days vs 11 days, P< 0.0005) and were significantly older (median 71 years vs 63 years, P < 0.0005) than well-nourished subjects. Only 36% of the malnourished patients had been previously identified as being at nutritional risk. CONCLUSIONS: Malnutrition in Australian hospitals is a continuing health concern and is associated with increased LOS and decreased survival after 12 months. The present study revealed that malnourished patients were not regularly identified. Further studies are required to determine whether routine identification of malnutrition and subsequent nutritional intervention are effective in improving clinical outcomes in these individuals.
Intern Med J. 2001 Nov;31(8):455-61
Hospital malnutrition: prevalence, identification and impact on patients and the healthcare system.
Malnutrition is a debilitating and highly prevalent condition in the acute hospital setting, with Australian and international studies reporting rates of approximately 40%. Malnutrition is associated with many adverse outcomes including depression of the immune system, impaired wound healing, muscle wasting, longer lengths of hospital stay, higher treatment costs and increased mortality. Referral rates for dietetic assessment and treatment of malnourished patients have proven to be suboptimal, thereby increasing the likelihood of developing such aforementioned complications. Nutrition risk screening using a validated tool is a simple technique to rapidly identify patients at risk of malnutrition, and provides a basis for prompt dietetic referrals. In Australia, nutrition screening upon hospital admission is not mandatory, which is of concern knowing that malnutrition remains under-reported and often poorly documented. Unidentified malnutrition not only heightens the risk of adverse complications for patients, but can potentially result in foregone reimbursements to the hospital through casemix-based funding schemes. It is strongly recommended that mandatory nutrition screening be widely adopted in line with published best-practice guidelines to effectively target and reduce the incidence of hospital malnutrition.
Int J Environ Res Public Health. 2011 Feb;8(2):514-27
Chronic Neuron- and Age-Selective Down-Regulation of TNF Receptor Expression in Triple-Transgenic Alzheimer Disease Mice Leads to Significant Modulation of Amyloid- and Tau-Related Pathologies.
Neuroinflammation, through production of proinflammatory molecules and activated glial cells, is implicated in Alzheimer’s disease (AD) pathogenesis. One such proinflammatory mediator is tumor necrosis factor α (TNF-α), a multifunctional cytokine produced in excess and associated with amyloid β-driven inflammation and cognitive decline. Long-term global inhibition of TNF receptor type I (TNF-RI) and TNF-RII signaling without cell or stage specificity in triple-transgenic AD mice exacerbates hallmark amyloid and neurofibrillary tangle pathology. These observations revealed that long-term pan anti-TNF-α inhibition accelerates disease, cautions against long-term use of anti-TNF-α therapeutics for AD, and urges more selective regulation of TNF signaling. We used adeno-associated virus vector-delivered siRNAs to selectively knock down neuronal TNF-R signaling. We demonstrate divergent roles for neuronal TNF-RI and TNF-RII where loss of opposing TNF-RII leads to TNF-RI-mediated exacerbation of amyloid β and Tau pathology in aged triple-transgenic AD mice. Dampening of TNF-RII or TNF-RI+RII leads to a stage-independent increase in Iba-1-positive microglial staining, implying that neuronal TNF-RII may act nonautonomously on the microglial cell population. These results reveal that TNF-R signaling is complex, and it is unlikely that all cells and both receptors will respond positively to broad anti-TNF-α treatments at various stages of disease. In aggregate, these data further support the development of cell-, stage-, and/or receptor-specific anti-TNF-α therapeutics for AD.
Am J Pathol. 2013 Jun;182(6):2285-97
Pro-inflammatory cytokines and their effects in the dentate gyrus.
The older notion of a central nervous system existing in essential isolation from the immune system has changed dramatically in recent years as the body of evidence relating to the interactions between these two systems has grown. Here we address the role of a particular subset of immune modulatory molecules, the pro-inflammatory cytokines, in regulating neuronal function and viability in the dentate gyrus of the hippocampus. These inflammatory mediators are known to be elevated in many neuropathological conditions, such as Alzheimer’s disease, Parkinson’s disease and ischaemic injury that follows stroke. Pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1beta) and interleukin 18 (IL-18), have been shown to regulate neurotoxicity; although, due to the complexity of the cytokine action in neurons and glia, the effect may be either facilitatory or protective, depending on the circumstances. As well as their role in neurotoxicity and neuroprotection, the pro-inflammatory cytokines have also been shown to be potent regulators of synaptic function. In particular, TNF-alpha, IL-1beta and IL-18 have all been shown to inhibit long-term potentiation, a form of neuronal plasticity widely believed to underlie learning and memory, both in the early p38 mitogen activated protein kinase-dependant phase and the later protein synthesis-dependant phase. In this article we address the mechanisms underlying these cytokine effects in the dentate gyrus of the hippocampus.
Prog Brain Res. 2007;163:339-54
Neuroinflammation and synaptic loss.
Neuroinflammation plays a critical role in the progression of many neurodegenerative, neuropsychiatric and viral diseases. In neuroinflammation, activated microglia and astrocytes release cytokines and chemokines as well as nitric oxide, which in turn activate many signal transduction pathways. The cytokines, interleukin-1 beta and tumor necrosis factor alpha, regulate transcription of a number of genes within the brain, which can lead to the formation of pro-inflammatory products of the arachidonic acid cascade. Formation of pro-inflammatory agents and associated cytotoxic products during neuroinflammation can be detrimental to neurons by altering synaptic proteins. Neuroinflammation as well as excitotoxic insults reduce synaptic markers such as synaptophysin and drebrin. Neurodegenerative, neuropsychiatric illnesses and viral infections are accompanied by loss of both pre- and post-synaptic proteins. These synaptic changes may contribute to the progressive cognitive decline and behavioral changes associated with these
Neurochem Res. 2012 May;37(5):903-10
A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.
OBJECTIVE: Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively. METHODS: An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score. RESULTS: Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413 nmol/L, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls. CONCLUSIONS: High-dose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects. CLASSIFICATION OF EVIDENCE: This trial provides Class II evidence that high-dose vitamin D use for 52 weeks in patients with multiple sclerosis does not significantly increase serum calcium levels when compared to patients not on high-dose supplementation. The trial, however, lacked statistical precision and the design requirements to adequately assess changes in clinical disease measures (relapses and Expanded Disability Status Scale scores), providing only Class level IV evidence for these outcomes.
Neurology. 2010 Jun 8;74(23):1852-9
Control of autoimmune diseases by the vitamin D endocrine system.
1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the biologically active form of vitamin D(3), is a secosteroid hormone essential for bone and mineral homeostasis. It regulates the growth and differentiation of multiple cell types, and displays immunoregulatory and anti-inflammatory properties. Cells involved in innate and adaptive immune responses--including macrophages, dendritic cells, T cells and B cells--express the vitamin D receptor (VDR), and can both produce and respond to 1,25(OH)(2)D(3). The net effect of the vitamin D system on the immune response is an enhancement of innate immunity coupled with multifaceted regulation of adaptive immunity. Epidemiological evidence indicates a significant association between vitamin D deficiency and an increased incidence of several autoimmune diseases, and clarification of the physiological role of endogenous VDR agonists in the regulation of autoimmune responses will guide the development of pharmacological VDR agonists for use in the clinic. The antiproliferative, prodifferentiative, antibacterial, immunomodulatory and anti-inflammatory properties of synthetic VDR agonists could be exploited to treat a variety of autoimmune diseases, from rheumatoid arthritis to systemic lupus erythematosus, and possibly also multiple sclerosis, type I diabetes, inflammatory bowel diseases, and autoimmune prostatitis.
Nat Clin Pract Rheumatol. 2008 Aug;4(8):404-12
New insights into nitric oxide and coronary circulation.
Since its discovery over 20 years ago as an intercellular messenger, nitric oxide (NO), has been extensively studied with regard to its involvement in the control of the circulation and, more recently, in the prevention of atherosclerosis. The importance of NO in coronary blood flow control has also been recognized. NO-independent vasodilation causes increased shear stress within the blood vessel which, in turn, stimulates endothelial NO synthase activation, NO release and prolongation of vasodilation. Reactive hyperemia, myogenic vasodilation and vasodilator effects of acetylcholine and bradykinin are all mediated by NO. Ischemic preconditioning, which protects the myocardium from cellular damage and arrhythmias, is itself linked with NO and both the first and second windows of protection may be due to NO release. Exercise increases NO synthesis via increases in shear stress and pulse pressure and so it is likely that NO is an important blood flow regulatory mechanism in exercise. This phenomenon may account for the beneficial effects of exercise seen in atherosclerotic individuals. Whilst NO plays a protective role in preventing atherosclerosis via superoxide anion scavenging, risk factors such as hypercholesterolemia reduce NO release leading the way for endothelial dysfunction and atherosclerotic lesions. Exercise reverses this process by stimulating NO synthesis and release. Other factors impacting on the activity of NO include estrogens, endothelins, adrenomedullin and adenosine, the last appearing to be a compensatory pathway for coronary control in the presence of NO inhibition. These studies reinforce the pivotal role played by the substance in the control of coronary circulation.
Life Sci. 1999;65(21):2167-74
Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells.
Cimetidine has been shown to have beneficial effects in colorectal cancer patients. In this study, a total of 64 colorectal cancer patients who received curative operation were examined for the effects of cimetidine treatment on survival and recurrence. The cimetidine group was given 800 mg day(-1) of cimetidine orally together with 200 mg day(-1) of 5-fluorouracil, while the control group received 5-fluorouracil alone. The treatment was initiated 2 weeks after the operation and terminated after 1 year. Robust beneficial effects of cimetidine were noted: the 10-year survival rate of the cimetidine group was 84.6% whereas that of control group was 49.8% (P<0.0001). According to our previous observations that cimetidine blocked the expression of E-selectin on vascular endothelium and inhibited the adhesion of cancer cells to the endothelium, we have further stratified the patients according to the expression levels of sialyl Lewis antigens X (sL(x)) and A (sL(a)). We found that cimetidine treatment was particularly effective in patients whose tumour had higher sL(x) and sL(a) antigen levels. For example, the 10-year cumulative survival rate of the cimetidine group with higher CSLEX staining, recognizing sL(x), of tumours was 95.5%, whereas that of control group was 35.1% (P=0.0001). In contrast, in the group of patients with no or low levels CSLEX staining, cimetidine did not show significant beneficial effect (the 10-year survival rate of the cimetidine group was 70.0% and that of control group was 85.7% (P=n.s.)). These results clearly indicate that cimetidine treatment dramatically improved survival in colorectal cancer patients with tumour cells expressing high levels of sL(x) and sL(a).
Br J Cancer. 2002 Jan 21;86(2):161-7
Radiation-induced dementia in patients cured of brain metastases.
When a patient with cancer develops a brain metastasis, death is usually imminent, but aggressive treatment in some patients with limited or no systemic disease yields long-term survival. In such patients, delayed deleterious effects of therapy are particularly tragic. We report 12 patients who developed delayed complications of whole brain radiotherapy (WBRT) given as sole treatment (4 patients) or in combination with surgical resection (8 patients). Within 5 to 36 months (median, 14) all patients developed progressive dementia, ataxia, and urinary incontinence causing severe disability in all and leading to death in 7. No patient had tumor recurrence when neurologic symptoms began. Cortical atrophy and hypodense white matter were identified by CT in all. Contrast-enhancing lesions were seen in 3 patients; 2 of the lesions yielded radionecrosis on biopsy. Autopsies on 2 patients revealed diffuse chronic edema of the hemispheric white matter in the absence of tumor recurrence. Corticosteroids and ventriculoperitoneal shunt offered significant but incomplete improvement in some patients. The total dose of WBRT was only 2,500 to 3,900 cGy, but daily fractions of 300 to 600 cGy were employed. We believe that these fractionation schedules, several of which are used commonly, predispose to delayed neurologic toxicity, and that more protracted schedules should be employed for the safe and efficacious treatment of good-risk patients with brain metastases. The incidence of WBRT-induced dementia was only 1.9 to 5.1% in the 2 populations reviewed here; however, this underestimates the incidence because only severely affected patients could be identified from chart review.
Neurology. 1989 Jun;39(6):789-96