Sudden infant death syndrome (SIDS) is the leading cause of death in infants between the ages of 1 and 12 months in developed countries. SIDS is by definition a diagnosis of exclusion, and its mechanism of action is unknown. The SIDS–Critical Diaphragm Failure (CDF) hypothesis postulates that the cause of death in SIDS is respiratory failure caused by CDF. Four principal risk factors contribute to CDF in young infants: undeveloped respiratory muscles, non-lethal infections, prone resting position, and REM sleep. Even relatively minor infections can cause an acute and significant reduction in diaphragm force generation capacity that in conjunction with other risk factors can precipitate CDF. CDF-induced acute muscle weakness leaves few, if any pathological marks on the affected tissue.Understanding the underlying mechanism of SIDS may help in formulating new approaches to child care that can help to further reduce the incidence of SIDS.
Cachexia affects up to two thirds of all cancer patients and is a significant cause of morbidity and mortality. It is a complex metabolic syndrome associated with the underlying illness and characterized by loss of skeletal muscle tissue with or without loss of fat mass. Cachexia’s other prominent clinical symptoms include anorexia, systemic inflammation, pediatric growth failure, and hypogonadism. The relationship between the symptoms of cancer cachexia and the underlying illness is unclear, and there is an urgent need for a better understanding of the pathophysiology of this syndrome. Normal Zn metabolism is often disrupted in cancer patients, but the possible effects of systemic Zn dyshomeostasis in cachexia have not been investigated. We propose that the acute phase response can mediate Zn redistribution and accumulation in skeletal muscle tissue and contribute to the activation of the ubiquitin–proteasome pathway that regulates protein catabolism. This chronic redistribution deprives Zn from other tissues and organs and compromises critical physiological functions in the body. The cardinal symptoms of Zn deficiency are anorexia, systemic inflammation, growth failure in children, and hypogonadism. These symptoms also prominently characterize cancer cachexia suggesting that the role of systemic Zn dyshomeostasis in cachexia should be investigated.
D-Myo-inositol 1,2,6-triphosphate (alpha trinositol, AT) has been shown to attenuate muscle atrophy in a murine cachexia model through an increase in protein synthesis and a decrease in degradation. The mechanism of this effect has been investigated in murine myotubes using a range of catabolic stimuli, including proteolysis-inducing factor (PIF), angiotensin II (Ang II), lipopolysaccharide, and tumour necrosis factor- / interferon-. At a concentration of 100M AT was found to attenuate both the induction of protein degradation and depression of protein synthesis in response to all stimuli. The effect on protein degradation was accompanied by attenuation of the increased expression and activity of the ubiquitinproteasome pathway. This suggests that AT inhibits a signalling step common to all four agents. This target has been shown to be activation (autophosphorylation) of the dsRNA-dependent protein kinase (PKR) and the subsequent phosphorylation of eukaryotic initiation factor 2 on the -subunit, together with downstream signalling pathways leading to protein degradation. AT also inhibited activation of caspase-3/-8, which is thought to lead to activation of PKR. The mechanism of this effect may be related to the ability of AT to chelate divalent metal ions, since the attenuation of the increased activity of the ubiquitin-proteasome pathway by PIF and Ang II, as well as the depression of protein synthesis by PIF, were reversed by increasing concentrations of Zn 2+. The ability of AT to attenuate muscle atrophy by a range of stimuli suggests that it may be effective in several conditions.
The sudden infant death syndrome (SIDS)–critical diaphragm failure (CDF) hypothesis was first published by Siren and Siren in 2011 (1). Since its publication, the hypothesis has continued to generate interest and several colleagues have contributed perspectives and insights to it (2–5). The basic premise of the hypothesis is that the diaphragm is a vital organ that must continuously generate adequate force to maintain ventilation, and that CDF is a terminal event and the cause of death in SIDS. I have argued in two follow-up articles that all SIDS factors either increase the workload of the respiratory muscles, the diaphragm being the primary muscle affected, or reduce its force generating capacity (6, 7). The SIDS–CDF hypothesis posits that SIDS has many contributing factors but only one cause, namely, the failure of the vital respiratory pump. There are several known SIDS factors, such as the prone sleeping position, non-lethal infections, deep sleep, gestational prematurity, low birth weight, cigarette smoke, male gender, and altitude, but of these, some such as the prone sleeping position more significantly both impact diaphragm function and correlate with SIDS. However, SIDS cases are multifactorial and as such can be caused by different combinations of factors. An infection combined with a prone sleeping position and elevated room temperature could lead to SIDS, whereas in other circumstances, low birth weight, cigarette smoke, prone sleeping position, and altitude could result in CDF and SIDS. The SIDS–CDF hypothesis also posits that SIDS does not have a congenital or genetic origin, and that efforts to identify significant genetic anomalies in SIDS victims are unlikely to be successful (8–11).
BACKGROUND: D-myo-inositol-1,2,6-triphosphate (a-trinositol, AT) is a polyanionic molecule capable of chelating divalent metal ions with anti-tumour and anti-cachectic activity in a murine model. METHODS: To investigate the role of zinc in this process, mice bearing cachexia-inducing MAC16 tumour were treated with AT, with or without concomitant administration of ZnSO 4 . RESULTS: At a dose of 40 mg kg À1 , AT effectively attenuated both weight loss and growth of the MAC16 tumour, and both effects were attenuated by co-administration of Zn 2 þ . The concentration of zinc in gastrocnemius muscle increased with increasing weight loss, whereas administration of AT decreased the levels of zinc in plasma, skeletal muscle and tumour, which were restored back to control values after administration of ZnSO 4 . CONCLUSION: These results suggest that zinc is important in both tumour growth and cachexia in this animal model.
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