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      SIDS–CDF Hypothesis Revisited: Cause vs. Contributing Factors

      1 , *

      Frontiers in Neurology

      Frontiers Media S.A.

      SIDS, diaphragm, respiratory failure, hyperthermia, magnesium deficiency

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          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 ( 25). 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 ( 811).

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          Most cited references 42

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          Interaction between bedding and sleeping position in the sudden infant death syndrome: a population based case-control study.

          To determine the relation between sleeping position and quantity of bedding and the risk of sudden unexpected infant death. A study of all infants dying suddenly and unexpectedly and of two controls matched for age and date with each index case. The parents of control infants were interviewed within 72 hours of the index infant's death. Information was collected on bedding, sleeping position, heating, and recent signs of illness for index and control infants. A defined geographical area comprising most of the county of Avon and part of Somerset. 72 Infants who had died suddenly and unexpectedly (of whom 67 had died from the sudden infant death syndrome) and 144 control infants. Compared with the control infants the infants who had died from the sudden infant death syndrome were more likely to have been sleeping prone (relative risk 8.8; 95% confidence interval 7.0 to 11.0; p less than 0.001), to have been more heavily wrapped (relative risk 1.14 per tog above 8 tog; 1.03 to 1.28; p less than 0.05), and to have had the heating on all night (relative risk 2.7; 1.4 to 5.2; p less than 0.01). These differences were less pronounced in the younger infants (less than 70 days) than the older ones. The risk of sudden unexpected death among infants older than 70 days, nursed prone, and with clothing and bedding of total thermal resistance greater than 10 tog was increased by factors of 15.1 (2.6 to 89.6) and 25.2 (3.7 to 169.0) respectively compared with the risk in infants of the same age nursed supine or on their side and under less than 6 tog of bedding. Overheating and the prone position are independently associated with an increased risk of sudden unexpected infant death, particularly in infants aged more than 70 days. Educating parents about appropriate thermal care and sleeping position of infants may help to reduce the incidence of the sudden infant death syndrome.
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            Effect of oral magnesium supplementation on physical performance in healthy elderly women involved in a weekly exercise program: a randomized controlled trial.

            Magnesium deficiency is associated with poor physical performance, but no trials are available on how magnesium supplementation affects elderly people's physical performance.
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              Effect of proteasome inhibitors on endotoxin-induced diaphragm dysfunction.

              Infections produce severe respiratory muscle dysfunction. It is known that the proteasome proteolytic system is activated in skeletal muscle in sepsis, and it has been postulated that this degradative pathway is responsible for inducing skeletal muscle weakness and wasting. The objective of this study was to determine if administration of proteasomal inhibitors (MG132, epoxomicin, bortezomib) can prevent sepsis-induced diaphragm weakness. Rats were given either 1) saline (0.5 ml ip), 2) endotoxin (12 mg/kg ip), 3) endotoxin plus MG132 (2.5 mg/kg), 4) endotoxin plus epoxomicin (1 micromol/kg), or 5) endotoxin plus bortezomib (0.05 mg/kg). Animals were killed either 48 or 96 h after injections, and assessments were made of diaphragm proteolysis, force-frequency relationships, mass, protein content, and caspase activation. Endotoxin increased proteolysis (P <0.001). MG132, epoxomicin, and bortezomib each prevented the endotoxin-induced increase in proteolysis (P <0.01). Endotoxin induced severe reductions in diaphragm force generation by 48 h (P <0.01); none of the proteasomal inhibitors prevented loss of force. Endotoxin induced significant reductions in diaphragm mass and protein content by 96 h (P <0.01); neither MG132 nor epoxomicin prevented loss of mass or protein, but bortezomib attenuated the reduction in protein content (P <0.05). Endotoxin increased diaphragm caspase-3 activity (P <0.01); caspase-3 activity remained high when either MG132, epoxomicin, or bortezomib were given. These data suggest proteasomal inhibitors are not an adequate treatment to prevent endotoxin-induced diaphragmatic dysfunction.

                Author and article information

                URI :
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                16 January 2017
                : 7
                1Independent Researcher , Ridley Park, Singapore
                Author notes

                Edited by: Anna Maria Lavezzi, University of Milan, Italy

                Reviewed by: Kumar Sannagowdara, Medical College of Wisconsin, USA; Bülent Eren, Council of Forensic Medicine of Turkey, Turkey

                *Correspondence: Pontus M. A. Siren, pontusmax@

                Specialty section: This article was submitted to Neuropediatrics, a section of the journal Frontiers in Neurology

                Copyright © 2017 Siren.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 48, Pages: 5, Words: 3873


                magnesium deficiency, hyperthermia, respiratory failure, diaphragm, sids


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