118 P. M. A. Siren & M. J. Siren or diaphragm protein content, obvious depletion of major diaphragm protein bands or speciﬁc loss of myosin or actin stores’ (57). Sepsis reduces muscle strength long before contractile protein levels decline signiﬁcantly (34). Others have reported similar results (62,63), conﬁrming that even though infections can cause acute and severe diaphragm dysfunction, they leave few, if any pathological marks in the affected tissue. These ﬁndings are of some importance, because the absence of signiﬁcant pathophysiological abnormalities in the inspiratory musculature of SIDS cases has led to the erroneous conclusion that the diaphragm does not play a role in the etiology of the syndrome (10). The one pathological ﬁnding that characterizes over 70% of SIDS cases is intrathoracic petechiae (64). Goldwater reported recently that SIDS cases demon- strate intrathoracic petechial hemorrhages in the thy- mus (89.5%), pleura (80%), and epicardium (79.9%) (16). SIDS-related intrathoracic petechiae are not characteristic of asphyxia, strangulation (16), upper airway obstruction (17), or cardiac arrest (64). Rather, experimental evidence suggests that an infec- tion together with gasping or a ‘struggle to breathe’ episode is required for the formation of characteristic intrathoracic petechial hemorrhages (17,65). Interest- ingly, the clinical signs of respiratory muscle fatigue are rapid shallow breathing, paradoxic chest wall/ abdominal movements, and respiratory pauses com- bined with hyperventilation (20,66). The data presented above strongly suggest that even minor infections can cause a signiﬁcant and rapid reduction in diaphragm force-generating capacity without affecting muscle mass or histology. Surprisingly, the pathophysiological implications of infection-induced acute diaphragmatic weakness have not been previously considered in the context of SIDS even though it is well known that young infants have undeveloped and potentially vulnerable respiratory muscles. Mitochondrial dysfunction and the role of melatonin in SIDS The molecular mechanisms behind infection-induced acute diaphragm weakness have been actively investi- gated. Systemic infection displays consistent similari- ties to the pathogenesis of SIDS (67), and can induce a signiﬁcant (P < 0.001) reduction in the mitochondrial function (e.g. ATP-generating capacity) of the dia- phragm muscle tissue (68). There is substantial evi- dence that excessive free-radical generation plays a central role in infection-induced myopathy and causes mitochondrial impairment. Infection causes signiﬁcant changes in oxidative phosphorylation and induces the selective depletion of several electron transport chains in the respiratory muscles (32). Newborns and infants born prematurely are especially prone to oxidative stress because they are exposed to high oxygen con- centrations and have reduced antioxidant defense mechanisms and high levels of free iron that are required for the Fenton reaction (69). Existing evi- dence strongly suggests that infections can produce rapid and profound alterations in the mitochondrial function of the diaphragm and severely disrupt its energy metabolism. Melatonin (N-acetyl-5-methoxytryptamine) is a highly conserved small amphiphilic molecule that is biosynthesized from tryptophan. Serotonin is converted to melatonin in the pineal gland by arylalkylamine N-acetyltransferase (AA-NAT) and hydroxyindole O-methyltransferase (HIOMT) (70). Serotonin is a rate-limiting factor for melatonin. Melatonin has been shown to protect against oxidative stress in various divergent experimental systems (71). It is a highly effec- tive antioxidant and free-radical scavenger that can signiﬁcantly attenuate mitochondrial failure and pre- serve cell function and survival (72–74). In the clinical setting, melatonin has been shown to improve the clin- ical outcome in the septic newborn (75). Gitto and colleagues observe that ‘several clinical studies that used melatonin showed that it reduces oxidative stress in newborns with sepsis, distress or other conditions where there is excessive ROS/RNS (reactive oxygen species/reactive nitrogen species) production’(69). However, young infants exhibit transient melatonin deﬁciency for the ﬁrst 2–4 months of life (76). Pineal dysfunction and impaired melatonin metab- olism have been associated with SIDS (77,78). Sturner and colleagues examined melatonin levels from the ventricular cerebrospinal ﬂuid (CSF) in SIDS deaths compared to non-SIDS cases. After adjusting for age differences, melatonin levels were signiﬁ- cantly (P < 0.05) lower among the SIDS infants (91 ± 29 pmol/L; n = 32) than among those dying of other causes (180 ± 27; n = 35) (79). Young infants who experienced a life-threatening event (ALTE) demonstrated signiﬁcantly (P < 0.05) lower uri- nary excretion of the main melatonin metabolite 6-sulfatoxymelatonin compared to controls (1588 ng/24 h versus 3961 ng/24 h) (80). Serotonergic deﬁ- ciency has repeatedly been associated with SIDS (81), suggesting that the role of the tryptophan–serotonin– melatonin pathway in the etiology of SIDS should be further investigated. The prone sleeping position and SIDS A change in the recommended sleeping position for young infants from prone to supine has reduced