Our observations are best explained by postulating that the lungs grow partly by neoalveolarization throughout childhood and adolescence. This has important implications: developing lungs have the potential to recover from early life insults and respond to emerging alveolar therapies. Conversely, drugs, diseases, or environmental exposures could adversely affect alveolarization throughout childhood.

Rationale: Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair. Objectives: To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance. Methods: We recruited schoolchildren aged 10-14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37-42 wk; n ¼ 61); (2) mild preterm (32-36 wk; n ¼ 21); (3) extreme preterm (,32 wk, not oxygen dependent at 4 wk; n ¼ 19); and (4) extreme preterm with chronic lung disease (,32 wk and oxygen dependent beyond 4 wk; n ¼ 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance. Measurements and Main Results: The two extreme preterm groups had a lower FEV 1 (P ¼ 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm 2 /second (95% confidence interval, 0.089-0.095) in the term group. Corresponding values were 0.096 (0.091-0.101), 0.090 (0085-0.095), and 0.089 (0.083-0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders. Conclusions: Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.Keywords: alveolar structure; lung acinus; bronchopulmonary dysplasia; neonatal chronic lung disease Advances in preterm care have led to increased survival of extremely premature babies, with increasing numbers reaching adulthood. This has shifted the focus of research from survival toward long-term sequelae of prematurity (1, 2). Infants born extremely preterm are known to have arrested alveolar development, manifesting as fewer and larger alveoli (3, 4). Schoolage and adult survivors of extreme preterm birth are known to have long-term respiratory problems, particularly decreased forced expiratory volumes and increased residual lung volumes, suggesting airway damage (5, 6). There are insufficient data regarding structure and development of the periphery of the lung in long-term survivors of preterm birth because studies on this cohort have relied on traditional lung function tests that only provide an overall estimate of function.The short-and long-term outcomes described previously correlate with gestational age (GA) at birth and the presence of chronic lung disease of prematurity (CLD), one of the early pulmonary sequelae of extreme preterm birth (6-8). Most evidence regard...

Traumatic brain injury (TBI) triggers a series of complex pathophysiological processes. These include abnormalities in brain energy metabolism; consequent to reduced tissue pO2 arising from ischemia or abnormal tissue oxygen diffusion, or due to a failure of mitochondrial function. In vivo magnetic resonance spectroscopy (MRS) allows non-invasive interrogation of brain tissue metabolism in patients with acute brain injury. Nuclei with “spin,” e.g., 1H, 31P, and 13C, are detectable using MRS and are found in metabolites at various stages of energy metabolism, possessing unique signatures due to their chemical shift or spin–spin interactions (J-coupling). The most commonly used clinical MRS technique, 1H MRS, uses the great abundance of hydrogen atoms within molecules in brain tissue. Spectra acquired with longer echo-times include N-acetylaspartate (NAA), creatine, and choline. NAA, a marker of neuronal mitochondrial activity related to adenosine triphosphate (ATP), is reported to be lower in patients with TBI than healthy controls, and the ratio of NAA/creatine at early time points may correlate with clinical outcome. 1H MRS acquired with shorter echo times produces a more complex spectrum, allowing detection of a wider range of metabolites.31 P MRS detects high-energy phosphate species, which are the end products of cellular respiration: ATP and phosphocreatine (PCr). ATP is the principal form of chemical energy in living organisms, and PCr is regarded as a readily mobilized reserve for its replenishment during periods of high utilization. The ratios of high-energy phosphates are thought to represent a balance between energy generation, reserve and use in the brain. In addition, the chemical shift difference between inorganic phosphate and PCr enables calculation of intracellular pH.13 C MRS detects the 13C isotope of carbon in brain metabolites. As the natural abundance of 13C is low (1.1%), 13C MRS is typically performed following administration of 13C-enriched substrates, which permits tracking of the metabolic fate of the infused 13C in the brain over time, and calculation of metabolic rates in a range of biochemical pathways, including glycolysis, the tricarboxylic acid cycle, and glutamate–glutamine cycling. The advent of new hyperpolarization techniques to transiently boost signal in 13C-enriched MRS in vivo studies shows promise in this field, and further developments are expected.

A key pathophysiological process and therapeutic target in the critical early post-injury period of traumatic brain injury (TBI) is cell mitochondrial dysfunction; characterised by elevation of brain lactate/pyruvate (L/P) ratio in the absence of hypoxia. We previously showed that succinate can improve brain extracellular chemistry in acute TBI, but it was not clear if this translates to a change in downstream energy metabolism. We studied the effect of microdialysis-delivered succinate on brain energy state (phosphocreatine/ATP ratio (PCr/ATP)) with 31P MRS at 3T, and tissue NADH/NAD+ redox state using microdialysis (L/P ratio) in eight patients with acute major TBI (mean 7 days). Succinate perfusion was associated with increased extracellular pyruvate (+26%, p < 0.0001) and decreased L/P ratio (−13%, p < 0.0001) in patients overall (baseline-vs-supplementation over time), but no clear-cut change in 31P MRS PCr/ATP existed in our cohort (p > 0.4, supplemented-voxel-vs-contralateral voxel). However, the percentage decrease in L/P ratio for each patient following succinate perfusion correlated significantly with their percentage increase in PCr/ATP ratio (Spearman's rank correlation, r = −0.86, p = 0.024). Our findings support the interpretation that L/P ratio is linked to brain energy state, and that succinate may support brain energy metabolism in select TBI patients suffering from mitochondrial dysfunction.

PhaseTools enables the substantial increase of signal-to-noise in MRE experiments at negligible additional computational cost. PhaseTools is freely released with this study, making robust real-time phase unwrapping available to any group using phase-based imaging.