Pituitary function in children following infectious diseases of the central nervous system

Recent studies in adults suggest that pituitary deficiencies develop in a considerable proportion of patients who recover from infectious meningitis. The aim of this study was to evaluate pituitary function of children with a history of meningitis. Seventy-nine children were admitted to the Safra Children’s Hospital due to meningitis between 2007 and 2010. Twenty-four families were lost for follow-up, 55 were interviewed by phone and 14 (9 males) participated in the study. Evaluation included medical history, physical examination, auxological measurements and basal levels of TSH, fT4, cortisol and IGF1. Children with abnormal results were followed for a year and dynamic testing was performed when indicated. Mean age at time of infectious meningitis was 3.8 ± 5.4 years (range 0.03–15.8), and at clinical evaluation 6.4 ± 6.4 (range 1.2–20). The interval between the acute event and evaluation was 2.7 ± 1.2 years. Thyroid function tests and basal cortisol levels were normal for all children. Three children had low IGF1 levels; however over a year of follow-up two of them had normal height and growth velocity, making growth hormone deficiency unlikely. One child had low height SDS, but exhibited a normal response to a growth hormone stimulation test. Pituitary dysfunction with overt clinical symptoms is not a frequent consequence of acute meningitis in children. Follow-up of growth and puberty of children post-meningitis by the primary care physician is probably sufficient. Invasive assessments should be reserved for selected cases where there is slow growth or other clinical suspicion of hypopituitarism.     

Pathogenic Bacterial Species Associated with Endodontic Infection Evade Innate Immune Control by Disabling Neutrophils

Endodontic infections, in which oral bacteria access the tooth pulp chamber, are common and do not resolve once established. To investigate the effects of these infections on the innate immune response, we established a mouse subcutaneous chamber model, where a mixture of four oral pathogens commonly associated with these infections (endodontic pathogens [EP]), i.e., Fusobacterium nucleatum, Streptococcus intermedius, Parvimonas micra, and Prevotella intermedia, was inoculated into subcutaneously implanted titanium chambers. Cells that infiltrated the chamber after these infections were primarily neutrophils; however, these neutrophils were unable to control the infection. Infection with a nonpathogenic oral bacterial species, Streptococcus mitis, resulted in well-controlled infection, with bacterial numbers reduced by 4 to 5 log units after 7 days. Propidium iodide (PI) staining of the chamber neutrophils identified three distinct populations: neutrophils from EP-infected chambers were intermediate in PI staining, while cells in chambers from mice infected with S. mitis were PI positive (apoptotic) or negative (live). Strikingly, neutrophils from EP-infected chambers were severely impaired in their ability to phagocytose and to generate reactive oxygen species in vitro after removal from the chamber compared to cells from S. mitis-infected chambers. The mechanism of neutrophil impairment was necrotic cell death as determined by morphological analyses. P. intermedia alone could induce a similar neutrophil phenotype. We conclude that the endodontic pathogens, particularly P. intermedia, can efficiently disable and kill infiltrating neutrophils, allowing these infections to become established. These results can help explain the persistence of endodontic infections and demonstrate a new virulence mechanism associated with P. intermedia.     

The association between systolic blood pressure reduction during clonidine suppression testing and the decrease in plasma catecholamines and metanephrines

Borderline isolated norepinephrine (NE) and normetanephrine (NMT) elevation is common among patients with suspected pheochromocytoma and paraganglioma (PPGL). The clonidine suppression test (CST) may help establish the etiology in these cases. Prolonged laboratory processing and/or paucity of reliable biochemical assays may limit the utility of CST. The aim of this study was to evaluate whether blood pressure (BP) reduction during CST is associated with alterations in plasma NMT/NE, thereby potentially providing an immediate indication of CST results. In this cross‐sectional study, the authors included all consecutive patients with suspected PPGL who underwent CST from January 1, 2014, to December 31, 2019. Linear regression models were conducted to evaluate the association between BP reduction and decrease in plasma NMT/NE. The final analysis included 36 patients (17 males). The decrease in systolic BP (SBP) 90 minutes postclonidine was associated with a decrease in plasma NMT (R = 0.668, P = .025) and NE (R = 0.562, P = .005). A 40% decrease in NMT and NE correlated with a 9.74% and 7.16% decrease in SBP, respectively. Subgroup analyses demonstrated that the association between SBP reduction and the decrease in plasma NMT (R = 0.764, P = .046) and NE (R = 0.714, P = .003) strengthens among patients with hypertension and among those with diabetes mellitus (R = 0.974, P = .026 for NMT). In conclusion, SBP reduction during CST is associated with plasma NMT and NE decrease. Therefore, the decrease in SBP 90 minutes postclonidine may serve as an immediate complementary clinical tool for PPGL diagnosis.     

Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the pro-atherogenic effects of interleukin-1 in apoE-deficient mice

ObjectiveRecent studies indicate that regulatory T cells (Tregs) attenuate murine atherosclerosis. Since interleukin (IL)-2 induces Tregs proliferation, we tested the impact of L19-IL2, a fusion antibody specific to extra-domain B of fibronectin (ED-B) containing an active human IL-2 molecule, in experimental atherosclerosis.Methods and resultsL19-IL2 or appropriate controls were given intravenously to 6 month old Western diet-fed apoE^?/? mice on day 1, 3, and 5. Human IL-2 was detected on day 7 within atherosclerotic plaques of L19-IL2-treated mice, and magnetic resonance imaging of the plaques showed a significant adventitial gadolinium enhancement on day 7 and 13, suggesting microvascular leakage as a result of the pharmacodynamic activity of L19-IL2. Treatment with L19-IL2 significantly reduced the size of pre-established atherosclerotic plaques at the thoracic aorta (Sudan III stained area) and in the aortic root area (microscopic, morphometric analysis) on day 7 as compared to controls (L19, D1.3-IL2, NaCl) as well as compared to baseline (day 0). Tregs markers Foxp3 and CTLA4 were highly increased in plaques after L19-IL2 treatment compared to controls (p < 0.01), whereas the macrophage marker Mac3 was significantly reduced (p < 0.03). Co-treatment with IL-2-receptor blocking antibody PC61 abrogated L19-IL2-induced plaque reduction compared with IgG control (p < 0.03).ConclusionL19-IL2 delivers functional IL-2 to pre-established atherosclerotic plaques of WD-fed apoE^?/? mice resulting in significant plaque size reduction mediated by local Tregs.