Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders. Treg cells represent the most actively replicating compartment within the CD4(+) cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)-signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and extracellular signal-related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.

Preschool referral to a PCD center was not associated with better spirometry or BMI. PCD children and adolescents receiving centralized care show steady BMI and spirometry during medium term follow-up. There was a high prevalence of Pseudomonas aeruginosa infection, but the evolution of spirometry or BMI was not affected by this microorganism in medium term. Despite our longitudinal analysis showed no differences between the three centers, the assessment of spirometry and BMI over time represents a quality improvement tool. Future studies are needed to highlight the role of spirometry and BMI in long term PCD management and identify subgroups of patients with a higher risk of early lung failure or nutritional problems.

No abstract

Clinical and experimental data, together with epidemiological studies, have suggested that the pathogenesis of multiple sclerosis (MS) might involve factors that link the immune system with metabolic status. Moreover, recent research has shown that leptin, the adipocyte-derived hormone that controls food intake and metabolism, can promote experimental autoimmune encephalomyelitis, an animal model of MS. In patients with MS, the association of leptin with disease activity has been dissected at the molecular level, providing new mechanistic explanations for the role of this hormone in MS. Here, we review the intricate relationship between leptin and other metabolic modulators within a framework that incorporates the latest advances linking the CNS, immune tolerance and metabolic status. We also consider the translational implications of these new findings for improved management of MS.

Despite its extensive use, there is no evidence that spirometry is useful in the assessment of progression of lung disease in primary ciliary dyskinesia (PCD). We hypothesize that high-resolution computed tomography (HRCT) is a better indicator of PCD lung disease progression than spirometry. We retrospectively evaluated two paired spirometry and HRCT examinations from 20 PCD patients (age, 11.6 years; range, 6.5-27.5 years). The evaluations were performed in stable state and during unstable lung disease. HRCT scans were scored blind by two raters. Compared to the first assessment, at the second evaluation spirometry did not change while HRCT scores significantly worsened (P < 0.01). Age was significantly related to HRCT total (r = 0.5; P = 0.02) and bronchiectasis scores (r = 0.5; P = 0.02). At both evaluations, HRCT total score correlated with FEV(1) (r = -0.5, P = 0.01; r = -0.7, P = 0.001, respectively) and FVC Z scores (r = -0.6, P = 0.006; r = -0.7, P = 0.001, respectively), and bronchiectasis score was related to FEV(1) (r = -0.5, P = 0.03; r = -0.6; P = 0.002, respectively) and FVC Z scores (r = -0.6, P = 0.008; r = -0.7, P = 0.001, respectively). No relationship was found between the change in HRCT scores and the change in spirometry. In PCD, structural lung disease may worsen despite spirometry being stable.

Advances in prenatal and postnatal diagnosis, perioperative management, and postoperative care have dramatically increased the number of scientific reports on congenital thoracic malformations (CTM). Nearly all CTM are detected prior to birth, generally by antenatal ultrasound. After delivery, most infants do well and remain asymptomatic for a long time. However, complications may occur beyond infancy, including in adolescence and adulthood. Prenatal diagnosis is sometimes missed and detection may occur later, either by chance or because of unexplained recurrent or persistent respiratory symptoms or signs, with difficult implications for family counseling and substantial delay in surgical planning. Although landmark studies have been published, postnatal management of asymptomatic children is still controversial and needs a resolution. Our aim is to provide a focused overview on a number of unresolved issues arising from the lack of an evidence-based consensus on the management of patients with CTM. We summarized findings from current literature, with a particular emphasis on the vigorous controversies on the type and timing of diagnostic procedures, treatments and the still obscure relationship between CTM and malignancies, a matter of great concern for both families and physicians. We also present an algorithm for the assessment and follow-up of CTM detected either in the antenatal or postnatal period. A standardized approach across Europe, based on a multidisciplinary team, is urgently needed for achieving an evidence-based management protocol for CTM.

Background: Non-cystic fibrosis (CF) bronchiectasis is now identified more often than in the past. Objectives: It was the aim of this study to assess the high-resolution computed tomography (HRCT) localization and extent of bronchiectasis and to determine whether asthma status, atopy and bronchiectasis distribution are associated with the etiology of bronchiectasis. Methods: We retrospectively analyzed clinical, laboratory, functional and HRCT data of 105 children with non-CF bronchiectasis at 2 tertiary respiratory units in Italy. Forty cases had bronchiectasis associated with ongoing underlying conditions, namely primary ciliary dyskinesia, primary immunodeficiency or aspiration. Results: Age at the onset of chronic cough/wheeze and at the first X-ray-documented pneumonia as well as atopy prevalence were lower in patients with ongoing underlying conditions than in those without (p = 0.049, p = 0.003 and p = 0.0008, respectively). In most cases, bronchiectasis was multilobar, and a mean of 2.5 lobes were involved. The right side was more often involved than the left (88 vs. 70%; p = 0.002), and the upper lobes were relatively spared (p < 0.000001). Right lung involvement and multilobar disease were more prevalent in children younger than 2 years at first pneumonia (p < 0.05). Conclusions: Clinical information combined with laboratory data provides additional insights into the characteristics of non-CF bronchiectasis in a large population of Italian children. This study highlights the need for longitudinal evaluations, also using HRCT, of severe and non-resolving pneumonia in children.

To assess the prevalence and possible pathogenetic involvement of raised intracranial pressure in patients presenting with unresponsive chronic migraine (CM), we evaluated the intracranial opening pressure (OP) and clinical outcome of a single cerebrospinal fluid withdrawal by lumbar puncture in 44 consecutive patients diagnosed with unresponsive chronic/transformed migraine and evidence of sinus stenosis at magnetic resonance venography. The large majority of patients complained of daily or near-daily headache. Thirty-eight (86.4 %) had an OP >200 mmH2O. Lumbar puncture-induced normalization of intracranial pressure resulted in prompt remission of chronic pain in 34/44 patients (77.3 %); and an episodic pattern of headache was maintained for 2, 3 and 4 months in 24 (54.6 %), 20 (45.4 %) and 17 (38.6 %) patients, respectively. The medians of overall headache days/month and of disabling headache days/month significantly decreased (p < 0.0001) at each follow-up versus baseline. Despite the absence of papilledema, 31/44 (70.5 %) patients fulfilled the ICHD-II criteria for “Headache attributed to Intracranial Hypertension”. Our findings indicate that most patients diagnosed with unresponsive CM in specialized headache clinics may present an increased intracranial pressure involved in the progression and refractoriness of pain. Moreover, a single lumbar puncture with cerebrospinal fluid withdrawal results in sustained remission of chronic pain in many cases. Prospective controlled studies are needed before this procedure can be translated into clinical practice. Nonetheless, we suggest that intracranial hypertension without papilledema should be considered in all patients with almost daily migraine pain, with evidence of sinus stenosis, and unresponsive to medical treatment referred to specialized headache clinics.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-014-7355-2) contains supplementary material, which is available to authorized users.