Scoliosis and rare diseases: our experience with the Prader-Willi syndrome.

INTRODUCTION: Prader-Willi syndrome (PWS) represents a difficult challenge for spine surgeons, due to the association of a structural scoliosis, with a prevalence between 15 and 86%. Conservative therapy is a viable option, but surgery is increasingly becoming the treatment of choice. METHODS: The authors reviewed a series of 15 patients affected by PWS treated at their institution between 2008 and 2023. The mean age at index treatment was 9 years and 3 months (range 1-15 years) with a prevalence of female subjects. Primary scoliotic curve ranged from 14 to 102°, and mean thoracic kyphosis was 56° (range 20-75°). Eleven patients underwent conservative treatment, while four were treated surgically. RESULTS: Mean follow-up was 5 years and 3 months (range 2-12 years). Among the 11 patients treated conservatively, only two showed improvements of the coronal curve, while the remaining nine displayed a worsening of the deformity during follow-up. Complication rate after surgery was 75%. One patient developed paraplegia after pedicle screw positioning. One patient displayed rod breakage and PJK that required revision surgery proximally. Hardware deep infection was seen in one case where it was necessary to proceed with instrumentation removal after 10 years. DISCUSSION AND CONCLUSIONS: Spine surgery represents a convincing option in patients affected by PWS, but the risks of complications are high. Correct patient selection must be the main objective, and multilevel pedicle screw fixation should be the procedure of choice. Traditional growing rod should be prudently evaluated in every single case.

Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses.

Mesenchymal stromal cells (MSCs) support hematopoiesis and exert immunoregulatory activities. Here, we analyzed the functional outcome of the interactions between MSCs and monocytes/macrophages. We showed that MSCs supported the survival of monocytes that underwent differentiation into macrophages, in the presence of macrophage colony-stimulating factor. However, MSCs skewed their polarization toward a peculiar M2-like functional phenotype (M(MSC) ), through a prostaglandin E2-dependent mechanism. M(MSC) were characterized by high expression of scavenger receptors, increased phagocytic capacity, and high production of interleukin (IL)-10 and transforming growth factor-ß. These cytokines contributed to the immunoregulatory properties of M(MSC) , which differed from those of typical IL-4-induced macrophages (M2). In particular, interacting with activated natural killer (NK) cells, M(MSC) inhibited both the expression of activating molecules such as NKp44, CD69, and CD25 and the production of IFNγ, while M2 affected only IFNγ production. Moreover, M(MSC) inhibited the proliferation of CD8(+) T cells in response to allogeneic stimuli and induced the expansion of regulatory T cells (Tregs). Toll-like receptor engagement reverted the phenotypic and functional features of M(MSC) to those of M1 immunostimulatory/proinflammatory macrophages. Overall our data show that MSCs induce the generation of a novel type of alternatively activated macrophages capable of suppressing both innate and adaptive immune responses. These findings may help to better understand the role of MSCs in healthy tissues and inflammatory diseases including cancer, and provide clues for novel therapeutic approaches. Stem Cells 2016;34:1909-1921.

Upper limb nerve injuries in developmental age.

Our series includes 105 children with peripheral nerve injuries of the upper limb due to trauma. The aim of this study is to validate our therapeutic approach to peripheral nerve injuries of the upper limb in children and to identify the suitable waiting time before surgical exploration. Case series examination included evaluation of (1) type of lesion; (2) topographical site of nerve injury; (3) motor and sensory outcome; (4) recovery time; (5) results after surgery. Open injuries (Sunderland V) received immediate treatment with direct suturing or nerve grafts or biological tubules in case of loss of nerve substance. After closed nerve injury, a waiting period of variable duration should precede surgery. Most of the cases had peripheral nerve injuries associated to fracture and cutting lesions followed by injuries due to other causes. Open or closed injuries of the median and radial nerves had a generally favorable prognosis, whereas ulnar nerve injuries (both isolated and associated) had a poor prognosis. Stable skeletal fixation is essential in fractures at risk of nerve involvement. During nerve exploration, secondary surgery interventions were never associated. In the absence of adequate clinical and instrumental response, the authors suggest to resort to nerve surgery at 6 months from injury to accelerate recovery time. Secondary surgery should be delayed as patient's recovery time can be very long. (c) 2009 Wiley-Liss, Inc. Microsurgery, 2009.

MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2.

Various studies analyzed the inhibitory effect exerted by mesenchymal stem cells (MSCs) on cells of the innate or acquired immunity. Myeloid dendritic cells (DCs) are also susceptible to such inhibition. In this study, we show that MSCs strongly inhibit DC generation from peripheral blood monocytes. In the presence of MSCs, monocytes supplemented with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) did not acquire the surface phenotype typical of immature (CD14(-), CD1a(+)) or mature (CD80(+), CD86(+), CD83(+)) DCs, failed to produce IL-12, and did not induce T-cell activation or proliferation. Analysis of the molecular mechanism(s) responsible for the inhibitory effect revealed a major role of prostaglandin E(2) (PGE(2)). Thus, addition of the PGE(2) inhibitor NS-398 restored DC differentiation and function. Moreover, PGE(2) directly added to cultures of monocytes blocked their differentiation toward DCs in a manner similar to MSCs. Although IL-6 has been proposed to play a role in MSC-mediated inhibition of DC differentiation, our data indicate that PGE(2) and not IL-6 represents the key inhibitory mediator. Indeed, NS-398 inhibited PGE(2) production and restored DC differentiation with no effect on IL-6 production. These data emphasize the role of MSCs in inhibiting early DC maturation and identifying the molecular mechanisms responsible for the inhibitory effect.

Sciatic nerve injection palsy in the child: early microsurgical treatment and long-term results.

Sciatic nerve injury caused by intramuscular injection in the gluteal region in the child seems as a sensory-motor palsy of the lower limb of variable degree. In preterm children or in children with severe perinatal distress, requiring intensive care, a drop foot is often missed or misdiagnosed as a malformative clubfoot or late diagnosed. Intramuscular drug injection (mainly antibiotics) during early infancy is another cause of injury. There are very few literature reports on postinjection trauma and on therapeutic indications in the child. The Authors report their experience in early microsurgical exploration of the sciatic nerve. From 1990 to 2004, we observed at different times from diagnosis 17 children with sciatic nerve palsy following intramuscular injection. Nine of them underwent nerve exploration surgery in the gluteal region (neurolysis in seven and nerve grafting in two). Conservative treatment was successful in only three cases showing early signs of recovery (at about 3 months of life). Complete recovery was observed only in five early treated cases, while late treated cases had only mild improvement after surgery. During surgery, anatomical variations predisposing to nerve injury were observed. The authors havingobserved better results and faster recovery in the early treated patients, stress the importance of a rapid therapeutic decision to avoid or limit foot deformities, sensory defects and lower limb length discrepancy due to paralysis during growth.

Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2.

Recently, a number of clinical trials used either mesenchymal stem cells (MSCs) or natural killer (NK) cells in an attempt to improve the effectiveness of hematopoietic stem cell transplantation (HSCT). In view of the relevant role of both MSCs and NK cells in HSCT, we have recently explored the result of possible interactions between the 2 cell types. We found that activated NK cells could kill MSCs, whereas MSCs strongly inhibited interleukin-2 (IL-2)-induced NK-cell proliferation. In this study, we further analyzed the inhibitory effect exerted by MSCs on NK cells. We show that MSCs not only inhibit the cytokine-induced proliferation of freshly isolated NK cells but also prevent the induction of effector functions, such as cytotoxic activity and cytokine production. Moreover, we show that this inhibitory effect is related to a sharp down-regulation of the surface expression of the activating NK receptors NKp30, NKp44, and NKG2D. Finally, we demonstrate that indoleamine 2,3-dioxygenase and prostaglandin E2 represent key mediators of the MSC-induced inhibition of NK cells.

Lower limb nerve injuries in children.

The aim of this paper is to emphasize the seriousness of pediatric peripheral nerve injuries of lower limbs and to stress the importance of early exploration of the injured nervous trunk in order to reduce the number of unfavorable outcomes. Among 136 traumatic peripheral nerve injuries in the children we treated, 31 nerve injuries of the lower limbs were observed. Causes of injury and time to recovery were evaluated. The sciatic nerve was involved in 19 cases, peroneal nerve in 11, root avulsions of the spinal cord in 1. We observed complete recovery in 12 cases and incomplete or no recovery at all in 19. The mean time to recovery in patients who underwent surgery was 18 months (range: 1-32). Considering the rate of spontaneous recovery of postinjection nerve injuries of the sciatic nerve and early onset of skeletal deformities, a closed nerve injury of the lower limb with no recovery within 3 months should always undergo surgery, even if complete functional outcome is not always guaranteed.