Complications of systemic juvenile idiopathic arthritis: risk factors and management recommendations.

Systemic juvenile idiopathic arthritis (SJIA) is an inflammatory condition characterized by fever, lymphadenopathy, arthritis, rash and serositis. Systemic inflammation has been associated with dysregulation of the innate immune system, suggesting that SJIA is an autoinflammatory disorder. IL-1 and IL-6 play a major role in the pathogenesis of SJIA, and treatment with IL-1 and IL-6 inhibitors has shown to be highly effective. However, complications of SJIA, including macrophage activation syndrome, limitations in functional outcome by arthritis and long-term damage from chronic inflammation, continue to be a major issue in SJIA patients' care. Translational research leading to a profound understanding of the cytokine crosstalk in SJIA and the identification of risk factors for SJIA complications will help to improve long-term outcome.

Lower limb lymphedema and neurological complications after lymphadenectomy for gynecological cancer.

OBJECTIVE: Lymphadenectomy is a frequent procedure for surgical staging of gynecological malignancies. Nevertheless, minor complications, such as lower limb lymphedema (LLL) and neurological complications (NCs), after pelvic and aorto-caval lymphadenectomy still remain underinvestigated. The present study considers short-term and long-term incidence and risk factors for LLL and NC in patients with gynecological cancer who underwent lymphadenectomy. MATERIALS AND METHODS: In 2 different institutions, University of Turin and University of Lausanne, a total of 152 patients who received lymphadenectomy for endometrial, cervical, or ovarian cancer were retrospectively identified. During the follow-up, data about LLL and NC were collected by means of a questionnaire. Short-term and long-term incidence of LLL and NC was evaluated, and risk factors, such as age, body mass index, type of cancer, surgical approach, number and extension of the removed lymph nodes, presence of lymph node metastasis, and adjuvant treatments, were analyzed. RESULTS: Short-term incidence of LLL and NC after lymphadenectomy was high (36%) and predictive of long-term persistence. Between the analyzed risk factors, number of removed lymph nodes and adjuvant radiotherapy were significantly associated with an increased incidence of minor complications (P < 0.05). CONCLUSIONS: Lower limb lymphedema and NC are more frequent than expected. They are related to the radicality of lymphadenectomy and adjuvant radiotherapy. They affect the quality of life of the patients treated for gynecological cancer and their perceptions of healing. Minor complications are commonly persistent and need a prompt diagnosis and a specialized management to improve their prognosis.

Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.

Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.