Successful anti-TNF-α treatment in a girl with LAD-1 disease and autoimmune manifestations.

Leukocyte adhesion deficiency type 1 (LAD-1) is an autosomal recessive disorder, caused by the absence or reduced expression of the beta-2 integrins on granulocytes, and characterized by the inability of these cells to emigrate from the bloodstream towards the sites of tissue inflammation. A twelve-year-old girl with a diagnosis of LAD-1 syndrome and recurrent skin and mucosal infections since birth, presented with a two week history of fever, abdominal pain, vomiting, weight loss and polyarthralgia. She underwent an exploratory laparotomy with the finding of inflamed terminal ileum and colon and a normal appendix. Colonoscopy and videocapsule endoscopy showed multiple ileal and colonic mucosal ulcerations, which were compatible with inflammatory bowel disease, confirmed on histological examination. Given the lack of response to conventional therapy (prednisone and mesalamine), a monoclonal anti-TNF-α antibody was started at a dosage of 5 mg/kg at weeks 0,2,4,6 and then every 8 weeks. We observed a significant improvement of all clinical and laboratory parameters after the first weeks of therapy. Five months later, we anticipated the drug's administration every 5 weeks because of a precocious recurrence of symptoms. After 30 months of treatment no relapse nor any relevant side effects have been observed, and corticosteroids were withdrawn. Interestingly, our patient presented a small subset of CD18+ T cells, similarly to previously reported LAD-1 patients with mild phenotype, inflammatory bowel disease and CD18+ somatic revertant T cells. To the best of our knowledge, this is the first LAD-1 pediatric patient with inflammatory autoimmune complications who experienced a positive response to anti-TNF-α treatment.

Non-tuberculous mycobacterial osteomyelitis: an unusual cause of hip pain in immunocompetent children.

Non-tuberculous mycobacteria (NTM) are an unusual cause of osteomyelitis in immunocompetent children. Diagnosis is often difficult due to the paucity of clinical symptoms and a subtle course of the disease. NTM comprise a group of about 91 identified species of environmental mycobacteria that cause infections most frequently in immunocompromised individuals or in patients with predisposing factors. Cervical lymphadenitis is the most common presentation of NTM infection in children. Invasive and recurrent infections with these organisms have been associated with a genetic defect of the interferon gamma-receptor. We report a 3-year-old immunocompetent girl who presented a NTM osteomyelitis of the left femur. Four months before she had been treated with medical and surgical therapy for a mycobacterium avium complex cervical lymphadenitis. Polymerase chain reaction assay on bone aspirate specimens confirmed the diagnosis of mycobacterium avium osteomyelitis. The patient was treated successfully with clarithromycin and rifampicin for 6 months.

Peroxisome proliferator-activated receptor-gamma agonists and diabetes: current evidence and future perspectives.

Since their initial availability in 1997, the thiazolidinediones (TZDs) have become one of the most commonly prescribed classes of medications for type 2 diabetes. In addition to glucose control, the TZDs have a number of pleiotropic effects on myriad traditional and non-traditional risk factors for diabetes. TZDs may benefit cardiovascular parameters, such as lipids, blood pressure, inflammatory biomarkers, endothelial function and fibrinolytic state. In this review, we summarise the experimental, preclinical and clinical data regarding the effects of the TZDs in conditions for which they are indicated and discuss their potential in the treatment of other conditions.

Long-term follow-up of children treated for acute lymphoblastic leukemia and the recovery of beta-cell function.

We studied the evolution of beta-cell function in 32 children treated for acute lymphoblastic leukemia (ALL) through a long-term follow-up after completion of therapy. Our results show that although alterations of the glucose metabolism persists after stop-therapy they are reversible with time.

Effects of irbesartan on intracellular antioxidant enzyme expression and activity in adolescents and young adults with early diabetic angiopathy.

OBJECTIVE: Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with diabetic nephropathy. The objective of this study was to evaluate the effects of irbesartan, an angiotensin II receptor antagonist, on IAP in adolescents and young adults with type 1 diabetes and early signs of retinopathy and nephropathy. RESEARCH DESIGN AND METHODS: This prospective, matched case-control study was conducted between November 2001 and December 2002 among 14 type 1 diabetic patients with early signs of angiopathy (ages 14-21 years), 11 type 1 diabetic patients without angiopathy (ages 12-22 years), and 10 healthy volunteers (ages 16-22 years). Skin fibroblasts were obtained by skin biopsies from the anterior part of the forearm and cultured in Dulbecco's modified Eagle's medium. The activity and mRNA expression of CuZn superoxide dismutase (CuZnSOD), Mn superoxide dismutase (MnSOD), catalase (CAT), and glutathione peroxidase (GPX) were measured before and after 6 months of treatment with irbesartan (150 mg/day); on both occasions, antioxidant enzyme activity was evaluated at different glucose concentrations (5 and 22 mmol/l). RESULTS: At a normal glucose concentration (5 mmol/l), the activity and mRNA expression of CuZnSOD (0.50 +/- 0.21 units/mg protein, 4.4 +/- 1.5 mRNA/glyceraldehyde-3-phosphate dehydrogenase), MnSOD (0.26 +/- 0.04 units/mg protein, 0.08 +/- 0.07 mRNA), CAT (0.32 +/- 0.08 units/mg protein, 4.8 +/- 1.3 mRNA), and GPX (0.53 +/- 0.09 units/mg protein, 2.2 +/- 0.9 mRNA) were not different among the three groups (only values of diabetic subjects with angiopathy are shown). At high glucose concentrations, the activity and mRNA expression of CuZnSOD increased similarly in all groups (diabetic subjects with angiopathy: 0.93 +/- 0.26 units/mg protein, 9.4 +/- 2.1 mRNA); that of CAT and GPX increased in only control subjects and diabetic subjects without angiopathy (diabetic subjects with angiopathy: 0.33 +/- 0.09 units/mg protein and 5.0 +/- 1.4 mRNA; 0.54 +/- 0.10 units/mg protein and 2.3 +/- 1.0 mRNA, respectively). MnSOD did not change in any group. Treatment with irbesartan in adolescents with diabetic angiopathy was able to restore CAT and GPX activity and mRNA expression after exposure to high glucose concentrations. Markers of oxidative stress (serum malondialdehyde, fluorescent products of lipid peroxidation, monocyte chemoattractant protein-1, and 8-isoprostanes prostaglandin F(2alpha)) were significantly reduced after treatment with irbesartan. CONCLUSIONS: Adolescents and young adults with early signs of diabetic angiopathy have defective intracellular antioxidant enzyme production and activity. Treatment with irbesartan can substantially improve the activity and production of these enzymes in skin fibroblasts.

Treating diabetic retinopathy by tackling growth factor pathways.

Diabetic retinopathy (DR) remains a major cause of new cases of blindness onset in adults. The prevalence of diabetic eye disease is strongly related to the duration of diabetes, blood pressure and glycemic control, although a multifactorial pathogenesis is likely to be probable. Despite the effectiveness of current prevention (by tight metabolic and blood pressure control) and treatment (with laser photocoagulation) methods, and with the help of screening programs, diabetic eye disease is still a problem. Recent advances in our understanding of the pathogenesis of microvascular complications and particularly of the role of growth factors (GFs) in retinal changes have allowed significant advances in the medical management of DR. Studies of the biochemical process underlying DR have clearly demonstrated an important role for a number of aberrantly expressed GFs or their second messengers (eg, vascular endothelial growth factor, growth hormone, insulin-like growth factor-1, protein kinase C and pigment epithelium derived factor) possibly acting together in the development of structural changes characterizing early stages of vascular DR. The critical role of GF expression has led to new experimental therapeutic intervention in DR. In fact, timely pharmacological intervention in GF synthesis and activities may arrest the development of early vascular changes. As the effects of GFs become better understood, pharmacological manipulation of GF synthesis and action will be useful in the early stages of vascular change with the potential to prevent diabetes-related visual loss.