Lack of Il12rb2 signaling predisposes to spontaneous autoimmunity and malignancy

The interleukin-12 receptor beta2 (Il12rb2) gene is silenced in tumor cells from different human B-cell malignancies as opposed to their normal counterparts. It was hypothesized that this silencing allows neoplastic B cells to escape the control exerted by IL-12 on their growth. The aim of this study was to investigate whether targeted inactivation of the Il12rb2 gene in mice resulted into increased susceptibility to spontaneous tumor formation and immunopathology. Il12rb2 gene-deficient animals developed in the first year of life immune-complex mesangial glomerulonephritis with serum antinuclear antibodies. In older animals, multiorgan lymphoid infiltrates with features of vasculitis and Sj?gren syndrome were detected in association with systemic B- and T-cell activation. In half of aged animals, lymph node plasmacytoma or lung carcinoma was observed. A mechanism for spontaneous development of autoimmune pathology and B-cell tumors is suggested by a strong IL-6 up-regulation detected in splenocytes and lymphoid infiltrates associated with oligoclonal B-cell expansion. The emergence of lung tumors may likely be attributed to an interferon-gamma (IFN-gamma) deficiency secondary to lack of IL-12 signaling. The development of autoimmunity, lymphoproliferation, and B-cell tumors in Il12rb2 knockout (KO) mice suggests that IL-12 functions physiologically to restrain aberrant B-cell activation.     

Activity of GH/IGF-I axis in trauma and septic patients during artificial nutrition: different behavior patterns?

The aim of this study was to compare several parameters of GH/IGF-I axis activity in septic and trauma patients during Intensive Care Unit (ICU) stay. To this goal, 13 patients with sepsis (SEP) and 16 with trauma (TRA) were studied. Thirty-three adult subjects (AS) were studied as controls. Serum IGF-I and -II, IGFBP-1, -2 and -3, GH and GHBP levels were studied on day 1, 3, 5 and 7 after ICU admission, during comparable artificial nutrition in SEP and TRA and basally in AS. In 5 patients with SEP and 6 with TRA, the GH response to GHRH was evaluated on day 3. On ICU day 1, IGF-I and -II and IGFBP-3 in SEP were lower (p<0.05) than in TRA which, in turn, were lower (p<0.01) than in AS. IGF-I increased (p<0.05) both in SEP and TRA, but, on ICU day 7, those in SEP persisted lower than in TRA, which became similar to those in AS. IGF-II levels increased (p<0.05) in SEP only, persisting lower (p<0.05) than in TRA. On ICU day 1, GH in SEP and TRA were similar and did not vary until day 7, overlapping those in AS. The GH response to GHRH in SEP and TRA was similar and lower (p<0.01) than in AS. These findings indicate that IGF-I activity is impaired more in septic than in trauma patients. Reduced IGF-I activity probably reflects peripheral GH resistance though basal and GHRH-induced GH levels were not increased in these conditions.     

Long-term effects of pneumatic dilatation on symptoms and lower oesophageal sphincter pressure in achalasia

BACKGROUND: Pneumatic dilatation is an effective treatment for achalasia. Although follow-up studies have shown that its clinical benefit persists for years, it is still unknown whether the decrease in lower oesophageal sphincter (LOS) pressure is maintained over time. Our aim is to assess the long-term effects of pneumatic dilatation on symptoms and LOS pressure in patients with idiopathic achalasia. METHODS: Eleven consecutive patients with achalasia (7 men) underwent I (n = 5) or 2 (n = 6) pneumatic dilatations (Rigiflex dilator) in order to achieve a stable (>1 year) clinical remission. Clinical scores (0-12, with scores of <3 indicating remission) and LOS pressure (sleeve manometry) were determined before treatment, after 3 and 12 months, and then every year for 6 years. RESULTS: No operative complications occurred. The patients showed a marked clinical improvement (2.0 (2.0-2.0), median (IQ range), after 3 months versus 8.0 (7.2-9.0) before treatment; P < 0.001), which was maintained throughout the follow-up period. Concurrently, there was a marked decrease in LOS pressure (5.0 (4.0-7.0) mmHg after 3 months versus 25.0 (20.0-36.2) before treatment; P < 0.001), which also remained stable over time. CONCLUSIONS: One or two pneumatic dilatations induce stable clinical remission and a decrease in LOS pressure that remains unchanged over time. Our data further support the use of dilatations as first-line treatment of achalasia.     

Restenosis rate after percutaneous transluminal coronary angioplasty: a literature overview

In order to elucidate factors affecting the rate of angioplasty restenosis, we reviewed 212 published reports on restenosis after percutaneous transluminal coronary angioplasty. We used five specific methodologic standards to select the 31 reports most likely to produce unbiased results. Sixty one factors judged to be related to restenosis rate were investigated. Only shorter duration of data collection (p=0.0003) was related to higher restenosis rate. This factor may be related to inexperience in choosing subjects or performing procedures. Other factors whose association with restenosis rate did not reach our predetermined level of statistical significance (p less than .01) were angioplasties of the left circumflex artery (p=.02), angioplasty of total occlusions (p=.02) and advanced age (p=.05). The association of shorter data collection with higher restenosis rates suggests that improved outcome may result from consolidation to a few centers specializing in this technique.     

Efficacy and age-related effects of nitric oxide-releasing aspirin on experimental restenosis

Restenosis after percutaneous transluminal coronary angioplasty is caused by neointimal hyperplasia, which involves impairment of nitric oxide (NO)-dependent pathways, and may be further exacerbated by a concomitant aging process. We compared the effects of NO-releasing-aspirin (NCX-4016) and aspirin (ASA) on experimental restenosis in both adult and elderly rats. Moreover, to ascertain the efficacy of NCX-4016 during vascular aging, we fully characterized the release of bioactive NO by the drug. Sprague-Dawley rats aged 6 and 24 months were treated with NO releasing-aspirin (55 mg/kg) or ASA (30 mg/kg) for 7 days before and 21 days after standard carotid balloon injury. Histological examination and immunohistochemical double-staining were used to evaluate restenosis. Plasma nitrite and nitrate and S-nitrosothiols were determined by a chemiluminescence-based assay. Electron spin resonance was used for determining nitrosylhemoglobin. Treatment of aged rats with NCX-4016 was associated with increased bioactive NO, compared with ASA. NO aspirin, but not ASA, reduced experimental restenosis in old rats, an effect associated with reduced vascular smooth muscle cell proliferation. NCX-4016, but not ASA, was well tolerated and virtually devoid of gastric damage in either adult or old rats. Thus, impairment of NO-dependent mechanisms may be involved in the development of restenosis in old rats. We suggest that an NCX-4016 derivative could be an effective drug in reducing restenosis, especially in the presence of aging and/or gastrointestinal damage.     

Endovascular stenting for stenoses in surgically reconstructed brachiocephalic bypass grafts: immediate and midterm outcomes.

PURPOSE: To report the use of endovascular stenting for treatment of patients with symptomatic obstruction of brachiocephalic surgical reconstructions. METHODS: Twenty-two patients (17 men; mean age 65+/-6 years) with 24 symptomatic obstructions of brachiocephalic Dacron bypass grafts (2 aorto-innominate, 9 subclavian-carotid, and 11 carotid-subclavian) were treated with balloon-expandable stents delivered via a percutaneous brachial access or surgical exposure of the common carotid artery. A distal protection device was utilized in the 9 patients with subclavian-carotid bypass grafts. All patients were followed by clinical and Doppler examinations. RESULTS: Procedural success was 100%; 1 (4.5%) patient developed transient intraprocedural aphasia owing to intolerance to the distal protection balloon occlusion. All 22 patients reported complete relief of their presenting symptoms. Over a 29-month follow-up, 3 (13.6%) restenoses were found, but none was due to stent compression. CONCLUSIONS: Stenting for obstructed brachiocephalic reconstructions appears to be a safe, effective, and durable therapeutic strategy.