Reduction of urinary 8-epi-prostaglandin F2α during cyclo-oxygenase inhibition in rats but not in man

1. 8-epi-prostaglandin (PG) F_2α, a major F₂ isoprostane, is produced in vivo by free radical-dependent peroxidation of lipid-esterified arachidonic acid. Both cyclo-oxygenase isoforms (COX-1 and COX-2) may also form free 8-epi-PGF_2α as a minor product. It has been recently seen in human volunteers that the overall basal formation of 8-epi-PGF_2α in vivo is mostly COX-independent and urinary 8-epi-PGF_2α is therefore an accurate marker of ‘basal'' oxidative stress in vivo.
2. To test the validity of this marker in the rat, we evaluated in vivo the effect of COX inhibition on the formation of 8-epi-PGF_2α vs prostanoids. Two structurally unrelated COX inhibitors (naproxen: 30 mg kg⁻¹ day⁻¹; indomethacin: 4 mg kg⁻¹ day⁻¹) were given i.p. to rats kept in metabolic cages. In vivo formation of 8-epi-PGF_2α was assessed by measuring its urinary excretion. Prostanoid biosynthesis was assessed by measuring urinary excretion of major metabolites of thromboxane (TX) and prostacyclin (2,3-dinor-TXB₁ and 2,3-dinor-6-keto-PGF_1α). All compounds were selectively measured by immunopurification/gas chromatography-mass spectrometry.
3. Naproxen reduced urinary excretion of 2,3-dinor-TXB₁ and 2,3-dinor-6-keto-PGF_1α but, unexpectedly, also that of 8-epi-PGF_2α (82, 49 and 52% inhibition, respectively). Indomethacin had a similar effect (77, 69 and 55% inhibition). Esterified 8-epi-PGF_2α in liver and plasma remained unchanged after indomethacin.
4. These findings prompted us to re-assess the contribution of COX activity to the systemic production of 8-epi-PGF_2α in man. We gave naproxen (1 g day⁻¹) to healthy subjects (four nonsmokers and four smokers). Urinary 8-epi-PGF_2α remained unchanged in the two groups (9.63±0.99 before vs 10.24±1.01 after and 20.14±3.00 vs 19.03±2.45 ng h⁻¹ 1.73 m⁻²), whereas there was a marked reduction of major urinary metabolites of thromboxane and prostacyclin (about 90% for both 11-dehydro-TXB₂ and 2,3-dinor-TXB₂; >50% for 2,3-dinor-6-keto-PGF_1α).
5. To investigate whether rat COX-1 produces 8-epi-PGF_2α more efficiently than human COX-1, we measured the ex vivo formation of 8-epi-PGF_2α and TXB₂ simultaneously in whole clotting blood. Serum levels of 8-epi-PGF_2α and TXB₂ were similar in rats and man.
6. We conclude that a significant amount of COX-dependent 8-epi-PGF_2α is present in rat but not in human urine under normal conditions. This implies that urinary 8-epi-PGF_2α cannot be used as an index of near-basal oxidant stress in rats. On the other hand, our data further confirm the validity of this marker in man.

     

Percutaneous transluminal renal angioplasty in patients with solitary kidney

We report our experience with percutaneous transluminal angioplasty of renal arteries (PTRA) in solitary kidney patients. Our series includes 31 patients (mean age: 52 years). 7 with solitary kidney following surgical nephrectomy and 24 with functioning solitary kidney. PTR indicated in presence of stenoses ranging from 60–95 % of vessel lumen. Procedure, with 29 patients were technically successful and mean values for stenosis dropped from 77 % to 33 %. In order to assess the results technically, changes in arterial blood pressure (according to Martin's classification) and creatinine levels were considered. Of 25 followed-up patients, 13 were cured (52%), 8 improved (32%),and 4 were unchanged (16%%). Complications were observed during procedures in five patients (16. 1 % ), superimposing that of nonsolitary kidney patients. Good revasculariiation, reduction of blood pressure, preservation or even improvement of renal function and low complications, make PTRA the best procedure with solitary kidney patients.     

Approach and treatment of the adult acquired flatfoot deformity

Adult acquired flatfoot deformity (AAFD), embraces a wide spectrum of deformities. AAFD is a complex pathology consisting both of posterior tibial tendon insufficiency and failure of the capsular and ligamentous structures of the foot. Each patient presents with characteristic deformities across the involved joints, requiring individualized treatment. Early stages may respond well to aggressive conservative management, yet more severe AAFD necessitates prompt surgical therapy to halt the progression of the disease to stages requiring more complex procedures. We present the most current diagnostic and therapeutic approaches to AAFD, based on the most pertinent literature and our own experience and investigations.     

Endograft infection following emergency repair for abdominal aortic aneurysm dissection and the undervalued role of the bowel reservoir

Endograft infection after emergency endovascular aortic repair (EVAR) procedure has received less attention than other complications, and usually occurs soon after endograft positioning. Consequently, clear guidelines for the prevention and treatment of endograft infection have yet to come. We report a case of an 85‐year‐old patient treated with an emergency EVAR procedure for a fissured abdominal aortic aneurysm, whose immediate follow up was complicated by a prolonged upper gastrointestinal occlusion. Six months, later he developed an endograft infection due to intestinal flora. After exclusion of all other possible causes, bacterial translocation from the bowel appeared the only plausible mechanism. This case highlights the importance of the gastrointestinal tract as a potential source of endograft infection, and suggests how a clinical condition representing potential reservoir of infection should be managed properly.     

SRC homology-2-containing protein tyrosine phosphatase-1 restrains cell proliferation in human medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a rare tumor originating from thyroid parafollicular C cells, where, in the inherited form, constitutive activation of the RET protooncogene is responsible for unrestrained cell proliferation. We previously demonstrated that somatostatin (SRIF) reduces cell growth in the human MTC cell line TT, which expresses all SRIF receptor (SSTR) subtypes and responds differently to selective SSTR agonists. The antiproliferative mechanism of SRIF and its analogs in MTC is still unclear. Src homology-2-containing protein tyrosine phosphatase-1 (SHP-1), a cytoplasmic protein tyrosine phosphatase (PTP), is activated by somatotropin release-inhibiting factor and reduces mutated RET autophosphorylation in a heterologous system. In this study, we explore the role of PTP activation, in particular of SHP-1, in TT cells, where RET is constitutively activated. In TT cells, SRIF stimulated the PTP activity of SHP-1, which was associated with proliferation inhibition and with reduction in the MAPK pathway activation. Blockade of PTP activity with sodium orthovanadate induced cell proliferation and MAPK phosphorylation and blunted the inhibitory effects of SRIF. Moreover, SHP-1 associates with SSTR2 depending on its activation. By using a MAPK kinase inhibitor, we demonstrated that TT cell growth depends on MAPK pathway activation. Furthermore, in TT cells overexpressing SHP-1, cell proliferation and MAPK signaling were strongly down-regulated, whereas in TT cells transfected with a dominant negative form of SHP-1, cell proliferation and MAPK signaling were markedly induced. Our data demonstrate that SRIF inhibitory effects on TT cell proliferation are mediated, at least in part, by SHP-1, which acts through a MAPK-dependent mechanism.