The role of CC chemokine receptor 5 (CCR5) in islet allograft rejection

Chemokines are important regulators in the development, differentiation, and anatomic location of leukocytes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4(+) T helper 1 (Th1) cells. We sought to determine the role of CCR5 in islet allograft rejection in a streptozotocin-induced diabetic mouse model. BALB/c islet allografts transplanted into CCR5(-/-) (C57BL/6) recipients survived significantly longer (mean survival time, 38 +/- 8 days) compared with those transplanted into wild-type control mice (10 +/- 2 days; P < 0.0001). Twenty percent of islet allografts in CCR5(-/-) animals without other treatment survived >90 days. In CCR5(-/-) mice, intragraft mRNA expression of interleukin-4 and -5 was increased, whereas that of interferon-gamma was decreased, corresponding to a Th2 pattern of T-cell activation in the target tissues compared with a Th1 pattern observed in controls. A similar Th2 response pattern was also observed in the periphery (splenocytes responding to donor cells) by enzyme-linked immunosorbent spot assay. We conclude that CCR5 plays an important role in orchestrating the Th1 immune response leading to islet allograft rejection. Targeting this chemokine receptor, therefore, may provide a clinically useful strategy to prevent islet allograft rejection.     

Extent of liver resection influences the outcome in patients with cirrhosis and small hepatocellular carcinoma

BACKGROUND: The long-term outcome after resection of hepatocellular carcinoma (HCC) is influenced by parameters related to the tumor and the underlying liver disease. However, the extent of the resection, which can be limited or anatomical (including the tumor and its portal territory), is controversial. METHODS: Among 64 Child-Pugh A patients with cirrhosis who underwent curative liver resection for small HCC (< or = 4 cm) between 1990 and 1996, 34 patients underwent limited resection with a margin width of at least 1 cm, and 30 patients underwent anatomic resection of at least 1 liver segment with complete removal of the portal area containing the tumor. The 2 groups were comparable in terms of epidemiologic and pathologic parameters. The major end points were: (1) in-hospital mortality and morbidity; (2) overall and disease-free survival; and (3) rate and topography of recurrence. RESULTS: The 30-day mortality (6% vs 7%) and morbidity (52% vs 47%) rates after limited and anatomic liver resection were not statistically different. The 5- and 8-year overall survival rates after limited versus anatomic resection were, respectively, 35% versus 54% (P <.05) and 6% versus 45% (P <.05). The 5- and 8-year disease-free survival rates were, respectively, 26% versus 45% and 0% versus 21% (P <.05). Local recurrence was more frequently observed after limited resections than after anatomic resections (50% vs 10%, P <.05). CONCLUSIONS: In patients with cirrhosis and a small HCC, anatomic resection achieves better disease-free survival than limited resection without increasing the postoperative risk. Therefore, anatomical resection should be the treatment of choice and considered as the reference surgical treatment compared with other treatments.     

Comparative study of functional responses and morphometric state of distal radial arteries in male and female

BACKGROUND: Differences can exist in terms of physiology and morphology of blood vessels on the basis of gender. Radial artery is now considered to be the second choice for coronary artery bypass grafting. However, there is a lack of comparative studies on the function and morphometery of radial arteries in female and male patients. METHODS: Radial arteries from 9 female and 9 male patients undergoing coronary artery bypass grafting were used to compare the effects of vasoconstrictors, noradrenaline and 5-hydroxytryptamine, as well as the influence of endothelium-dependent (with methacholine) and endothelium-independent (with sodium nitroprusside) relaxations. Furthermore, morphomteric measurements of smooth muscle thickness, lumen perimeter, lumen area, and intima area (including plaque) of distal radial arteries from female and male patients were also made. RESULTS: Radial arteries from female patients when compared to male patients were significantly more sensitive to the actions of noradrenaline, and somewhat more sensitive towards the actions of 5-hydroxytryptamine. However, no significant differences were found between the relaxant effects of methacholine in radial arteries of female and male patients. In contrast, radial arteries from female patients when compared to male patients were significantly less sensitive to the relaxant effects of sodium nitroprusside. Morphometric measurements of blood vessels from female and male patients revealed that vessels obtained from female patients had a smaller lumen area and perimeter than vessels from male patients. In contrast, there were no significant differences between tunica intima area (including plaque area) or smooth muscle thickness in radial arteries of female patients when compared to male patients. However, the radial arteries from female patients had a significantly greater ratio of tunica intima area (including plaque) to lumen area when compared with radial arteries from male patients. CONCLUSIONS: Differences exist between the functional behavior and morphometery of radial arteries of female and male patients. It is possible that postbypass, radial artery graft may show different characteristics in female versus male patients.     

Greater trochanteric preserving hip arthroplasty in the treatment of infantile septic arthritis: long-term results

Background  

Balanced forces around the hip joint are critical for normal development of the hip joint, so it should be considered in every hip reconstructive procedure.     

Analysis of MGMT promoter methylation status on intraoperative fresh tissue section from frameless neuronavigation needle biopsy: a preliminary study of ten patients

Background

After a brain biopsy, the genetic analysis can fail because of insufficient material, extensive tumor necrosis, and formalin fixation under conditions that adversely affected the quality of the DNA or because the assay result was indeterminant. The freezing of fresh tumor tissue at surgery could greatly improve the success of DNA extraction and methyl guanine methyl transferase (MGMT) promoter methylation testing. The concentration of the DNA samples can also be improved from a withdrawal in an area with a high probability of neoplastic cells.

Methods

The present study reports the results of ten frameless image-guided intracranial needle biopsies from April 2008 until February 2009, among a total of 28 frameless neuronavigation brain biopsy performed from May 2007 to February 2009. The protocol sampling provided withdrawal specimens correlated with neuroimaging characteristics of the lesions. The molecular determination of MGMT promoter was assessed with the nested methylation-specific polymerase chain reaction on fresh or cryopreserved needle bioptic tissue.

Results

The genetic characterization was feasible in all the bioptic samples. The MGMT promoter was methylated in six patients, including a brain infection. The image-guided trajectory of the biopsy and the intraoperative frozen section increased the diagnostic yield.

Conclusions

To the best of the authors' knowledge, this is the first report with the MGMT promoter status analysis on needle bioptic fresh tissue. In the future, the availability of the molecular genetic characterization of a brain tumor before open surgery will provide important information for the optimal treatment.     

Involvement of nitric oxide pathway in the acute anticonvulsant effect of melatonin in mice

Melatonin, the major hormone produced by the pineal gland, is shown to have anticonvulsant effects. Nitric oxide (NO) is a known mediator in seizure susceptibility modulation. In the present study, the involvement of NO pathway in the anticonvulsant effect of melatonin in pentylenetetrazole (PTZ)-induced clonic seizures was investigated in mice. Acute intraperitoneal administration of melatonin (40 and 80 mg/kg) significantly increased the clonic seizure threshold induced by intravenous administration of PTZ. This effect was observed as soon as 1 min after injection and lasted for 30 min with a peak effect at 3 min after melatonin administration. Combination of per se non-effective doses of melatonin (10 and 20 mg/kg) and nitric oxide synthase (NOS) substrate L-arginine (30, 60 mg/kg) showed a significant anticonvulsant activity. This effect was reversed by NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 30 mg/kg), implying an NO-dependent mechanism for melatonin effect. Pretreatment with L-NAME (30 mg/kg) and N(G)-nitro-L-arginine (L-NNA, 10 mg/kg) inhibited the anticonvulsant property of melatonin (40 and 80 mg/kg) and melatonin 40 mg/kg, respectively. Specific inducible NOS (iNOS) inhibitor aminoguanidine (100 and 300 mg/kg) did not affect the anticonvulsant effect of melatonin, excluding the role of iNOS in this phenomenon, while pretreatment of with 7-NI (50 mg/kg), a preferential neuronal NOS inhibitor, reversed this effect. The present data show an anticonvulsant effect for melatonin in i.v. PTZ seizure paradigm, which may be mediated via NO/L-arginine pathway by constitutively expressed NOS.     

Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin

Low-molecular-weight heparins (LMWH) exhibit potent anticoagulant efficacy via their plasmatic effects on thrombin and factor Xa. These agents are also effective in releasing endothelial tissue factor pathway inhibitor (TFPI), the natural inhibitor of tissue factor, and exhibit significant anti-metastatic effects in experimental animal models. However, the potential for bleeding complications has slowed down the more widespread adoption of LMWH therapy in cancer patients. In this study, the effect of a non-anticoagulant form of LMWH (NA-LMWH) on experimental lung metastasis and tumor cell-induced platelet aggregation in vivo was compared to the LMWH enoxaparin. Using the B16 melanoma mouse model of metastasis, subcutaneous (s.c.) injection of NA-LMWH or enoxaparin (10 mg/kg), three hours before intravenous (i.v.) injection of metastatic melanoma cells, followed by daily doses for 14 days, reduced lung tumor formation by 70% (P < 0.001). I.v. injection of tumor cells resulted in a significant (50-62%, P < 0.01) fall in platelet counts. Pre-injection (i.v.) of enoxaparin completely abolished the tumor cell-induced thrombocytopenia, whereas NA-LMWH had no effect. Four hours after a single s.c. dose, enoxaparin but not NA-LMWH prolonged the clotting time three-fold and delayed the time to clot initiation more than 10-fold as measured by a Sonoclot analyzer and by thromboelastography, respectively. Enoxaparin but not NA-LMWH demonstrated a significant anticoagulant effect in mice. Both NA-LMWH and enoxaparin caused similar TFPI release from endothelial cells in vitro. These data provide evidence to support the potential of NA-LMWH as an anti-metastatic agent without any significant impact on coagulation.     

Comparison of dapoxetine versus paroxetine in patients with premature ejaculation: a double-blind, placebo-controlled, fixed-dose, randomized study

PURPOSE: To compare the efficacy and safety of dapoxetine, paroxetine, and placebo for the oral pharmacotherapy of premature ejaculation. MATERIALS AND METHODS: Three hundred forty potent men with premature ejaculation were recruited to this study. Patients were randomly assigned to receive 60 mg dapoxetine (group 1, n = 115), or 20 mg paroxetine (group 2, n = 113) or placebo (group 3, n = 112) orally daily during a 12-week period for each agent. The efficacy of the 3 treatments was assessed every 2 weeks during treatment and at the end of study using responses to International Index of Erectile Function (IIEF), intravaginal ejaculatory latency time (IELT) evaluation, mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects. RESULTS: At the end of the 12-week treatment with dapoxetine, paroxetine, and placebo, the mean IELT was increased from 38, 31 and 34 seconds to 179, 370 and 55 seconds, respectively (P = 0.01 in group 1 and P = 0.001 in group 2). Baseline mean intercourse satisfaction domain values of International Index of Erectile Function of 10, 11, and 11 reached 14, 17 and 12 at the end of the 12-week treatment in groups 1, 2, and 3 respectively (P = 0.03 in groups 1, 2). The mean weekly intercourse episodes increased from pretreatment values of 1.4, 1.3, and 1.3 to 2.2, 2.5 and 1.4, for dapoxetine, paroxetine and placebo, respectively (P = 0.04 in groups 1, 2). The incidence of adverse effects with dapoxetine and paroxetine was significantly higher (P = 0.04 in groups 1, 2) compared to that of placebo. CONCLUSIONS: Paroxetine appears to provide significantly better results in terms of IELT and intercourse satisfaction versus dapoxetine. Each treatment was well tolerated.     

Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO‐incompatible pancreas and kidney transplantation

Summary We describe the presumably first intentional ABO‐incompatible deceased‐donor kidney and pancreas transplantation with a severe antibody‐mediated rejection during a rebound of isoagglutinins. Rejection was successfully treated with eculizumab, which inhibits the terminal pathway of complement. Complement analysis (C3, C3d,g, and a modified assay of classical complement‐related hemolytic function) documented complement activation and confirmed that eculizumab completely blocked complement function. At 6 months, the patient had normal kidney and pancreas function, and histological evaluations revealed no evidence of sustained graft damage. This successful transplantation suggests that ABO barriers can safely be overcome without extensive preconditioning, when the complement inhibitor eculizumab is included.