Silibinin prevents cholestasis-associated retrieval of the bile salt export pump, Bsep, in isolated rat hepatocyte couplets: possible involvement of cAMP

Estradiol-17beta-d-glucuronide (E(2)17G) and taurolithocholate (TLC) induce acute cholestasis-associated with retrieval of the bile salt export pump (Bsep), which parallels with alteration in transport activity. cAMP stimulates the apically directed vesicular trafficking of transporters, partially preventing these alterations. The hepatoprotector, silymarin, which inhibits cAMP-phosphodiesterase, prevents the cholestasis induced in vivo by both estrogens and TLC. We aimed to assess the ability of silibinin (Sil), the silymarin active component, to prevent the retrieval of Bsep induced by TLC and E(2)17G, and the associated alteration in its transport function. The possible involvement of cAMP as a second messenger and the intracellular signalling pathways implicated were also evaluated. Functional studies were performed analysing the proportion of isolated rat hepatocyte couplets (IRHC) accumulating the fluorescent bile salt analogue, cholyl-lysylfluorescein (CLF), into their sealed canalicular vacuoles. Cellular localisation of Bsep was assessed by immunofluorescent staining. Intracellular levels of cAMP were measured by ELISA. Sil (2.5microM) elevated by 40+/-3% intracellular cAMP, and mimicked the ability of dibutyryl-cAMP (10microM) to prevent internalisation of Bsep and the TLC (2.5microM)- and E(2)17G (50microM)-induced impairment in the capacity of IRHC to accumulate CLF apically. Preventive effects of Sil and dibutyryl-cAMP were not abolished by the specific protein kinase A inhibitors, KT5720 and H89. Contrarily, the intracellular Ca(2+) chelator, BAPTA/AM, significantly blocked the protective effect of both compounds. We conclude that Sil prevented TLC- and E(2)17G-induced bile salt secretory failure, at least in part, by avoiding redistribution of Bsep, by a mechanism probably involving cAMP-induced cytosolic Ca(2+) elevations.     

Effect of androgen deprivation therapy in the thyroid function test of patients with prostate cancer

We have assessed the effect of androgen deprivation therapy (ADT) in the thyroid function test in prostate cancer patients. Serum levels of tri-iodothyronine (T3), thyroxine (T4), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were determined in a cross-sectional study that included 279 patients diagnosed with prostate cancer. A subset of 96 patients free of prostate-specific antigen relapse after radical prostatectomy became a control group and 183 patients under continuous ADT formed the study group. Sixty-four patients out of the study group were treated with luteinizing hormone-releasing hormone (LHRH) agonist and 119 with LHRH agonist plus bicalutamide. The average time of ADT was 42.5 months (3-218). Results were as follows. Mean T3 level was 122.7 ng/dl (72.6-213.0) in the control group and 123.8 ng/dl (64.4-228.2) in patients under ADT, p=0.472. Mean T4 level was 7.66 (1.81-4.30) and 7.66 microg/dl (3.60-13.30), respectively, p=0.884. Mean TSH level was 1.58 (0.44-11.70) and 1.81 mU/dl (0.15-6.58), respectively, p=0.007. Mean FT4 level was 1.24 (0.80-1.90) and 1.18 ng/dl (0.80-1.90), respectively, p=0.018. No statistically significant differences between the T3, T4, TSH and FT4 serum levels were detected according to the modality of ADT. The serum level of TSH was higher than 5 mU/l in six patients (2.1%); however, all cases had a normal FT4 serum level. This mild hypothyroidism was detected in two of the 96 patients of the control group (2.1%) and in four of the 183 under ADT (2.2%). Our data show that ADT seems to alter the thyroid function test. A statistically significant increase in TSH serum level and a decrease in FT4 serum level were detected in patients under ADT. However, only a mild hypothyroidism was detected in about 2% of the patients with prostate cancer, independently of ADT.     

Oxidative damage is present in plasma and circulating neutrophils 4?weeks after a high mountain expedition

It is well known that exposure to extreme environments, such as in high-mountain expeditions, is associated with increased production of reactive oxygen species and related oxidative damage. However, there is little information concerning antioxidant recovery after this type of expedition. Thus, the aim of this study is to analyze the antioxidant recovery status at sea level of five expert alpinists 4?weeks after climbing Cho-Oyu (8,201?m). Body composition, cardiorespiratory capacity, and circulating parameters were almost similar to the values obtained at the beginning of the study. However, the alpinists presented high erythrocyte number, related hemogram values, and ferritin. Sodium, alkaline phosphatase, and γ-glutamyltransferase plasma levels were lower. Concerning oxidative stress, plasma uric acid levels were significantly increased, as well as malondialdehyde and protein carbonyls. Neutrophils displayed significantly higher levels of malondialdehyde and lower catalase activity. Therefore, these data indicate that the oxidative stress during a high mountain expedition is the most probable cause to explain an incomplete recovery in plasma and neutrophil antioxidant status.     

Endovascular treatment of two aortoduodenal fistulae

We report the endovascular treatment of two patients presenting with aortoduodenal fistulae. The first patient was a 66-year-old man admitted with hematemesis. He was on clopidogrel and had received a cryopreserved aortic graft for a mycotic abdominal aortic aneurysm five years earlier. Computed tomography (CT) showed aortic pseudoaneurysms in close contact with the duodenum. Endovascular repair was carried out. Twenty-seven months after the procedure the patient remains asymptomatic. The second patient was a 78-year-old man admitted with abdominal pain and nausea. CT revealed an abdominal aortic pseudoaneurysm and aortoduodenal fistula. He suffered from severe chronic obstructive pulmonary disease that greatly increased his surgical morbidity and mortality. An endovascular repair was performed under epidural anesthesia. The patient died of a postoperative pneumonia 38 days after surgery. These two cases illustrate the importance of endovascular aortic repair especially when an open surgical procedure is either difficult or impossible.     

Statement of Ethics in Neurosurgery of the World Federation of Neurosurgical Societies

This Statement of Ethics in Neurosurgery was developed by the Committee for Ethics and Medico-Legal Affairs of the World Federation of Neurosurgical Societies to help neurosurgeons resolve problems in the treatment of individual patients and meet obligations to the larger society. This document is intended as a framework rather than a set of rules. It cannot cover every situation and should be used with flexibility. However, it is our intent that the fundamental principles enunciated here should serve as a guide in the day-to-day practice of neurosurgery.