Raising plasma phosphorus levels by phosphorus-enriched, bicarbonate-containing dialysate in hemodialysis patients

In 6 hemodialysis patients, enriching the "base concentrate" of a bicarbonate-containing dialysate-generating system with phosphorus succeeded in raising plasma phosphorus levels.     

Validation of serotonin (5-hydroxtryptamine) as an in vitro substrate probe for human UDP-glucuronosyltransferase (UGT) 1A6.

Investigation of human UDP-glucuronosyltransferase (UGT) isoforms has been limited by a lack of specific substrate probes. In this study serotonin was evaluated for use as a probe substrate for human UGT1A6 using recombinant human UGTs and tissue microsomes. Of the 10 commercially available recombinant UGT isoforms, only UGT1A6 catalyzed serotonin glucuronidation. Serotonin-UGT activity at 40 mM serotonin concentration varied more than 40-fold among human livers (n = 54), ranging from 0.77 to 32.9 nmol/min/mg of protein with a median activity of 7.1 nmol/min/mg of protein. Serotonin-UGT activity kinetics of representative human liver microsomes (n = 7) and pooled human kidney, intestinal and lung microsomes and recombinant human UGT1A6 typically followed one enzyme Michaelis-Menten kinetics. Serotonin glucuronidation activity in these human liver microsomes had widely varying V(max) values ranging from 0.62 to 51.3 nmol/min/mg of protein but very similar apparent K(m) values ranging from 5.2 to 8.8 mM. Pooled human kidney, intestine, and lung microsomes had V(max) values (mean +/- standard error of the estimates) of 8.8 +/- 0.4, 0.22 +/- 0.00, and 0.03 +/- 0.00 nmol/min/mg of protein (respectively) and apparent K(m) values of 6.5 +/- 0.9, 12.4 +/- 2.0, and 4.9 +/- 3.3 mM (respectively). In comparison, recombinant UGT1A6 had a V(max) of 4.5 +/- 0.1 nmol/min/mg of protein and an apparent K(m) of 5.0 +/- 0.4 mM. A highly significant correlation was found between immunoreactive UGT1A6 protein content and serotonin-UGT activity measured at 4 mM serotonin concentration in human liver microsomes (R(s) = 0.769; P < 0.001) (n = 52). In conclusion, these results indicate that serotonin is a highly selective in vitro probe substrate for human UGT1A6.     

4-Hydroxynonenal regulates mitochondrial function in human small airway epithelial cells

Prolonged exposure to oxidative stress causes Acute Lung Injury (ALI) and significantly impairs pulmonary function. Previously we have demonstrated that mitochondrial dysfunction is a key pathological factor in hyperoxic ALI. While it is known that hyperoxia induces the production of stable, but toxic 4-hydroxynonenal (4-HNE) molecule, it is unknown how the reactive aldehyde disrupts mitochondrial function. Our previous in vivo study indicated that exposure to hyperoxia significantly increases 4-HNE-Protein adducts, as well as levels of MDA in total lung homogenates. Based on the in vivo studies, we explored the effects of 4-HNE in human small airway epithelial cells (SAECs). Human SAECs treated with 25 μM of 4-HNE showed a significant decrease in cellular viability and increased caspase-3 activity. Moreover, 4-HNE treated SAECs showed impaired mitochondrial function and energy production indicated by reduced ATP levels, mitochondrial membrane potential, and aconitase activity. This was followed by a significant decrease in mitochondrial oxygen consumption and depletion of the reserve capacity. The direct effect of 4-HNE on the mitochondrial respiratory chain was confirmed using Rotenone. Furthermore, SAECs treated with 25 μM 4-HNE showed a time-dependent depletion of total Thioredoxin (Trx) proteins and Trx activity. Taken together, our results indicate that 4-HNE induces cellular and mitochondrial dysfunction in human SAECs, leading to an impaired endogenous antioxidant response.     

Unruptured sinus of Valsalva aneurysm with right ventricular outflow obstruction

The recommended operative management of unruptured sinus of Valsalva aneurysm consists of closure of the mouth of the aneurysm with or without aortic valve surgery. We report a case of unruptured aneurysm producing right ventricular outflow tract obstruction. Closure of the mouth of the aneurysm failed to relieve the obstruction, which was subsequently achieved by excising the aneurysmal wall overlying the outflow tract.     

Skin necrosis and protein C deficiency associated with vitamin K depletion in a patient with renal failure.

Skin necrosis similar to that induced by warfarin was seen in a patient who had never received the drug but who was vitamin K-deficient due to malnutrition and prolonged treatment with broad-spectrum antibiotics. He also had end-stage renal failure and was receiving prophylactic subcutaneous heparin therapy because of immobilization. His plasma protein C antigen level and, disproportionately, his plasma protein C functional activity were decreased. Both protein C values improved after vitamin K therapy, discontinuation of heparin, and initiation of hemodialysis. We surmise that skin necrosis occurred as a result of protein C deficiency caused by vitamin K depletion. Production of abnormal (descarboxy) protein C/protein S due to vitamin K deficiency and increased protein C inhibitory activity associated with renal failure and/or heparin administration may have contributed to the clinical picture. This rare but serious complication of a relatively common disorder, viz., vitamin K deficiency, reinforces the importance of vitamin K supplementation in malnourished patients who receive long-term antibiotic maintenance therapy.     

Validation of the Maryland Aggregate Pathology Index (MAPI), a pre‐implantation scoring system that predicts graft outcome

Predicting graft outcome after renal transplantation based on donor histological features has remained elusive and is subject to institutional variability. We have shown in a retrospective study that the Maryland Aggregate Pathology Index score reliably predicts graft outcome. We sought to validate the scoring system in our center and a second transplant center. We analyzed 140 deceased donor kidneys pre‐implantation biopsies from center 1 and 65 from center 2. The patients had a mean follow‐up of 695 ± 424 and 656 ± 305 d respectively. Although MAPI scores were similar, there were significant differences in donor and recipient parameters between both centers. Despite this, MAPI was predictive of graft outcome for both centers by Cox univariate, multivariate and time dependent ROC analysis. For center 1 and 2, three yr graft survival within each MAPI group was statistically equivalent. The three‐yr graft survival at center 1 for low, intermediate, and high MAPI groups were 84.3%, 56.5%, and 50.0%, respectively, p ≤ 0.0001, and at center 2 were 83.3%, 33.3%, and 33.3%, p = 0.006. MAPI, which is based on a pre‐implantation biopsy, demonstrated similar predictive and outcome results from both centers. As expanded criteria donors (ECD) criteria have redefined marginal kidneys, MAPI has the potential to further define ECD kidneys, increase utilization, and ultimately improve outcomes.     

Intentional internal iliac artery occlusion to facilitate endovascular repair of aortoiliac aneurysms

PURPOSE: The safety of intentional occlusion of patent internal iliac arteries (IIAs) to facilitate the endovascular repair of aortoiliac artery aneurysms (abdominal aortic aneurysms [AAAs] and iliac aneurysms [IAs]) was evaluated. METHODS: We analyzed the techniques and clinical sequelae of selective occlusion of one or both IIAs in 103 patients and correlated these findings with the results of preoperative angiograms to identify vascular anatomy that may predict postoperative pelvic ischemia. To quantify the clinical presentation of pelvic ischemia, we developed these criteria: class 0, no symptoms; class I, nonlimiting claudication with exercise; class II, new onset impotence, with or without moderate to severe buttock pain, leading to physical limitation with exercise; class III, buttock rest pain, colonic ischemia, or both. IIA occlusion was achieved in 100% of the patients by means of either catheter-directed embolization or orificial coverage with a stent-graft. No patient in this study had angiographic evidence of significant visceral occlusive disease before the procedure. Sixty-four patients had isolated AAAs, 23 patients had AAAs and IAs, and 16 patients had isolated IAs. Ninety-two patients had one IIA selectively occluded, and 11 patients had both IIAs selectively occluded. RESULTS: After IIA occlusion, 12 patients were categorized in class I, 9 patients were categorized in class II, and 1 patient was categorized in class III, for a total of 22 patients (21%) with pelvic ischemia. Sixteen (17%) of 92 patients had unilateral IIA occlusions, and six (17%) of 11 patients had bilateral IIA occlusions. Five patients in class I improved and had no symptoms within 1 year, and one patient in class II was downgraded to class I because of improved symptoms. Two unique preoperative angiographic findings were identified in the remaining 16 patients (16%) with chronic pelvic claudication: (1) stenosis of the remaining IIA origin (> 70%) with nonopacification of more than three of the six IIA branches (63%); and (2) small caliber, diseased or absent medial and lateral femoral circumflex arteries ipsilateral to the side of the IIA occlusion (25%). One patient with class III ischemia died of cardiovascular collapse associated with colon infarction caused by either acute ischemia or particulate embolization. CONCLUSION: The incidence of pelvic ischemia after IIA occlusion is 20% immediately after endovascular aortoiliac aneurysm repair. A total of 25% of patients had no symptoms within 1 year. Two preoperative radiologic findings may help identify patients who are at risk for pelvic ischemia: stenosis of the patent IIA and disease deep femoral ascending branches ipsilateral to the occluded IIA. The risk of colon ischemia appears to be small after selective IIA occlusion to facilitate endovascular AAA repair.     

Neuroprotective properties of cultured neural progenitor cells are associated with the production of sonic hedgehog

Numerous studies have shown that abnormal motor behavior improves when neural progenitor cells (NPCs) are transplanted into animal models of neurodegeneration. The mechanisms responsible for this improvement are not fully understood. Indirect anatomical evidence suggests that attention of abnormal motor behavior is attributed, at least in part, to the secretion of trophic factors from the transplanted NPCs. However, there is little direct evidence supporting this hypothesis. Here we show that NPCs isolated from the subventricular zone (SVZ) of neonatal mice are highly teratogenic when transplanted into the neural tube of developing chick embryos and are neuroprotective for fetal dopaminergic neurons in culture because they release sonic hedgehog (Shh). In addition, the neuroprotective properties of NPCs can be exploited to promote better long-term survival of transplanted fetal neurons in an animal model of Parkinson's disease. Thus, cultured NPCs isolated from the SVZ can secrete at least one potent mitogen (Shh) that dramatically affects the fate of neighboring cells. This trait may account for some of the improvement in motor behavior often reported in animal models of neurodegeneration after transplantation of cultured NPCs that were isolated from the SVZ.