Endothelial bound lipoprotein lipase (LpL) depletion in hypoalbuminemia results from decreased endothelial binding, not decreased secretion

Hypertriglyceridemia in nephrotic (NS) and Nagase analbuminemic rats (Analb) results from reduced triglyceride clearance. NS and Analb have reduced or absent albumin, reduced plasma oncotic pressure (π), but Analb lack proteinuria. The heparin releasable lipoprotein lipase (LpL) pool in both models is greatly reduced, suggesting reduced LpL is related to low albumin or π and not proteinuria. To determine the cause of endothelial LpL reduction, we studied effectors of endothelial LpL (eLpL) levels from gene expression, to delivery and endothelial binding. eLpL was measured as heparin releasable activity. eLpL and secretion rate was measured in isolated hearts perfused with heparin. mRNA levels were measured in rat hearts by kinetic RT-PCR. Finally, binding of 125I-LpL by competition assays rat endothelial cells measured serum-induced changes in affinity. eLpL in vivo was reduced in nephrotic and Analb rats. While the eLpL pool was reduced in isolated perfused hearts, neither LpL secretion by isolated hearts nor myocardial mRNA was reduced in NS or Analb. Binding of LpL to RAEC preincubated with serum from either NS or Analb was reduced compared to control. LpL mRNA levels and release rate was not altered in hearts from NS rats, while eLpL is depleted, suggesting that reduced eLpL in NS is not the result of reduced delivery. The finding that NS serum alters LpL binding to RAEC suggests LpL depletion results from decreased binding rather than defective delivery. This in turn is a consequence of reduced serum albumin or π but does not require proteinuria

Loss of SRY-box2 (SOX2) expression and its impact on survival of patients with oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is a highly aggressive malignancy with poor survival, which is highly variable amongst patients with comparable conventional prognosticators. Therefore molecular biomarkers are urgently needed to improve the prediction of survival in these patients. SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor involved in embryonal development of the gastrointestinal tract as well as in carcinogenesis. The purpose of this study was to see whether SOX2 expression is associated with survival in patients with OAC. METHODS: SOX2 was studied by immunohistochemistry in patients who had undergone potentially curative oesophagectomy for adenocarcinoma. Protein expression of SOX2 was evaluated using tissue microarrays from resection specimens, and results were analysed in relation to the clinical data by Cox regression analysis. SOX2 was evaluated in two independent OAC cohorts (Rotterdam cohort and a multicentre UK cohort). RESULTS: Loss of SOX2 expression was independently predictive of adverse overall survival in the multivariable analysis, adjusted for known factors influencing survival, in both cohorts (Rotterdam cohort: hazard ratio (HR) 1·42, 95 per cent c.i. 1·07 to 1·89, P = 0·016; UK cohort: HR 1·54, 1·08 to 2·19, P = 0·017). When combined with clinicopathological staging, loss of SOX2 showed an increased effect in patients with pT1-2 tumours (P = 0·010) and node-negative OAC (P = 0·038), with an incrementally adverse effect on overall survival for stage I OAC with SOX2 loss (HR 3·18, 1·18 to 8·56; P = 0·022). CONCLUSION: SOX2 is an independent prognostic factor for long-term survival in OAC, especially in patients with stage I OAC

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS)

textabstractBackground. A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial. Methods/design. The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm. The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up. Discussion. This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen. Trial registration. ISRCTN80832026

The comparative biology of New Zealand oystercatchers

Oystercatchers comprise a distinctive group of mollusc-eating shorebirds. They form an extremely uniform monogeneric family which has not undergone any major adaptive radiations into a diversity of ecological niches, but rather has dispersed from original centres of distribution to occupy identical niches in new geographical localities. The uniformity of structure and habit displayed within the group has been attributed by Larson (1957) to a high ecobiotic specialisation with centripetal selection involved. Throughout their range, oystercatchers exploit identical ecological niches which require specialised habits for successful utilisation. The specialised feeding habits of oystercatchers are well documented (Murphy, 1925; Dewar, 1940; Larson, 1957; Tinbergen and Norton-Griffiths, 1964; Dare, 1966), and a natural consequence of this specialisation is that it is restrictive to adaptive radiation

Are there simple measures to reduce the risk of HIV infection through blood transfusion in a Zambian district hospital?

To quantify the potential impact of simple measures to reduce the risk of iatrogenic HIV infection through blood transfusion in a Zambian district hospital. Three studies were conducted at St. Francis' Hospital, Katete, Zambia: (1) From 1991 to 1995 HIV seroprevalence among all listed blood donors and the impact of proper subgroup selection were studied retrospectively; (2) the sensitivity of locally used rapid antibody assays (HIV-spot/Wellcozyme HIV 1 & 2) for the detection of HIV in donor blood and the influence of the expiration date of the tests on this sensitivity were determined prospectively from June 1993 until March 1994 by screening all consecutive surgical patients and blood donors; (3) the number of unnecessary blood transfusions was determined retrospectively from January 1995 through January 1996 and prospectively from February 1996 through March 1996, and possibilities to reduce the total number of blood transfusions were considered. (1) Excluding prisoners, who have an HIV seroprevalence of 19-25%, from the donor population significantly reduces the overall HIV seroprevalence from 13-16% to 8-9% (P < 0. 01). (2) Under local circumstances the sensitivity of the used rapid antibody assays was 6.8-17.9% lower than claimed by the manufacturer. Usage of non-expired tests increased the sensitivity significantly from 88.2% to 91.7% (P < 0.05). (3) None of the 294 studied blood transfusions can be classified as inappropriate according to international standards. Simple measures such as proper subgroup selection among blood donors and correct use of non-expired tests may decrease the risk of iatrogenic HIV transmission. Stricter indications for blood transfusions will not substantially reduce the number of transfusion