HDL cholesterol levels are an important factor for determining the lifespan of erythrocytes

OBJECTIVE: Scavenger receptor class B, type I (SR-BI) is a multifunctional receptor that promotes the selective uptake of cholesteryl esters from high-density lipoprotein (HDL). Disruption of SR-BI in mice results in a dramatic increase in HDL cholesterol. Interestingly, mice lacking SR-BI also develop anemia, as evidenced by accumulation of reticulocytes in the circulation. The objective of the current study was to delineate the mechanism underlying development of anemia in the absence of SR-BI. METHODS: Expression of important mediators of erythropoiesis, as well as key enzymes in the degradation of erythrocytes, were analyzed using real-time polymerase chain reaction in SR-BI wild-type and SR-BI knockout mice. In addition, in vivo studies were performed using biotinylated erythrocytes to determine erythrocyte survival. RESULTS: mRNA expression of TAL-1, GATA-1, FOG-1, erythropoietin receptor, and ferrochelatase, important mediators of erythropoiesis, was increased in spleens of SR-BI-deficient mice. In addition, the relative amount of early Ter119(high)CD71(high) -expressing erythroblasts was increased in SR-BI-deficient spleens. Interestingly, also expression of hemeoxygenase 1 and biliverdin reductase, enzymes involved in the degradation of erythrocytes, was increased. Furthermore, an elevated amount of conjugated bilirubin, the breakdown product of hemoglobin, was found in bile. Using biotinylated erythrocytes, we show that survival of erythrocytes was decreased in SR-BI-deficient mice. Thus, the observed increased erythropoiesis in the SR-BI-deficient mice is most likely a direct response to the reduced erythrocyte lifespan. Finally, we show that increased HDL cholesterol levels due to SR-BI deficiency induce erythrocyte cholesterol:phospholipid ratios, resulting in decreased deformability and increased osmotic fragility, thereby providing an explanation for the observed reduced lifespan. CONCLUSIONS: SR-BI is not only essential for HDL cholesterol homeostasis and atherosclerosis susceptibility, but also for maintaining normal erythrocyte lifespan.     

Oral rehydration solution containing a mixture of non-digestible carbohydrates in the treatment of acute diarrhea: a multicenter randomized placebo controlled study on behalf of the ESPGHAN working group on intestinal infections

OBJECTIVE: A randomized, double-blind, placebo-controlled multicenter study to evaluate efficacy and safety of a mixture of non-digestible carbohydrates (NDC) as an adjunct to oral rehydration therapy in treatment of acute infectious diarrhea in children with mild to moderate dehydration. METHODS: 144 boys aged 1 to 36 months with diarrhea defined as three or more watery stools per day for >1 day but <5 days with mild or moderate dehydration (World Health Organization criteria) were randomly assigned to receive hypotonic oral rehydration solution (ORS) (Na 60 mmol/L, glucose 111 mmol/L) with or without a mixture of NDC (soy polysaccharide 25%, alpha-cellulose 9%, gum arabic 19%, fructooligosaccharides 18.5%, inulin 21.5%, resistant starch 7%). RESULTS: Intention-to-treat analysis did not show significant differences in mean 48 hour stool volume (ESPGHAN-ORS with NDC versus ESPGHAN-ORS, 140 +/- 124 g/kg versus 143 +/- 114 g/kg; P = 0.41). Duration of diarrhea after randomization was similar in both groups (82 +/- 39 hours versus 97 +/- 76 hours, P = 0.24). There were no significant differences in the duration of hospital stay (111 +/- 44 hours versus 126 +/- 78 hours; P = 0.3). Unscheduled intravenous rehydration was similar in both groups (21.4% versus 16.2%, P = 0.42). CONCLUSION: In boys with acute non-cholera diarrhea with mild to moderate dehydration a mixture of non-digestible carbohydrates was ineffective as an adjunct to oral rehydration therapy.     

Detecting recurrent laryngeal carcinoma after radiotherapy: room for improvement

Detecting recurrent laryngeal carcinoma after radiotherapy for a primary tumour can be difficult. Early detection however, is an important prognostic factor. Although a biopsy should be performed in case of clinical suspicion, repeated negative biopsies do not exclude the presence of viable tumour. The trauma caused by biopsies in irradiated tissue may initiate infection, further oedema and failure to heal. We investigated these problems and evaluated the current care and its usefulness. A survey of the current practice concerning diagnostic procedures for detecting recurrent laryngeal carcinoma after radiotherapy in the major institutions treating head and neck cancer in The Netherlands was performed by means of a questionnaire. Furthermore, we performed a comprehensive analysis of the extent and yield of diagnostic work-up in a cohort of patients clinically suspected of a recurrence, who had undergone direct laryngoscopy between 1986 and 1998 in our institution, with a follow-up of at least 6 months. In case of suspected recurrence, 94% of the departments use direct laryngoscopy under general anaesthesia with the taking of biopsies as a diagnostic technique. Imaging does not play an important role. In our department 207 laryngoscopies were evaluated in 131 patients. In 70 patients the first laryngoscopy was negative. Of these initial negative laryngoscopies, 22 (31%) turned out to be false negative within 6 months. Thirty-seven patients remained disease free. They underwent 65 unnecessary laryngoscopies to come to this conclusion. In the decision to perform direct laryngoscopy, the conventional work up leaves room for improvement. Too many unnecessary laryngoscopies are performed. New imaging techniques such as FDG-PET or new applications of CT or MRI may improve the yield of direct laryngoscopy.     

Towards a minimally invasive staging strategy in NSCLC: analysis of PET positive mediastinal lesions by EUS-FNA

STUDY OBJECTIVE: To asses the value of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) in the nodal staging of patients with (suspected) non-small cell lung cancer (NSCLC) and a (18)FDG positron emission tomography (PET) scan suspect for N2/N3 mediastinal lymph node (MLN) metastases. BACKGROUND: Due to the imperfect specificity of positron emission tomography, PET positive MLN should be biopsied in order to confirm or rule out metastasis. Currently, invasive surgical diagnostic techniques such as mediastinoscopy/-tomy are standard procedures to obtain MLN tissue. The minimally invasive technique of EUS-FNA has a high diagnostic accuracy (90-94%) for the analysis of MLN in patients with enlarged MLN on computed tomography of the chest (CT). DESIGN AND PATIENTS: Thirty-six patients with proven n=26 or suspected n=10 non-small cell lung cancer and a PET scan suspect for N2/N3 lymph node metastases underwent EUS-FNA. When EUS-FNA did not confirm metastasis and the PET lesion was within reach of mediastinoscopy, a mediastinoscopy was performed. EUS-FNA negative patients with PET lesions beyond the reach of mediastinoscopy or those with a negative mediastinoscopy were referred for surgical resection of the tumour and MLN sampling or dissection. RESULTS: EUS-FNA confirmed N2/N3 disease in 25 of the 36 patients (69%) and was highly suspicious in one. In the remaining 10 patients, one PET positive and one PET negative N2 metastasis was detected at thoracotomy. The PPV, NPV, sensitivity, specificity and accuracy of EUS-FNA in analysing PET positive MLN were 100%, 80%, 93%, 100% and 94%, respectively. No complications of EUS-FNA were recorded. CONCLUSIONS AND SIGNIFICANCE: EUS-FNA yields minimally invasive confirmation of MLN metastases in 69% of the patients with potential mediastinal involvement at FDG PET. The combination of PET and EUS-FNA might qualify as a minimally invasive staging strategy for NSCLC.     

Toxicokinetics of three polychlorinated biphenyl technical mixtures in rainbow trout (Oncorhynchus mykiss)

Accumulation and depuration parameters of polychlorinated biphenyls (PCBs) in fish have been reported only for a few congeners. As well, there is little information on the ability of fish to biotransform PCBs. To address these issues, juvenile rainbow trout (Oncorhynchus mykiss) were exposed to dietary concentrations of three Aroclor mixtures (1248, 1254, 1260) in food for 30 d followed by an additional 160 d of nonspiked food at 8 degrees C. Accumulation, depuration, and potential biotransformation of 92 PCB congeners were assessed. Half-lives (t1/2) of PCB congeners ranged from 79 to 182 d, assimilation efficiencies ranged from 40 to 50% and biomagnification factors (BMF) ranged from 2.9 to 6.9. No evidence of significant biotransformation of any PCB congeners was found. All 92 congeners fell on the same t1/2 to Kow relationship as 16 preselected PCB congeners previously shown to persist in fish and no hydroxylated PCB metabolites (OH-PCBs) were detected in the plasma after 30 d of exposure. These findings suggest that OH-PCBs observed in feral fish may be accumulated from sources other than internal metabolism of the parent congeners, at least for juvenile fish at cool temperatures. Because t1/2s in this experiment were slower than t1/2s reported in other work, water temperature also may be an important factor in determining the t1/2s of all PCB congeners in fish.     

Biological and chemical factors of importance in the bioaccumulation and trophic transfer of persistent organochlorine contaminants in Arctic marine food webs

Recent studies of arctic marine food webs have provided detailed insights regarding the biological and chemical factors that influence the bioaccumulation and trophic transfer of persistent organochlorine (OC) contaminants in aquatic systems. The present paper summarizes the recent literature with an emphasis on identifying important ecological factors for explaining variability of OC concentrations among organisms. The Arctic ecosystem has a number of unique attributes, including long food chains, reduced diversity of species, similar food webs across the entire region, and limited influence from pollution point sources. Lipid content, body size, age, gender, reproduction, habitat use, migration, biotransformation, seasonal changes in habitat conditions, feeding ecology, and trophic position have all been demonstrated to influence OC concentrations and bioaccumulation in arctic marine biota. The relative importance of each factor varies among OCs and organisms. Diet or trophic level is the dominant factor influencing OC concentrations and dynamics in seabirds and marine mammals, although biotransformation can significantly influence nonrecalcitrant OCs, such as hexachlorocyclohexane isomers. Dietary accumulation of OCs is also an important route of exposure for arctic fish and zooplankton, and biomagnification of OCs may also occur among these organisms. To date, only limited attempts have been made to model trophic transfer of OCs in the arctic marine food web. Although models developed to assess OC dynamics in aquatic food webs have included some biological variables (e.g., lipid content, feeding rate, diet composition, and growth rate), selection of processes included in these models as well as their mathematical solutions and parameterization all introduce simplification. This reduces biological validity of the models and may be particularly problematic in a highly seasonal environment, such as the Arctic Ocean.     

Expression of multidrug resistance-associated proteins in rhabdomyosarcomas before and after chemotherapy: the relationship between lung resistance-related protein (LRP) and differentiation

Rhabdomyosarcomas generally respond well to chemotherapy, and the residual lesions often are better differentiated than their primaries. This phenomenon may be explained by selective multidrug resistance (MDR) of differentiated tumor cell populations. We assess the role of MDR proteins in chemotherapy-induced differentiation in rhabdomyosarcomas in a clinical setting. Paraffin-embedded samples of 13 pairs of primary untreated rhabdomyosarcomas and their residual, recurrent, or metastatic lesions after chemotherapy were assessed for expression of MDR proteins, including P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP-1), and lung resistance-related protein (LRP). Expression was semiquantitatively scored based on the percentage of isolated immunoreactive tumor cells as follows: 0, negative; 0.5, <5%; 1, 5% to 25%; 2, 26% to 50%; 3, 51% to 75%, and 4, >75%. All specimens after chemotherapy, except the late recurrences, were better differentiated than their primary, untreated specimens. Pgp or MRP-1 expression did not change significantly, but LRP expression increased significantly after chemotherapy. In both untreated and treated samples, LRP was expressed primarily in differentiated cells. The findings indicate that the in vivo expression of LRP, but not of Pgp and MRP-1, is induced by chemotherapeutic treatment in rhabdomyosarcomas. The preferential expression of LRP in differentiated cells and the subsequent more extensive expression after chemotherapy suggests that LRP plays a role in therapy-induced differentiation.