Abstract. Renal proximal tubule cells are responsible for the reabsorption of proteins that are present in the tubular lumen. This occurs by receptor-mediated endocytosis, a process that has a requirement for some GTP-binding proteins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase used for the therapeutic reduction of cholesterol-containing plasma lipoproteins. However, they can also reduce intracellular levels of isoprenoid pyrophosphates that are derived from the product of the enzyme, mevalonate, and are required for the prenylation and normal function of GTP-binding proteins. The hypothesis that inhibition of HMG-CoA reductase in renal proximal tubule cells could reduce receptor mediated-endocytosis was therefore tested. Five different statins inhibited the uptake of FITC-labeled albumin by the proximal tubule-derived opossum kidney cell line in a dose-dependent manner and in the absence of cytotoxicity. The reduction in albumin uptake was related to the degree of inhibition of HMG-CoA reductase. Simvastatin (e.g., statin) inhibited receptor-mediated endocytosis of both FITC-albumin and FITC-␤ 2 -microglobulin to similar extents but without altering the binding of albumin to the cell surface. The effect on albumin endocytosis was prevented by mevalonate and by the isoprenoid geranylgeranyl pyrophosphate but not by cholesterol. Finally, evidence that the inhibitory effect of statins on endocytosis of proteins may be caused by reduced prenylation and thereby decreased function of one or more GTP-binding proteins is provided. These data establish the possibility in principle that inhibition of HMG-CoA reductase by statins in proximal tubule cells may reduce tubular protein reabsorption.Statins are inhibitors of the enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, the major rate-limiting step of the sterol pathway (1). The statins are widely used for the therapeutic reduction of cholesterol-containing atherogenic lipoproteins (2-4). This is brought about as a result of depletion of intracellular mevalonate leading to reduction of the regulatory sterol pool, which in turn causes upregulation of HMGCoA reductase and other enzymes of the sterol pathway, most importantly the LDL receptors principally in the liver (5-7). However, a range of additional effects of statins on cells that are independent of cholesterol homeostasis has been described; these include, proliferation (8), signal transduction (9), and apoptosis (10). Many of these cholesterol-independent effects of statins have been shown to result from depletion of mevalonate and its nonsterol metabolites, particularly the isoprenoid pyrophosphates, such as farnesol pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), that are required for the posttranslation modification of a variety of cell proteins, including the superfamily of small GTP-binding proteins (11)(12)(13). Endocytosis is one cell function that requires multiple GTP-binding proteins (14,15) a...

We present results from an analysis of high-latitude ionosphere-thermosphere (IT) coupling to the solar wind during a moderate magnetic storm which occurred on 5-6 August 2011. During the storm, a multipoint set of observations of the ionosphere and thermosphere was available. We make use of ionospheric measurements of electromagnetic and particle energy made by the Defense Meteorological Satellite Program and neutral densities measured by the Gravity Recovery and Climate Experiment satellite to infer (1) the energy budget and (2) timing of the energy transfer process during the storm. We conclude that the primary location for energy input to the IT system may be the extremely high latitude region. We suggest that the total energy available to the IT system is not completely captured either by observation or empirical models.

Coulter profiles with differential white cell counts, serum ferritin, and haptoglobin levels were determined in venous blood samples obtained from 90 males (M) and 25 females (F) immediately before and after completion of a competitive marathon (42.2 km) race. In an additional 20 male runners, the same measurements were performed serially during the 24 h following their completion of the race. In the pre-race samples from 90 M and 25 F, hypoferritinemia was present in 4/22 M and 1 F found to be mildly anemic. Neutropenia was detected in 4 M and 3 F and mild thrombocytopenia in 2 M. Haptoglobin levels were normal in all the female runners but reduced (less than 0.3 g/l) in 6 M. All post-race samples (88 M and 25 F) were characterized by a reactive neutrophilia and thrombocytosis including those with pre-race neutropenia or thrombocytopenia. An unexpected and incompletely explained sex difference in packed cell volume (PCV) response was observed. In males, the mean PCV increased from 0.425 +/- 0.021 to 0.444 +/- 0.028 (P less than 0.0001) whereas in females it decreased from 0.437 +/- 0.029 to 0.423 +/- 0.036 (P less than 0.05). In the post-race samples, anhaptoglobinemia was found in 13/88 M and 4/25 F. In the 20 male runners studied serially for 24 h after the race, the major changes involved a progressive increase in mean plasma volume (17.4% +/- 12.2% at 24 h) compared with the pre-race value, a progressive and significant increase in MCH and MCHC probably indicating a loss in red cell water and the gradual reversion of the reactive neutrophilia and thrombocytosis to basal levels.

SUMMARY With the advent of electronic particle counters of the Coulter S type the mean cell volume (MCV) has become an integral and useful feature of the red cell profile. Abnormally high values, often of minor degree, are particularly common but their precise clinical significance may be difficult to establish. This study defines the normal range and determines the incidence and distribution of the high MCV in routine hospital practice. Two hundred consecutive adult patients with an MCV of 100 fl or more were identified from the Coulter S analysis of 6542 blood samples and the underlying cause was established in 800%. Some of the clinical and economic implications of these findings are presented and briefly discussed.Red cell size has for many years been used to classify anaemia (Wintrobe, 1930). Early studies employed diffraction (Pijper, 1919) or the painstaking measurement of projected images (PriceJones, 1933) to detect changes in cell diameter in addition to the microscopic inspection of fixed and stained blood films with or without the aid of an eyepiece micrometer (Thorell, 1964). More recently cell size was related to mean cell volume (MCV), an index derived from the red cell count and packed cell volume. The adoption of this measurement, however, was restricted by the inaccuracies associated with visual red cell counting (Biggs and Macmillan, 1948) and the centrifuged haematocrit (England et al., 1972).A radical change followed the advent of electronic particle counters employing gating techniques (Mattern et al., 1957) that facilitated the rapid measurement of red cell volumes and their subsequent computation as MCV. While the electronically derived MCV has been generally regarded as more accurate than that of earlier methods it harbours several sources of error (England and Down, 1976) and, in our view, has also created new clinical, laboratory, and economic problems.The high capital cost, automation, and large work capacity of such instruments have all contributed towards the centralisation of routine "Present address:

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