Circulating leptin has saturable transport into intrathecal space in humans

BACKGROUND: Leptin is an adipocyte-derived hormone that is thought to provide a negative feedback signal to control body fat mass by interacting with its hypothalamic receptor. The present study was undertaken to examine the uptake of leptin in cerebrospinal fluid (CSF) space in humans and whether the transport of leptin into CSF space is an active phenomenon or due to free access through the blood-CSF barrier. METHODS: We determined serum and CSF leptin concentrations by radioimmunoassay in 17 men [42 +/- 4 years, mean +/- SE; body mass index (BMI) 27.3 +/- 1.8 kg m-2] and 22 women (40 +/- 3 years, BMI 25.1 +/- 1.0 kg m-2). The function of the blood-CSF barrier was evaluated by determining the CSF/serum albumin ratio. RESULTS: Serum leptin concentration was lower in male (5.8 +/- 1.6 microgram L-1) than in female subjects (13.1 +/- 1.7 microgram L-1, P = 0. 001), whereas the concentrations of leptin in CSF were virtually identical in male (0.34 +/- 0.03 microgram L-1) and female (0.36 +/- 0. 03 microgram L-1) subjects. Serum leptin was correlated positively with BMI both in men (r = 0.89, P < 0.01, n = 10) and in women (r = 0.61, P < 0.05, n = 14), whereas no correlation between CSF leptin concentration and BMI was found in either group. The CSF/serum leptin ratio correlated negatively with serum leptin concentration both in men (r = -0.93, P < 0.001) and in women (r = -0.77, P < 0. 001) and with BMI both in men (r = -0.75, P = 0.02, n = 10) and in women (r = -0.64, P < 0.02, n = 14). The CSF/serum albumin ratio was not correlated with the CSF/serum leptin ratio in either group. CSF leptin concentrations and the CSF/serum leptin ratio were virtually identical in subjects with impaired and normal blood-CSF barrier function. CONCLUSION: Thus, our data support the presence of a saturable and active transporter of leptin from circulation into intrathecal space.     

The treatment of severe hypertension with trandolapril, verapamil, and hydrochlorothiazide. Trandolapril/Verapamil Multicenter Study Group

A multiple drug regimen consisting of trandolapril, verapamil and hydrochlorothiazide (HCTZ) were sequentially added in an open-label evaluation of patients with severe hypertension. Ninety patients (58 white and 32 black patients) were titrated on one or more drugs and followed for a 19-week maintenance period. Statistically significant (P = 0.001) mean (+/-s.d.) decreases in supine diastolic blood pressure (DBP) were 9.0 (+/-9.3) mm Hg for trandolapril, 13.9 (+/-11.0) mm Hg for the trandolapril + verapamil (TV) combination, and 19.0 (+/-12.3) mm Hg when hydrochlorothiazide was added to the combination. The decrease in BP observed on TV combination therapy plus HCTZ was significantly (P = 0.001) greater than the decrease observed for the TV combination, which was significantly (P = 0.001) greater than the decrease observed for trandolapril monotherapy. Clinical responder rates were 44.8%, 56% and 77.7% for trandolapril monotherapy, trandolapril + verapamil combination therapy and triple therapy, respectively. Black and white patients had similar response rates, but black patients appeared to benefit more from the addition of HCTZ; 20% of black patients achieved a post-treatment supine DBP <90 mm Hg compared to 12.8% of white patients. This study demonstrates that the addition of verapamil to trandolapril has an additive effect on BP that is maintained throughout the day.     

Discriminating the volume of motion-defined solids

We investigated the ability of human observers to discriminate an important global 3-D structural property, namely volume, of motion-defined objects. We used convex transparent wire-frame objects consisting of about 12 planar triangular facets. Two objects, vertically separated by 7 degrees, were shown simultaneously on a computer display. Both revolved at 67 degrees/sec around a common vertical axis through their centers of mass. Observers watched the objects monocularly for an average of three full rotations before they responded. We measured volume discrimination as a function of absolute volume (3-48 cm3; 1 m viewing distance) and shape (cubes, rods, and slabs of different regularity). We found that (1) volume discrimination performance can be described by Weber's law, (2) Weber fractions depend strongly on the particular combination of shapes used (regular shapes, especially cubes, are easiest to compare, and similar shapes are easier to compare than different shapes), and (3) humans use a representation of volume that is more veridical and stable in the sense of repeatability than a strategy based on the average visible (2-D) area would yield.     

Osteoclast-mediated bone resorption is stimulated during short-term administration of granulocyte colony-stimulating factor but is not responsible for hematopoietic progenitor cell mobilization

The cellular and molecular mechanisms responsible for hematopoietic progenitor cell (HPC) mobilization from bone marrow (BM) into peripheral blood after administration of cytokines such as granulocyte colony-stimulating factor (G-CSF) are still unknown. In this study we show that high concentrations of soluble calcium induce the detachment of BM CD34(+) HPC adherent on fibronectin, a major component of BM extracellular matrix. Because G-CSF has been shown to induce osteoporosis in patients with congenital neutropenia and in G-CSF-overexpressing transgenic mice, we hypothesized that short-term G-CSF administration may be sufficient to induce bone resorption, resulting in the release of soluble calcium in the endosteum leading in turn to the inhibition of attachment to fibronectin and the egress of HPC from the BM. We show herein that in humans, serum osteocalcin concentration, a specific marker of bone formation, is strongly reduced after 3 days of G-CSF administration. Furthermore, in patients mobilized with G-CSF either alone or in association with stem cell factor or interleukin-3, the reduction of serum osteocalcin is significantly correlated with the number of HPC mobilized in peripheral blood. Urine levels of deoxypyridinoline (DPyr), a specific marker of bone resorption, gradually elevated during the time course of G-CSF administration until day 7 after cessation of G-CSF, showing a simultaneous stimulation of bone degradation during G-CSF-induced HPC mobilization. In an in vivo murine model, we found that the number of osteoclasts was dramatically increased paralleling the elevation of DPyr after G-CSF administration. When pamidronate, an inhibitor of osteoclast-mediated bone resorption, was administered together with G-CSF in mice, the G-CSF-induced increase of DPyr levels was completely abolished whereas the numbers of colony-forming cells mobilized in peripheral blood were not decreased, but unexpectedly increased relative to the numbers elicited by G-CSF alone. Collectively, our data therefore show that short-term administration of G-CSF induces bone degradation by a simultaneous inhibition of bone formation and an enhanced osteoclast-mediated bone resorption. This increased bone resorption is inhibited by pamidronate without reducing G-CSF-induced HPC mobilization, suggesting that the activation of bone resorption after G-CSF administration is not the direct cause of HPC mobilization as initially hypothesized, but a parallel event.     

Renal cell carcinoma: the Ochsner Medical Institution experience (1945-1978)

We reviewed 161 patients operated upon for renal cell carcinoma between 1945 and 1978. Life table and survival analyses were computed to compare the effects of stage, tumor differentiation, cell type, surgical technique, renal vein involvement and sex on the years of survival. Patients with stage I and well differentiated tumors had the best prognosis. All patients surviving 10 years or more had well differentiated tumors. The type of nephrectomy did not affect survival and lymphadenectomy was only of value in staging the disease. The stage and differentiation of the tumor were more important to outcome than choice of therapy.     

How should multiple organ dysfunction syndrome be assessed? A review of the variations in current scoring systems

There are many scores for evaluating multiple organ dysfunction (MODS) which differ appreciably, and this makes it difficult to compare results from different research groups. In addition the variables used to describe organ dysfunction are not always as organ-specific as they should be. In this review we have studied 20 MODS scoring systems to illustrate the variety in variables used to assess organ dysfunction.     

Craniofacial resection. An alternative incision and skull base repair

Neoplasia of the superior group of paranasal sinuses (frontal, ethmoidal and sphenoidal) has an extremely poor prognosis. Resection, preceded or followed by radiotherapy offers a 5 year survival of less than 30% (1). Satisfactory surgical excision has been undermined by difficulties of access to the cribriform plate area, a common site for residual disease. Furthermore the practice of piecemeal removal invariably resulted in inadequate clearance. The craniofacial approach allows not only excellent access to the anterior skull base but also in bloc excision. The results of treating 7 patients with craniofacial resection for tumours in this area are presented. Particular reference is made to a horizontal forehead skin crease incision for intracranial access. A new technique using a combination of surgical, pericranium, partial thickness skin and fibrin glue to repair the skull base defect is described.