Integrated study of low density lipoprotein metabolism and very low density lipoprotein metabolism in non-insulin-dependent diabetes

The metabolisms of VLDL, IDL, and LDL and their interconversions have been studied in ten obese untreated male Pima Indian diabetics compared to 16 age-, sex-, and weight-matched nondiabetics. VLDL was elevated in the diabetics and had abnormal composition, as indicated by a significantly higher ratio of triglyceride/apo B. Fractional catabolic rates for both VLDL apoB and VLDL triglyceride were lower in diabetics, and diabetics had increased production of VLDL triglyceride but not VLDL apoB compared to obese nondiabetics. A higher proportion of VLDL apoB was removed without conversion to LDL in diabetics. LDL cholesterol and apoB were higher in diabetics, but production of LDL apoB was not different from nondiabetics. Fractional catabolic rate for LDL apoB, however, was significantly lower in the diabetics. The data indicate that the triglyceride-rich VLDL in non-insulin-dependent diabetics are less readily converted to LDL, whereas the elevated LDL in this group of diabetics is due to impaired clearance. Thus, decreased conversion of VLDL to LDL and impaired LDL clearance are two opposing phenomena which may influence the LDL concentration of diabetics in either direction. Thus, despite minimal changes in LDL concentration, there are multiple defects in the metabolism of LDL in non-insulin dependent diabetes which may contribute to the increased atherogenesis in this disorder.     

The provision of renal replacement therapy for adults in England and Wales: recent trends and future directions

We assessed the level of provision of renal replacement therapy for adults in England and Wales. All autonomous main renal units in England (n = 52) and Wales (n = 5) were surveyed in 1996. Data for England were compared to the 1993 National Renal Review. The acceptance rate in England 1995 was 82 (80-85) per million population (p.m.p.) compared with 67 (65-70) p.m.p. in 1991-2. The rate in 1995 in Wales was 109 (98- 122) p.m.p. The prevalence rate in England was 476 p.m.p. at end-1995 compared to 393 p.m.p. in 1993, in Wales it was 487 p.m.p. The number of main renal units in England did not rise between 1993 and 1995; capacity was increased by use of more treatment shifts and temporary haemodialysis stations, and by opening more satellite units. The main growth was in hospital haemodialysis. There was an uneven geographical distribution of services. Patients accepted were older with more comorbidity. The use of better-quality processes of dialysis increased. The steady-state position for RRT will not be reached for over a decade. Health authorities will face continued pressure to fund increases in quantity and quality improvements. A stronger evidence base of the effectiveness of therapies, and a national registry to monitor the equity and cost-effectiveness of services are needed.      

Manipulation of liver regeneration with macrophages to influence the hepatic progenitor cell niche

Insufficient regeneration of the adult liver is believed to cause failure to recover from severe liver disease. An undifferentiated cell population with stem-cell-like qualities known as hepatic progenitor cells (HPCs) is hypothesised to have a central role in regeneration of the adult liver during massive or chronic liver disease. Stem cells in other organ systems are believed to reside in a specialised microenvironment or niche that supports their maintenance and function. The existence of a hepatic stem cell niche might provide a means of therapeutically manipulating endogenous HPCs in vivo as a regenerative therapy.To investigate the physiological potential of HPCs to regenerate the mammalian liver, we have established a novel model of hepatocellular injury and HPC activation using genetic manipulation of hepatocytes. After hepatocyte senescence and death in this model (AhCre Mdm2^flox), HPCs expand and bring about the complete regeneration of the liver parenchyma.We demonstrate that a stereotypical niche, consisting partly of macrophages, exists in both animal models and correlating human disease. Using cell tracking, we show active recruitment of extrahepatic macrophages into this niche during injury. In health, intravenous injection of macrophages results in macrophage engraftment to the liver niche, with subsequent HPC activation and changes to liver structure and function.Within the niche, macrophages use paracrine signalling to control both HPC proliferation and cell fate via TWEAK (tumour-necrosis-factor-like weak inducer of apoptosis) and the Wnt signalling pathway, respectively. After hepatocellular injury, macrophages ingest hepatocyte debris, and release Wnt which promotes HPC differentiation into hepatocytes. TWEAK is vital for HPC proliferation in the AhCre Mdm2^flox model of regeneration. Here, the absence of TWEAK signalling results in liver failure and mortality.This work has demonstrated for the first time the ability of a solid organ to fully regenerate in the adult mammal from progenitor cells, and additionally highlights mechanisms by which this process can be modulated by either small molecule or cell therapy.FundingUniversity of Edinburgh.     

Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation

The pharmacokinetics of tacrolimus have been studied in healthy volunteers and in adults undergoing bone marrow transplantation. However, there is little information on the pharmacokinetics of tacrolimus in children undergoing BMT. We studied pharmacokinetics of tacrolimus in seven patients (age 8-17 years) undergoing allogeneic stem cell transplantation. Four patients received matched unrelated donor (MUD) transplants, two underwent HLA-matched related donor transplants, and one underwent an umbilical cord blood donor transplant. All patients received tacrolimus by continuous infusion at 0.03-0.04 mg/kg/day beginning on the day prior to transplant. Tacrolimus whole blood concentrations were monitored by microparticle enzyme immunoassay. Our goal was to maintain a blood tacrolimus level of 10-20 microg/ml. Once patients were tolerating oral medications, tacrolimus infusion was converted to oral dosing using a 4:1 conversion. Dose of tacrolimus and resulting tacrolimus concentrations were recorded and the total body clearance of tacrolimus was calculated retrospectively. The mean clearance, based on first steady-state tacrolimus concentrations necessary for achieving a therapeutic level (10-20 microg/ml), was 108.1 ml/h/kg (range 79.7-142.0 ml/h/kg), greater than that reported in adult BMT patients (71 +/- 34 ml/h/kg). The average dose required to achieve that therapeutic range was 0.0354 mg/kg/day as an intravenous continuous infusion. Over the entire course of intravenous tacrolimus, mean clearance was 97.0 ml/h/kg (range 33.4-153.3 ml/h/kg). In six of the seven patients, clearance values dropped after 2-4 weeks of therapy by an average of 32.5 ml/h/kg. In two patients, sharp drops in clearance were temporally related to changes in liver function tests. Three of the seven patients died of severe acute GVHD; all these had undergone matched unrelated donor transplantation, and two of these three had initial clearance levels over 120 ml/h/kg. Thus, children appear to have more rapid tacrolimus clearance than adults and may need to begin therapy earlier in order to obtain stable and optimal levels. More studies are needed to confirm these preliminary results.     

First-generation neuronal precursors in the crayfish brain are not self-renewing

Adult-born neurons in crayfish (Procambarus clarkii) are the progeny of 1st-generation precursor cells (functionally analogous to neuronal stem cells in vertebrates) that are located in a neurogenic niche on the ventral surface of the brain. The daughters of these precursor cells migrate along the processes of bipolar niche cells to proliferation zones in the cell clusters where the somata of the olfactory interneurons reside. Here they divide again, producing offspring that differentiate into olfactory local and projection neurons. The features of this neuronal assembly line, and the fact that it continues to function when the brain is isolated and perfused or maintained in organotypic culture, provide opportunities unavailable in other organisms to explore the sequence of cellular and molecular events leading to the production of new neurons in adult brains. Further, we have determined that the 1st-generation precursor cells are not a self-renewing population, and that the niche is, nevertheless, not depleted as the animals grow and age. We conclude, therefore, that the niche is not a closed system and that there must be an extrinsic source of neuronal stem cells. Based on in vitro studies demonstrating that cells extracted from the hemolymph are attracted to the niche, as well as the intimate relationship between the niche and vasculature, we hypothesize that the hematopoietic system is a likely source of these cells.     

A rapid microagglutination test for the diagnosis of Legionella pneumophila (serogroup 1) infection

A rapid microagglutination test has been developed which can be performed in 30 minutes. Ninety-seven percent of 96 patients diagnosed as having Legionella pneumophila (serogroup 1) infection by indirect immunofluorescence were also detected by the rapid microagglutination test.     

Verhandlungen ärztlicher Gesellschaften

Ohne Zusammenfassung     

Crayfish brain interneurons that converge with serotonin giant cells in accessory lobe glomeruli

Freshwater crayfish have well-developed olfactory systems with an array of receptors that project exclusively to areas in the brain that are functionally specialized for the processing of odors. The accessory lobes are large bilateral areas of neuropil that are anatomically associated with the olfactory lobes. The accessory lobes receive no primary afferents and do not contain the endings of motor efferents; thus, their role in olfaction is still obscure. Intracellular dye filling of interneurons in the deutocerebral commissure in the crayfish brain has shown that they end bilaterally in glomeruli in the accessory lobes, have cell somata in a dorsal cluster medial to the olfactory lobes, and have unilateral projections to the deutocerebral commissure neuropil. Each deutocerebral commissure interneuron has only 6 to 15 output glomeruli in each accessory lobe and does not share glomeruli with other deutocerebral commissure interneurons. The deutocerebral commissure interneurons converge with the dorsal giant serotonin neurons in the accessory lobe glomeruli. Deutocerebral commissure interneurons can be separated into classes according to their projections to the protocerebrum, central body, and deutocerebrum. Physiological responses of the deutocerebral commissure interneurons following photic stimulation of the eyes and electrical stimulation of the second antennae lead to the conclusion that the deutocerebral commissure represents an input to the accessory lobes from the protocerebral neuropils and that visual and tactile inputs are included in the processing performed in the accessory lobes. © 1995 Wiley-Liss, Inc.