Cyclosporine in glomerular disease

Cyclosporine was introduced in 1981 as an immunosuppressive agent in renal transplantation. Its use was soon extended to the treatment of various glomerular disorders. In light of its known immunomodulating effects, the use of cyclosporine has been most prominent in those glomerular diseases thought to have an immune basis. The most careful studies of cyclosporine in glomerular diseases have been performed in the pediatric population with idiopathic nephrotic syndrome (i.e., minimal change disease and focal segmental glomerulosclerosis), although data are accumulating regarding efficacy and safety in adults with idiopathic nephrotic syndrome. In patients who are steroid-dependent, cyclosporine therapy can induce complete or partial remission in a significant proportion of cases; success rates in patients with steroid-resistant nephrotic syndrome are less encouraging. Treatment with cyclosporine allows for dose reduction or elimination of corticosteroids, and the consequent salutary effect on growth in the child and glucose and bone metabolism in all patients. Studies that suggest a potential benefit of cyclosporine in recurrent nephrotic syndrome in renal allografts and in other glomerular diseases are also discussed.     

Direct finite element design optimisation of the cagelessreluctance synchronous machine

The finite element analysis method is used directly in optimisation algorithms to optimise in multidimensions the design of the cageless reluctance synchronous machine. Two optimisation methods are evaluated to minimise or maximise the function value. These are the direction set method of Powell and the quasi-Newton algorithm. Both methods proved to be successful, with some advantages and disadvantages. Using these methods at a power level below 10 kW, results are given of structures of the reluctance synchronous machine which have been optimised according to specific criteria. Calculated and measured results show that the maximum torque optimum designed reluctance synchronous machine has the advantages of high power density and high efficiency     

Comparison between normal and reverse thin crystalline silicon solar cells

The newly developed ingot growing techniques, as the three-grain and the columnar multigrain ingot processes, are now offering the possibility of slicing thinner wafers (≤ 100 μm). In this paper we present the results obtained on p type large area (≥ 100 cm²) and 100 μm thick wafers by using both conventional and reverse cell manufacturing technologies.The conventional cells are provided with aluminium or boron BSF plus screen-printed silver mirror or a silver-aluminium net; the reverse cells have a FSF and the deep back junction completely covered by a screen-printed or CVD silver layer.The constructing parameters have been chosen on the base of one and two dimensions modeling and both raw material and devices have been completely characterized.This work shows that very thin wafers do not introduce serious problems for the conventional manufacturing of solar cells. The efficiencies of the normal and of the reverse cells are found to be comparable and are of the same order than those of thicker cells, however at a significant lower cost. The main obtained result has to be related to the demonstration of a cell manufacturing feasibility starting from very thin wafers.     

Apoptosis in the failing human heart

BACKGROUND: Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. However, whether programmed cell death (apoptosis) is implicated in the terminal stages of heart failure is not known. We therefore studied the magnitude of myocyte apoptosis in patients with intractable congestive heart failure. METHODS: Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hearts of 3 patients who died soon after myocardial infarction. Samples from 11 normal hearts were used as controls. Apoptosis was evaluated histochemically, biochemically, and by a combination of histochemical analysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined. RESULTS: Heart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin condensation and fragmentation by confocal microscopy. All these findings reflect apoptosis of myocytes. The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting. CONCLUSIONS: Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.     

A base-pairing interaction between U2 and U6 small nuclear RNAs occurs in > 150S complexes in HeLa cell extracts: implications for the spliceosome assembly pathway

In mammalian cells, base pairing between the U2 and U6 small nuclear RNAs is required during pre-RNA splicing. We show by psoralen crosslinking of HeLa nuclear extract that U2.U6 base pairing occurs within abundant ribonucleoprotein complexes that sediment at > 150 S in glycerol gradients. All of the spliceosomal RNAs (U1, U2, U4, U5, and U6) cosediment with these large complexes, suggesting that they may be related to small nuclear RNA-containing structures called speckles/coiled bodies or snurposomes, which have been visualized in mammalian or amphibian nuclei, respectively. In contrast to nuclear extract, S100 extract, which is splicing-defective and lacks the > 150S complexes, does not contain base-paired U2.U6. However, U2.U6 base pairs form in S100 extract that has been made splicing-competent by supplementation with Ser/Arg-rich (SR) proteins, ATP, and an adenovirus splicing substrate. During splicing in supplemented S100 extract, U2.U6 base pairing precedes the appearance of splicing intermediates and occurs initially in an approximately 60S spliceosome complex but also in progressively larger (100-300 S) complexes. Possible functional relationships between the 60S spliceosome and the > 150S complexes are discussed.     

Incomplete inversion and double-valued fundamental linewidth ofinfrared HeNe and HeXe lasers

We have measured the quantum-limited linewidths of small HeNe 3.39 μm and HeXe 3.51 μm lasers. In contrast to the expected Schawlow-Townes behaviour strong deviations from the inverse power dependence are observed, leading to a double-valued relation between the linewidth and the output power. This phenomenon is analyzed in terms of the increase of spontaneous emission, by a factor N_sp, due to incompleteness of the inversion. Our analysis shows that typically N_sp has a value ranging from 1-10. Combining existing models for the pump power dependence of the level populations with measurements of the small signal gain, we are able to explain the observed double-valued linewidth behaviour in a quantitative way     

Pathogenesis of malignant ascites formation: initiating events that lead to fluid accumulation

Initiating events leading to the accumulation of malignant ascites in the peritoneal cavity were investigated in two syngeneic transplantable murine ascites-producing tumors, MOT mouse ovarian tumor and the TA3/St mammary carcinoma. The transport of two tracers, 125I-labeled human serum albumin (125I-HSA) and 51Cr-labeled red blood cells (51Cr-RBC), into and out of the peritoneal cavity was studied at early times after i.p. tumor cell injection, prior to abundant fluid accumulation, and at intervals of 5 to 360 min after i.v. or i.p. tracer injection. Tracer influx and efflux rates were estimated from the mass of tracer passing into or out of the peritoneal cavity following a bolus injection of tracer into either the blood or the peritoneal cavity. Efflux of 125I-HSA from the peritoneal cavity was markedly reduced (3- to 5-fold) within 1 day of i.p. injection of either type of tumor cell. Significantly reduced efflux preceded any increase in tumor cell number and by itself did not induce peritoneal fluid accumulation. 125I-HSA tracer influx from plasma to peritoneal fluid did not increase detectably until 5 to 7 days after tumor cell injection, when the tumor cell number had increased by 10- to 100-fold. Only at relatively late stages of ascites tumor growth, when the flow rate into the peritoneal cavity had increased relative to the flow rate out of the peritoneum, was there net peritoneal fluid accumulation. Thus, increased influx, in addition to impaired efflux, were required for malignant ascites accumulation. Following i.p. injection, the efflux rates of 125I-HSA always exceeded those of 51Cr-RBC, even in ascites tumor-bearing animals. Furthermore, 125I-HSA tracer disappeared from the peritoneal cavity more rapidly than it appeared in the plasma, suggesting that 125I-HSA moves more rapidly through the channels by which 51Cr-RBC egress from the peritoneum (primarily diaphragmatic lymphatics) and/or has access to additional pathways not open to 51Cr-RBC. Finally, flow rates into and out of the blood and peritoneum were used to obtain kinetic parameters that characterized tracer transport: k1, the rate constant for tracer transport from the blood to the peritoneum; k2, the rate constant for tracer transport from the peritoneal cavity to the blood; and k6, the rate constant for tracer transport from the peritoneal cavity to surrounding interstitial tissue.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physiologic correlates to running performance in pre-pubertal distance runners

In adults, four major variables have been shown to be associated with success in distance running performance: submaximal oxygen consumption (running economy), peak oxygen consumption (Peak VO2), ventilatory threshold (VT) and fractional utilisation (FU). The primary aim of this study was to describe the relationship between the 3000 m race times of run-trained prepubertal boys to these four variables. Thirteen male run-trained pre-pubertal boys (age 11.7 +/- 1.1 yrs, mean +/- SD), volunteered to take part in a 3000 m time trial and laboratory assessment, consisting of treadmill running at four submaximal speeds (8, 9.6, 11.2 and 12.8 km.h-1) as well as a peak VO2 test. The group demonstrated a heterogeneous array of peak VO2 data. A high level of association (p < 0.05) was found between mass-relative peak VO2 and 3000 m time trial results (r = -0.83). In addition ventilatory threshold expressed as %peak VO2, VO2 at VT and estimated velocity at VT was also highly related to 3000 m time trial (r = -0.78, -0.77 and -0.77) respectively. Fractional utilisation (%peak VO2) was significantly (p < 0.05) associated with race time at the final two submaximal running speeds only (11.2 and 12.8 km.h-1) (r = 0.61 and 0.67, respectively). Respiratory Exchange Ratio (RER) was also found to be significantly (p < 0.05) associated with 3000 m race time at 11.2 and 12.8 km.h-1. Overall peak VO2 appeared to be the single most important factor associated with success at 3000 m.     

d-Tubocurarine accentuates the burn-induced upregulation of nicotinic acetylcholine receptors at the muscle membrane

BACKGROUND: Increases in acetylcholine receptors (AChRs) at the muscle membrane, induced by burn injury, have been associated with a hyperkalemic response to succinylcholine and resistance to d-tubocurarine-like drugs. Muscle relaxants often are administered to burn-injured patients in the intensive care unit to facilitate mechanical ventilation. This study in rats tested whether continuous administration of d-tubocurarine in subparalytic doses exaggerates the upregulation of AChRs induced by burn trauma. Subparalytic doses were used to avoid the confounding effects of immobilization. METHODS: Three days after an approximate 50% body surface area burn or sham injury, the animals received an infusion of 3.03 +/- 0.05 micrograms/h of d-tubocurarine or equal volume of saline directly to the left gastrocnemius muscle via catheter connected to a subcutaneously implanted osmotic pump. After 7 days of d-tubocurarine or saline infusion, the AChRs were quantitated using 125I-alpha-bungarotoxin. The AChRs on the d-tubocurarine or saline-infused left gastrocnemius were compared to the contralateral gastrocnemius in the same group. The right or left gastrocnemius AChRs were compared to the ipsilateral muscles between groups. These intra- and intergroup comparisons allowed the delineation of the effects of catheter irritation, burns, or d-tubocurarine on AChRs. RESULTS: Daily examination of the withdrawal response to toe-pinch revealed no evidence of paralysis. Weight loss in the burn-injury animals receiving d-tubocurarine or saline was similar, confirming that the infusion of d-tubocurarine did not impair the mobility of the animals to move and feed. The plasma d-tubocurarine concentration after 7 days of infusion was 26.0 +/- 12 ng/ml (mean +/- SE). Regardless of burn or sham injury or of d-tubocurarine or saline infusion, the concentration of AChRs on the left was consistently greater than in the contralateral right gastrocnemius muscles within the same group, indicating that manipulation of the area alone can result in upregulation of AChRs. The AChRs in the right gastrocnemius of burn-injured animals were greater than those in the same muscle of sham-injured animals, regardless of saline (7.24 +/- 0.9 vs. 5.7 +/- 0.5 fmoles/mg protein, P = 0.06) or d-tubocurarine (7.3 +/- 0.4 vs. 5.7 +/- 0.5, P < 0.05) infusion to the burn-injury groups. AChRs in the left gastrocnemius of burn-injury animals receiving d-tubocurarine were significantly greater than those in burn- or sham-injury animals receiving saline (13.9 +/- 1.1 vs. 9.8 +/- 1.2 and 7.1 +/- 0.5 fmoles/mg protein, respectively, P < 0.05). CONCLUSIONS: Burn-induced upregulation of AChRs is accentuated by infusion of subparalytic doses of d-tubocurarine. Concomitant administration of d-tubocurarine to burn-injured patients may result in further exaggeration of the aberrant responses to neuromuscular relaxants.