Controlled trial of methylprednisolone pulses and low dose oral prednisone for the minimal change nephrotic syndrome.

In a multicentre, randomised, prospective trial 89 patients (67 children and 22 adults) with the minimal change nephrotic syndrome were treated with three intravenous pulses of methylprednisolone followed by low dose oral prednisone for six months (group given methylprednisolone) or with high dose oral prednisone for four weeks followed by low dose oral prednisone for five months (control group). Five patients in the group given methylprednisolone and one in the control group did not respond initially. The time to response was shorter in children treated with methylprednisolone. No significant differences between the two groups were observed in the number of patients who relapsed or number of relapses per patient per year. Patients given methylprednisolone tended to relapse earlier than patients in the control group. Side effects related to treatment were significantly fewer in the group given methylprednisolone than in the control group. These data suggest that a short course of methylprednisolone pulses followed by low dose oral prednisone is only marginally less effective than a regimen of high dose oral steroids but can improve the ratio of risk to benefit associated with treatment of the minimal change nephrotic syndrome.     

Cystine Deprivation Induces Oligodendroglial Death: Rescue by Free Radical Scavengers and by a Diffusible Glial Factor

Abstract: In this study we examined the effect on oligodendroglial survival of exogenous cystine deprivation. Oligodendroglia isolated from mixed glial primary cultures derived from brains of 1-day-old rats, and then grown for 3 days, were markedly dependent on extracellular cystine for survival. The EC₅₀ values for cystine for a 24-h exposure ranged from 2 to 65 µ M . After 6 h of cystine deprivation, the cellular glutathione level decreased to 21 ± 13% of the control. Free radical scavengers (α-tocopherol, ascorbate, idebenone, and N-tert -butyl-α-phenylnitrone) were protective against cystine deprivation but had no effect on the glutathione level. An iron chelator, desferrioxamine mesylate, also was protective. These findings suggest that intracellular hydroxyl radicals are important for this toxicity. In contrast to the observations in 3-day-old cultures, the dependence on exogenous cystine for cell viability was not observed consistently in oligodendroglia cultured for 6 days before the onset of cystine deprivation. Several observations suggested that this loss of cystine dependence was due to a diffusible factor. Sensitivity to the toxicity of cystine deprivation in day 6 cultures increased as the volume of medium was increased from 0.3 to 2 ml. Furthermore, preincubation of cystine-depleted medium with astrocyte cultures eliminated the toxicity of the cystine deprivation. HPLC assay of the conditioned cystine-depleted medium showed no significant change in cystine or cysteine concentration. We conclude that oligodendroglia are highly susceptible to cystine deprivation in day 3 cultures and that this susceptibility is due to the accumulation of intracellular free radicals in the setting of glutathione depletion. The resistance of day 6 oligodendroglial cultures is caused at least in part by a diffusible factor.     

Antibodies to junctional sarcoplasmic reticulum proteins: probes for the Ca2+-release channel.

The junctional face membrane plays a key role in excitation-contraction coupling in skeletal muscle. A protein of 350 kDa, tentatively identified as a component of the junctional feet, connects transverse tubules to terminal cisternae of sarcoplasmic reticulum [Kawamoto, Brunschwig, Kim & Caswell (1986) J. Cell Biol. 103, 1405-1414]. The membrane topology and protein composition of sarcoplasmic reticulum Ca2+-release channels of rabbit skeletal muscle were investigated using an immunological approach, with anti-(junctional face membrane) and anti-(350 kDa protein) polyclonal antibodies. Upon preincubation of the terminal cisternae with anti-(junctional face membrane) antibodies, Ca2+-ATPase and Ca2+-loading activities were not affected, whereas anti-(350 kDa protein) antibodies stimulated Ca2+-ATPase activity by 25% and inhibited Ca2+-loading activity by 50% (at an antibody/terminal cisternae protein ratio of 1:1). Specific photolabelling of terminal cisternae proteins with [14C]doxorubicin was prevented by both anti-(junctional face membrane) and anti-(350 kDa protein) antibodies. Stimulation of Ca2+ release by doxorubicin was prevented by both anti-(junctional face membrane) and anti-(350 kDa protein) antibodies. Half-maximal inhibition was obtained at an antibody/terminal cisternae protein ratio of 1:1. Kinetic measurements of Ca2+ release indicated that anti-(350 kDa protein) antibodies prevented Ca2+-induced Ca2+ release, whereas the ATP-stimulation and the inhibition by Mg2+ were not affected. These results suggest that: (i) Ca2+- and doxorubicin-induced Ca2+ release is mediated by Ca2+ channels which are selectively localized in the junctional face membrane; (ii) the 350 kDa protein is a component of the Ca2+-release channel in native terminal cisternae vesicles; and (iii) the Ca2+-activating site of the channel is separate from other allosteric sites.     

Chemical composition and antimicrobial activity of 2 Peruvian plants]

In this work we determined the hydrocarbon , sterol and triterpenoid composition of two plants used as antibacterial drug in traditional peruvian medicine, Berberis rariflora and Chenopodium multifidum. In both plants the presence of unsaturated hydrocarbons is very low, whereas the presence of odd hydrocarbons is considerable. The delta 7 sterols are more abundant than delta 5 sterols. We found also a great presence of stigmasterol derivatives in both plants, whereas lanosterol derivates are more abundant in B. rariflora. The microbiological tests shows for both plants an evident antibacterial activity against Gram(+) bacteria.     

Effects of atrial natriuretic factor on blood pressure and the renin-angiotensin-aldosterone system

Atrial natriuretic factor (ANF) antagonizes vasoconstriction induced by numerous smooth muscle agonists and also lowers blood pressure in intact animals. ANF has particularly marked relaxant effects on angiotensin II-contracted vessels in vitro. Sensitivity to the blood pressure-lowering effect of ANF in vivo appears to be enhanced in renin-dependent models of renovascular hypertension compared with other experimental hypertensive models. The depressor action of low, possibly physiological doses of ANF in two-kidney, one-clip Goldblatt rats is due to a decrease in total peripheral resistance. On the other hand, high doses of ANF can lower cardiac output, particularly in volume-expanded models such as deoxycorticosterone-salt hypertension. ANF markedly inhibits renin secretion in intact animals, probably via increased glomerular filtration rate and load of sodium chloride to the macula densa. This effect is masked when renal perfusion is impaired (e.g., via unilateral renal artery constriction), in which case ANF may stimulate renin secretion slightly. ANF also reduces plasma aldosterone in vivo and inhibits basal and agonist-induced aldosterone release from isolated adrenal cortical cells. This effect appears to be especially marked for angiotensin-induced aldosterone production in vivo and in vitro. These findings indicate that ANF has potentially important interactions with the renin-angiotensin-aldosterone system and suggest a role for ANF in the homeostatic control of blood pressure as well as of extracellular fluid volume.     

Effects of atrial natriuretic factor on human platelet function

We examined the hypothesis that atrial natriuretic factor (ANF), a substance with known vasorelaxant activities, shares with other vasodilators the property of inhibiting platelet function. Aggregation of citrated platelet-rich plasma (PRP) from 23 healthy volunteers induced by ADP, adrenaline, arachidonic acid, collagen, gamma-thrombin, the endoperoxide analogue U-44069, serotonin, the calcium ionophore A-23187 or platelet aggregating factor was measured after incubation of PRP with ANF for 3 minutes at concentrations of 4 X 10(-9), 4 X 10(-8) and 4 X 10(-7) M or vehicle as control. ANF decreased ADP-induced aggregation significantly (P less than 0.02), but only at the highest concentration used and to a minor extent (control: 73.6 +/- 11.2%; after ANF 4 X 10(-7) M: 60.0 +/- 17.1%, mean +/- S.D., n = 39) by a selective inhibitory effect on the secondary wave; neither aggregation by all other agents tested nor thromboxane B2 generation induced by ADP and adrenaline was altered by incubation with ANF. Although ANF thus has detectable effects on ADP-induced platelet aggregation in vitro, these data suggest that ANF is unlikely to be a physiologically significant modulator of platelet function.     

Dermorphin decreases plasma LH levels in human: evidence for a modulatory role of gonadal steroids

The purpose of this study was to evaluate the effects of dermorphin, a new synthetic powerful opiate-like heptapeptide, on plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in fertile and postmenopausal women. In fertile subjects, dermorphin (5.5 micrograms/kg min for 30 min) decreases plasma LH (p less than 0.01 vs. baseline and placebo values), but not plasma FSH. The area under the curve during dermorphin infusion was significantly lower than during placebo infusion (p less than 0.01). Pretreatment with the opioid receptor antagonist naloxone, blocked the decrease of plasma LH levels. In postmenopausal women not subjected to any treatment, dermorphin infusion did not significantly modify plasma LH and FSH levels. On the contrary, its administration to postmenopausal subjects treated with conjugated estrogens and medroxyprogesterone acetate significantly decreased plasma LH levels (p less than 0.01, vs. baseline, placebo and area under the curve). Considering the modulatory role exerted by ovarian steroids on the activity of such receptors, these data also indicate that opioid systems play a very important part in the hypothalamus-pituitary-ovarian axis.     

Synthesis and LTD4-antagonist activity of desamino-2-nor-leukotriene analogs

A series of desamino-2-nor-leukotriene analogs has been prepared by the reaction of various thiols with several methyl trans-4,5-epoxy-6Z-alkenoates, followed by deprotection. The products were assessed for their ability to antagonize the LTD4-induced contraction of the isolated guinea pig trachea. Several compounds displayed potent leukotriene antagonist activity, i.e., KB values in the sub-micromolar range, while only minimally affecting basal airway tone. The most potent analog, 4-hydroxy-5-(2-carboxyethylthio)-6Z-nonadecenoic acid, antagonized both LTD4- and LTE4-induced contractions of the trachea in an apparently competitive fashion. These agents possess increased potency relative to SK&F 101132, the first leukotriene analog identified as having LT-antagonist activity. Thus, these results demonstrate that deletion of the peptide amino group can produce leukotriene analogs which have minimal intrinsic contractile activity on the isolated guinea pig trachea, yet possess potent leukotriene-antagonistic effects.