The prevalence of grandmothers as primary caregivers in a poor pediatric population.

In the wake of the HIV/AIDS and crack cocaine epidemics, poor urban communities face growing numbers of older adults, largely grandmothers, who have become surrogate parents to children orphaned by these epidemics. This study is the first in the United States to determine the prevalence of older surrogate parents among families registered at pediatric clinics. The three clinics selected were in low income neighborhoods of New York City with a high incidence of female HIV/AIDS and substance abuse. Using a 50% random sample of 1,375 records of registered families, data were obtained on the number and ages of relatives serving as surrogate parents. In 11% of these 1,375 families with children 12 years and under a parent was not the caregiver. In 8% the caregiver was a grandmother. Forty-seven percent of these women were 55 years or older, 25% were 60 years or older and 8% were 70 years or older. Most of these women were caring for more than one child. Ten percent of the total of 2,445 children, 12 years and under, lived in non-parent headed families. Eight percent lived with a grandmother, 1% with other parental generation relatives and 1% in foster care. Given the stresses associated with caregiving in late life and the greater risk of poor health among low income African-American and Hispanic elderly, older surrogate parents from these communities are a potentially high health risk population whose own needs may go unrecognized and unattended. The young ages of the children suggest that many grandparents may continue to be caregivers as they reach their sixties, seventies and even eighties. Clinical and longitudinal data are needed to determine how prolonged surrogate parenting in late life affects the health of older caregivers and the children in their care. Coordination between health and social services for the elderly and for children are needed to promote effective programs for these families.

Effects of ion channel blockers and phorbol ester treatments on [3H]dopamine release and neurotensin facilitation of [3H]dopamine release from rat mesencephalic cells in primary culture.

In this work, we tested the effect of ion channel blockers and of phorbol ester treatments on [3H]dopamine ([3H]DA) release and neurotensin (NT)-induced facilitation of [3H]DA release from cultures of rat fetal mesencephalic cells. The potassium channel blockers tetraethylammonium and 4-aminopyridine increased basal [3H]DA release and decreased K(+)-evoked [3H]DA release, whereas apamin was without effect. K(+)-evoked [3H]DA release was decreased by omega-conotoxin and nifedipine, totally suppressed by cadmium, and unaffected by amiloride. These results show the differential sensitivity of [3H]DA release to blockade of various ion channels and suggest the involvement of N-type, L-type, and non-L-non-N-type, but not T-type, voltage-sensitive calcium channels in K(+)-evoked release. Phorbol 12-myristate 13-acetate increased both spontaneous and K(+)-evoked [3H]DA release, suggesting a modulatory action of protein kinase C on DA release in this system. Unexpectedly, however, the effects of the phorbol ester were not counteracted by the protein kinase C inhibitors H7, staurosporine, or polymyxin B. NT-induced facilitation of K(+)-evoked [3H]DA release was insensitive to most of the ion channel blockers, except cadmium (64% decrease in NT effect), suggesting that the corresponding potassium and calcium channels were not involved in the effect of NT on [3H]DA release in this system. The NT effect was totally suppressed by phorbol ester treatments, indicating a possible desensitization of the corresponding transduction mechanisms after protein kinase C activation.

SR 48692 inhibits neurotensin-induced [3H]dopamine release in rat striatal slices and mesencephalic cultures.

In rat striatal slices, the increase (114 +/- 11%) in K(+)-evoked [3H]dopamine release induced by neurotensin (10 nM) was antagonized by 2-[(1-(7-chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)pyrazol-3-yl) carboxylamino]tricyclo(3.3.1.1.3.7)decan-2-carboxylic acid (SR 48692, IC50 = 1.2 +/- 0.11 nM). SR 48692 (100 nM) also suppressed the neurotensin (10 nM)-induced increase (47%) in K(+)-evoked [3H]dopamine release in primary cultures of fetal rat mesencephalic cells. These results further characterize SR 48692 as a potent antagonist of neurotensin receptors in the rat.

In vivo and in vitro structure-activity studies with peptide and pseudopeptide neurotensin analogs suggest the existence of distinct central neurotensin receptor subtypes.

The present study was designed to compare, with respect to structure-activity relationships, the receptors that subserve the hypothermic and analgesic effects of neurotensin (NT) to the receptor that mediates the effects of NT in mesencephalic dopamine (DA) neurons, and to compare these receptors to the cloned adult rat brain NT receptor and to newborn mouse and rat brain NT receptors. The results show that NT receptors in homogenates from newborn mouse and rat brain and from COS 7 cells transfected with the cloned high-affinity NT receptor from the adult rat brain displayed virtually identical structure-activity relationships toward a series of 12 peptide and pseudopeptide NT analogs, as assessed by the ability of the compounds to inhibit the binding of [125I]NT binding in these systems. Furthermore, when eight of these analogs were tested for their ability to inhibit [125I]NT binding and to potentiate K(+)-evoked DA release in primary cultures of rat mesencephalic neurons, it was found that they all behaved as agonists with binding and biological potencies quite similar to those observed in the other binding assays. Finally and strikingly, when seven of these analogs with checked metabolic stability were tested in vivo for their hypothermic and analgesic (tail-flick test) effects after i.c.v. injection in the mouse, they exhibited relative potencies that were completely different from those obtained in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction by vasoactive intestinal peptide of interferon alpha/beta synthesis in glial cells but not in neurons.

Vasoactive intestinal peptide (VIP), a 28-amino acid peptide, plays a multifunctional neuromodulatory role in both peripheral and central nervous systems. We have recently reported that VIP induces interferon (IFN) alpha/beta synthesis in human colon adenocarcinoma cell line HT-29. It has been reported that VIP may counteract HIV-induced neuronal cell death; therefore, we postulated that the action of VIP may be mediated by a cascade regulation, involving the production of some cytokines such as IFN. Here we demonstrate that primary cultures of rat mesencephalic neurons and glial cells respond differently to VIP. Thus VIP enhanced 2'5' oligoadenylate (2'5' A) synthetase activity and inhibited vesicular stomatitis virus multiplication in glial cultures only. However, both cell cultures had functional adenylate cyclase coupled receptors for VIP. The increase in 2'5'A synthetase activity in glial cultures reached a maximum with 10(-6) M VIP and required cellular RNA and protein synthesis. Anti-IFN alpha/beta, but not anti-IFN gamma, antibodies abolished the induction of the antiviral and 2'5'A synthetase activities by VIP in rat glial-enriched cultures, suggesting that these inductions were mediated through IFN alpha/beta synthesis. Moreover, VIP or poly (i). poly (C12U) caused, in the glial cultures, the induction and secretion of an IFN of type alpha/beta with a titer value of 16 and 32 units/ml respectively. In contrast, neither of these two substances was able to induce IFN synthesis in neurons, which were, however, sensitive to IFN alpha/beta produced by VIP-treated glial cells. IFN produced by VIP in glial cells may therefore play an important role in defending the brain against viruses.

Potent cocaine analogs inhibit [3H]dopamine uptake in rat mesencephalic cells in primary cultures: pharmacological selectivity of embryonic cocaine sites.

The cellular localization of the cocaine binding sites in primary cultures of embryonic rat mesencephalic cells was previously reported to differ from that observed in adult rat brain. In order to know whether this different localization was associated with a different pharmacological selectivity, we tested the effect of new cocaine analogs on tritiated dopamine ([3H]DA) uptake in primary cultures of rat embryonic mesencephalic cells. In these cultures, [3H]DA was taken up by a nomifensine-sensitive, but desipramine and fluoxetine-insensitive process, reflecting selective uptake by the dopaminergic transporter. 3 beta-(4-Chlorophenyl)tropan-2 beta-carboxylic acid methyl ester (RTI-COC-31) was by far the most potent inhibitor of the [3H]DA uptake, presenting an IC50 of 3.8 nM, while the corresponding analog with an unsubstituted phenyl ring (WIN 35,065-2) was 38 times less potent. The enantiomer of WIN 35,065-2, namely WIN 35,065-3, was 30 times less potent than the former. A similar pattern was found for the relative ability of these compounds to inhibit binding of the radiolabeled cocaine derivative [125I]RTI-55 to membranes prepared from mesencephalic cultures. The order of potencies found for the three cocaine analogs on mesencephalic cultures was similar to that previously obtained in [3H] WIN 35,428 binding experiments and [3H]DA uptake inhibition in adult rat striatum, suggesting that the pharmacological selectivity of cocaine sites functionally related to the DA transporter in cultured embryonic neurons does not differ from that obtained in adult rat brain.

[Posology of analgesics in patients with kidney failure]. / Posologie des antalgiques chez l'insuffisant rénal.

Doses and dosing interval of analgesic drugs in renal failure are not always available in the data sheet compendium. The aim of the article is to analyse literature references and to present main pharmacokinetics modifications for each analgesic drug in renal failure. Pharmacokinetics parameters, doses and dosing intervals depending on creatinine concentrations are presented for each drug in a table.

Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor.

We describe the characteristics of SR 48692, a selective, nonpeptide antagonist of the neurotensin receptor. In vitro, this compound competitively inhibits 125I-labeled neurotensin binding to the high-affinity binding site present in brain tissue from various species with IC50 values of 0.99 +/- 0.14 nM (guinea pig), 4.0 +/- 0.4 nM (rat mesencephalic cells), 7.6 +/- 0.6 nM (COS-7 cells transfected with the cloned high-affinity rat brain receptor), 13.7 +/- 0.3 nM (newborn mouse brain), 17.8 +/- 0.9 nM (newborn human brain), 8.7 +/- 0.7 nM (adult human brain), and 30.3 +/- 1.5 nM (HT-29 cells). It also displaces 125I-labeled neurotensin from the low-affinity levocabastine-sensitive binding sites but at higher concentrations (34.8 +/- 8.3 nM for adult mouse brain and 82.0 +/- 7.4 nM for adult rat brain). In guinea pig striatal slices, SR 48692 blocks K(+)-evoked release of [3H]dopamine stimulated by neurotensin with a potency (IC50 = 0.46 +/- 0.02 nM) that correlates with its binding affinity. In a cell line derived from a human colon carcinoma (HT-29), SR 48692 competitively antagonizes neurotensin-induced intracellular Ca2+ mobilization with a pA2 (-log Kapp) values of 8.13 +/- 0.03, which is consistent with results obtained in binding studies. Moreover, SR 48692 is devoid of any intrinsic agonist activity. This compound is also active in vivo, since it reverses at low dose (80 micrograms/kg) the turning behavior induced by intrastriatal injection of neurotensin in mice with similar potency whatever the route of administration (i.p. or orally) and with a long duration of action (6 hr). Thus, being a potent and selective neurotensin receptor antagonist, SR 48692 may be considered as a powerful tool for investigating the role of neurotensin in physiological and pathological processes.

Mesencephalic dopaminergic neurons in primary cultures express functional neurotensin receptors.

The cellular distribution and functional aspects of neurotensin (NT) binding sites in rat mesencephalic cells in primary culture were investigated by an original approach combining anatomical and biochemical studies. Using a double-labeling protocol combining 125I-NT receptor radioautography and tyrosine hydroxylase (TH) immunocytochemistry, we obtained the first direct visualization of NT binding sites on TH-immunoreactive neurons. Eighty percent of the TH neurons were endowed with NT binding sites, which can be observed on both cell bodies and processes. TH-immunoreactive neurons were characterized as dopaminergic neurons by their ability to take up dopamine in a benztropine- and nomifensine-sensitive manner. In the mesencephalic cultures, NT increased potassium-evoked release of tritiated dopamine, and the relative potencies of various NT-related peptides to increase dopamine release were in good agreement with their abilities to bind to NT sites. These results show for the first time that cultured rat mesencephalic dopaminergic cells express functional NT receptors. Finally, the specificity and distribution of NT receptors on dopaminergic neurons in primary culture are quite similar to what was observed in the adult rat brain using pharmacological and radioautographic approaches. These data indicate that NT can influence the activity of dopaminergic neurons at very early stages of the rat brain development.

Bioavailability of fluoride in postmenopausal women: comparative study between sodium fluoride and disodium monofluorophosphate-calcium carbonate.

Fluoride (F) increases trabecular bone mass and can be used in the treatment of osteoporosis with crush fractures. As the bioavailability of sodium fluoride (NaF) can be impaired by concomitant absorption of calcium, both drugs have to be ingested separately. However, disodium monofluorophosphate-calcium carbonate (MFP-Ca), another F compound, allows a single administration. In a cross-over randomized study, we compared the bioavailability of both drugs under regular conditions of prescription. Ten postmenopausal women (aged 48-77 years) with glomerular filtration rate (GFR) greater than 70 ml/minute and without bone disease entered the study. Each received 25 mg of NaF [i.e., 11.3 mg F ion (F-)] fasting and 100 mg of Na2FPO3-1250 mg CaCO3 (i.e., 13.2 mg F-) with breakfast in a single dose separated by an 8-day washout. After dosing, plasma F levels and fractionated and total urinary F collection were determined during a 24-hour period using a specific electrode. Results show a significant shorter lag time absorption (Tmax = 1.4 +/- 0.2 hour) and a higher maximal concentration (Cmax = 260 +/- 60 ng/ml) for MFP-Ca than for NaF (Tmax = 2.5 +/- 0.4 hour; Cmax = 200 +/- 85 ng/ml). However, areas under curve (AUC) for MFP-Ca (1711 +/- 195 micrograms/liter/hour) and for NaF (1202 +/- 147 micrograms/liter/hour) were not significantly different. The relative bioavailability of both F compounds related to their fluoride content (i.e., 1.22 for AUC ratio) was equivalent, according to the Westlake method. These data provide the first evidence of comparable bioavailability of two F compounds in a population of postmenopausal women.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of neurotensin binding sites on rat mesencephalic cells in primary culture.

Many studies have reported the presence of high amounts of neurotensin (NT) binding sites in the mesencephalon of adult rat, and their possible role in mediating the effects of the peptide on the activity of mesencephalic dopaminergic neurons. In the present study, we demonstrate the presence of NT sites in primary cultures of embryonic rat mesencephalic cells. On these cells, a single class of high affinity 125I-NT binding sites was observed. The value of the apparent affinity constant (0.3 nM) did not show any significant change throughout time, from 3 to 14 days in culture. The number of sites, however, increased until day 11 and decreased thereafter. Acetylneurotensin (8-13), NT and neuromedin N were potent competitors of 125I-NT binding, while NT (1-10), NT (1-11) and levocabastine were uneffective. These results indicate that the sites detected in the mesencephalic cultures share common binding properties with the high-affinity NT sites already described in adult rat brain. The neuronal localization of the NT sites was suggested by their presence in neuron-enriched serum-free cultures and their absence in glial cultures. Autoradiographic studies confirmed the cellular localization of NT sites and indicated that, under our experimental conditions, cells labeled by 125I-NT represented 0.14% of the initially plated cell number. Taken together, these results show that the development of mesencephalic neurons in primary culture is associated with an increased expression of NT binding sites. Since such cultures have been shown previously to contain functional dopaminergic neurons, we suggest that they could provide a good model to investigate the modulation of the activity of these neurons by NT.

Changes in indocyanine green kinetics after the administration of enalapril to healthy subjects.

Enalapril maleate, an angiotensin converting enzyme inhibitor, is a vasodilator liable to modify regional blood flow. The effects of an oral dose of 40 mg enalapril maleate on indocyanine green (ICG) kinetics were assessed in nine healthy subjects. At 4 h after the administration of the drug, a 35% decrease in ICG clearance was observed (P less than 0.01) associated with a 23% decrease in its volume of distribution (P less than 0.02). The half-life of ICG was not altered significantly by enalapril. These results suggest that the administration of enalapril maleate to healthy subjects may reduce apparent liver plasma flow and plasma volume, as a consequence of the pooling of blood in the hepatosplanchnic area.

[The importance of software for the planning and adjusting of dosage. Application with aminoglycosides]. / Intérêt d'un logiciel informatique pour la prévision et l'adaptation des posologies. Application aux aminosides.

We are presenting a Mac Intosh--Apple computer program (Excel*) for the aminoglycosides (AG) drug monitoring useful in the following situations: --initiation of an AG's dosing regimen depending on the desired peak and through concentration (AG's pharmacokinetic parameters have been calculated according to the AG's literature values). --an adequate dosing regimen after revision of the patient's parameters (calculated with the observed concentrations). The technique has been validated comparing desired (des. C) and measured concentrations (mes. C). --either at the beginning of the treatment, --or after revision of the individual parameters. In the first case, the correlation coefficient obtained between 14 des C and 14 mes. C is equal to 0.91 and is improved when individual parameters are calculated (0.94).

[Value of bone fluoride determination in osteoporotic patients treated with sodium fluoride]. / Intérêt du dosage du fluor osseux chez l'ostéoporotique traité par le fluorure de sodium.

In order to find out whether the response of osteoporosis to sodium fluoride treatment or complications arising from this treatment are related to the retention of fluoride in bones, we measured bone fluoride concentrations in 30 patients with primary osteoporosis who had been treated with sodium fluoride for 1 to 8 years. We found a significant correlation (r = 0.74, P less than 0.001) between bone fluoride concentration and total amount of fluoride ingested. However, with any given amount of sodium fluoride, the bone fluoride concentration could vary by up to three times from a patient to another. There was a significant correlation between bone fluoride concentration and trabecular bone volume on the hand (r = 0.54, P less than 0.001) and thickness of osteoid borders measured on the same biopsy specimen on the other hand (r = 0.45, P less than 0.001). Five patients developed lower limb bone fissures after 11 to 18 months of sodium fluoride treatment, but their bone fluoride concentration was not significantly different from that of the 25 patients who had no fracture. These data suggest a relationship between the degree of stimulation of bone formation by fluoride and the bone concentration of that substance; however, peripheral fractures are not dependent on bone fluoride concentration.