Fragilidad, polifarmacia y riesgo de caídas en personas adultas mayores / Fragility, polypharmacy and risk of falls in older adults

Objetivo: Analizar la relación de fragilidad, polifarmacia y riesgo de caídas en las personas adultas mayores. Metodología: El diseño de estudio fue descriptivo, correlacional y transversal, conformado por 261 personas adultas mayores de Saltillo, Coahuila (México). Se utilizó una cédula de datos personales y prevalencia de polifarmacia, escala Frail y escala de Tinetti. Los datos se analizaron a través de SPSS versión 25 para Windows, se utilizaron frecuencias y porcentajes, medidas de tendencia central y dispersión. Resultados: El 19,2% de los participantes fueron frágiles, el 44,1% de las personas adultas mayores presentaron polifarmacia y el 37,5% reportó un alto riesgo de caídas. La fragilidad se correlacionó positiva y significativamente con la polifarmacia (rs = 0,274; p < 0,01) y el riesgo de caídas se correlacionó negativa y significativamente con fragilidad (rs = -0,333; p < 0,01). Conclusiones: Existe una relación entre la fragilidad y el riesgo de caídas en las personas adultas mayores, la polifarmacia no tuvo relación con el riesgo de las caídas (AU)

Objective: Analyze the relationship of frailty, polypharmacy and risk of falls in older adults. Methodology: The study design was descriptive, correlational and cross-sectional, made up of 261 older adults from Saltillo, Coahuila. A personal data card and the prevalence of polypharmacy, the Frail scale and the Tinetti scale were used. The data was analyzed through SPSS version 25 for Windows, frequencies and percentages, measures of central tendency and dispersion were used. Results: The 19.2% of participants were frail, 44.1% of older adults had polypharmacy, and 37.5% reported a high risk of falls. Frailty was positively and significantly correlated with polypharmacy (rs = 0.274; p < 0.01) and risk of falls was negatively and significantly correlated with frailty (rs = -0.333; p < 0.01). Conclusions: There is a relationship between frailty and the risk of falls in older adults, polypharmacy was not related to the risk of falls (AU)

Dystrophin Dp71: the smallest but multifunctional product of the Duchenne muscular dystrophy gene.

Dystrophin Dp71 is expressed in all tissues, with the exception of skeletal muscle, and is the main Duchenne muscular dystrophy (DMD) gene product in brain. As full-length dystrophin does in skeletal muscle, Dp71 associates with dystroglycans, sarcoglycans, dystrobrevins, syntrophins, and accessory proteins to form the dystrophin-associated protein complex (DAPC) in non-muscle tissues. Although it has been nearly 20 years since the discovery of Dp71, its study has become relevant only recently due to its direct involvement with the two main DMD non-muscular phenotypes: cognitive impairment and abnormal retinal physiology. In this review, we describe the historical background of Dp71 and the experimental models developed for its study. Additionally, we present and discuss the experimental evidence supporting the participation of Dp71 in different cellular processes, including cell adhesion, water homeostasis, cell division, and nuclear architecture. The functional diversity of Dp71 is attributed to the formation of Dp71-containing DAPC in numerous cell types and different subcellular compartments, including in plasma membrane and nucleus, as well as to the capability of Dp71-containing DAPC to work as the scaffold for proper clustering and anchoring of structural and signaling proteins to the plasma membrane and of nuclear envelope proteins to the inner nuclear membrane.

Gamma-aminobutyric acid transporter (BGT-1) expressed in human astrocytoma U373 MG cells: pharmacological and molecular characterization and phorbol ester-induced inhibition.

The properties of a transport system specific for gamma-aminobutyric acid (GABA) expressed in human U373 MG astrocytoma cells were examined. The uptake of [(3)H]GABA was dependent on both extracellular Na(+) and Cl(-) ions and was inhibited by (+/-)-nipecotic acid, guvacine, and beta-alanine, with a pharmacological profile corresponding to that reported for the human homologue of the GABA/betaine transporter (BGT-1). Accordingly, [(3)H]GABA uptake was also inhibited by betaine, and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of total RNA from U373 MG cells with specific BGT-1 primers resulted in the amplification of a 440 bp fragment that was further characterized by restriction analysis and sequencing. In addition, Western blot analysis with anti-BGT-1 antiserum revealed the presence of a characteristic 60 kDa band. The primary structure of the human BGT-1 protein predicts two putative phosphorylation sites for the Ca(2+)/diacylglicerol-dependent protein kinase (PKC), and treatment of U373 MG cells with the PKC activator phorbol 12-myristate-13-acetate (TPA) led to a concentration- and time-dependent decrease in [(3)H]GABA uptake. The maximal effect was detected at 2 hr of incubation, to disappear after 4 hr. TPA-induced reduction in [(3)H]GABA uptake was reversed by preincubation with staurosporine. Taken together, these results indicate that U373 MG cells express a GABA transporter of the BGT-1 subtype whose function is regulated by phosphorylation events through PKC.

The initial inositol 1,4,5-trisphosphate response induced by histamine is strongly amplified by Ca(2+) release from internal stores in smooth muscle.

We have studied the Ca(2+)-dependence and wortmannin-sensitivity of the initial inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) response induced by activation of either histamine or muscarinic receptors in smooth muscle from guinea pig urinary bladder. Activation of H(1) receptors with histamine (100 microM) produced a significant elevation in Ins(1,4,5)P(3) levels with only 5s stimulation and in the presence of external Ca(2+). However, this response was abolished fully by either the prolonged absence of external Ca(2+) or the depletion of internal Ca(2+) stores with thapsigargin (100nM) or ryanodine (10 microM). In contrast, the same conditions only slightly reduced the initial Ins(1,4,5)P(3) response induced by carbachol. The prolonged incubation of smooth muscle in 10 microM wortmannin to inhibit type III PI 4-kinase abolished both the early histamine-evoked Ins(1,4,5)P(3) and Ca(2+) responses. Conversely, wortmannin did not alter Ca(2+) release induced by carbachol, despite a partial reduction of its Ins(1,4,5)P(3) response. Collectively, these data indicate that the detectable histamine-induced increase in Ins(1,4,5)P(3) is more the consequence of Ca(2+) release from internal stores than a direct activation of phospholipase C by H(1) receptors. In addition, the effect of wortmannin implies the existence of a Ca(2+)-dependent amplification loop for the histamine-induced Ins(1,4,5)P(3) response in smooth muscle.

Histamine H(1) receptor activation inhibits the proliferation of human prostatic adenocarcinoma DU-145 cells.

BACKGROUND: Histamine stimulates cell proliferation in some tumor cell lines through the activation of H(1) receptors coupled to phosphoinositide hydrolysis. We therefore set out to study the presence of H(1) receptors in the prostate cancer cell line DU-145 and the effect of their stimulation on cell growth. METHODS: The presence of histamine receptors was studied by radioligand binding. Phosphoinositide hydrolysis was assessed by measuring [(1)H]-inositol phosphate ([(1)H]-IPs) accumulation and changes in the intracellular concentration of free Ca(2+) ([Ca(2+)](i)). Proliferation was assessed by cell counting and by [(1)H]-thymidine incorporation. RESULTS: DU-145 cells express H(1) receptors (110+/-14 fmol/mg of protein) whose stimulation results in [(1)H]-IPs accumulation (602+/-23% of basal, EC(50) 2.2+/-0.4 microM) and calcium mobilization (resting level 96+/-5 nM, Delta[Ca(2+)](i) 517+/-32 nM, EC(50) 6.2+/-0.1 microM). Incubation with histamine (100 microM, 24 hr) resulted in a decrease in both cell number and [(1)H]-thymidine incorporation, blocked by the H(1) antagonist mepyramine (1 microM). CONCLUSIONS: Histamine inhibits the proliferation of DU-145 cells through the activation of H(1) receptors coupled to phosphoinositide hydrolysis.

Histamine H1 receptor activation stimulates mitogenesis in human astrocytoma U373 MG cells.

In human astrocytoma U373 MG cells that express histamine H1 receptors (180 +/- 6 fmol/mg protein) but not H2 or H3 receptors, histamine stimulated mitogenesis as assessed by [3H]-thymidine incorporation (173 +/- 2% of basal; EC50, 2.5 +/- 0.4 microM). The effect of 100 microM histamine was fully blocked by the selective H1 antagonist mepyramine (1 microM) and was markedly reduced (93 +/- 4% inhibition) by the phospholipase C inhibitor U73122 (10 microM). The activator of protein kinase C (PKC) phorbol 12-tetradecanoyl-13-acetate (TPA, 100nM) stimulated [3H]-thymidine incorporation (270 +/- 8% of basal), and this response was not additive with that to 100 microM histamine. The incorporation of [3H]-thymidine induced by 100 microM histamine was partially reduced by the PKC inhibitor Ro 31-8220 (57 +/- 7% inhibition at 300 nM) and by the compound PD 098,059 (30 microM, 62 +/- 14% inhibition), an inhibitor of the mitogen-activated kinase (MAPK) kinases MEK1/MEK2. These results show that histamine H1 receptor activation stimulates the proliferation of human astrocytoma U373 MG cells. The action of histamine appears to be partially mediated by PKC stimulation and MAPK activation.

Characterisation of alpha1B-adrenoceptors linked to inositol phosphate formation and calcium mobilisation in human astrocytoma U373 MG cells.

The human U373 MG astrocytoma cell line has been widely used as a model system for the investigation of astrocyte function. The aim of this study was to establish which alpha1-adrenoceptors are present on these cells. The specific binding of [3H]prazosin to membranes of U373 MG cells (Bmax 32+/-3 fmol mg(-1) protein, Kd 0.27+/-0.03 nM) was inhibited in a monophasic manner by alpha1-antagonists that have different affinities for alpha1A-, alpha1B- and alpha1D-adrenoceptors. Estimates for pKi values were: prazosin 9.69+/-0.06, 5-methylurapidil 7.10+/-0.21; (+)-niguldipine 7.06+/-0.26; WB 4101 8.26+/-0.16; and BMY 7378 6.60+/-0.21. The specific binding of [3H]prazosin was reduced to low levels by pretreatment of cells with 10 microM chloroethylclonidine for 15 min. In the presence of 30 mM LiCl, 100 microM noradrenaline stimulated [3H]inositol phosphate accumulation by 2.1+/-0.1-fold of basal after 30-min incubation. The EC50 for the accumulation of [3H]IP1, the major product detected (85+/-2% of total [3H]IP1 + [3H]IP2 + [3H]IP3), was 0.38+/-0.05 microM. Noradrenaline-induced [3H]IP1 accumulation was also inhibited by alpha1-antagonists. Estimates for pKi values were: 5-methylurapidil 6.95+/-0.01; WB 4101 8.31+/-0.07; and BMY 7378 6.71+/-0.28. The accumulation of [3H]IP1 in response to 100 microM noradrenaline was not significantly affected by raising the extracellular Ca2+ concentration from 1.3 to 4 mM. Noradrenaline (100 microM) also produced an increase in intracellular Ca2+ (mean peak 86+/-5 nM above basal). Pretreatment with chloroethylclonidine (10 microM, 15 min) abolished noradrenaline-induced [3H]IP1 accumulation and Ca2+ mobilisation. Activation of the alpha1B-adrenoceptors by 10 microM phenylephrine increased [3H]thymidine uptake to 140+/-5% of control uptake. Taken together, these results indicate that U373 MG cells express a single class of alpha1-adrenoceptors, the alpha1B-subtype, which are coupled to phosphoinositide hydrolysis and calcium mobilisation, and which mediate a mitogenic response to alpha1-agonists.

Histamine H1 receptors and inositol phosphate formation in rat thalamus.

In membranes of rat thalamus the density of histamine H1 receptors, as estimated from saturation curves with [3H]mepyramine, was 66 +/- 5 fmol.mg protein-1 (Kd 1.3 +/- 0.1 nM). Specific [3H]mepyramine binding was inhibited by mepyramine (best fit to one-site model, Kd 2.2 +/- 0.2 nM) and by histamine (best fit to a two-site model, Ki high 0.35 +/- 0.04 microM and 54 +/- 7% of binding sites; Ki low 7.0 +/- 1.1 microM). In the presence of 300 microM GppNHp (5'-guanylylimidodiphosphate) the inhibition curve for histamine best-fit to a one-site model (Ki 3.1 +/- 0.3 microM). In cross-chopped slices and in the presence of 10 mM LiCl, histamine stimulated the accumulation of total [3H]inositol phosphates ([3H]IPs) with a maximum effect of 163 +/- 3% of basal accumulation, EC50 of 8 +/- 2 microM and Hill coefficient (nH) of 0.8 +/- 0.1. [3H]IPs accumulation induced by 100 microM histamine was inhibited by the selective H1 antagonist mepyramine (1 microM, 90 +/- 8% inhibition; Ki 2.1 +/- 0.4 nM) but not by 10 microM ranitidine (a selective H2 antagonist) or 1 microM thioperamide (a selective H3 antagonist). These results show the presence in rat thalamus of functional H1 receptors coupled in inositol phosphate accumulation.

Histamine H1 receptor activation stimulates [3H]GABA release from human astrocytoma U373 MG cells.

In U373 MG cells, a line derived from a human astrocytoma, histamine stimulated the release of [3H]gamma-aminobutyric acid ([3H]GABA) in a concentration-dependent manner (286 +/- 23% of basal release at 1 mM histamine). Neither Ca2+ removal nor Cd2+ (100 microM) affected [3H]GABA release evoked by 100 microM histamine but the response was significantly reduced by 10 microM U-73122 ({1-[6-((17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl)-amino)-hexyl]-1 H-pyrrole-2,5-dione}), an inhibitor of phospholipase C activation (79 +/- 8% inhibition) and by 10 microM dimethylbenzamil, a selective blocker of plasma membrane Na+/Ca2+ exchange (58 +/- 6% inhibition). In [3H]inositol-labelled cells histamine stimulated [3H]inositol phosphate accumulation (EC50, 17 +/- 2 microM; maximum effect, 203 +/- 4% of basal). Histamine-evoked Ca2+ mobilisation yielded an EC50 of 12 +/- 2 microM and maximum delta[Ca2+]i of 337 +/- 23 nM. Thapsigargin (1 nM) increased [Ca2+]i (delta[Ca2+]i 164 +/- 12 nM) and prevented any further increase by histamine (100 microM). The effects of histamine on [3H]GABA release, [3H]inositol phosphate accumulation and Ca2+ mobilisation were blocked by the selective histamine H1 receptor antagonist mepyramine. Taken together, these results indicate that histamine stimulates [3H]GABA release by increasing [Ca2+]i. The mechanism of release may be related to changes in transmembranal Na+ gradients and reversal of GABA carrier transport due to stimulation of plasma membrane Na+/Ca2+ exchange.

[Concentration and activity of alpha-1-antitrypsin in neonatal hepatitis]. / Concentración y actividad de alfa-1-antitripsina en hepatitis neonatal.

The concentration and activity of alpha 1-antitrypsin were studied in 20 children with the diagnosis of neonatal hepatitis. The concentration of alpha 1-AT was found normal or high in all of the patients (3.6 +/- 0.12 mg/ml). No case was found with PiZZ homozygote type alpha 1-AT deficiency. The activity of alpha l-AT was found decreased in 90% of the patients with neonatal hepatitis (control: 0.86 +/- 0.18 mg. trypsin inhibited by ml. of serum; neonatal hepatitis: 0.49 +/- 0.07 mg/ml.). The possibility that this may correspond to a disorder characteristic of neonatal hepatitis is mentioned.