RESUMEN
Caffeine is a regular part of the diet of many adults (coffee, tea, soft drinks, and energy drinks). Multiple molecular effects of caffeine suggest that it may promote bone loss. Given the extensive consumption of caffeine worldwide, any impact of caffeine consumption on bone strength and/or density would have large population health implications. The most well-established pharmacological effect of caffeine is non-specific antagonism of adenosine receptors. Adenosine regulates bone metabolism in a complex manner, with in vitro studies suggesting that direct stimulation of adenosine A2A and A2B receptors induces bone formation by activating osteoblasts and suppressing osteoclast differentiation and function. Thus, competitive inhibition of adenosine A2 receptors by caffeine may inhibit bone formation and promote bone resorption. However, antagonism of adenosine A1 receptors may have opposing effects. Caffeine has also been suggested to affect bone through derangement of calcium metabolism, alteration of vitamin D responses, and other mechanisms. In clinical and population-based studies, the impact of caffeine consumption on bone metabolism offers a mixed picture, with some but not all studies suggesting a potential link between caffeine intake and reduced bone mineral density or increased fracture risk. Differences in methodology, selected populations, and duration/timing of the studies may account for study outcome discrepancies. The in vitro effects of caffeine on cells involved in bone metabolism suggest that caffeine intake may promote osteoporosis, and some but not all clinical studies support a modest adverse caffeine impact. Herein, we describe the basic biology of caffeine as it pertains to bone, review the clinical literature to date, and consider the implications of the current data on clinical practice and future studies.
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Fracturas Óseas , Osteoporosis , Adenosina , Adulto , Densidad Ósea , Cafeína/efectos adversos , Café , Humanos , Osteoporosis/epidemiología , Osteoporosis/etiologíaRESUMEN
Patients with systemic lupus erythematosus (SLE) often require immunosuppression to induce remission of active disease exacerbations. Over the past two decades, treatment modalities for this condition have emerged leading to improved morbidity from disease related outcomes. However, as a result, infection risks and patterns have changed, leading to higher rates of opportunistic infections among this population. We report four cases of cytomegalovirus (CMV) in patients with SLE who received immunosuppressive therapy, including pulse steroids, antimetabolites such as mycophenolate mofetil, and alkylating agents such as cyclophosphamide. We propose that given the rise in prevalence of CMV, there is a need for appropriate screening for this opportunistic pathogen and studies to determine the risks and benefits of prophylactic or preemptive treatment for this virus.
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Infecciones por Citomegalovirus/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/virología , Adulto , Alquilantes/uso terapéutico , Antimetabolitos/efectos adversos , Antimetabolitos/uso terapéutico , Manejo de la Enfermedad , Femenino , Humanos , Terapia de Inmunosupresión/efectos adversos , Terapia de Inmunosupresión/métodos , Lupus Eritematoso Sistémico/inmunología , Persona de Mediana Edad , Esteroides/efectos adversos , Esteroides/uso terapéuticoRESUMEN
The effects of an oral fish oil treatment regimen on sensorimotor, blood-brain barrier, and biochemical outcomes of traumatic brain injury (TBI) were investigated in a juvenile rat model. Seventeen-day old Long-Evans rats were given a 15mL/kg fish oil (2.01g/kg EPA, 1.34g/kg DHA) or soybean oil dose via oral gavage 30min prior to being subjected to a controlled cortical impact injury or sham surgery, followed by daily doses for seven days. Fish oil treatment resulted in less severe hindlimb deficits after TBI as assessed with the beam walk test, decreased cerebral IgG infiltration, and decreased TBI-induced expression of the Mmp9 gene one day after injury. These results indicate that fish oil improved functional outcome after TBI resulting, at least in part from decreased disruption of the blood-brain barrier through a mechanism that includes attenuation of TBI-induced expression of Mmp9.
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Barrera Hematoencefálica/enzimología , Lesiones Encefálicas/enzimología , Aceites de Pescado/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/biosíntesis , Caminata , Animales , Barrera Hematoencefálica/patología , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/patología , Ratas , Ratas Long-EvansRESUMEN
The mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), is activated in experimental models of chronic pain, and is also activated by oestrogen. We used an established model of inflammatory trigeminal pain, injection of Complete Freund's Adjuvant (CFA) into the masseter muscle, to determine whether ERK activation may play a role in hormone-related trigeminal pain disorders. We measured withdrawal responses to stimulation of the masseter (V3, primary allodynia) and whisker pad (V2, secondary allodynia) using graded monofilaments. Oestrogen treatment in the presence of inflammation increased withdrawal response to stimulation of both masseter and whisker pad compared with inflammation alone, indicating an additive effect of inflammation and oestrogen on both primary and secondary allodynia. We examined ERK activation in trigeminal ganglia from each treatment group using western blot and immunohistochemistry. Both masseter inflammation and oestrogen treatment increased ERK activation, and combined treatment had an additive effect. Both masseter inflammation and oestrogen increased the percentage of pERK immunoreactive neurons in divisions 1 and 2 (V1/2), and combined treatment increased pERK immunoreactivity in V1/2 compared with inflammation alone. We stereotactically administered ERK antagonist U0126, or inactive control U0124, to the trigeminal ganglion of CFA+E2-treated rats. U0126 decreased withdrawal responses to mechanical stimulation of the whisker pad compared with U0124-treated rats. Because the secondary allodynia in V2 after inflammation in V3 was reduced by antagonizing ERK activation in the periphery, these data suggest a peripheral component to secondary allodynia mediated through ERK activation.
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Activación Enzimática/fisiología , Estrógenos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Dolor/enzimología , Ganglio del Trigémino/enzimología , Adyuvantes Inmunológicos/toxicidad , Animales , Western Blotting , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Estrógenos/metabolismo , Femenino , Inmunohistoquímica , Inflamación/inducido químicamente , Inflamación/fisiopatología , Músculo Masetero/efectos de los fármacos , Músculo Masetero/metabolismo , Ovariectomía , Dolor/fisiopatología , Ratas , Ratas Sprague-Dawley , Ganglio del Trigémino/efectos de los fármacosRESUMEN
Oestrogen increases facial allodynia through its actions on activation of the MAPK extracellular-signal regulated kinase (ERK) in trigeminal ganglion neurons. This goal of study was to determine which oestrogen receptor is required for behavioural sensitization. Immunohistochemical studies demonstrated the presence of oestrogen receptor alpha (ERalpha) in nuclei of larger neurons and cytoplasm of smaller neurons, and the novel oestrogen receptor G-protein coupled receptor 30 (GPR30) in small diameter neurons that also contained peripherin, a marker of unmyelinated C-fibres. Specific agonists for ERalpha (PPT) and GPR30 (G-1), but not ERbeta (DPN), activated ERK in trigeminal ganglion neurons in vitro. Both G-1 and PPT treatment increased allodynia after CFA injections into the masseter of ovariectomized Sprague-Dawley rats. Treatment with oestrogen increased expression of ERalpha but not GPR30, while masseter inflammation increased GRP30 but not ERalpha. Differential modulation of these ERK-coupled receptors by oestrogen and inflammation may play a role in painful episodes of temporomandibular disorder and migraine.
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Receptor alfa de Estrógeno/metabolismo , Dolor Facial/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Trastornos Somatomorfos/metabolismo , Ganglio del Trigémino/metabolismo , Animales , Western Blotting , Femenino , Inmunohistoquímica , Inflamación/metabolismo , Músculo Masetero/metabolismo , Músculo Masetero/patología , Microscopía Fluorescente , Neuronas , Ovariectomía , Umbral del Dolor , Ratas , Ratas Sprague-Dawley , Receptores de EstrógenosRESUMEN
This paper is designed to provide concepts and stimulate directions for further investigation of menstrual migraine. On the basis of experimental studies and literature review, we propose that abnormalities in how estrogen modulates neuronal function in migraine are due to a mismatch between its gene-regulation and membrane effects. In the interictal phase when estrogen levels peak, increased neuronal excitability is balanced by homeostatic gene regulation in brain cortex, and nociceptive systems. When levels fall at menses, mismatch in homeostatic gene regulation by estrogen unmasks non-nuclear mitogen-activated hyperexcitability of cell membranes, sensitizing neurons to triggers that activate migraine attacks. At the trough of estrogen levels, the down-regulating effect on inflammatory genes is lost and peptide modulated central sensitization is increased as is pain and disability of the migraine attack.
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Dismenorrea/tratamiento farmacológico , Estrógenos/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Neuronas/efectos de los fármacos , Femenino , HumanosRESUMEN
BACKGROUND: Previous studies have shown that HIV-infected children have abnormal cerebral metabolites, measured by proton MR spectroscopy (1H MRS), but the stability of these measurements over time has not been described in HIV-infected children. The authors recently reported a study of cerebral metabolites in 20 HIV-infected children (6 to 16 years of age); the current study followed 12 of these children (10.0 years +/- 3.7 years) and repeated the MR spectroscopy at 24.1 +/- 3.7 weeks and 42.2 +/- 3.5 weeks following the entry time with repeated neuropsychological testing. METHODS: 1H MR spectra were acquired at 1.5 T (GE Signa, PRESS localization, repetition time = 3,000 msec, echo time = 30 msec). Five brain regions were studied: right frontal white matter, left frontal white matter, right basal ganglia, right hippocampus, and midfrontal gray matter. The concentrations of N-acetylaspartate (NAA), choline (CHO), creatine (CR), and myo-inositol (mI) and the ratio of each metabolite to CR were determined. RESULTS: There were no changes in the metabolite concentrations or metabolite/CR ratios at the three time periods. Similarly, during this follow-up period, HIV-positive children showed no changes in clinical signs, HIV viral loads, CD4%, or CD4 counts, except for improved spatial memory with repeat testing. CONCLUSION: In a clinically and neurologically stable group of HIV-infected children, cerebral metabolites were stable over a 10-month time period, suggesting that it is possible to assess changes in cerebral metabolites as a measure of cerebral health, but longer follow-up in a larger sample is needed.
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Encéfalo/metabolismo , Infecciones por VIH/metabolismo , VIH-1 , Espectroscopía de Resonancia Magnética , Adolescente , Niño , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Espectroscopía de Resonancia Magnética/estadística & datos numéricos , ProtonesRESUMEN
Although migraine is more common in women than men and often linked to the menstrual cycle, few studies have investigated the biological basis of hormonal influences on the trigeminovascular system. In the present study we investigated the effect of physiological levels (10(-9) m) oestrogen on female rat trigeminal ganglia in vitro. Immunocytochemical analysis demonstrated the presence of oestrogen receptor-alpha in a predominantly cytoplasmic location and in neurites. Microarray analysis demonstrated that oestrogen treatment regulates several genes with potential relevance to menstrual migraine. The genes that were upregulated included synapsin-2, endothelin receptor type B, activity and neurotransmitter-induced early gene 7 (ania-7), phosphoserine aminotransferase, MHC-1b, and ERK-1. Down-regulated genes included IL-R1, bradykinin B2 receptor, N-tropomodulin, CCL20, GABA transporter protein, fetal intestinal lactase-phlorizin hydrolase, carcinoembryonic antigen-related protein, zinc finger protein 36, epsin 1 and cysteine string protein. Protein activity assays demonstrated that exposure of the cultured neurons to oestrogen leads to activation of ERK, which has been linked to inflammatory pain. Immunocytochemistry demonstrated that activated ERK was present in neurons containing peripherin, a marker of nociceptive neurons. Several of the genes in the present study may provide potential targets for understanding the association of oestrogen with migraine and other hormone-related orofacial pain.
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Estrógenos/farmacología , Trastornos Migrañosos/fisiopatología , Ganglio del Trigémino/efectos de los fármacos , Ganglio del Trigémino/fisiología , Animales , Células Cultivadas , Receptor alfa de Estrógeno/genética , Estrógenos/fisiología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Expresión Génica/efectos de los fármacos , Técnicas In Vitro , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Trastornos Migrañosos/genética , Neuronas Aferentes/citología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/fisiología , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosforilación/efectos de los fármacos , Ratas , Ganglio del Trigémino/citologíaRESUMEN
BACKGROUND: HIV-infected children have abnormal cerebral metabolites, measured by proton MR spectroscopy ((1)H-MRS), but how these abnormalities relate to brain function is unclear. METHODS: Metabolite concentrations in five brain regions of 20 HIV-infected and 13 control children were measured, and these findings were correlated with age, log(10) plasma viral load, CD4 count, and neuropsychological scores. RESULTS: Compared with control subjects, HIV patients had decreased choline concentration [Cho] in left frontal white matter (LFW) (-12%; p = 0.04); those with high viral load (>5,000 HIV RNA copies/mL) had decreased right basal ganglia (RBG) [Cho] (-15%; p = 0.005), and [Cr] (-13%; p = 0.02). Patients with high viral load also had higher [Cho] in the midfrontal gray matter (MFG) (+25%; p = 0.002) and lower myo-inositol [Ins] in the RBG (-18%; p = 0.04) than patients with low HIV viral load. N-Acetyl aspartate concentration ([NAA]) correlated with age in right frontal white matter (RFW) (r = 0.59, p = 0.04), LFW (r = 0.66, p = 0.02), and right hippocampus (RHIP) (r = 0.69, p = 0.02) only in control subjects. In contrast, [Ins] correlated with age in both RFW and LFW (r = 0.71, p = 0.0006; r = 0.65, p = 0.006) only in the HIV patients. Log(10) plasma viral load correlated positively with [Ins] in RFW (r = 0.54, p = 0.02) and [Cho] in MFG (r = 0.49, p = 0.04). Compared with control subjects, HIV patients had poorer spatial memory (p = 0.045) and delayed spatial memory correlated with [Cho] in RHIP (r = 0.68, p = 0.02). CONCLUSIONS: These data suggest that normal brain development may be affected in children infected with HIV at birth, particularly evidenced by the lack of age-related increases in the neuronal marker [NAA]. Early, aggressive treatment of infants with HIV before development of encephalopathy is warranted.
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Ácido Aspártico/análogos & derivados , Química Encefálica , Infecciones por VIH/metabolismo , Adolescente , Factores de Edad , Ácido Aspártico/análisis , Encéfalo/metabolismo , Encéfalo/patología , Recuento de Linfocito CD4 , Niño , Colina/análisis , Estudios de Cohortes , Creatina/análisis , Femenino , Infecciones por VIH/congénito , Infecciones por VIH/patología , Infecciones por VIH/psicología , VIH-1 , Humanos , Inositol/análisis , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Pruebas Neuropsicológicas , Protones , Carga ViralRESUMEN
Simian immunodeficiency virus has been shown to cause acquired immunodeficiency syndrome in macaque monkeys. Data gathered from clinical examination and fundus photography have shown that the lentivirus is capable of the induction of choroidal lesions and retinal hemorrhages in the macaque. These findings demonstrate the potential value of the macaque monkey eye as a model of the retinal pathology routinely seen in human AIDS patients.
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Oftalmopatías/virología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios , Animales , Oftalmopatías/patología , Fondo de Ojo , Macaca mulatta , Retina/patología , Retina/virologíaRESUMEN
Infection with human immunodeficiency virus-1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS) in humans, causes a spectrum of neuropathology that includes alterations in behavior, changes in evoked potentials, and neuronal degeneration. In the simian immunodeficiency virus (SIV) model of HIV infection, affected monkeys show clinical symptoms and neurological complications that mimic those observed in human neuro-AIDS. To investigate the relationship between morphological correlates and neurophysiological deficits, unbiased stereology was used to assess total neuron number, volume, and neuronal density for all neurons in the globus pallidus (GP) and for dopamine (DA)-containing neurons in the substantia nigra (SN) in eight macaques inoculated with macrophage-tropic, neurovirulent SIV (SIVmac R71/17E), and five control animals. There was a significant difference between rapid progressors and controls for both neuron number (P < .01) and neuronal density (P < .05) in the GP, and for neuron number (P < .05) in the SN. Neuron loss ranged from 6% to 70% in the GP and from 10% to 50% in the SN. Neuropathological analyses confirmed neuroAIDS-like changes in brain, including microglial nodules, extensive perivascular cuffing and/or the presence of multinucleated giant cells, and alterations in neuronal morphology in the majority of the rapid progressors. By comparison, slow progressors showed little, if any, neuropathology. These neuropathological changes in SIV-infected monkeys indicate that neuron death and morphological alterations in the basal ganglia may contribute to the motor impairments reported in the SIV model and, by analogy, in the subset of patients afflicted with motor impairment in human neuro-AIDS.
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Encéfalo/patología , Encéfalo/virología , Degeneración Nerviosa/patología , Neuronas/patología , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Animales , Ganglios Basales/patología , Ganglios Basales/virología , Recuento de Células , Progresión de la Enfermedad , Globo Pálido/patología , Globo Pálido/virología , Macaca mulatta , Masculino , Desempeño Psicomotor/fisiología , Síndrome de Inmunodeficiencia Adquirida del Simio/fisiopatología , Virus de la Inmunodeficiencia de los Simios , Sustancia Negra/patología , Sustancia Negra/virologíaRESUMEN
AIMS: To investigate if a second drop of 2.5% povidone-iodine ophthalmic solution placed within the first postnatal day would achieve better prophylaxis against ophthalmia neonatorum than a single drop applied at birth. METHODS: A masked, prospective, controlled trial was conducted over a 2 year period in a Kenyan hospital. Randomisation was achieved by alternating weeks of one or two eye drop application to both eyes. All 719 neonates received one drop of the povidone-iodine solution to both eyes at birth, while 317 received a second drop at hospital discharge or 24 (SD 4) hours after delivery, whichever was first. All infants developing conjunctivitis within a month after birth underwent microbiological analysis using Gram and Giemsa stains, direct fluorescent antibody assay for Chlamydia trachomatis, and culture. RESULTS: Of the neonates receiving the one eye drop application, 18.4% returned with a red eye with discharge, 4.0% had organisms found on the initial smear, and 8.2% had a positive culture. The corresponding proportions for the multidrop group were 24.3%, 4.7%, and 10.4%. Of those returning with an inflamed eye, there were no cases of Neisseria gonorrhoeae, 4.2% in the single dose group and 3.9% in the double dose group were positive for C trachomatis, and 5.4% and 6.5% respectively for Staphylococcus aureus. At discharge, the eyelid oedema score of the double dose group was mildly greater than the single dose group (1.4 (0.67) v 1.2 (0.73), p=0.0002). There was no statistically significant difference between the groups in any other category. CONCLUSION: There is no advantage to administering povidone-iodine prophylaxis against ophthalmia neonatorum twice in the first postnatal day over a single application at birth.
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Antiinfecciosos Locales/administración & dosificación , Países en Desarrollo , Oftalmía Neonatal/prevención & control , Povidona Yodada/administración & dosificación , Antiinfecciosos Locales/efectos adversos , Infecciones por Chlamydia/diagnóstico , Esquema de Medicación , Edema/inducido químicamente , Enfermedades de los Párpados/inducido químicamente , Femenino , Técnica del Anticuerpo Fluorescente Directa , Humanos , Recién Nacido , Kenia , Masculino , Soluciones Oftálmicas , Povidona Yodada/efectos adversos , Estudios ProspectivosRESUMEN
Recent studies demonstrate that combinations of androgens and progestagens are highly effective in the suppression of spermatogenesis in normal volunteers. To test whether progestagen and androgen delivery systems designed to produce steady serum levels will be as effective as other androgen plus progestagen combinations, we compared Norplant II and testosterone (T) transdermal patch to T patch alone on the suppression of spermatogenesis in normal men. Thirty-nine healthy male volunteers (age, 20-45 yr) were randomly assigned to one of two groups. Group 1 (n = 19) received two transdermal T patches daily (Testoderm TTS, each patch designed to deliver about 5 mg/d T) alone, and group 2 (n = 20) received combined Norplant II [Jadelle, four capsules delivering approximately 160 microg/d levonorgestrel (LNG)] plus T patch. Neither of these regimens were very effective, with suppression of spermatogenesis to severe oligozoospermia occurring in less than 60% of subjects. We then expanded the study to include two more groups to determine whether T patch or Norplant II was the main factor causing the inadequate suppression of spermatogenesis. Another 29 subjects were randomized to one of two groups. Group 3 (n = 15) received oral LNG (125 microg/d) plus T patch, and group 4 (n = 14) received Norplant II plus T enanthate (TE) injection (100 mg/wk i.m.). After a pretreatment phase of 4 wk, all subjects received treatment for 24 wk, followed by a recovery period of 12-24 wk. Steady-state serum LNG levels (800-1200 pmol/liter) were achieved from wk 3-24 after Norplant II insertion and decreased rapidly after the removal of the implants at wk 24. Trough serum LNG levels after oral LNG administration were at a comparable range (940-1300 pmol/liter). Azoospermia was achieved in 24%, 35%, 33%, and 93%, and severe oligozoospermia (<1 x 10(6)/ml) developed in 24%, 60%, 42%, and 100% of the subjects in groups 1, 2, 3, and 4, respectively, during treatment phase. All subjects in the Norplant II plus TE groups had persistent sperm concentrations less than 3 x 10(6)/ml from wk 12 until the end of treatment. Concomitant with the marked suppression of spermatogenesis in the Norplant II plus TE group, serum FSH and LH levels were most decreased in this group compared with all other groups. In the T patch-only group, serum SHBG was not suppressed, and total serum T was higher than baseline levels. In the other three groups administered progestagens, serum SHBGs were significantly suppressed, and serum total T remained similar to baseline levels. Serum free T levels were not changed in any group. Except for a suppression of serum high-density lipoprotein cholesterol, there was no significant change in weight, hematocrit, clinical chemistry, or prostate-specific antigen levels in any of the treatment groups. Although more efficacious than T patch alone, Norplant II or oral LNG plus T patch was not as effective in suppressing spermatogenesis to severe oligo- or azoospermia as in previous reports using oral LNG plus TE. This relative lesser efficacy occurred despite the achievement of serum LNG levels by Norplant II that were equivalent to those reported after administration of oral LNG. Substituting the transdermal T delivery system with TE injections resulted in very effective suppression of sperm output. The difference in spermatogenesis suppression of these combined regimens is likely due to less T delivered by the transdermal patch compared with the TE weekly injections. We conclude that Norplant II implants plus TE 100 mg/wk were very efficient in suppressing spermatogenesis to a level acceptable for contraceptive efficacy. This study demonstrates that the dose or route of administration of androgens is critical for sperm suppression in combined androgen-progestagen regimens for hormonal male contraception.
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Anticonceptivos Masculinos/administración & dosificación , Hormonas Esteroides Gonadales/administración & dosificación , Levonorgestrel/administración & dosificación , Testosterona/administración & dosificación , Administración Cutánea , Adolescente , Adulto , Peso Corporal , Coito , Anticoncepción/métodos , Anticonceptivos Masculinos/efectos adversos , Anticonceptivos Masculinos/sangre , Implantes de Medicamentos , Hormona Folículo Estimulante/sangre , Hormonas Esteroides Gonadales/sangre , Humanos , Levonorgestrel/efectos adversos , Levonorgestrel/sangre , Hormona Luteinizante/sangre , Masculino , Persona de Mediana Edad , Globulina de Unión a Hormona Sexual/metabolismo , Espermatogénesis/efectos de los fármacos , Testículo/anatomía & histología , Testículo/efectos de los fármacos , Testosterona/sangreRESUMEN
BACKGROUND: Pharmacogenetic data are largely unavailable for Mexican Americans, despite being one of the largest populations in America. METHODS: The CYP2D6 genotype (n = 349) and dextromethorphan hydroxylation phenotype (n = 285) were studied in 380 Mexican American subjects from Los Angeles County. RESULTS: The allelic frequency was 22.8% for CYP2D6*2, 10.3% for CYP2D6*4, 7.4% for CYP2D6*10, 2.3% for CYP2D6*5, 1% for CYP2D6*XN (duplication), and <1% for CYP2D6*3 and CYP2D6*17. By using the published antimode for Caucasians, we identified nine subjects as poor metabolizers, an incidence of 3.2%. Of the eight poor metabolizers who were also genotyped, five either were homozygous for the CYP2D6*4 allele (4 cases) or had a combination of CYP2D6*4 and CYP2D6*5 alleles. The mean log(10) dextromethorphan/dextrorphan ratio was -2.47 for those classified as extensive metabolizers. The number of functional alleles among the extensive metabolizers correlated strongly with the phenotype, suggesting a gene-dose effect. CONCLUSION: Compared with previous reports on Caucasian populations, studies show that Mexican Americans appear to possess a lower rate of CYP2D6*4. Frequencies for the other alleles appear to be less divergent between the two groups. This genotypic pattern might be responsible for the lower rate for the poor metabolizer status, as well as for the faster enzyme activity in the extensive metabolizer subjects that was also reflected in our data.
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Citocromo P-450 CYP2D6/genética , Americanos Mexicanos , Polimorfismo Genético/genética , Adolescente , Adulto , Alelos , Antitusígenos/farmacocinética , ADN/genética , Dextrometorfano/farmacocinética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Peso Molecular , FenotipoRESUMEN
Testosterone increases muscle mass and strength and regulates other physiological processes, but we do not know whether testosterone effects are dose dependent and whether dose requirements for maintaining various androgen-dependent processes are similar. To determine the effects of graded doses of testosterone on body composition, muscle size, strength, power, sexual and cognitive functions, prostate-specific antigen (PSA), plasma lipids, hemoglobin, and insulin-like growth factor I (IGF-I) levels, 61 eugonadal men, 18-35 yr, were randomized to one of five groups to receive monthly injections of a long-acting gonadotropin-releasing hormone (GnRH) agonist, to suppress endogenous testosterone secretion, and weekly injections of 25, 50, 125, 300, or 600 mg of testosterone enanthate for 20 wk. Energy and protein intakes were standardized. The administration of the GnRH agonist plus graded doses of testosterone resulted in mean nadir testosterone concentrations of 253, 306, 542, 1,345, and 2,370 ng/dl at the 25-, 50-, 125-, 300-, and 600-mg doses, respectively. Fat-free mass increased dose dependently in men receiving 125, 300, or 600 mg of testosterone weekly (change +3.4, 5.2, and 7.9 kg, respectively). The changes in fat-free mass were highly dependent on testosterone dose (P = 0.0001) and correlated with log testosterone concentrations (r = 0.73, P = 0.0001). Changes in leg press strength, leg power, thigh and quadriceps muscle volumes, hemoglobin, and IGF-I were positively correlated with testosterone concentrations, whereas changes in fat mass and plasma high-density lipoprotein (HDL) cholesterol were negatively correlated. Sexual function, visual-spatial cognition and mood, and PSA levels did not change significantly at any dose. We conclude that changes in circulating testosterone concentrations, induced by GnRH agonist and testosterone administration, are associated with testosterone dose- and concentration-dependent changes in fat-free mass, muscle size, strength and power, fat mass, hemoglobin, HDL cholesterol, and IGF-I levels, in conformity with a single linear dose-response relationship. However, different androgen-dependent processes have different testosterone dose-response relationships.
Asunto(s)
Composición Corporal/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Testosterona/farmacología , Adulto , Antagonistas de Andrógenos/farmacología , Agua Corporal/fisiología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Ejercicio Físico/fisiología , Hormona Liberadora de Gonadotropina/agonistas , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Hormona Luteinizante/sangre , Masculino , Músculo Esquelético/anatomía & histología , Músculo Esquelético/fisiología , Fenómenos Fisiológicos de la Nutrición , Conducta Sexual/efectos de los fármacos , Testosterona/antagonistas & inhibidores , Testosterona/sangreRESUMEN
Voltage-dependent amplification of ionotropic glutamatergic excitatory postsynaptic potentials (EPSPs) can, in many vertebrate neurons, be due either to the intrinsic voltage dependence of N-methyl-D-aspartate (NMDA) receptors, or voltage-dependent persistent sodium channels expressed on postsynaptic dendrites or somata. In the electrosensory lateral line lobe (ELL) of the gymnotiform fish Apteronotus leptorhynchus, glutamatergic inputs onto pyramidal cell apical dendrites provide a system where both amplification mechanisms are possible. We have now examined the roles for both NMDA receptors and sodium channels in the control of EPSP amplitude at these synapses. An antibody specific for the A. leptorhynchus NR1 subunit reacted strongly with ELL pyramidal cells and were particularly abundant in the spines of pyramidal cell apical dendrites. We have also shown that NMDA receptors contributed strongly to the late phase of EPSPs evoked by stimulation of the feedback fibers terminating on the apical dendritic spines; further, these EPSPs were voltage dependent. Blockade of NMDA receptors did not, however, eliminate the voltage dependence of these EPSPs. Blockade of somatic sodium channels by local somatic ejection of tetrodotoxin (TTX), or inclusion of QX314 (an intracellular sodium channel blocker) in the recording pipette, reduced the evoked EPSPs and completely eliminated their voltage dependence. We therefore conclude that, in the subthreshold range, persistent sodium currents are the main contributor to voltage-dependent boosting of EPSPs, even when they have a large NMDA receptor component.
Asunto(s)
Órgano Eléctrico/fisiología , Retroalimentación/fisiología , Lidocaína/análogos & derivados , Receptores de N-Metil-D-Aspartato/fisiología , Canales de Sodio/fisiología , Anestésicos Locales/farmacología , Animales , Anticuerpos , Química Encefálica/fisiología , Pez Eléctrico , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Antagonistas del GABA/farmacología , Immunoblotting , Inmunohistoquímica , Lidocaína/farmacología , Piperazinas/farmacología , Células Piramidales/química , Células Piramidales/fisiología , Piridazinas/farmacología , Conejos , Receptores de N-Metil-D-Aspartato/análisis , Receptores de N-Metil-D-Aspartato/inmunología , Tetrodotoxina/farmacologíaRESUMEN
OBJECTIVES: This study sought to assess the impact of child and parental birthplace on insurance status and access to health care among Latino children in the United States. METHODS: A cross-sectional, in-person survey of 376 random households with children aged 1 to 12 years was conducted in a predominantly Latino community. Children's insurance status and access to routine health care were compared among 3 child-parent groups: US born-US born (UU), US born-immigrant (UI), and immigrant-immigrant (II). RESULTS: Uninsured rates for the 3 groups of children were 10% (UU), 23% (UI), and 64% (II). Rates for lack of access to routine health care were 5% (UU), 12% (UI), and 32% (II). CONCLUSION: Latino children of immigrant parents are more likely to lack insurance and access to routine health care than are Latino children of US-born parents.
Asunto(s)
Servicios de Salud del Niño/economía , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Hispánicos o Latinos/estadística & datos numéricos , Cobertura del Seguro/estadística & datos numéricos , Censos , Niño , Servicios de Salud del Niño/provisión & distribución , Preescolar , Estudios Transversales , Emigración e Inmigración/clasificación , Accesibilidad a los Servicios de Salud/economía , Humanos , Lactante , Los Angeles/epidemiología , Pacientes no Asegurados/estadística & datos numéricos , Análisis MultivarianteRESUMEN
Atrial natriuretic peptide (ANP) has previously been localized in areas of mammalian brain associated with olfaction, cardiovascular function, and fluid/electrolyte homeostasis. Despite the presence of several types of natriuretic peptide receptors in mammalian cerebellum, neither intrinsic nor extrinsic sources of the natriuretic peptides have been described. In this report we describe the immunohistochemical localization of both intrinsic and extrinsic sources for ANP in human cerebellum. ANP-like immunoreactivity (ANP-LIR) was observed in climbing fibers in the cerebellar molecular layer that probably originated from isolated immunopositive neurons of the inferior olivary complex. Intrinsic sources of ANP-LIR included small subpopulations of protoplasmic and fibrous astrocytes and Bergmann glia, as well as Golgi and Lugaro neurons of the granule cell layer. These results suggest that, in addition to its presumptive roles in local vasoregulation, ANP may serve as a modulator of the activity of Purkinje neurons.
Asunto(s)
Astrocitos/metabolismo , Factor Natriurético Atrial/metabolismo , Cerebelo/metabolismo , Neuronas/metabolismo , Núcleo Olivar/metabolismo , Humanos , InmunohistoquímicaRESUMEN
Despite its importance in drug metabolism and disease susceptibility, CYP2D6 activity and genetic polymorphism have rarely been investigated in African-American populations. In order to bridge this gap, we examined the genotype and phenotype of the enzyme in 154 African-American (AA) and 143 Caucasian (C) normal volunteers. AAs are significantly more likely to possess *17 and *5, but less likely to have *4. Overall, the two groups were similar in their CYP2D6 activity as measured with dextromethorphan as the probe (metabolic ratio 2.21 +/- 0.78 for AAs; 2.11 +/- 0.86 for Cs; t = 1.02, NS). Two of four AAs and six of seven Cs were classified as poor metabolizers and have two nonfunctioning alleles. CYP2D6 activity is determined by *17, *4, *5 and age in AAs (r2 = 0.33, f = 18.8, P < 0.001) and by *4 and *XN in Cs (r2 = 0.14, f = 10.8, P < 0.001). These results support previous findings demonstrating the importance of *17 in determining CYP2D6 activity in AAs.
Asunto(s)
Población Negra/genética , Citocromo P-450 CYP2D6/genética , Dextrometorfano/metabolismo , Polimorfismo Genético , Adulto , Negro o Afroamericano , Factores de Edad , Alelos , California , Femenino , Duplicación de Gen , Frecuencia de los Genes , Humanos , Masculino , Factores Sexuales , Población Blanca/genéticaRESUMEN
OBJECTIVE: Androgen replacement has been reported to increase bone mineral density (BMD) in hypogonadal men. We studied the effects of 6 months of treatment with a new transdermal testosterone (T) gel preparation on bone turnover markers and BMD. DESIGN: This was a prospective, randomized, multicentre, parallel clinical trial where 227 hypogonadal men, mean age 51 years (range: 19-68 years) were studied in 16 academic and research institutions in the USA. Subjects were randomized to apply 1% T gel containing 50 or 100 mg T (delivering approximately 5-10 mg T/day) or two T patches (delivering 5 mg T/day) transdermally for 90 days. At day 91, depending on the serum T concentration, the T gel dose was adjusted upward or downward to 75 mg T/day until day 180. No dose adjustment occurred in the T patch group. MEASUREMENTS: Serum T, free T and oestradiol, bone turnover markers and BMD were measured on days 0, 30, 90 and 180 before and after treatment. RESULTS: Application of T gel 100 mg/day resulted in serum T concentrations 1.4 and 1.9-fold higher than in the T gel 50 mg/day and the T patch groups, respectively. Proportional increases occurred in serum oestradiol. Urine N-telopeptide/creatinine ratio, a marker for bone resorption, decreased significantly (P = 0.0019) only in the T gel 100 mg/day group. Serum bone osteoblastic activity markers (osteocalcin, procollagen and skeletal alkaline phosphatase) increased significantly during the first 90 days of treatment without intergroup differences but declined to baseline thereafter. BMD increased significantly both in the hip (+1.1 +/- 0.3%) and spine (+2.2 +/- 0.5%) only in the T gel 100 mg/day group (P = 0.0001). CONCLUSIONS: Transdermal testosterone gel application for 6 months decreased bone resorption markers and increased osteoblastic activity markers for a short period, which resulted in a small but significant increase in BMD. Ongoing long-term studies should answer whether the observed increases in BMD are sustained or continue to be dependent on the dose of testosterone administered.