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1.
Nature ; 581(7806): 47-52, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32376964

RESUMEN

The recently discovered flat electronic bands and strongly correlated and superconducting phases in magic-angle twisted bilayer graphene (MATBG)1,2 crucially depend on the interlayer twist angle, θ. Although control of the global θ with a precision of about 0.1 degrees has been demonstrated1-7, little information is available on the distribution of the local twist angles. Here we use a nanoscale on-tip scanning superconducting quantum interference device (SQUID-on-tip)8 to obtain tomographic images of the Landau levels in the quantum Hall state9 and to map the local θ variations in hexagonal boron nitride (hBN)-encapsulated MATBG devices with relative precision better than 0.002 degrees and a spatial resolution of a few moiré periods. We find a correlation between the degree of θ disorder and the quality of the MATBG transport characteristics and show that even state-of-the-art devices-which exhibit correlated states, Landau fans and superconductivity-display considerable local variation in θ of up to 0.1 degrees, exhibiting substantial gradients and networks of jumps, and may contain areas with no local MATBG behaviour. We observe that the correlated states in MATBG are particularly fragile with respect to the twist-angle disorder. We also show that the gradients of θ generate large gate-tunable in-plane electric fields, unscreened even in the metallic regions, which profoundly alter the quantum Hall state by forming edge channels in the bulk of the sample and may affect the phase diagram of the correlated and superconducting states. We thus establish the importance of θ disorder as an unconventional type of disorder enabling the use of twist-angle gradients for bandstructure engineering, for realization of correlated phenomena and for gate-tunable built-in planar electric fields for device applications.

2.
Nanoscale ; 12(5): 3174-3182, 2020 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-31967152

RESUMEN

Scanning nanoscale superconducting quantum interference devices (nanoSQUIDs) are of growing interest for highly sensitive quantitative imaging of magnetic, spintronic, and transport properties of low-dimensional systems. Utilizing specifically designed grooved quartz capillaries pulled into a sharp pipette, we have fabricated the smallest SQUID-on-tip (SOT) devices with effective diameters down to 39 nm. Integration of a resistive shunt in close proximity to the pipette apex combined with self-aligned deposition of In and Sn, has resulted in SOTs with a flux noise of 42 nΦ0 Hz-1/2, yielding a record low spin noise of 0.29 µB Hz-1/2. In addition, the new SOTs function at sub-Kelvin temperatures and in high magnetic fields of over 2.5 T. Integrating the SOTs into a scanning probe microscope allowed us to image the stray field of a single Fe3O4 nanocube at 300 mK. Our results show that the easy magnetization axis direction undergoes a transition from the 〈111〉 direction at room temperature to an in-plane orientation, which could be attributed to the Verwey phase transition in Fe3O4.

3.
Nature ; 539(7629): 407-410, 2016 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-27786173

RESUMEN

Energy dissipation is a fundamental process governing the dynamics of physical, chemical and biological systems. It is also one of the main characteristics that distinguish quantum from classical phenomena. In particular, in condensed matter physics, scattering mechanisms, loss of quantum information or breakdown of topological protection are deeply rooted in the intricate details of how and where the dissipation occurs. Yet the microscopic behaviour of a system is usually not formulated in terms of dissipation because energy dissipation is not a readily measurable quantity on the micrometre scale. Although nanoscale thermometry has gained much recent interest, existing thermal imaging methods are not sensitive enough for the study of quantum systems and are also unsuitable for the low-temperature operation that is required. Here we report a nano-thermometer based on a superconducting quantum interference device with a diameter of less than 50 nanometres that resides at the apex of a sharp pipette: it provides scanning cryogenic thermal sensing that is four orders of magnitude more sensitive than previous devices-below 1 µK Hz-1/2. This non-contact, non-invasive thermometry allows thermal imaging of very low intensity, nanoscale energy dissipation down to the fundamental Landauer limit of 40 femtowatts for continuous readout of a single qubit at one gigahertz at 4.2 kelvin. These advances enable the observation of changes in dissipation due to single-electron charging of individual quantum dots in carbon nanotubes. They also reveal a dissipation mechanism attributable to resonant localized states in graphene encapsulated within hexagonal boron nitride, opening the door to direct thermal imaging of nanoscale dissipation processes in quantum matter.

4.
J Clin Endocrinol Metab ; 101(6): 2313-24, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26938200

RESUMEN

CONTEXT: Conventional management of hypoparathyroidism has focused upon maintaining the serum calcium with oral calcium and active vitamin D, often requiring high doses and giving rise to concerns about long-term consequences including renal and brain calcifications. Replacement therapy with PTH has recently become available. This paper summarizes the results of the findings and recommendations of the Working Group on Management of Hypoparathyroidism. EVIDENCE ACQUISITION: Contributing authors reviewed the literature regarding physiology, pathophysiology, and nutritional aspects of hypoparathyroidism, management of acute hypocalcemia, clinical aspects of chronic management, and replacement therapy of hypoparathyroidism with PTH peptides. PubMed and other literature search engines were utilized. EVIDENCE SYNTHESIS: Under normal circumstances, interactions between PTH and active vitamin D along with the dynamics of calcium and phosphorus absorption, renal tubular handing of those ions, and skeletal responsiveness help to maintain calcium homeostasis and skeletal health. In the absence of PTH, the gastrointestinal tract, kidneys, and skeleton are all affected, leading to hypocalcemia, hyperphosphatemia, reduced bone remodeling, and an inability to conserve filtered calcium. Acute hypocalcemia can be a medical emergency presenting with neuromuscular irritability. The recent availability of recombinant human PTH (1-84) has given hope that management of hypoparathyroidism with the missing hormone in this disorder will provide better control and reduced needs for calcium and vitamin D. CONCLUSIONS: Hypoparathyroidism is associated with abnormal calcium and skeletal homeostasis. Control with calcium and active vitamin D can be a challenge. The availability of PTH (1-84) replacement therapy may usher new opportunities for better control with reduced supplementation requirements.


Asunto(s)
Calcio/uso terapéutico , Terapia de Reemplazo de Hormonas/métodos , Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/uso terapéutico , Vitamina D/uso terapéutico , Calcio/sangre , Manejo de la Enfermedad , Humanos , Hipocalcemia/sangre , Hipocalcemia/tratamiento farmacológico , Hipoparatiroidismo/sangre , Hormona Paratiroidea/sangre , Vitamina D/sangre
5.
Sci Rep ; 5: 7598, 2015 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-25564043

RESUMEN

The dynamics of quantized magnetic vortices and their pinning by materials defects determine electromagnetic properties of superconductors, particularly their ability to carry non-dissipative currents. Despite recent advances in the understanding of the complex physics of vortex matter, the behavior of vortices driven by current through a multi-scale potential of the actual materials defects is still not well understood, mostly due to the scarcity of appropriate experimental tools capable of tracing vortex trajectories on nanometer scales. Using a novel scanning superconducting quantum interference microscope we report here an investigation of controlled dynamics of vortices in lead films with sub-Angstrom spatial resolution and unprecedented sensitivity. We measured, for the first time, the fundamental dependence of the elementary pinning force of multiple defects on the vortex displacement, revealing a far more complex behavior than has previously been recognized, including striking spring softening and broken-spring depinning, as well as spontaneous hysteretic switching between cellular vortex trajectories. Our results indicate the importance of thermal fluctuations even at 4.2 K and of the vital role of ripples in the pinning potential, giving new insights into the mechanisms of magnetic relaxation and electromagnetic response of superconductors.

6.
Int J Med Robot ; 11(2): 150-8, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25219464

RESUMEN

BACKGROUND: It remains uncertain as to whether robotically assisted coronary bypass surgery (RACBS) is superior to non-robotic procedures. METHODS: Literature searches were conducted using MEDLINE, EMBASE and LILACS. Two review authors independently screened citations, assessed trial quality and performed data extraction. RESULTS: Three trials met the inclusion criteria. None was randomized. Compared with non-robotic approaches, RACBS was associated with longer surgical times, shorter intensive care unit and hospital stays, higher extubation rates and lower odds for atrial fibrillation as well as myocardial infarction. There were no differences for the odds of stroke and mortality between the interventions. CONCLUSIONS: Although robotic-assisted coronary bypass appears to be promising, the study designs were not adequate and may have a high risk of selection bias. There is a need for randomized trials to corroborate the findings and to determine the long-term benefits of RACBS compared with traditional surgical approaches.


Asunto(s)
Puente de Arteria Coronaria/métodos , Procedimientos Quirúrgicos Robotizados/métodos , Ensayos Clínicos Controlados como Asunto , Puente de Arteria Coronaria/efectos adversos , Puente de Arteria Coronaria/estadística & datos numéricos , Enfermedad de la Arteria Coronaria/cirugía , Humanos , Tiempo de Internación , Tempo Operativo , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Procedimientos Quirúrgicos Robotizados/efectos adversos , Procedimientos Quirúrgicos Robotizados/estadística & datos numéricos , Sesgo de Selección
7.
Am Heart J ; 163(3): 323-29, 329.e1, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22424001

RESUMEN

Translating evidence into clinical practice in the management of acute coronary syndromes (ACS) is challenging. Few ACS quality improvement interventions have been rigorously evaluated to determine their impact on patient care and clinical outcomes. We designed a pragmatic, 2-arm, cluster-randomized trial involving 34 clusters (Brazilian public hospitals). Clusters were randomized to receive a multifaceted quality improvement intervention (experimental group) or routine practice (control group). The 6-month educational intervention included reminders, care algorithms, a case manager, and distribution of educational materials to health care providers. The primary end point was a composite of evidence-based post-ACS therapies within 24 hours of admission, with the secondary measure of major cardiovascular clinical events (death, nonfatal myocardial infarction, nonfatal cardiac arrest, and nonfatal stroke). Prescription of evidence-based therapies at hospital discharge were also evaluated as part of the secondary outcomes. All analyses were performed by the intention-to-treat principle and took the cluster design into account using individual-level regression modeling (generalized estimating equations). If proven effective, this multifaceted intervention would have wide use as a means of promoting optimal use of evidence-based interventions for the management of ACS.


Asunto(s)
Síndrome Coronario Agudo/terapia , Manejo de la Enfermedad , Medicina Basada en la Evidencia/métodos , Hospitales Públicos/estadística & datos numéricos , Mejoramiento de la Calidad/organización & administración , Brasil , Método Doble Ciego , Humanos
9.
J Bone Miner Res ; 22 Suppl 2: V105-7, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18290711

RESUMEN

Hereditary vitamin D receptor defects (HVDRDs) is a more appropriate and precise title for an inborn error of metabolism commonly known as pseudo-vitamin D deficiency or vitamin D dependency, type II. It is a rare autosomal recessive disorder, approximately 70 kindreds were described, but its main importance is elucidating the physiology of vitamin D and calcium homeostasis in humans. Patients usually develop the clinical and biochemical aberrations, identical to vitamin D deficiency, but with high serum levels of calcitriol, within the first year of life (i.e., muscle weakness, bone pain, deformities, and fractures). Defective calcium gut absorption leads to hypocalcemia, secondary hyperparathyroidism, hypophosphatemia, and defective mineralization of newly formed bone matrix. The disease is not cured by vitamin D replacement therapy, although some patients respond to very high doses of vitamin D or its metabolites. Cells derived from patients, mainly cultured skin fibroblasts, were used to assess steps in calcitriol action from cellular uptake to bioresponse and to elucidate the molecular aberrations in the vitamin D receptor (VDR). Point mutations in the VDR gene were identified in every patient examined, and the same defect was observed in the obligatory heterozygotes. The functional characterization of the patient's VDR reflected the localization of the mutation (18 different ones described to date), thus providing vital information about the structure-function relationship in the human VDR and the essentiality of the VDR as the mediator of vitamin D action.


Asunto(s)
Deficiencia de Vitamina D/patología , 25-Hidroxivitamina D 2/metabolismo , Calcifediol/metabolismo , Humanos , Receptores de Calcitriol/metabolismo , Deficiencia de Vitamina D/metabolismo
10.
Emerg Infect Dis ; 12(6): 894-9, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16707043

RESUMEN

During the 2003-04 influenza season, 17 cases of Staphylococcus aureus community-acquired pneumonia (CAP) were reported from 9 states; 15 (88%) were associated with methicillin-resistant S. aureus (MRSA). The median age of patients was 21 years; 5 (29%) had underlying diseases, and 4 (24%) had risk factors for MRSA. Twelve (71%) had laboratory evidence of influenza virus infection. All but 1 patient, who died on arrival, were hospitalized. Death occurred in 5 (4 with MRSA). S. aureus isolates were available from 13 (76%) patients (11 MRSA). Toxin genes were detected in all isolates; 11 (85%) had only genes for Panton-Valentine leukocidin. All isolates had community-associated pulsed-field gel electrophoresis patterns; all MRSA isolates had the staphylococcal cassette chromosome mec type IVa. In communities with a high prevalence of MRSA, empiric therapy of severe CAP during periods of high influenza activity should include consideration for MRSA.


Asunto(s)
Infecciones Comunitarias Adquiridas/microbiología , Gripe Humana/microbiología , Orthomyxoviridae , Neumonía Bacteriana/microbiología , Infecciones Estafilocócicas/microbiología , Infecciones Estafilocócicas/virología , Staphylococcus aureus/aislamiento & purificación , Adolescente , Adulto , Niño , Preescolar , Infecciones Comunitarias Adquiridas/virología , ADN Bacteriano/química , ADN Bacteriano/genética , Electroforesis en Gel de Campo Pulsado , Femenino , Genotipo , Humanos , Lactante , Gripe Humana/inmunología , Gripe Humana/virología , Masculino , Resistencia a la Meticilina , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Neumonía Bacteriana/virología , Staphylococcus aureus/efectos de los fármacos
11.
Drugs Aging ; 23(4): 289-98, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16732688

RESUMEN

This article reviews the long-term safety profile of bisphosphonates for the treatment and prevention of osteoporosis in postmenopausal women. Bisphosphonates inhibit osteoclastic resorption and reduce the rate of bone turnover, thereby reducing fracture risk. Placebo-controlled trials of oral amino-bisphosphonates of up to 4 years' duration and continuous treatment for up to 10 years in extensions of these trials (without continuous placebo comparison groups) have reported that bone quality remains normal, and suggest that the early reductions in fracture risk may be sustained for as long as treatment continues. Studies in animals using high doses of bisphosphonates have also reported normal quality bone with increased strength. The adverse experience profile (including upper gastrointestinal tolerability) of the oral bisphosphonates alendronic acid and risedronic acid has been similar to placebo in randomised trials with thousands of participants, whereas the incidence of flu-like symptoms was increased with the high doses used in oral monthly and intravenous ibandronic acid. Thus, the existing data are reassuring for long-term continued daily (or its weekly equivalent) administration of alendronic acid and risedronic acid, with no evidence of an adverse effect on bone health. For other dosing regimens, additional data are needed to evaluate their long-term safety.


Asunto(s)
Difosfonatos/uso terapéutico , Osteoporosis Posmenopáusica/tratamiento farmacológico , Animales , Densidad Ósea/efectos de los fármacos , Ensayos Clínicos como Asunto , Difosfonatos/efectos adversos , Difosfonatos/farmacocinética , Esquema de Medicación , Femenino , Humanos
12.
J Cell Biochem ; 97(5): 1094-103, 2006 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-16294320

RESUMEN

The c-myc oncoprotein plays a critical role in the regulation of cellular proliferation and apoptosis. To mediate these biological functions, a variety of target genes are activated or repressed by c-myc, but few genes have yet been identified that directly mediate c-myc's role in proliferation or apoptosis. During a screen for genes that are repressed by c-myc, we identified the alpha1 subunit of gamma aminobutyric acid receptor (GABAAR-alpha1) as a novel target of c-myc. GABAAR is the major inhibitory neurotransmitter receptor in the mammalian central nervous system and is involved in developmental events in the brain, such as neurite outgrowth, neuronal survival, neuronal migration, and proliferation. We show here that GABAAR-alpha1 expression is rapidly and directly repressed by c-myc. GABAAR-alpha1 expression is elevated in c-myc null cells and upregulation of GABAAR-alpha1 correlates with downregulation of c-myc protein expression during neuronal cell differentiation. We also show that overexpression of GABAAR-alpha1 causes apoptosis, which is blocked by the coexpression of Bcl-2 or Bcl-XL. Induction of apoptosis is specific for the alpha1 subunit, since neither the beta1 or beta2 subunits of GABAAR induced apoptosis. Derepression of GABAAR-alpha1 expression upon downregulation of c-myc represents a unique apoptotic mechanism and a distinct function for the alpha1 subunit, independent of its role as a component of the GABAAR in the plasma membrane. In addition, the regulation of GABAAR-alpha1 expression by c-myc provides a potential direct role for the Myc proteins in neurological processes and neurodegenerative disorders.


Asunto(s)
Apoptosis , Proteínas Proto-Oncogénicas c-myc/fisiología , ARN Mensajero/metabolismo , Receptores de GABA-A/metabolismo , Supresión Genética , Animales , Caspasa 3 , Caspasas/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Ratones , Células 3T3 NIH , Ratas , Receptores de GABA-A/genética , Transcripción Genética
13.
Free Radic Biol Med ; 39(2): 266-78, 2005 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-15964518

RESUMEN

Calcitriol, the hormonal form of vitamin D3, sensitizes breast cancer cells to reactive oxygen species (ROS)-dependent cytotoxicity induced by various anticancer modalities. This effect could be due to increased generation of ROS and/ or to increased sensitivity of the target cells to ROS. This work examined the effect of calcitriol on the damage inflicted on breast cancer cells by the direct action of ROS represented by H2O2. Treatment of MCF-7 cells with H2O2 resulted in activation of caspase 7 as well as induction of caspase-independent cell death. Both were enhanced by 48-72 h of pretreatment with calcitriol. This effect was not due to modulation of H2O2 degradation or to a specific effect on *OH-mediated cytotoxicity. The H2O2-induced drop in mitochondrial membrane potential and release of cytochrome c were enhanced by calcitriol. These findings indicate that calcitriol sensitizes breast cancer cells to ROS-induced death by affecting event(s) common to both caspase-dependent and -independent modes of cell death upstream to mitochondrial damage.


Asunto(s)
Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Peróxido de Hidrógeno/farmacología , Vitamina D/farmacología , Western Blotting , Calcitriol/química , Calcitriol/farmacología , Caspasas/metabolismo , Línea Celular Tumoral , Sinergismo Farmacológico , Activación Enzimática , Humanos , Peróxido de Hidrógeno/metabolismo , Membranas Intracelulares/metabolismo , Potenciales de la Membrana , Mitocondrias/metabolismo , Oxidantes/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especies Reactivas de Oxígeno , Factores de Tiempo
14.
Osteoporos Int ; 16(5): 468-74, 2005 May.
Artículo en Inglés | MEDLINE | ID: mdl-15448985

RESUMEN

Treatment with alendronate, a potent and specific inhibitor of bone resorption, is known to significantly reduce fracture risk among women with postmenopausal osteoporosis. The purpose of this meta-analysis was to assess the consistency of the effect of alendronate in reducing the risk of hip fracture among different studies and populations. Data from completed, randomized, treatment studies were pooled in a meta-analysis. The duration of the studies ranged from 1-4.5 years. The dose of alendronate ranged from 5-20 mg/day, with over 95% of patients receiving either 5 or 10 mg/day during the trials. In patients with a T-score of less than or equal to -2.0, or with a vertebral fracture, the effect on hip fracture risk consistently favored patients receiving alendronate therapy, with an overall reduction in risk of hip fracture of 45% [95% confidence interval (CI) 16% to 64%, P=0.007]. For patients who met the criteria of osteoporosis, as defined by the World Health Organization (WHO), the overall risk reduction was 55% (95% CI 29% to 72%, P=0.0008). In both analyses we performed a sensitivity analysis by removing one study at a time. The strength of the evidence was not dependent on any one study. We conclude that therapy with alendronate is associated with significant and clinically important reductions in the incidence of hip fracture in women with postmenopausal osteoporosis. The overall reduction is consistent among different patient populations.


Asunto(s)
Alendronato/uso terapéutico , Fracturas de Cadera/prevención & control , Osteoporosis Posmenopáusica/complicaciones , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Densidad Ósea/efectos de los fármacos , Femenino , Fracturas de Cadera/etiología , Fracturas de Cadera/fisiopatología , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
15.
J Steroid Biochem Mol Biol ; 89-90(1-5): 361-4, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15225801

RESUMEN

Calcitriol, the hormonal form of Vitamin D, potentiates the activity of some agents of the anti-cancer immune system including tumor necrosis factor-alpha (TNF-alpha). Different signaling pathways activated by TNF-alpha may be targets for calcitriol action. Activation of p38 MAP kinase was shown to have both pro- and anti-apoptotic actions in TNF-alpha-induced programmed cell death depending on cell context. Treatment of MCF-7 breast cancer cells with TNF-alpha resulted in activation of p38 MAP kinase that persisted for at least 24h. Whereas calcitriol had no effect on the earlier phase of p38 MAP kinase activation (up to 1h), it inhibited the activation of this pathway between one and 24h after exposure to TNF-alpha. Both calcitriol and the p38 MAP kinase inhibitor SB203580 enhanced TNF-alpha-induced cytotoxicity and drop in mitochondrial membrane potential, but their combined effect was sub-additive. Taken together, these findings suggest that p38 MAP kinase plays an anti-apoptotic role in TNF-alpha-induced cytotoxicity in MCF-7 cells and that the synergistic interaction between TNF-alpha and calcitriol, leading to mitochondrial damage and subsequent cell death, is partially due to modulation of this signaling pathway.


Asunto(s)
Neoplasias de la Mama/patología , Calcitriol/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Neoplasias de la Mama/enzimología , Línea Celular Tumoral , Sinergismo Farmacológico , Humanos , Potenciales de la Membrana , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos
16.
N Engl J Med ; 350(12): 1189-99, 2004 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-15028823

RESUMEN

BACKGROUND: Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. METHODS: The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study. RESULTS: Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit. CONCLUSIONS: The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects.


Asunto(s)
Alendronato/uso terapéutico , Densidad Ósea/efectos de los fármacos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Anciano , Alendronato/efectos adversos , Alendronato/farmacología , Estatura/efectos de los fármacos , Remodelación Ósea/efectos de los fármacos , Método Doble Ciego , Femenino , Fracturas Óseas/epidemiología , Fracturas Óseas/prevención & control , Humanos , Persona de Mediana Edad , Radiografía , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/prevención & control , Factores de Tiempo
17.
Int J Cancer ; 106(2): 178-86, 2003 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-12800192

RESUMEN

Calcitriol, the hormonal form of vitamin D, potentiates the activity of some common anticancer drugs and agents of the anticancer immune system, including tumor necrosis factor alpha (TNFalpha). TNFalpha-induced cytotoxicity is due to both caspase-dependent and -independent pathways. Cotreatment with calcitriol enhanced both modes of TNFalpha-induced death in MCF-7 breast cancer cells. It increased caspase-3-like activity as assayed by the cleavage of poly-(ADP-ribose)polymerase and of the fluorogenic substrate ac-DEVD-AMC. It also enhanced TNFalpha-induced caspase-independent cytotoxicity in the presence of the pan-caspase inhibitor zD-2,6-dichlorobenzoyloxymethylketone. The antioxidants N-acetylcysteine, reduced glutathione, lipoic acid and ascorbic acid markedly reduced the enhancing effect of the hormone on TNFalpha-induced caspase activation. N-acetylcysteine and reduced glutathione also decreased caspase-independent cytotoxicity in the presence or absence of calcitriol, indicating that reactive oxygen species (ROS) have a key role in the cross talk between TNFalpha and calcitriol. Mitochondrial damage is common to both TNFalpha-induced caspase-dependent and -independent pathways and may underlie excessive production of ROS. Mitochondrial membrane potential (DeltaPsi) was assessed by the specific potential-sensitive fluorescent probe JC-1. The hormone augmented the drop in DeltaPsi and release of cytochrome c from mitochondria, induced by TNFalpha. The effect of calcitriol on DeltaPsi was mimicked by rotenone, which increased both the drop in DeltaPsi and caspase activation induced by TNFalpha. It is possible that the interaction of TNFalpha and calcitriol on the level of the mitochondria is the underlying mechanism responsible for the enhancement of TNFalpha-induced, ROS-mediated caspase-dependent and -independent cell death.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Calcitriol/farmacología , Caspasas/metabolismo , Inhibidores Enzimáticos/farmacología , Mitocondrias/fisiología , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Apoptosis/fisiología , Western Blotting , Neoplasias de la Mama/metabolismo , Agonistas de los Canales de Calcio/metabolismo , Agonistas de los Canales de Calcio/farmacología , Caspasa 3 , Inhibidores de Caspasas , División Celular , Grupo Citocromo c/metabolismo , Activación Enzimática , Citometría de Flujo , Humanos , Potenciales de la Membrana/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2 , Rotenona/farmacología , Transducción de Señal , Células Tumorales Cultivadas , Desacopladores/farmacología
18.
J Cell Biochem ; 89(3): 440-9, 2003 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-12761878

RESUMEN

The hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), and keratinocyte growth factor (KGF) belong to the network of autocrine and paracrine mediators in the skin. Both were shown to modulate keratinocyte proliferation, to reverse epidermal atrophy, to increase wound healing, and to reduce chemotherapy-induced alopecia. The overlap between their activities may suggest that vitamin D exerts some of its actions by modulation of KGF activities in the skin. This notion was examined by using HaCaT keratinocytes cultured in serum-free medium in the absence of exogenous growth factors and in the presence of the EGF receptor tyrosine kinase inhibitor AG 1478 that blocks their autonomous proliferation. These cells could be stimulated to proliferate by different fibroblast growth factors (FGFs). The relative mitogenic efficacy of basic FGF, acidic FGF, or KGF was in correlation with their affinities for the KGF receptor (KGFR). Forty-eight hour co-treatment with 1,25(OH)(2)D(3) enhanced KGFR-mediated cell proliferation in a dose dependent manner. Both ERK1/2 and c-Jun N-terminal kinase (JNK) were activated by the FGFs. Treatment with 1,25(OH)(2)D(3) increased the activation of ERK but reduced the activation of JNK. Treatment with 1,25(OH)(2)D(3) increased the levels of KGFR in the presence but not in the absence of KGF, probably due to inhibition of ligand-induced receptor degradation. Inhibition of protein kinase C with bisindolylmaleimide did not interfere with the effect of 1,25(OH)(2)D(3) on KGFR-mediated ERK activation. Our results support the notion that the paracrine KGF-KGFR system in the skin can act in concert with the autocrine vitamin D system in keratinocytes to promote keratinocyte proliferation and survival under situations of stress and injury.


Asunto(s)
Queratinocitos/citología , Mitosis/efectos de los fármacos , Receptores de Factores de Crecimiento de Fibroblastos/fisiología , Vitamina D/fisiología , Western Blotting , Línea Celular , Humanos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos
19.
Arthritis Rheum ; 48(4): 1102-8, 2003 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-12687554

RESUMEN

OBJECTIVE: To evaluate the effects of discontinuing or continuing alendronate (ALN) therapy on bone mineral density (BMD) after patients on a long-term regimen of glucocorticoids (GCs) completed a 1-year treatment period with ALN. METHODS: Eligible patients were individuals with GC-induced osteoporosis who had received ALN (5 or 10 mg) for 1 year in a prior clinical trial and, at the end of the year, were still taking GCs at an average daily dose of > or =7.5 mg of prednisone or equivalent. Patients were contacted 3-5 years after completion of the prior ALN trial for followup measurements of the lumbar spine BMD and hip BMD, and retrospective information was collected about serious or drug-related adverse experiences and concomitant medication use. Some patients remained on GCs, and some remained on ALN, either alone or in combination with other drugs. The primary response parameter was the percentage change in lumbar spine BMD from the end of year 1 to the followup visit. Change in BMD at the hip was a secondary response parameter. RESULTS: Ninety (49.2%) of the eligible 183 patients participated in the retrospective study. The followup period, which began at the end of year 1 of the original clinical trial, ranged from 3.3 years to 4.6 years. The mean number of days of treatment with ALN was 507. Fifty patients were included in the analysis because they had received supraphysiologic doses of GCs (doses above the lowest tertile of GC use for the study population; that is, higher than approximately 6 mg/day), and they had not taken (defined as <6 months of use) other bone-affecting agents except ALN. Eleven of the 50 patients discontinued taking ALN (duration of use <90 days), 8 took ALN between 90 days and 300 days, and 31 continued to take ALN for >300 days after year 1 of the clinical trial. GC users who discontinued treatment with ALN (<90 days of therapy) had numerically greater decreases in BMD at the lumbar spine, femoral neck, and total hip from the end of year 1 (mean change -5.1%, -9.2%, and -6.6%, respectively), compared with patients who continued to take ALN for >300 days (mean change 0.1%, -0.9%, and 1.8%, respectively). CONCLUSION: Substantial loss of BMD in the lumbar spine and hip was seen in patients who discontinued treatment with ALN but who continued to take >6 mg/day of GCs. However, patients receiving GCs who remained on the ALN regimen appeared to benefit from continued ALN treatment, since BMD was maintained in this latter group.


Asunto(s)
Alendronato/farmacología , Densidad Ósea/efectos de los fármacos , Glucocorticoides/efectos adversos , Prednisona/efectos adversos , Adulto , Anciano , Alendronato/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Glucocorticoides/administración & dosificación , Cadera/diagnóstico por imagen , Humanos , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/efectos de los fármacos , Vértebras Lumbares/metabolismo , Persona de Mediana Edad , Osteoporosis/inducido químicamente , Osteoporosis/prevención & control , Prednisona/administración & dosificación , Radiografía , Estudios Retrospectivos , Resultado del Tratamiento
20.
Ann N Y Acad Sci ; 1010: 350-3, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-15033750

RESUMEN

Calcitriol, the hormonal form of vitamin D, inhibited caspase-3-like activation in HaCaT keratinocytes exposed to hyperosmotic and oxidative stresses, heat shock, and the inflammatory cytokine TNF. The hormone also protected the cells from caspase-independent cell death induced by hyperosmotic and oxidative stresses. The protection against hyperosmotic stress is not affected by inhibitors of the EGF receptor, ERK or PI13 kinase pathways, neither is it due to reduced activity of the proapoptotic p38 MAP kinase. These results are in accordance with previous in vivo findings that vitamin D protects epidermal keratinocytes from apoptosis due to UV radiation or chemotherapy.


Asunto(s)
Calcitriol/farmacología , Queratinocitos/citología , Queratinocitos/fisiología , Estrés Oxidativo , Factor de Necrosis Tumoral alfa/farmacología , Caspasa 3 , Inhibidores de Caspasas , Muerte Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Lactante , Queratinocitos/efectos de los fármacos
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