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High-quality optical resonant cavities require low optical loss, typically on the scale of parts per million. However, unintended micron-scale contaminants on the resonator mirrors that absorb the light circulating in the cavity can deform the surface thermoelastically and thus increase losses by scattering light out of the resonant mode. The point absorber effect is a limiting factor in some high-power cavity experiments, for example, the Advanced LIGO gravitational-wave detector. In this Letter, we present a general approach to the point absorber effect from first principles and simulate its contribution to the increased scattering. The achievable circulating power in current and future gravitational-wave detectors is calculated statistically given different point absorber configurations. Our formulation is further confirmed experimentally in comparison with the scattered power in the arm cavity of Advanced LIGO measured by in situ photodiodes. The understanding presented here provides an important tool in the global effort to design future gravitational-wave detectors that support high optical power and thus reduce quantum noise.
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A new species of the genus Aporcella collected from a watermelon field in Nigeria is described, including its morphological and molecular (small subunit (SSU) and large subunit (LSU) ribosomal DNA (rDNA)) characterization. Aporcella femina sp. n. is distinguished by its 3.21-3.64 mm-long body, inner cuticle layer with fine but distinct transverse striation, lip region offset by deep constriction, 22-25 µm broad, odontostyle 20-26 µm, neck 661-811 µm long, pharyngeal expansion occupying 52-56% of the total neck length, female genital system didelphic-amphidelphic, uterus 191-350 µm or 1.9-3.3 mid-body diameters long, V = 52-57, tail short and convex conoid (35-48 µm, c = 72-98, c' = 0.7-0.9) and males absent. Phylogenetic analyses based on the partial sequence of SSU and LSU (D2-D3) rDNA revealed a close relationship of A. femina sp. n. with other Aporcella species, confirming the monophyly of the genus as well as its association to a clade made of several taxa characterized by the absence of pars refringens vaginae.
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Nematodos , Animales , ADN Ribosómico/genética , Femenino , Masculino , Nematodos/anatomía & histología , Nematodos/genética , Nigeria , FilogeniaRESUMEN
Aims Since its emergence, significant interest surrounds the use of SARS-CoV-2 serological tests as an alternative or as an adjunct to molecular testing. However, given the speed of this pandemic, paralleled with the pressure to develop and provide serological tests in an expediated manner, not every assay has undergone the rigorous evaluation that is usually associated with medical diagnostic assays. We aimed to examine the performance of several commercially available SARS-CoV-2 IgG antibody assays among participants with confirmed COVID-19 disease and negative controls. Methods Serum taken between day 17 and day 40 post onset of symptoms from 41 healthcare workers with RT-PCR confirmed COVID-19 disease, and pre-pandemic serum from 20 negative controls, were tested for the presence of SARS-CoV-2 IgG using 7 different assays including point-of-care (POC) and laboratory-based assays. Results Assay performance varied. The lab-based Abbott diagnostics SARS-CoV-2 IgG assay proved to be the assay with the best positive and negative predictive value, and overall accuracy. The POC Nal von Minden GmbH and Biozek assays also performed well. Conclusion Our research demonstrates the variations in performance of several commercially available SARS-CoV-2 antibody assays. These findings identify the limitations of some serological tests for SARS-CoV-2. This information will help inform test selection and may have particular relevance to providers operating beyond accredited laboratories.
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Prueba de COVID-19/estadística & datos numéricos , COVID-19/diagnóstico , Personal de Salud/estadística & datos numéricos , SARS-CoV-2/aislamiento & purificación , Anticuerpos Antivirales/sangre , Humanos , Inmunoglobulina G/sangre , Sistemas de Atención de Punto/estadística & datos numéricos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/normasRESUMEN
Interferometric gravitational wave detectors operate with high optical power in their arms in order to achieve high shot-noise limited strain sensitivity. A significant limitation to increasing the optical power is the phenomenon of three-mode parametric instabilities, in which the laser field in the arm cavities is scattered into higher-order optical modes by acoustic modes of the cavity mirrors. The optical modes can further drive the acoustic modes via radiation pressure, potentially producing an exponential buildup. One proposed technique to stabilize parametric instability is active damping of acoustic modes. We report here the first demonstration of damping a parametrically unstable mode using active feedback forces on the cavity mirror. A 15 538 Hz mode that grew exponentially with a time constant of 182 sec was damped using electrostatic actuation, with a resulting decay time constant of 23 sec. An average control force of 0.03 nN was required to maintain the acoustic mode at its minimum amplitude.
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Manihot , Tylenchoidea , África , Animales , Enfermedades de las Plantas , Raíces de Plantas , Tylenchoidea/genética , VerdurasRESUMEN
Heparin is one of the oldest drugs still in widespread clinical use. Its discovery in 1916 predates the establishment of the Food and Drug Administration. Since 1935, over 15,000 research papers have been published on the effects of heparin. Because the exact chemical formula of heparin is unknown, synthetic manufacturing has proven difficult. In 2008, a worldwide recall of heparin occurred. Scientists determined that a contaminant known as oversulfated chondroitin sulfate was responsible for the numerous deaths and adverse events. This contaminant was first traced to a chemical plant in Changzou, China. This article will review the discovery of heparin and the adulteration process that jeopardized the world's heparin supply.
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Sulfatos de Condroitina , Contaminación de Medicamentos , Recall de Medicamento , Heparina , China , HumanosRESUMEN
Chronic kidney disease-mineral and bone disorder (CKD-MBD) defines a triad of interrelated abnormalities of serum biochemistry, bone and the vasculature associated with chronic kidney disease (CKD). The new kidney disease: improving global outcomes (KDIGO) guidelines define the quality and depth of evidence supporting therapeutic intervention in CKD-MBD. They also highlight where patient management decisions lack a strong evidence base. Expert interpretation of the guidelines, along with informed opinion, where evidence is weak, may help develop effective clinical practice. The body of evidence linking poor bone health and reservoir function (the ability of bone to buffer calcium and phosphorus) with vascular calcification and cardiovascular outcomes is growing. Treating renal bone disease should be one of the primary aims of therapy for CKD. Evaluation of the biochemical parameters of CKD-MBD (primarily phosphorus, calcium, parathyroid hormone and vitamin D levels) as early as CKD Stage 3, and an assessment of bone status (by the best means available), should be used to guide treatment decisions. The adverse effects of high phosphorus intake relative to renal clearance (including stimulation of hyperparathyroidism) precede hyperphosphatemia, which presents late in CKD. Early reduction of phosphorus load may ameliorate these adverse effects. Evidence that calcium load may influence progression of vascular calcification with effects on mortality should also be considered when choosing the type and dose of phosphate binder to be used. The risks, benefits, and strength of evidence for various treatment options for the abnormalities of CKD-MBD are considered.
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Enfermedades Óseas Metabólicas/terapia , Calcinosis/terapia , Enfermedades Renales/terapia , Enfermedades Vasculares/terapia , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/metabolismo , Calcinosis/etiología , Calcinosis/metabolismo , Calcio/sangre , Enfermedad Crónica , Medicina Basada en la Evidencia , Humanos , Enfermedades Renales/complicaciones , Enfermedades Renales/metabolismo , Hormona Paratiroidea/sangre , Fósforo/sangre , Guías de Práctica Clínica como Asunto , Resultado del Tratamiento , Estados Unidos , Enfermedades Vasculares/etiología , Enfermedades Vasculares/metabolismo , Vitamina D/sangreRESUMEN
The banana weevil Cosmopolites sordidus (Germar) (Coleoptera: Curculionidae) is a serious constraint to banana (Musa spp.) production throughout the world. The entomopathogenic fungus Beauveria bassiana (Balsamo) Vuillemin (Ascomycota: Hypocreales) offers a potential weevil management option, but conventional delivery mechanisms have limited its success. As an endophyte, however, B. bassiana can be efficiently delivered to banana planting materials for the potential management of C. sordidus. However, entomopathogens can change morphology and efficacy against their target host when successively sub-cultured on artificial media or when exposed to certain physical and chemical environmental conditions. Whether such changes occur in B. bassiana after an endophytic phase inside a banana plant remains unknown. The primary aim of our study was to evaluate the viability, growth, sporulation and pathogenicity of endophytic B. bassiana. To attain this, two sets of experiments, namely morphological characterization and larval bioassays, were conducted under laboratory conditions. In these experiments, growth and pathogenicity of the wild-type B. bassiana strain G41, obtained originally from banana farms, was compared with the endophytic B. bassiana strain G41, re-isolated from the rhizome of B. bassiana-inoculated banana plants at one month post-inoculation. Morphological characterization, conidial germination, colony growth and sporulation rate was assessed on SDAY media while pathogenicity was determined 15 days after immersing the larvae of C. sordidus in different conidial doses. No differences were observed in colony appearance and growth rate between the endophytic and wild-type strain. Percentage conidial germination for the endophytic strain (91.4-94.0%) was higher than for the wild-type (86.6-89.7%). LD50 equated 1.76 x 10(5) and 0.71 x 10(5) conidia/ml for the wild-type and endophytic B. bassiana strains, respectively, but did not differ between strains. Our study demonstrated that, after an endophytic phase inside the banana plant, B. bassiana retains it morphology and pathogenicity against the banana weevil larvae; and thus can offer protection against the damaging larvae feeding inside the rhizome.
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Beauveria/fisiología , Escarabajos/microbiología , Animales , Bioensayo , Interacciones Huésped-Patógeno , Larva/microbiología , Control Biológico de VectoresRESUMEN
BACKGROUND: Patients with diabetic nephropathy are at high risk for further progressive renal function loss. Treatments that decrease albuminuria have been linked with renal and cardiovascular protection. However, even when taking optimal treatment, residual renal and cardiovascular risk remains high which correlates with the magnitude of residual albuminuria. Use of vitamin D receptor activators, such as calcitriol and paricalcitol, is associated with improved sur- vival. A small study with paricalcitol showed reductions in albuminuria. The VITAL study tests the hypothesis whether paricalcitol persistently reduces albuminuria in diabetic subjects already receiving angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) therapy. METHODS: Randomization in this double-blind trial is equal allocation to paricalcitol 1 micro/day, 2 microg/day, or placebo. Inclusion criteria include: a diagnosis of type 2 diabetes, urinary albumin/creatinine ratio (UACR) between 100-3,000 mg/g, estimated glomerular filtration rate (eGFR) between 15-90 ml/min/1.73 m(2), serum calcium <9.8 mg/dl, and parathyroid hormone (PTH) between 35-500 pg/ml. RESULTS: Baseline characteristics of the 281 subjects are: 69% men, mean age 64.9 +/- 10.4 years, eGFR 40.7 +/- 16.7 ml/min, median UACR (interquartile range) 612.3 mg/g (281-1,181 mg/g) and PTH 98.4 +/- 63.8 pg/ml. CONCLUSION: This trial will be the first clinical test of the hypothesis that paricalcitol possesses pleiotropic effects and can modulate albuminuria in the setting of ACEI and/or ARB therapy. Results will have important clinical implications and are expected in November 2009.
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Albuminuria/tratamiento farmacológico , Ergocalciferoles/uso terapéutico , Receptores de Calcitriol/efectos de los fármacos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: Cinacalcet lowers plasma parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism (sHPT), but the bone histologic response has not been described. This prospective, double-blind, placebo-controlled trial assessed the effects of cinacalcet on bone histology and serum markers of bone metabolism in dialysis patients with sHPT. METHODS: Patients with intact PTH (iPTH) > or = 300 pg/ml were randomly assigned 2:1 to receive cinacalcet or placebo with concurrent vitamin D and/or phosphate binder therapy. Cinacalcet (30 - 180 mg/day) was used to achieve iPTH levels < or = 200 pg/ml. Bone biopsies were performed before and after one year of treatment. RESULTS: Baseline and end-of-study data were available from 32 patients (19 cinacalcet, 13 placebo). Baseline bone turnover was elevated in 27, reduced in 3 and normal in 2 patients. Serum bone-specific alkaline phosphatase (BSAP) and N-telopeptide (NTx) were elevated. Cinacalcet treatment decreased PTH and diminished activation frequency, bone formation rate/bone surface, and fibrosis surface/bone surface. Adynamic bone was observed in three patients receiving cinacalcet; in two of these, PTH levels were persistently low (< 100 pg/ml). The histomorphometric parameter changes in bone corresponded to PTH, BSAP and NTx reductions. Bone mineralization parameters remained normal. CONCLUSIONS: Treatment with cinacalcet lowered PTH and reduced bone turnover and tissue fibrosis among most dialysis patients with biochemical evidence of sHPT.
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Conservadores de la Densidad Ósea/uso terapéutico , Remodelación Ósea/efectos de los fármacos , Hiperparatiroidismo Secundario/tratamiento farmacológico , Fallo Renal Crónico/fisiopatología , Naftalenos/uso terapéutico , Diálisis Renal , Biomarcadores/sangre , Biopsia , Densidad Ósea/efectos de los fármacos , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/sangre , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/tratamiento farmacológico , Trastorno Mineral y Óseo Asociado a la Enfermedad Renal Crónica/etiología , Cinacalcet , Método Doble Ciego , Femenino , Fibrosis , Humanos , Hiperparatiroidismo Secundario/complicaciones , Ilion/patología , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Both the common bacterial blight (CBB) pathogen (Xanthomonas campestris pv. phaseoli) and X. fuscans subsp. fuscans, agent of fuscous blight, cause indistinguishable symptoms in common bean, Phaseolus vulgaris. Yield losses can exceed 40%. Lack of information about the specificity between X. campestris pv. phaseoli strains and major quantitative trait loci (QTL) or alleles conferring resistance makes the task of identifying genetic changes in host-pathogen interactions and the grouping of bacterial strains difficult. This, in turn, affects the choice of pathogen isolates used for germplasm screening and complicates breeding for CBB resistance. Common bean host genotypes carrying various sources and levels of resistance to CBB were screened with 69 X. campestris pv. phaseoli and 15 X. fuscans subsp. fuscans strains from around the world. Differential pathogenicity of the CBB pathogen was identified on the 12 selected bean genotypes. The X. fuscans subsp. fuscans strains showed greater pathogenicity than X. campestris pv. phaseoli strains having the same origin. African strains were most pathogenic. The largest variation in pathogenicity came from X. campestris pv. phaseoli strains that originated in Caribbean and South American countries. Pathogenic variation was greater within X. campestris pv. phaseoli than within X. fuscans subsp. fuscans strains. Implications for breeding for CBB resistance are discussed.
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Brain histaminergic neurons play a prominent role in arousal and maintenance of wakefulness (W). H(3)-receptors control the activity of histaminergic neurons through presynaptic autoinhibition. The role of H(3)-receptor antagonists/inverse agonists (H(3)R-antagonists) in the potential therapy of vigilance deficiency and sleep-wake disorders were studied by assessing their effects on the mouse cortical EEG and sleep-wake cycle in comparison to modafinil and classical psychostimulants. The H(3)R-antagonists, thioperamide and ciproxifan increased W and cortical EEG fast rhythms and, like modafinil, but unlike amphetamine and caffeine, their waking effects were not accompanied by sleep rebound. Conversely, imetit (H(3)R-agonist) enhanced slow wave sleep and dose-dependently attenuated ciproxifan-induced W, indicating that the effects of both ligands involve H(3)-receptor mechanisms. Additional studies using knockout (KO) mice confirmed the essential role of H(3)-receptors and histamine-mediated transmission in the wake properties of H(3)R-antagonists. Thus ciproxifan produced no increase in W in either histidine-decarboxylase (HDC, histamine-synthesizing enzyme) or H(1)- or H(3)-receptor KO-mice whereas its waking effects persisted in H(2)-receptor KO-mice. These data validate the hypothesis that H(3)R-antagonists, through disinhibition of H(3)-autoreceptors, enhancing synaptic histamine that in turn activates postsynaptic H(1)-receptors promoting W. Interestingly amphetamine and modafinil, despite their potent arousal effects, appear unlikely to depend on histaminergic mechanism as their effects still occurred in HDC KO-mice. The present study thus distinguishes two classes of wake-improving agents: the first acting through non-histaminergic mechanisms and the second acting via histamine and supports brain H(3)-receptors as potentially novel therapeutic targets for vigilance and sleep-wake disorders.
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Compuestos de Bencidrilo/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Histamina/metabolismo , Receptores Histamínicos H3/fisiología , Animales , Compuestos de Bencidrilo/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Electroencefalografía/efectos de los fármacos , Agonistas de los Receptores Histamínicos/uso terapéutico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Ratones , Ratones Noqueados , Modafinilo , Modelos Animales , Sueño/efectos de los fármacos , Sueño/fisiología , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Vigilia/efectos de los fármacos , Vigilia/fisiologíaRESUMEN
Low and declining soil fertility has been recognized for a long time as a major impediment to intensifying agriculture in sub-Saharan Africa (SSA). Consequently, from the inception of international agricultural research, centres operating in SSA have had a research programme focusing on soil and soil fertility management, including the International Institute of Tropical Agriculture (IITA). The scope, content, and approaches of soil and soil fertility management research have changed over the past decades in response to lessons learnt and internal and external drivers and this paper uses IITA as a case study to document and analyse the consequences of strategic decisions taken on technology development, validation, and ultimately uptake by smallholder farmers in SSA. After an initial section describing the external environment within which soil and soil fertility management research is operating, various dimensions of this research area are covered: (i) 'strategic research', 'Research for Development', partnerships, and balancing acts, (ii) changing role of characterization due to the expansion in geographical scope and shift from soils to farms and livelihoods, (iii) technology development: changes in vision, content, and scale of intervention, (iv) technology validation and delivery to farming communities, and (v) impact and feedback to the technology development and validation process. Each of the above sections follows a chronological approach, covering the last five decades (from the late 1960s till today). The paper ends with a number of lessons learnt which could be considered for future initiatives aiming at developing and delivering improved soil and soil fertility management practices to smallholder farming communities in SSA.
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This paper presents an analysis of the transient behavior of the Advanced LIGO (Laser Interferometer Gravitational-wave Observatory) suspensions used to seismically isolate the optics. We have characterized the transients in the longitudinal motion of the quadruple suspensions during Advanced LIGO's first observing run. Propagation of transients between stages is consistent with modeled transfer functions, such that transient motion originating at the top of the suspension chain is significantly reduced in amplitude at the test mass. We find that there are transients seen by the longitudinal motion monitors of quadruple suspensions, but they are not significantly correlated with transient motion above the noise floor in the gravitational wave strain data, and therefore do not present a dominant source of background noise in the searches for transient gravitational wave signals. Using the suspension transfer functions, we compared the transients in a week of gravitational wave strain data with transients from a quadruple suspension. Of the strain transients between 10 and 60 Hz, 84% are loud enough that they would have appeared above the sensor noise in the top stage quadruple suspension monitors if they had originated at that stage at the same frequencies. We find no significant temporal correlation with the suspension transients in that stage, so we can rule out suspension motion originating at the top stage as the cause of those transients. However, only 3.2% of the gravitational wave strain transients are loud enough that they would have been seen by the second stage suspension sensors, and none of them are above the sensor noise levels of the penultimate stage. Therefore, we cannot eliminate the possibility of transient noise in the detectors originating in the intermediate stages of the suspension below the sensing noise.
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Routine monitoring of body iron stores is an essential component of overall management for the patient on hemodialysis. Adequate iron levels are important for the prevention and treatment of iron-deficiency anemia, which is associated with reduced physical functioning, cardiovascular disease, and poor quality of life. Hemodialysis patients are at especially high risk for iron-deficiency anemia, owing to continuous blood losses and supraphysiologic levels of erythropoiesis driven by recombinant human erythropoietin therapy. Unfortunately, the accurate determination of iron status in these patients can be a challenging task, which is made more difficult by inflammation, infections, and the large number of comorbid conditions that can affect commonly used indices of body iron stores. Despite their limitations, transferrin saturation (TSAT) and serum ferritin remain the cornerstones of iron status assessment. Because these values can be altered by a number of non-iron-related factors, it is necessary to go beyond these measures and draw upon additional sources of information to determine the patient's iron status. Other important factors to consider when assessing the need for iron therapy include evidence of underlying inflammatory processes that may block iron mobilization and distort the standard iron indices, the results of alternative iron indices, and the patient's recent history of iron administration. Frequently, the response to a gram of intravenous (i.v.) iron is a safe and effective way to determine the role of iron deficiency in the anemia of the problematic patient. The chronic inflammatory state associated with malnutrition and clinical or subclinical infections substantially increases the risk of misdiagnosing the patient with iron overload and may place the patient at risk of iron deficiency owing to inappropriate withdrawal of i.v. iron therapy. To avoid the risks of withholding iron therapy, the nephrologist must keep this relationship in mind whenever serum ferritin testing suggests replete iron stores, whereas TSAT testing suggests insufficient iron availability.
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Anemia Ferropénica/diagnóstico , Anemia Ferropénica/etiología , Ferritinas/sangre , Hemosiderosis/sangre , Transferrina/análisis , Médula Ósea/química , Eritroblastos/química , Eritropoyesis/fisiología , Ferritinas/análisis , Hemoglobinas/análisis , Hemosiderosis/fisiopatología , Humanos , Inflamación/sangre , Hierro/metabolismo , Hierro/uso terapéutico , Hígado/química , Sistema Mononuclear Fagocítico/química , Desnutrición Proteico-Calórica/sangre , Receptores de Transferrina/análisis , Diálisis Renal/efectos adversos , Reticulocitos/química , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Treatment of secondary hyperparathyroidism (SHPT) includes use of calcitriol (1,25D(3)) to suppress parathyroid hormone (PTH), but dosing of 1,25D(3) is limited by the development of hypercalcemia and a high calcium x phosphorus (Ca x P) product due to gut absorption of calcium and phosphorus as well as enhanced bone resorption. The vitamin D analog 19-Nor-1,25(OH)2-vitamin D2 (paricalcitol) and the prohormone 1alpha-OH-vitamin D2 (doxercalciferol) have been proposed as alternatives which may cause less hypercalcemia and elevated Ca x P, while still suppressing PTH. METHODS: We performed a prospective study to assess the acute bone mobilization effects of very high doses of paricalcitol and doxercalciferol. 13 hemodialysis patients received 160 mcg of paricalcitol and 120 mcg of doxercalciferol on 2 separate occasions in a research center while on a low calcium, low phosphorus diet, and sevelamer alone as a phosphorus binder. Changes in Ca, PO4, and PTH were measured over 36 h. RESULTS: Serum phosphorus rose faster, and peaked significantly higher at 36 h following doxercalciferol (2.12 +/- 0.11 mmol/l) than paricalcitol (1.85 +/- 0.07 mmol/l; p = 0.025). Ca x P product also rose more following doxercalciferol than paricalcitol, and peaked higher at 36 h (5.02 +/- 0.26 vs. 4.54 +/- 0.21 mmol/l; p = 0.061). In contrast, suppression of PTH at 36 h was comparable (63% after paricalcitol and 65% with doxercalciferol). CONCLUSION: Consistent with animal studies, paricalcitol provides profound PTH suppression, while stimulating bone resorption and/or intestinal absorption less than doxercalciferol, resulting in less elevation of serum phosphorus and Ca x P.
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Ergocalciferoles/administración & dosificación , Fósforo/sangre , Diálisis Renal , Adulto , Anciano , Conservadores de la Densidad Ósea/administración & dosificación , Calcio/sangre , Femenino , Humanos , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
BACKGROUND: Paricalcitol, a vitamin D analog, is commonly administered three times weekly to control secondary hyperparathyroidism in hemodialysis patients. Less frequent dosing would be more convenient, require less nursing time, and be an option in other dialysis modalities. No studies have examined the efficacy of once-weekly dosing of paricalcitol. METHODS: Chronic hemodialysis patients receiving a stable dose of paricalcitol three times weekly with intact PTH (iPTH) 100-500 ng/l were monitored during a two-week baseline, then were converted to a single mid-week paricalcitol dose equal to the previous cumulative weekly dose. Serum calcium and phosphorus were monitored weekly and iPTH levels determined during study Weeks 4 and 8. A single paricalcitol dose adjustment was made during study Week 5 based on iPTH to achieve a target value of 150-300 ng/l. Phosphate binders and calcium dialysate bath were kept constant during the study. RESULTS: In the 25 patients, mean iPTH was 295 +/- 107 ng/l at baseline, and not significantly different at Week 4 (307 +/- 111 ng/l) or Week 8 (285 +/- 98 ng/l). Paricalcitol dose increases mid-study were almost exclusively in patients with iPTH > 300 ng/l. Calcium, phosphorus, and calcium x phosphorus product were not significantly different on weekly therapy. (Only one patient developed a calcium > 2.55 mmol/l during the study.) CONCLUSION: Once-weekly dosing of paricalcitol is an effective option in treatment of secondary hyperparathyroidism. Less frequent dosing may better allocate nursing time and potentially benefit other patient populations with CKD and ESRD.
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Ergocalciferoles/administración & dosificación , Hiperparatiroidismo Secundario/tratamiento farmacológico , Fallo Renal Crónico/terapia , Diálisis Renal/efectos adversos , Calcio/sangre , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Hiperparatiroidismo Secundario/sangre , Hiperparatiroidismo Secundario/complicaciones , Inyecciones Intravenosas , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Fósforo/sangre , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Calpain, a calcium-activated neutral protease family, has been implicated in the neuropathologic sequelae accompanying various neurological disorders. We have characterized the distribution and time course of calpain activation following brain injury in the rat, using a monoclonal antibody that recognizes calpain-generated breakdown products (BDPs) of spectrin. Adult male Sprague-Dawley rats received lateral fluid percussion brain injury of moderate severity (2.2-2.4 atm, n = 35) or served as controls (uninjured, n = 12). One group of animals (n = 21) were sacrificed at either 30 minutes (min), 1 day, or 3 days post-injury, and selected brain regions were prepared for Western blot analysis. The remaining animals (n = 26) were sacrificed at 90 min, 4 hours (h), 1 day, or 7 days post-injury, and immunohistochemistry was performed. Spectrin BDPs were found predominantly in the hemisphere ipsilateral to the injury site, located primarily in cortical and hippocampal regions which exhibit neuronal death. Calpain-mediated spectrin breakdown was detected at 90 min in dendrites and axons, and by 4 h in neuronal perikarya. By 1 day post-injury, cortical and hippocampal regions of calpain activation had increased in size. Delayed spectrin breakdown was observed in the thalamus, both at 3 days and 7 days after injury. These results suggest that calpain may play an important role in the neurodegenerative process following brain injury.
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Lesiones Encefálicas/metabolismo , Calpaína/metabolismo , Espectrina/metabolismo , Animales , Western Blotting , Encéfalo/metabolismo , Activación Enzimática , Inmunohistoquímica , Masculino , Conejos , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Distribución TisularRESUMEN
Leptin is a 16-kDa protein recently identified as the obese gene product involved in body weight regulation. Administration of recombinant leptin to ob/ob mice, which have a genetic defect in leptin production, reduces food intake and increases energy expenditure. Leptin is synthesized by fat cells, and in normal humans, plasma concentrations are proportional to adiposity. The physiological actions and the degradation pathways of leptin in humans are unknown. We investigated renal elimination of leptin by comparing plasma leptin concentrations in end-stage renal disease (ESRD) patients with normal controls. Our hypothesis was that if renal filtration is a significant route of elimination, the hormone would accumulate in ESRD patients. Mean plasma levels in 141 ESRD patients (26.8 +/- 5.7 and 38.3 +/- 5.6 micrograms/L for males and females, respectively) were significantly higher (P < 0.001) than mean values obtained in normal controls (11.9 +/- 3.1 and 21.2 +/- 3.0 micrograms/L for males and females, respectively). Leptin concentrations in ESRD patients correlated directly with body mass index (BMI; r = 0.77 for men and 0.78 for women). The rate of increase in leptin concentrations with BMI was significantly greater in ESRD patients (5.5 and 6.6 micrograms/L/U BMI for men and women, respectively) than in normal controls (1.4 and 2.6 micrograms/L/U for men and women, respectively). Pre- and postdialysis leptin levels in hemodialysis patients were similar. Western blot of plasma from ESRD patients with high leptin levels showed bands corresponding to the intact protein (16 kDa) with no lesser or greater molecular mass species observed. Leptin concentrations in patients with ESRD did not correlate with measures of residual renal function (serum creatinine, beta 2-microglobulin, PTH, or GH levels). Similarly, we found no correlation between leptin levels and the number of years patients had been on dialysis or with recent weight changes. We conclude that intact leptin is increased in ESRD patients, but does not appear to cause decreased weight. As leptin levels did not correlate with residual renal function, increased production may account for the high levels observed.