Gastric Carcinogenesis and Potential Role of the Transient Receptor Potential Vanilloid 1 (TRPV1) Receptor: An Observational Histopathological Study.

The potential role of the transient receptor potential Vanilloid 1 (TRPV1) non-selective cation channel in gastric carcinogenesis remains unclear. The main objective of this study was to evaluate TRPV1 expression in gastric cancer (GC) and precursor lesions compared with controls. Patient inclusion was based on a retrospective review of pathology records. Patients were subdivided into five groups: Helicobacter pylori (H. pylori)-associated gastritis with gastric intestinal metaplasia (GIM) (n = 12), chronic atrophic gastritis (CAG) with GIM (n = 13), H. pylori-associated gastritis without GIM (n = 19), GC (n = 6) and controls (n = 5). TRPV1 expression was determined with immunohistochemistry and was significantly higher in patients with H. pylori-associated gastritis compared with controls (p = 0.002). TRPV1 expression was even higher in the presence of GIM compared with patients without GIM and controls (p < 0.001). There was a complete loss of TRPV1 expression in patients with GC. TRPV1 expression seems to contribute to gastric-mucosal inflammation and precursors of GC, which significantly increases in cancer precursor lesions but is completely lost in GC. These findings suggest TRPV1 expression to be a potential marker for precancerous conditions and a target for individualized treatment. Longitudinal studies are necessary to further address the role of TRPV1 in gastric carcinogenesis.

Cobalamin cbiP mutant shows decreased tolerance to low temperature and copper stress in Listeria monocytogenes.

BACKGROUND: Listeria monocytogenes is a foodborne pathogen that causes listeriosis in humans. This pathogen activates multiple regulatory mechanisms in response to stress, and cobalamin biosynthesis might have a potential role in bacterial protection. Low temperature is a strategy used in the food industry to control bacteria proliferation; however, L. monocytogenes can grow in cold temperatures and overcome different stress conditions. In this study we selected L. monocytogenes List2-2, a strain with high tolerance to the combination of low temperature + copper, to understand whether the cobalamin biosynthesis pathway is part of the tolerance mechanism to this stress condition. For this, we characterized the transcription level of three cobalamin biosynthesis-related genes (cbiP, cbiB, and cysG) and the eutV gene, a transcriptional regulator encoding gene involved in ethanolamine metabolism, in L. monocytogenes strain List2-2 growing simultaneously under two environmental stressors: low temperature (8 °C) + copper (0.5 mM of CuSO4 × 5H2O). In addition, the gene cbiP, which encodes an essential cobyric acid synthase required in the cobalamin pathway, was deleted by homologous recombination to evaluate the impact of this gene in L. monocytogenes tolerance to a low temperature (8 °C) + different copper concentrations. RESULTS: By analyzing the KEGG pathway database, twenty-two genes were involved in the cobalamin biosynthesis pathway in L. monocytogenes List2-2. The expression of genes cbiP, cbiB, and cysG, and eutV increased 6 h after the exposure to low temperature + copper. The cobalamin cbiP mutant strain List2-2ΔcbiP showed less tolerance to low temperature + copper (3 mM) than the wild-type L. monocytogenes List2-2. The addition of cyanocobalamin (5 nM) to the medium reverted the phenotype observed in List2-2ΔcbiP. CONCLUSION: These results indicate that cobalamin biosynthesis is necessary for L. monocytogenes growth under stress and that the cbiP gene may play a role in the survival and growth of L. monocytogenes List2-2 at low temperature + copper.

The effects of weight cycling on lifespan in male C57BL/6J mice.

OBJECTIVE: With the increasing rates of obesity, many people diet in an attempt to lose weight. As weight loss is seldom maintained in a single effort, weight cycling is a common occurrence. Unfortunately, reports from clinical studies that have attempted to determine the effect of weight cycling on mortality are in disagreement, and to date, no controlled animal study has been performed to assess the impact of weight cycling on longevity. Therefore, our objective was to determine whether weight cycling altered lifespan in mice that experienced repeated weight gain and weight loss throughout their lives. METHODS: Male C57BL/6J mice were placed on one of three lifelong diets: a low-fat (LF) diet, a high-fat (HF) diet or a cycled diet in which the mice alternated between 4 weeks on the LF diet and 4 weeks on the HF diet. Body weight, body composition, several blood parameters and lifespan were assessed. RESULTS: Cycling between the HF and LF diet resulted in large fluctuations in body weight and fat mass. These gains and losses corresponded to significant increases and decreases, respectively, in leptin, resistin, GIP, IGF-1, glucose, insulin and glucose tolerance. Surprisingly, weight cycled mice had no significant difference in lifespan (801±45 days) as compared to LF-fed controls (828±74 days), despite being overweight and eating a HF diet for half of their lives. In contrast, the HF-fed group experienced a significant decrease in lifespan (544±73 days) compared with LF-fed controls and cycled mice. CONCLUSIONS: This is the first controlled mouse study to demonstrate the effect of lifelong weight cycling on longevity. The act of repeatedly gaining and losing weight, in itself, did not decrease lifespan and was more beneficial than remaining obese.

Oral hygiene and gingival health in Flemish pre-school children.

OBJECTIVES: The study aimed to describe oral hygiene habits, oral hygiene status and gingival health in Flemish pre-school children and to explore factors associated with these clinical oral health variables. METHODS: Cross-sectional data from 1,071 3-year-old and 1,119 5-year-old children from four geographical areas in Flanders (Belgium) were analysed Buccal plaque accumulation and gingival health were assessed on six index teeth. Data on oral hygiene and dietary habits, oral health behaviour and socio-demographic variables were obtained through questionnaires. RESULTS: 34% of 3-year-olds and 25% of 5-year-olds started brushing before the age of one, 17% of 3-year-olds and 23% of 5-year-olds brushed twice a day. Roughly, 30% of 3-year-olds and 37% of 5-year-olds presented with visible plaque accumulation. In both age groups, only 3 to 4% of children presented with signs of gingival inflammation. Multiple logistic regression models revealed that in both age groups children whose mothers had a college or university degree, had a smaller chance of presenting with visible plaque than children whose mothers had a lower educational level. With gingival health as dependent variable, multiple logistic regression analysis confirmed the major association between bacterial plaque accumulation and the presence of gingivitis. In the oldest age group, children's former exposure to passive smoking was also significantly associated with gingivitis. CONCLUSION: Parents should be motivated to start brushing at an early age and brush thoroughly in order to maintain good oral health in their offspring. Special attention should go to children raised by mothers with a lower educational level.

Correcting for misclassification for a monotone disease process with an application in dental research.

Motivated by a longitudinal oral health study, we evaluate the performance of binary Markov models in which the response variable is subject to an unconstrained misclassification process and follows a monotone or progressive behavior. Theoretical and empirical arguments show that the simple version of the model can be used to estimate the prevalence, incidences, and misclassification parameters without the need of external information and that the incidence estimators associated with the model outperformed approaches previously proposed in the literature. We propose an extension of the simple version of the binary Markov model to describe the relationship between the covariates and the prevalence and incidence allowing for different classifiers. We implemented a Bayesian version of the extended model and show that, under the settings of our motivating example, the parameters can be estimated without any external information. Finally, the analyses of the motivating problem are presented.

[Kinematic gait pattern with silicone ankle-foot ortesis in patients with drop foot]. / Patrón cinemático de la marcha con ortesis de tobillo-pie de silicón en pacientes con pie caído.

INTRODUCTION: The Drop foot is a condition that is usually handled with short orthosis, usually made of polypropylene. It has also been described as being treated with silicon orthosis, little studied but which seem to improve the kinematic pattern of gait and, given its comfort, be more accepted by patients. Our study describes the kinematic characteristics of gait and patient satisfaction when using a silicon foot ankle orthosis, and compares this pattern to the non-use of the orthosis, in patients with a drop foot. MATERIAL AND METHODS: Pseudo-experimental descriptive study in patients with dropped feet from 2010 to 2012, in which the kinematic variables of the gait pattern were evaluated from gait laboratories and in addition to the satisfaction of subjects with silicon orthosis and non-use of them. RESULTS: Five patients with a drop foot were the subject of the study. Gait analysis of patients using the orthosis found an improvement in ankle position at initial contact, average walking speed and step length, as well as increased cadence. However, in terms of comfort compared to the non-use of the orthosis, the result was meager. CONCLUSIONS: Silicon foot ankle orthosis improve the position of the ankle in the initial contact, as well as the temporo-spatial parameters of the gait.

INTRODUCCIÓN: El pie caído es una condición que suele manejarse con ortesis cortas, normalmente fabricadas en polipropileno. Se ha descrito también su tratamiento con ortesis de silicón, poco estudiadas pero que parecen mejorar el patrón cinemático de la marcha y, dada su comodidad, ser más aceptadas por los pacientes. Nuestro estudio describe cuáles son las características cinemáticas de la marcha y la satisfacción referida por los pacientes al usar una ortesis tobillo pie de silicón y compara dicho patrón con el no uso de la ortesis en casos con pie caído. MATERIAL Y MÉTODOS: Estudio seudoexperimental descriptivo en pacientes con pie caído desde el año 2010 al 2012, en el que se evaluaron las variables cinemáticas del patrón de marcha a partir de laboratorios de marcha y además de la satisfacción de los sujetos con las ortesis de silicón y con el no uso de las mismas. RESULTADOS: Cinco casos con pie caído fueron objeto del estudio. El análisis de marcha de los pacientes que usaron la ortesis constató una mejora de la posición del tobillo en el contacto inicial, en la velocidad promedio de marcha y en la longitud del paso, así como un aumento de la cadencia. Sin embargo, en términos de comodidad en comparación con el no uso de la ortesis, el resultado fue exiguo. CONCLUSIONES: Las ortesis tobillo pie de silicón mejoran la posición del tobillo en el contacto inicial, así como los parámetros temporoespaciales de la marcha.

Contrasting evolutionary responses in two co-distributed species of Galaxias (Pisces, Galaxiidae) in a river from the glaciated range in Southern Chile.

Life-history traits are among the most important factors affecting population abundance and genetic diversity of species. Here, we analysed the genetic patterns of two Galaxias species with different life-history traits to investigate how these biological differences impacted their evolution in the Valdivia River basin, Southern Chile. We analysed mitochondrial DNA (mtDNA) sequences from 225 individuals of Galaxias maculatus and 136 of G. platei to compare patterns of genetic diversity, structure and demographic growth across the basin. Galaxias maculatus presented higher genetic diversity and higher genetic structure than G. platei. Demographic analyses showed G. maculatus kept a higher population size over time, with a signal of demographic expansion in the last 250 kyr. Whereas Galaxias platei, exhibited lower, but constant population size over time. Furthermore, haplotype networks revealed higher lineage diversity in G. maculatus with a tendency to occupy different areas of the basin. Coalescent simulations ruled out that genetic differences between species could be explained by stochastic processes (genetic drift), suggesting species-specific biological differences as responsible for the observed genetic differences. We discuss how differences in life-history traits and past glaciations interact to shape the evolutionary history of the two Galaxias species.

Population pharmacokinetics of albendazole in patients with neurocysticercosis.

OBJECTIVES: To determine a population pharmacokinetic model of the antihelmintic drug, albendazole, and identify the factors influencing the pharmacokinetic parameters in patients with neurocysticercosis. METHODS: A prospective study was performed in 90 patients receiving 30 mg/kg/day of albendazole for 8 days. Blood samples were collected at steady state. Plasma concentrations of albendazole sulfoxide, the main active metabolite of albendazole, were determined by HPLC. The population pharmacokinetics analysis was performed using non-linear mixed-effect modeling (NONMEM). A one-compartment model with first order absorption and elimination was used. RESULTS: Body weight was included empirically on CL/F and V/F using an allometric relationship. Although none of the investigated covariates had a significant influence on the pharmacokinetic parameters of albendazole, the final model identified two subpopulations on the bioavailability parameter. One subpopulation comprising of 27% of the total population had a bioavailability of 28%, with the remaining subpopulation defined to have complete bioavailability. The CL/F and V/F for a standard 70 kg individual was determined to be 51.6 l/h and 4560 l, respectively. Interindividual variability in CL/F was 32%; the residual unexplained variability was 32%. CONCLUSIONS: The considerable variability reported in albendazole pharmacokinetics and plasma concentrations is likely due to issues related to bioavailability. With one-fourth of the population absorbing as little as 30% of the drug relative to others, low drug exposures might be responsible for treatment failures. Therapeutic drug monitoring may be warranted to optimize the eradication of the infecting parasite.

Abbreviated AUC monitoring of cyclosporine more adequately identified patients at risk for acute rejection during induction of immunosuppressive therapy after kidney transplantation than recommended C2 concentration values.

OBJECTIVE: Monitoring of cyclosporine (CsA) is critical during the induction of immunosuppressive therapy. Although most centers have incorporated C2 levels, our unit still uses an abbreviated AUC model which includes concentrations at C1, C2, and C6 post-dose (AUC(1-6)). The objective of this study was to compare both strategies of CsA monitoring during the first 30 days after kidney transplantation. PATIENTS AND METHODS: The study included 89 recipients induced with CsA microemulsion and steroids. AUC(1-6) profiles were performed around days 3, 10, and 30 after transplantation with a target of 5500 to 6000 ng*h/mL considered therapeutic. For comparison purposes, a value of C2 >/= 1500 ng/mL was also considered therapeutic. Mean C2 and AUC(1-6) values were low dated with biopsy-proven acute rejection episodes (BPAR) during the study period. RESULTS: Twenty patients received living donor kidneys and overall there were 46 females. During this period, 253 AUC(1-6) were performed including 44 (17.4%) below the therapeutic range. When the analysis included only C2, 171 (67.6%) were below the therapeutic target (P < .001). Five patients experience BPAR and only AUC(1-6) at day 10 discriminated rejectors versus nonrejectors (5645 +/- 1390 and 8221 +/- 2502, respectively; P = .008). C2 was not significantly different at any time in either group. CONCLUSIONS: In this study, abbreviated AUC monitoring more adequately identified patients at risk for acute rejection than C2. Recommended C2 concentration levels need to be redefined in our patients.

Giant nonlinear damping in nanoscale ferromagnets.

Magnetic damping is a key metric for emerging technologies based on magnetic nanoparticles, such as spin torque memory and high-resolution biomagnetic imaging. Despite its importance, understanding of magnetic dissipation in nanoscale ferromagnets remains elusive, and the damping is often treated as a phenomenological constant. Here, we report the discovery of a giant frequency-dependent nonlinear damping that strongly alters the response of a nanoscale ferromagnet to spin torque and microwave magnetic field. This damping mechanism originates from three-magnon scattering that is strongly enhanced by geometric confinement of magnons in the nanomagnet. We show that the giant nonlinear damping can invert the effect of spin torque on a nanomagnet, leading to an unexpected current-induced enhancement of damping by an antidamping torque. Our work advances the understanding of magnetic dynamics in nanoscale ferromagnets and spin torque devices.

Increased Glucosinolate Production in Brassica oleracea var. italica Cell Cultures Due to Coronatine Activated Genes Involved in Glucosinolate Biosynthesis.

In this work, the effect of different elicitors and culture conditions on the production of glucosinolates in broccoli cell cultures was studied. The results showed that 0.5 µM coronatine was the best elicitor for increasing glucosinolate production (205-fold increase over untreated cells after 72 h of treatment). Furthermore, the expression levels of some genes related to the biosynthetic pathway of glucosinolates as well as three Myb transcription factors also have been studied. The highest glucosinolate levels found in coronatine-treated cells were closely correlated with the highest gene expression levels of Cyp79b2, Cyp83b1, St5a, Myb51, and Myb122 after 6 h of treatment. The data shown in this study provide new insight into the key metabolic steps involved in the biosynthesis of glucosinolates, which will be of use for future applications of metabolic engineering techniques in broccoli.

Solitary focus in the liver in a thyroid cancer patient after a whole body scan with 131 iodine.

A 51-year-old woman diagnosed with follicular variant of papillary thyroid carcinoma underwent a total thyroidectomy followed four weeks later by an ablative dose of 3.7 GBq of 131I. A whole body scan 5 days after ablation showed an intense uptake within the thyroid bed and a focal uptake located in the right lung base or liver dome. Computed tomography examination revealed a hypodense hepatic node in segment VII resembling a liver metastasis. Histological examination after ultrasound-guided fine-needle aspiration characterized the lesion as a liver abscess. The abscess regressed after antibiotic therapy. Liver metastases from papillary thyroid carcinoma are uncommon. On the other hand, false positive findings of 131I whole body scans have been described. A focal hepatic uptake might represent a metastasis (rare in papillary carcinomas) or be related to other causes (cysts, inflammation or infection, non-thyroidal neoplasms, etc.).

Spin caloritronic nano-oscillator.

Energy loss due to ohmic heating is a major bottleneck limiting down-scaling and speed of nano-electronic devices, and harvesting ohmic heat for signal processing is a major challenge in modern electronics. Here, we demonstrate that thermal gradients arising from ohmic heating can be utilized for excitation of coherent auto-oscillations of magnetization and for generation of tunable microwave signals. The heat-driven dynamics is observed in Y3Fe5O12/Pt bilayer nanowires where ohmic heating of the Pt layer results in injection of pure spin current into the Y3Fe5O12 layer. This leads to excitation of auto-oscillations of the Y3Fe5O12 magnetization and generation of coherent microwave radiation. Our work paves the way towards spin caloritronic devices for microwave and magnonic applications.Harvesting ohmic heat for signal processing is one of major challenges in modern electronics and spin caloritronics, but not yet well accomplished. Here the authors demonstrate a spin torque oscillator device driven by pure spin current arising from thermal gradient across an Y3Fe5O12/Pt interface.

Cobalamin cbiP mutant shows decreased tolerance to low temperature and copper stress in Listeria monocytogenes

BACKGROUND: Listeria monocytogenes is a foodborne pathogen that causes listeriosis in humans. This pathogen activates multiple regulatory mechanisms in response to stress, and cobalamin biosynthesis might have a potential role in bacterial protection. Low temperature is a strategy used in the food industry to control bacteria proliferation; however, L. monocytogenes can grow in cold temperatures and overcome different stress conditions. In this study we selected L. monocytogenes List2-2, a strain with high tolerance to the combination of low temperature +copper, to understand whether the cobalamin biosynthesis pathway is part of the tolerance mechanism to this stress condition. For this, we characterized the transcription level of three cobalamin biosynthesis related genes ( cbiP , cbiB, and cysG ) and the eutV gene, a transcriptional regulator encoding gene involved in ethanolamine metabolism, in L. monocytogenes strain List2-2 growing simultaneously under two environmental stressors: low temperature (8 °C) +copper (0.5 mM of CuSO4 ×5H2O). In addition, the gene cbiP , which encodes an essential cobyric acid synthase required in the cobalamin pathway, was deleted by homologous recombination to evaluate the impact of this gene in L. monocytogenes tolerance to a low temperature (8 °C) +different copper concentrations. RESULTS: By analyzing the KEGG pathway database, twenty-two genes were involved in the cobalamin biosynthesis pathway in L. monocytogenes List2-2. The expression of genes cbiP , cbiB, and cysG, and eutV increased 6 h after the exposure to low temperature +copper. The cobalamin cbiP mutant strain List2-2Δ cbiP showed less tolerance to low temperature +copper (3 mM) than the wild type L. monocytogenes List2-2. The addition of cyanocobalamin (5 nM) to the medium reverted the phenotype observed in List2-2Δ cbiP . CONCLUSION: These results indicate that cobalamin biosynthesis is necessary for L. monocytogenes growth under stress and that the cbiP gene may play a role in the survival and growth of L. monocytogenes List2-2 at low temperature +copper.

Influence of the kidney histology at the time of donation on long term kidney function in living kidney donors.

Living donation is the best choice for kidney transplantation, obtaining long-lasting good results for the recipient. Some concern still remains regarding the donor's long-term health. Kidney biopsy was routinely performed in our donor population at the time of donation many years ago. We found the existence of morphological kidney disease in those samples, in spite of normal clinical evaluations before donation. We attempted to correlate those abnormalities with long-term clinical outcomes. Donors were at least 10 years after surgery. A medical interview, including the SF-36 Health Survey, laboratory evaluation, and ambulatory blood pressure monitoring was performed on 27 donors meeting the inclusion criteria. Two donors had died after donation from unrelated causes with no known nephropathy. Histological analysis showed abnormalities in 16 of 29 donors. We found an increased prevalence of hypertension compared to the general population. Interestingly, there was no proteinuria in the donor population, and none developed clinical nephropathy. All subjects felt emotionally rewarded with donation, stating that their lives had no limitations. Our results suggest that kidney biopsy is neither necessary nor useful prior to donation because, although many donors had morphological kidney disease, none developed clinical nephropathy in the long term.

Evaluación del efecto acaricida de Momordica charantia, Megaskepasma erythrochlamys y Gliricidia sepium sobre Rhipicephalus microplus / Acaricidal effect of Momordica charantia, Megaskepasma erythrochlamys and Gliricidia sepiumon the Rhipicephalus microplus

RESUMEN Objetivo. Se evaluó la actividad acaricida de Momordica charantia (Mc), Megaskepasma erythrochlamys (Me) y Gliricidia sepium (Gs) sobre Rhipicephalus microplus (Rm). Materiales y métodos. Se realizó la marcha fitoquímica preliminar de hojas del extracto metanólico de Mc (EMc), del extracto etanólico de Me (EMe) y del extracto acetónico de Gs (EGs) a través de la técnica de colorimetría y cromatografía en capa delgada (CCD). La actividad acaricida se realizó a través de pruebas in-vitro utilizando la prueba de inmersión de larvas (LIT) y la prueba de inmersión de adultos (AIT). Para las pruebas in-situ se usaron bovinos en pastoreo infestados naturalmente con garrapatas, utilizando las CL50 obtenidas en las pruebas in-vitro AIT; posteriormente las teleoginas se llevaron a incubación para evaluar su capacidad reproductiva. Resultados. Se determinó la presencia de varios grupos de metabolitos secundarios de interés acaricida. Se demostró el efecto acaricida de los extractos de las plantas sobre teleoginas; aunque sólo EGs mostró actividad larvicida. Los extractos a 160 mg/mL afectaron el ciclo de vida de Rm inhibiendo la ovoposición en un 46.9%, 66.1% y 84.03% (p<0.05) para EGs, EMc y EMe, respectivamente. Por otro lado, en las pruebas in situ se observó diferencia significativa (p<0.05) entre el tratamiento de EMc y EMe respecto a los grupos controles. Conclusiones. Los resultados obtenidos son prometedores para fortalecer la posibilidad de vinculación de los extractos de estas plantas dentro de planes integrados de control de garrapatas en sistemas de producción de bovinos.

ABSTRACT Objective. The acaricidal activity of Momordica charantia (Mc), Megaskepasma erythrochlamys (Me) and Gliricidia sepium (Gs) on Rhipicephalus microplus (Rm) was evaluated. Materials and methods. Preliminary phytochemical analysis of leaves of the methanolic extract of Mc (EMc), the ethanolic extract of Me (EMe) and the acetone extract of Gs (EGs) were carried out through the technique of colorimetry and thin layer chromatography (CCD). The acaricidal activity was performed through in-vitro tests using the larval immersion test (LIT) and the adult immersion test (AIT). For in-situ tests, grazing cattle naturally infested with ticks were used, using the LC50 obtained from the in-vitro AIT tests; later the teleogines were taken to incubation to evaluate their reproductive capacity. Results. The presence of several groups of secondary metabolites of acaricidal interest was determined. The acaricidal effect of the extracts of the plants on teleogines was demonstrated; although only EGs showed larvicidal activity. Extracts at 160 mg/mL affected the life cycle of Rm by inhibiting ovoposition in 46.9%, 66.1% and 84.03% (p<0.05) for EGs, EMc and EMe, respectively. On the other hand, the in-situ tests showed a significant difference (p<0.05) between the treatment of EMc and EMe with respect to the control groups. Conclusions. The results obtained are promising to strengthen the possibility of linking the extracts of these plants into integrated plans for the control of ticks in cattle systems.

Comparison of two parathyroid hormone assays for the rat: the new immunoradiometric and the older competitive binding assay.

A competitive binding assay for parathyroid hormone (PTH INS) has been used since 1986 to measure PTH in rats. During the past year an immunoradiometric assay for the measurement of PTH (PTH IRMA) in the rat was developed. The purpose of the present study was to compare results obtained with the PTH INS and IRMA and to provide a framework for comparison for investigators who have used the PTH INS in previous studies. A total of 99 rats were studied; 27 rats had normal renal function, and 72 rats had surgically induced renal failure. In the azotemic rats, the magnitude of hyperparathyroidism was varied by changing the calcium and phosphorus composition of the diet. The correlation between the two PTH assays in the 99 rats was r = 0.98, p < 0.001. For the 27 rats with normal renal function, the correlation even within the narrow range of normal PTH values was significant, r = 0.71, p < 0.001. In the 72 azotemic rats, in which the highest INS PTH value was approximately 17 times normal, the correlation between the two PTH assays was r = 0.98, p < 0.001. The PTH IRMA provides distinct advantages, such as extended standard range, shortened incubation time, increased sensitivity, and technical simplicity, but our results indicate that the PTH INS provided an accurate measurement of PTH. Furthermore, our results should provide investigators who have used the PTH INS in previous studies with a framework for comparison with studies in which the PTH IRMA was used.

Effect of a low calcium dialysate on parathyroid hormone secretion in diabetic patients on maintenance hemodialysis.

Diabetic patients on maintenance dialysis often are characterized by a relative parathyroid hormone (PTH) deficiency and a form of renal osteodystrophy with low bone turnover known as adynamic bone. The goal of the present study was to determine whether a reduction in the dialysate calcium concentration would increase the predialysis (basal) PTH and maximal PTH level. Thirty-three diabetic maintenance hemodialysis patients with basal PTH values less than 300 pg/ml were randomized to be dialyzed with either a regular (3.0 mEq/liter or 3.5 mEq/liter, group I) or low (2.25 mEq/liter or 2.5 mEq/liter, group II) calcium dialysate for 1 year. At baseline and after 6 months and 12 months of study, low (1 mEq/liter) and high (4 mEq/liter) calcium dialysis studies were performed to determine parathyroid function. At baseline, basal (I, 126+/-20 vs. II, 108+/-19 pg/ml) and maximal (I, 269 pg/ml+/-40 pg/ml vs. II, 342 pg/ml+/-65 pg/ml) PTH levels were not different. By 6 months, basal (I, 98+/-18 vs. II, 200+/-34 pg/ml, p = 0.02) and maximal (I, 276 pg/ml+/-37 pg/ml vs. II, 529 pg/ml+/-115 pg/ml; p = 0.05) PTH levels were greater in group II. Repeated measures analysis of variance (ANOVA) of the 20 patients who completed the entire 12-month study showed that only in group II patients were basal PTH (p = 0.01), maximal PTH (p = 0.01), and the basal/maximal PTH ratio (p = 0.03) different; by post hoc test, each was greater (p < 0.05) at 6 months and 12 months than at baseline. When study values at 0, 6, and 12 months in all patients were combined, an inverse correlation was present between basal calcium and both the basal/maximal PTH ratio (r = -0.59; p < 0.001) and the basal PTH (r = -0.60; p < 0.001). In conclusion, in diabetic hemodialysis patients with a relative PTH deficiency (1) the use of a low calcium dialysate increases basal and maximal PTH levels, (2) the increased secretory capacity (maximal PTH) during treatment with a low calcium dialysate suggests the possibility of enhanced parathyroid gland growth, and (3) the inverse correlation between basal calcium and both the basal/maximal PTH ratio and the basal PTH suggests that the steady-state PTH level is largely determined by the prevailing serum calcium concentration.

Urinary cyclic adenosine 3',5'-monophosphate response in McCune-Albright syndrome: clinical evidence for altered renal adenylate cyclase activity.

The recent finding of an activating mutation in the Gs alpha protein, the protein that couples receptors to stimulation of adenylate cyclase, from endocrine and nonendocrine tissues of patients with McCune-Albright syndrome (MAS) suggests that alterations in adenylate cyclase activity may account for the clinical abnormalities in these patients. Many patients with MAS have hypophosphatemia. This may result from the presence of the activating Gs alpha mutation in proximal renal tubules or the elaboration of a phosphaturic factor from fibrous dysplasia. We, therefore, sought to characterize renal cAMP generation and phosphate handling in MAS patients. Intravenous infusion of PTH is a classic clinical test used to evaluate hormonal responsiveness of renal proximal tubule adenylate cyclase and examine PTH-dependent phosphate clearance. We performed PTH infusion in 6 MAS patients, 10 normal subjects, and 6 patients with pseudohypoparathyroidism (PHP). The basal urinary cAMP (UcAMP) level in the MAS group [5.5 +/- 2.6 nmol/dL glomerular filtration (GF)] was elevated (P < 0.05) compared to those in both normal subjects (3.2 +/- 1.2 nmol/dL GF) and patients with PHP (1.9 +/- 0.6 nmol/dL GF). However, PTH-stimulated peak UcAMP (15.0 +/- 7.0 nmol/dL GF) and the peak/basal UcAMP ratio (3.1 +/- 1.7) in MAS were significantly lower than the respective values in normal subjects (30.8 +/- 16.9 nmol/dL GF and 9.3 +/- 2.9; P < 0.05 for both) and were statistically similar to the blunted levels in PHP (respectively, 3.1 +/- 1.5 nmol/dL GF and 2.0 +/- 1.7). By contrast, the PTH-induced phosphaturic response in MAS patients was similar to that in the normal subjects. Our study provides clinical evidence that MAS patients have altered renal adenylate cyclase activity, manifested by an elevated basal UcAMP, but a blunted UcAMP response to PTH stimulation. These observations are presumably due to a mutation in the Gs alpha protein in the renal tubules. Despite the blunted UcAMP excretion, the phosphaturic response to PTH in MAS patients is intact.

Dynamics of skeletal resistance to parathyroid hormone in the rat: effect of renal failure and dietary phosphorus.

UNLABELLED: Secondary hyperparathyroidism develops in renal failure and is generally ascribed to factors directly affecting parathyroid hormone (PTH) production and/or secretion. These include hypocalcemia, phosphorus retention, and a calcitriol deficiency. However, not often emphasized is that skeletal resistance to PTH is an important factor. Our study evaluated: (1) the relative effects of uremia and dietary phosphorus on the skeletal resistance to PTH; and (2) how, during a PTH infusion, the dynamics of skeletal resistance to PTH were affected by renal failure. Renal failure was surgically induced and, based on serum creatinine, rats were divided into normal, moderate renal failure, and advanced renal failure. In each group, three diets with the same calcium (0.6%) but different phosphorus contents were used: high (1.2%, HPD); moderate (0.6%, MPD); and low (0.2%, LPD) phosphorus. The study diet was given for 14-16 days followed by a 48 h infusion of rat PTH(1-34) (0.11 microg/100 g per hour), a dose five times greater than the normal replacement dose. During the PTH infusion, rats received a calcium-free, low phosphorus (0.2%) diet. In both moderate and advanced renal failure, the PTH level was greatest in the HPD group (p < 0.05) and, despite normal serum calcium values, PTH was greater in the MPD than the LPD group (p < 0.05). Despite phosphorus restriction and normal serum calcium and calcitriol levels in the azotemic LPD groups, the PTH level was greater (p < 0.05) in the LPD group with advanced rather than moderate renal failure. During PTH infusion, the increase in serum calcium was progressively less (p < 0.05) in all groups as renal function declined. Furthermore, despite normal and similar serum phosphorus values at the end of PTH infusion, the serum calcium concentration was less (p < 0.05) in the HPD group than the other two groups and similar in the LPD and MPD groups. IN CONCLUSION: (1) uremia and phosphorus each had separate and major effects on skeletal resistance to PTH; (2) skeletal resistance to PTH was an important cause of secondary hyperparathyroidism, even in moderate renal failure; (3) during PTH infusion, the dynamics of skeletal resistance to PTH changed because all groups received a low phosphorus diet, and the adaptation to a new steady state was delayed by the degree of renal failure and the previous dietary phosphorus burden; and (4) normal serum phosphorus may not be indicative of body phosphorus stores during states of disequilibrium.