The M20 IL-1 inhibitor prevents onset of adjuvant arthritis

Cytokines, specifically IL-1 and TNF, have been implicated as important mediators of joint destruction in rheumatoid arthritis (RA). Elevated levels of IL-1 in the joint fluid of patients with RA have been reported, as well as the presence of IL-1 inhibitory activity. We have reported the characterization of an inhibitor derived from a myelomonocytic cell line cloned in our laboratory which is specific for IL-1. This IL-1 inhibitor is protein in nature which specifically inhibits activityin vitro andin vivo. Previous studies showed that the inhibitor reduced acute inflammatory reactions associated with IL-1 (fever, leukocytosis, local foot pad swelling, lymph node enlargement and acute phase reactants). Thus it was of interest to study whether the M20 IL-1 inhibitor could modify adjuvant-induced chronic inflammation in rats, which is often used as a model for human RA. Administration of complete Freund's adjuvant (CFA) into Lewis rats, resulted in a severe adjuvant arthritis (AA) which reached peak severity after 14 days. Daily administration of IL-1 inhibitor, beginning after injection of CFA, abolished the appearance of AA. The parameters investigated were: joint swelling (the increase in diameter of joints), peri-articular erythema, limping of the rats and histological examination. The effect of the M20 IL-1 inhibitor was shown to be dose dependent and the IL-1 inhibitor alone had no adverse effects. These results indicate that the M20 IL-1 inhibitor may have a role in the treatment of AA and may be used to reduce pathological processes in joint inflammation.     

Effect of anaesthesia on insulin-induced hypoglycemia in rabbits

The aim of this study was to determine how anaesthetized rabbits survive much longer than awake rabbits after receiving an insulin overdose. Insulin appeared to act in both groups of rabbits because there was a prompt fall in circulating glucose, free fatty acids, and beta-hydroxybutyrate concentrations. Carbohydrate appeared to be the principal energy source for anaesthetized rabbits because their respiratory quotient approached unity. Although the fall in glycemia was similar in both groups of rabbits, the circulating lactate concentration rose only in the anaesthetized group. This rise in lactate in the initial 60 min after insulin was given could account for most of the fall in glycemia if the source of lactate was the glucose pool. The decline in hepatic glycogen was close to 100 mumol/g liver; this would account for about one-third of the total energy turnover and close to one-half of the measured glucose appearance in these anaesthetized rabbits. As judged from the rate of oxygen consumption, muscle glycogen seemed to supply two-thirds of the fuel to be oxidized in these rabbits. However, only one-third of the lactate released from muscle was first converted to glucose and the remainder was oxidized directly to CO2. Although insulin provided the metabolic setting for a rapid rate of glucose oxidation, this rate appeared to be diminished when the overall rate of oxygen consumption was lower during anaesthesia.     

Percepción de los endocrinólogos clínicos sobre los potenciales efectos perjudiciales del tratamiento supresor de la TSH en el carcinoma diferenciado de tiroides

ObjectiveTo explore the opinion of clinical endocrinologists as to the deleterious effects of thyrotropin (TSH) suppressive therapy in patients with differentiated thyroid carcinoma (DTC).Materials and methodsA self-administered survey was sent by e-mail to a group of endocrinologists with expertise in the treatment of patients with differentiated thyroid carcinoma. The questionnaire consisted of three questions related to: 1) the possible adverse effects of this therapy on different organ systems, 2) the clinical significance of these effects and 3) the usefulness of treatment guidelines for DTC.ResultsA total of 91 endocrinologists responded with a wide divergence of opinions. No question had more than 80% of answers in a particular option. Of the possible side effects of suppressive therapy, a high degree of ignorance to three of them (increased left ventricular mass, reentrant tachycardia and diastolic dysfunction). Most respondents felt that the seven items, dementia and Alzheimer, decreased quality of life, decreased bone mineral density (BMD) in premenopausal women and men, thromboembolic disease, signs and symptoms of hyperthyroidism and increased risk of fractures were not affected by suppressive therapy, while most responded positively to two items (increased heart rate and decreased BMD in postmenopausal women). Eighty percent of the respondents felt that in any case these effects were not clinically significant and 33% considered that treatment guidelines should be reviewed.ConclusionsClinical endocrinologists seem to have a very heterogeneous opinion regarding the potential harmful effects of TSH-suppressive therapy for DTC     

Increase in mast cell number and altered vascular permeability in thirsty rats.

The intravenous administration of 2M NaCl causes marked swelling, vacuolization and degranulation of rat mesenteric mast cells. 72 h of water deprivation (with food available) doubled the number of mast cells in the rat mesentery. Both experimental conditions induced venular labeling. $\text{In vitro}$, up to 300 mM NaCl did not elicit the release of amines from the mast cell. These results led us to infer the existence of some intermediary between hyperosmolarity and mast cell activation. Increased venular permeability, mast cell degranulation and proliferation are common features in inflammatory processes. Sodium salicylate, a non steroidal anti-inflammatory drug, was found to inhibit specifically cell dehydration thirst. A connection between inflammation and the peripheral mechanisms which trigger the central elaboration of the sensation of thirst is suggested.     

Association Mapping and Significance Estimation via the Coalescent

The central questions asked in whole-genome association studies are how to locate associated regions in the genome and how to estimate the significance of these findings. Researchers usually do this by testing each SNP separately for association and then applying a suitable correction for multiple-hypothesis testing. However, SNPs are correlated by the unobserved genealogy of the population, and a more powerful statistical methodology would attempt to take this genealogy into account. Leveraging the genealogy in association studies is challenging, however, because the inference of the genealogy from the genotypes is a computationally intensive task, in particular when recombination is modeled, as in ancestral recombination graphs. Furthermore, if large numbers of genealogies are imputed from the genotypes, the power of the study might decrease if these imputed genealogies create an additional multiple-hypothesis testing burden. Indeed, we show in this paper that several existing methods that aim to address this problem suffer either from low power or from a very high false-positive rate; their performance is generally not better than the standard approach of separate testing of SNPs. We suggest a new genealogy-based approach, CAMP (coalescent-based association mapping), that takes into account the trade-off between the complexity of the genealogy and the power lost due to the additional multiple hypotheses. Our experiments show that CAMP yields a significant increase in power relative to that of previous methods and that it can more accurately locate the associated region.     

Regulation of ethanol metabolism in the rat

The purpose of these experiments was to examine the factors which regulate ethanol metabolism in vivo. Since the major pathway for ethanol removal requires flux through hepatic alcohol dehydrogenase, the activity of this enzyme was measured and found to be 2.9 mumol/(min X g liver). Ethanol disappearance was linear for over 120 min in vivo and the blood ethanol fell 0.1 mM/min; this is equivalent to removing 20 mumol ethanol/min and would require that flux through alcohol dehydrogenase be about 60% of its measured maximum velocity. To test whether ethanol metabolism was limited by the rate of removal of one of the end products (NADH) of alcohol dehydrogenase, fluoropyruvate was infused to reoxidize hepatic NADH and to prevent NADH generation via flux through pyruvate dehydrogenase. There was no change in the rate of ethanol clearance when fluoropyruvate was metabolized. Furthermore, enhancing endogenous hepatic NADH oxidation by increasing the rate of urea synthesis (converting ammonium bicarbonate to urea) did not augment the steady-state rate of ethanol oxidation. Hence, transport of cytoplasmic reducing power from NADH into the mitochondria was not rate limiting for ethanol oxidation. In contrast, ethanol oxidation at the earliest time periods could be augmented by increasing hepatic urea synthesis.     

Reduced concentrations of Z protein in Morris hepatomas. Possible role in abnormal regulation of lipid metabolism.

The cytoplasmic concentration of Z protein (Mr approximately 12,000) was significantly reduced in a series of implanted Morris hepatomas with varying degrees of differentiation. Approximately half of the [14C]palmitoyl-CoA added to cytosol fractions from control or host livers was bound to the Z protein region whereas a much smaller proportion was bound to this region in the cytosol of nine Morris hepatomas studied. The possible implications of these findings are discussed in relation to the abnormal regulation of lipid metabolism in hepatomas.     

Historical Pedigree Reconstruction from Extant Populations Using PArtitioning of RElatives (PREPARE)

Recent technological improvements in the field of genetic data extraction give rise to the possibility of reconstructing the historical pedigrees of entire populations from the genotypes of individuals living today. Current methods are still not practical for real data scenarios as they have limited accuracy and assume unrealistic assumptions of monogamy and synchronized generations. In order to address these issues, we develop a new method for pedigree reconstruction, , which is based on formulations of the pedigree reconstruction problem as variants of graph coloring. The new formulation allows us to consider features that were overlooked by previous methods, resulting in a reconstruction of up to 5 generations back in time, with an order of magnitude improvement of false-negatives rates over the state of the art, while keeping a lower level of false positive rates. We demonstrate the accuracy of compared to previous approaches using simulation studies over a range of population sizes, including inbred and outbred populations, monogamous and polygamous mating patterns, as well as synchronous and asynchronous mating.