Synthesis of Some 2-Alkylated-5-Aminoimidazoles Related to Intermediates in Purine Nucleotide de novo and Thiamine Biosynthesis

Abstract

Routes to 2-alkylated-5-aminoimidazole nucleosides have been investigated in which the 2-substituent has up to 3 carbon atoms and capable of being interconverted into suitable oxy and 0x0 alkyl derivatives for use in enzyme inhibition and biochemical incorporation studies involving both purine nucleotide de novo and thiamine biosynthesis.     

Nitric oxide and cardiovascular effects: new insights in the role of nitric oxide for the management of osteoarthritis

Nitric oxide (NO) is an important mediator in both health and disease. In addition to its effects on vascular tone and platelet function, it plays roles in inflammation and pain perception that may be of relevance in osteoarthritis. Many patients with osteoarthritis take nonsteroidal anti-inflammatory drugs (NSAIDs) long term for pain control. Over recent years concern has been raised about the possible cardiovascular side effects of NSAIDs. The reasons for this possible increased cardiovascular risk with NSAIDs are not yet entirely clear, although changes in blood pressure, renal salt handling and platelet function may contribute. Recently, drugs that chemically link a NSAID with a NO donating moiety (cyclo-oxygenase-inhibiting NO-donating drugs [CINODs]) were developed. NO is an important mediator of endothelial function, acting as a vasodilator and an inhibitor of platelet aggregation, and having anti-inflammatory properties. The potential benefits of CINODs include the combination of effective analgesic and anti-inflammatory actions with NO release, which might counterbalance any adverse cardiovascular effects of NSAIDs. Effects of CINODs in animal studies include inhibition of vasopressor responses, blood pressure reduction in hypertensive rats and inhibition of platelet aggregation. CINODs may also reduce ischemic damage to compromised myocardial tissue. In addition, endothelial dysfunction is a recognized feature of inflammatory arthritides, and therefore a drug that might provide slow release of NO to the vasculature while treating pain is an attractive prospect in these conditions. Further studies of the effects of CINODs in humans are required, but these agents represent a potential exciting advance in the management of osteoarthritis.     

The substitution of arginine for glycine 85 of the alpha 1(I) procollagen chain results in mild osteogenesis imperfecta. The mutation provides direct evidence for three discrete domains of cooperative melting of intact type I collagen.

We report a case of mild osteogenesis imperfecta in a 56-year-old male undergoing aortic valve replacement surgery. The primary defect in this patient was the substitution of arginine for glycine 85 in one of the two chains of alpha 1(I) procollagen. The thermal stability of the type I collagen synthesized by the patient's cultured skin fibroblasts was examined by enzymatic digestion. Digestion of the mutant type I collagen with trypsin and chymotrypsin at increasing temperatures sequentially generated three discrete collagenous fragments, approximately 90, 170, and 230 amino acids shorter than normal type I collagen. This incremental thermal denaturation is indicative of cooperative melting blocks within the type I collagen. This is the first demonstration of such cooperative blocks of melting in intact, essentially normal post-translationally modified type I collagen. This direct evidence for cooperative melting domains of uncut type I collagen suggests that discrete blocks of amino acids function as core sites stabilizing the collagen helix. The location of mutations of the alpha chains of type I collagen relative to these discrete blocks of amino acids may influence the severity of the disease phenotype.     

Radioiodine treatment for graves’ disease: a 10-year Australian cohort study

Background

Radioactive iodine (I¹³¹) is a common definitive treatment for Graves’ Disease. Potential complications include worsening, or new development of Graves’ eye disease and development of a radiation thyroiditis. The purpose of the present study was to assess outcomes of patients treated with I¹³¹ in an Australian tertiary centre over 10 years.

Methods

Data from 101 consecutive patients treated with I¹³¹ for a diagnosis of Graves’ disease between 2005 to 2015 was collected and reviewed retrospectively. Baseline TSH receptor antibody titre, pre-treatment free thyroxine (FT4), technetium scan uptake, initial treatment, duration of treatment, reason for definitive therapy, complications, and time to remission (defined as euthyroidism or hypothyroidism after 12 months) were recorded.

Results

Of the 92 patients with adequate outcome data, 73 (79.3%) patients achieved remission with a single dose of I¹³¹. Of the remaining 19 patients, 12 had a second dose and became hypothyroid. TSH receptor antibody titre at diagnosis was significantly lower in the group that achieved remission with the first dose compared with those who did not (P =?0.0071). There was no difference in technetium uptake, I¹³¹ dose, duration of therapy or pre-treatment free thyroxine (FT4). I¹³¹ was complicated by development of eye disease in 3 patients and 1 (of 11 with pre-existing eye disease) had worsening eye disease. A clinically apparent flare of hyperthyroidism following I¹³¹ was evident in 8 patients (8.6%).

Conclusion

Radioiodine is an effective therapy for Graves’ Disease with few complications. The majority of patients achieve remission with a single dose. Those who require a second dose are more likely to have higher TSH receptor antibody titres at diagnosis. To the best of our knowledge, this is the first study to report outcomes from radioiodine treatment for Graves’ disease in an Australian population.

     

Boldness related to size in the hermit crab Coenobita compressus at undisturbed,but not disturbed beach

There is growing interest in the consequences of consistent individual behavioral differences within and between populations. We compared the magnitude, repeatability, and plasticity of boldness in the terrestrial hermit crab Coenobita compressus in three habitats with different degrees of disturbance in Costa Rica. We encourage researchers to test additional sites to assess the generality of our results. Boldness decreased with crab size at the less disturbed sites, while no relationship between size and boldness was found at the disturbed site. Boldness increased with habitat disturbance, perhaps because bolder crabs succeed in exploiting food around people. Repeatability and plasticity were similar across sites. We hypothesize that population differences may be the result of developmental plasticity when aquatic larvae settle on a beach or selection for boldness at the disturbed site acting on each new generation.     

Prokaryotes in the WAIS Divide ice core reflect source and transport changes between Last Glacial Maximum and the early Holocene

We present the first long‐term, highly resolved prokaryotic cell concentration record obtained from a polar ice core. This record, obtained from the West Antarctic Ice Sheet (WAIS) Divide (WD) ice core, spanned from the Last Glacial Maximum (LGM) to the early Holocene (EH) and showed distinct fluctuations in prokaryotic cell concentration coincident with major climatic states. The time series also revealed a ~1,500‐year periodicity with greater amplitude during the Last Deglaciation (LDG). Higher prokaryotic cell concentration and lower variability occurred during the LGM and EH than during the LDG. A sevenfold decrease in prokaryotic cell concentration coincided with the LGM/LDG transition and the global 19 ka meltwater pulse. Statistical models revealed significant relationships between the prokaryotic cell record and tracers of both marine (sea‐salt sodium [ssNa]) and burning emissions (black carbon [BC]). Collectively, these models, together with visual observations and methanosulfidic acid (MSA) measurements, indicated that the temporal variability in concentration of airborne prokaryotic cells reflected changes in marine/sea‐ice regional environments of the WAIS. Our data revealed that variations in source and transport were the most likely processes producing the significant temporal variations in WD prokaryotic cell concentrations. This record provided strong evidence that airborne prokaryotic cell deposition differed during the LGM, LDG, and EH, and that these changes in cell densities could be explained by different environmental conditions during each of these climatic periods. Our observations provide the first ice‐core time series evidence for a prokaryotic response to long‐term climatic and environmental processes.     

Glucagon Receptor Antagonism Improves Glucose Metabolism and Cardiac Function by Promoting AMP-Mediated Protein Kinase in Diabetic Mice

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