Modeling of levothyroxine in newborns and infants with congenital hypothyroidism: challenges and opportunities of a rare disease multi-center study

Journal of Pharmacokinetics and Pharmacodynamics - Modeling of retrospectively collected multi-center data of a rare disease in pediatrics is challenging because laboratory data can stem from...     

Metabolism of succinic acid methyl esters in myocytes

The metabolism of the dimethyl ester of succinic acid (SAD) was examined in myocytes. When expressed in terms of CO(2) output, the oxidation of SAD (10 mM) only represented 30-40% of that of an equimolar concentration of D-glucose. Except for a modest decrease in D-[5-(3)H]glucose utilization, SAD failed to affect the catabolism of exogenous D-glucose. SAD also failed, like D-glucose, to augment O(2) consumption by the myocytes. These findings indicate that SAD is less efficiently metabolized in myocytes than in hepatocytes or pancreatic islets. It is nevertheless argued that the methyl esters of succinic acid could be efficiently used as nutrients by myocytes in situations of ATP depletion.     

Erratum to: A systematic review of community pharmacist therapeutic knowledge of dietary supplements

International Journal of Clinical Pharmacy -     

Stimulus-secretion coupling of arginine-induced insulin release: comparison with lysine-induced insulin secretion

L-Lysine, like-L-arginine, L-ornithine, or L-homoarginine, accumulated in rat pancreatic islets and stimulated 86Rb efflux, 45Ca uptake and efflux, and insulin release in islets exposed to D-glucose (7.0 mM). The effect of L-lysine differed from that of the other cationic amino acids by such features as the absence of a threshold concentration for stimulation of insulin release, a much lesser sensitivity of the secretory response to intracellular acidification, and the stimulation of 86Rb net uptake over 60 min of incubation. This coincided with the fact that even in the absence of another exogenous nutrient, L-lysine was well oxidized, augmented NH4+ production, increased both the ATP content and ATP/ADP ratio, caused a time-related decrease in 86Rb fractional outflow, and provoked either a transient (10 mM L-lysine) or sustained (20 mM L-lysine) stimulation of insulin secretion. It is proposed, therefore, that the functional response of the pancreatic B-cell to L-lysine involves not only a biophysical mechanism similar to that responsible for the insulinotropic action of L-homoarginine, but also a significant, albeit modest, metabolic component, which reflects the capacity of L-lysine to act as a fuel in islet cells.     

Deficient activity of FAD-linked glycerophosphate dehydrogenase in islets of GK rats

Summary In pancreatic islet extracts of rats with hereditary non-insulin-dependent diabetes mellitus (GK rats), the activity of the mitochondrial FAD-linked glycerophosphate dehydrogenase, as measured by either a radioisotopic or colorimetric procedure, only represented 30 to 40% of that found in control rats. This decrease in enzymic activity was not attributable to any sizeable change in either islet DNA content or the relative contribution of insulin-producing beta cells to total islet mass. It contrasted with a normal activity of other mitochondrial dehydrogenases and hexokinase isoenzymes. It coincided, however, with an increased activity of glutamate-pyruvate transaminase, as already observed in adult rats injected with streptozotocin during the neonatal period. The decreased activity of islet FAD-linked glycerophosphate dehydrogenase also contrasted with an increased activity of the same enzyme in the liver of GK, as compared to control rats. In the light of these findings and recent metabolic data collected in intact islets of GK rats, it is proposed that a deficiency of beta-cell FAD-linked glycerophosphate dehydrogenase, the key enzyme of the glycerol phosphate shuttle, may represent a cause of inherited non-insulin-dependent diabetes.     

Patterns of protective associations differ for antibodies to P. falciparum‐infected erythrocytes and merozoites in immunity against malaria in children

Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically‐modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force‐of‐infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens. These findings have implications for vaccine design and serosurveillance of malaria transmission and immunity.     

Workplace Exposures and the Risk of Amyotrophic Lateral Sclerosis

Background

Occupation has been suggested to play a role in amyotrophic lateral sclerosis (ALS) etiology, but detailed information on the importance of specific workplace exposures is lacking.

Objectives

Our aim was to assess the relationship between workplace exposures and the risk of ALS and to evaluate potential interactions between these exposures and smoking.

Methods

We conducted a case–control study in New England between 1993 and 1996, comprising 109 cases and 253 controls who completed a structured interview covering occupations and workplace exposures. Unconditional logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for ALS. Analyses were conducted among the entire study population and after stratification by smoking.

Results

We observed a higher risk of ALS for construction workers excluding supervisors (OR = 2.9; 95% CI, 1.2–7.2) and precision metal workers (OR = 3.5; 95% CI, 1.2–10.5). Self-reported exposures to paint strippers; cutting, cooling, or lubricating oils; antifreeze or coolants; mineral or white spirits; and dry cleaning agents each appeared to be associated with a 60–90% higher risk. Specific chemicals related to a > 50% increase in risk of ALS included aliphatic chlorinated hydrocarbons, glycols, glycol ethers, and hexane. Relative risks associated with these workplace exposures and chemicals were greater among nonsmokers and persisted in mutually adjusted models.

Conclusions

Our data suggest that certain occupations and workplace exposures may be associated with increased risk of ALS. These results need to be confirmed in independent populations.     

Progressive Secondary Neurodegeneration and Microcalcification Co-Occur in Osteopontin-Deficient Mice

In the brain, osteopontin (OPN) may function in a variety of pathological conditions, including neurodegeneration, microcalcification, and inflammation. In this study, we addressed the role of OPN in primary and secondary neurodegeneration, microcalcification, and inflammation after an excitotoxic lesion by examining OPN knock-out (KO) mice. Two, four, and ten weeks after injection of the glutamate analogue ibotenate into the corticostriatal boundary, the brains of 12 mice per survival time and strain were evaluated. OPN was detectable in neuron-shaped cells, in microglia, and at the surface of dense calcium deposits. At this primary lesion site, although the glial reaction was attenuated in OPN-KO mice, lesion size and presence of microcalcification were comparable between OPN-KO and wild-type mice. In contrast, secondary neurodegeneration at the thalamus was more prominent in OPN-KO mice, and this difference increased over time. This was paralleled by a dramatic rise in the regional extent of dense microcalcification. Despite these differences, the numbers of glial cells did not significantly differ between the two strains. This study demonstrates for the first time a genetic model with co-occurrence of neurodegeneration and microcalcification, mediated by the lack of OPN, and suggests a basic involvement of OPN action in these conditions. In the case of secondary retrograde or transneuronal degeneration, OPN may have a protective role as intracellular actor.Co-occurrence of neurodegeneration, parenchymal (micro-) calcification, and inflammation can be observed in a number of brain diseases, including Fahr’s, Alzheimer’s, diffuse Lewy body and Parkinson’s disease, Down’s syndrome, and hypoxia.^1,2,3,4,5,6Osteopontin (OPN) is a glycophosphoprotein with intra- and extracellular functions influencing cell survival, inflammation, microcalcification and the maintenance of tissue integrity after an injury.⁷ The manifold higher abundance of OPN in cerebrospinal fluid than in blood^8,9 argues for a crucial role of this protein in central nervous system (CNS) physiology and pathology. In the developing and adult (rodent) brain, neurons of the olfactory bulb, retina, striatum, and brainstem are OPN-positive.^10,11,12,13 In the aging human brain, OPN is found in pyramidal neurons—more pronounced in Alzheimer’s disease¹⁴—and in dopaminergic neurons of Parkinson’s disease patients.⁸ Transient expression of neuronal OPN has been observed under experimental conditions like cryolesioning¹⁵ and status epilepticus.¹⁶ In addition, OPN is detectable in microglial cells of lesioned CNS tissue after ischemia,¹⁷ excitotoxicity,¹² spinal cord contusion,¹⁸ as well as in multiple sclerosis plaques¹⁹ and in microglial cells of the substantia nigra of Parkinson’s disease patients.⁸ OPN may also be located extracellularly.^8,17 The role of OPN in CNS diseases remains controversial. OPN has been shown to be protective in models of stroke^17,20,21 and spinal cord contusion.¹⁸ However, OPN inhibited axonal regeneration after injury in the optic nerve,²² and the absence of the protein led to a better outcome in models of multiple sclerosis¹⁹ and Parkinson’s disease.⁸OPN inhibits calcification in bone and at ectopic sites.^{23,24,25,26,27} To our knowledge, the role of OPN in brain microcalcification is unknown. In addition, the co-occurrence of neurodegeneration and microcalcification has not yet been investigated with a genetic model. In our present study, we were interested in whether OPN deficiency–induced neurodegeneration is paralleled by microcalcification, and which functions of the protein may be primarily involved.