Sex and age-related changes in L-arginine metabolism in peripheral blood leukocytes in young caucasians with type 1 diabetes mellitus

339-350We found that hyperactivation of cytoplasmic (anti-inflammatory) and mitochondrial (pro-inflammatory) arginase isoforms in peripheral blood leukocytes (PBL) is more pronounced in women than in male patients with type 1 diabetes mellitus (T1DM) who received insulin for one year, especially in adolescents young adults 15 years old (12.0 - 25.0) compared with children/adolescents 9.3 years old (4.5-11.8). Long-term treatment with insulin up to 14 years (on average 5.3-5.9) reduces the activity of arginase, especially in puberty girls with a tendency to normalize mitochondrial arginase, while in prepubertal boys the activity of both arginase isoforms almost doubles and remains elevated in puberty boys and can be involved in inhibiting nitric oxide synthase (NOS) and decreasing the bioavailability of NO. This is confirmed by the concomitant continuous decrease in the levels of nitric oxide synthase (NOS) products, stable metabolites of NO (nitrite) and L-citrulline in the cytoplasm and mitochondria of PBL in prepubertal girls and boys, in the latter, regardless of age and insulin therapy, while in girls of puberty changes not found, apparently, due to the increased level of sex hormones that promote the expression and activity of NOS, which contribute to the inhibition of arginase. Further studies are needed to understand whether sex and age-related changes found in L-arginine metabolism in PBL can be useful in assessing the stage and progression of T1DM and the effectiveness of therapy

Sex and age-related changes in L-arginine metabolism in peripheral blood leukocytes in young caucasians with type 1 diabetes mellitus

We found that hyperactivation of cytoplasmic (anti-inflammatory) and mitochondrial (pro-inflammatory) arginase isoforms in peripheral blood leukocytes (PBL) is more pronounced in women than in male patients with type 1 diabetes mellitus (T1DM) who received insulin for one year, especially in adolescents young adults 15 years old (12.0 - 25.0) compared with children/adolescents 9.3 years old (4.5-11.8). Long-term treatment with insulin up to 14 years (on average 5.3-5.9) reduces the activity of arginase, especially in puberty girls with a tendency to normalize mitochondrial arginase, while in prepubertal boys the activity of both arginase isoforms almost doubles and remains elevated in puberty boys and can be involved in inhibiting nitric oxide synthase (NOS) and decreasing the bioavailability of NO. This is confirmed by the concomitant continuous decrease in the levels of nitric oxide synthase (NOS) products, stable metabolites of NO (nitrite) and L-citrulline in the cytoplasm and mitochondria of PBL in prepubertal girls and boys, in the latter, regardless of age and insulin therapy, while in girls of puberty changes not found, apparently, due to the increased level of sex hormones that promote the expression and activity of NOS, which contribute to the inhibition of arginase. Further studies are needed to understand whether sex and age-related changes found in L-arginine metabolism in PBL can be useful in assessing the stage and progression of T1DM and the effectiveness of therapy

Reappraising metalloproteinases in rheumatoid arthritis and osteoarthritis: destruction or repair?

Metalloproteinases such as the matrix metalloproteinases (MMPs) and disintegrin-metalloproteinases with thrombospondin motifs (ADAMTSs) have been implicated in the pathological destruction of joint tissues in rheumatoid arthritis and osteoarthritis. These enzymes degrade extracellular matrix macromolecules and modulate factors governing cell behavior. They may also be involved in tissue repair, but become a part of the destructive disease process due to overexpression. Studies investigating the roles of metalloproteinases have thrown light on the failure of the early clinical trials of MMP inhibitors as therapeutic agents in arthritic diseases. It is now clear that a more accurate knowledge of the enzymes in the different cells and their precise roles in the disease process is required for these approaches to be successful. The next generations of metalloproteinase inhibitors should have added specificity, gained from an understanding not only of the catalytic domain structures but the role of extracatalytic motifs in substrate binding, or by the generation of engineered tissue inhibitors of metalloproteinases. Inhibition of the enzymes by modulating gene expression or preventing protein activation could also be considered. Work on the development of effective biomarkers is also essential before an effective evaluation of the new generations of specific inhibitors can be made

The context of child sexual abuse, and points of departure

This chapter sets out the context of child sexual abuse and marks out several points of departure from which the rest of the book proceeds. It first defines the concept of child sexual abuse. Then, it reviews the best literature on the prevalence of child sexual abuse both generally, and in specific contexts, around the world. It reviews other important epidemiological features, referring to evidence about gender, age of onset, the relationship between those who inflict abuse and the child, frequency of offending, factors influencing offending, and theories of offending. It notes the common health and behavioural consequences of child sexual abuse. Significantly, it then reviews literature on the common non-disclosure of child sexual abuse by both girls and boys: a critical feature of this context. The chapter than shows that the gravity of child sexual abuse should be and is recognised in international policy and in most social norms. An appropriately nuanced approach is then urged, in recognition of a spectrum of cases that demand appropriately differentiated responses. Finally, the chapter explains that the book also proceeds on the basis that in any civilised society, individuals, institutions and broader social systems and nation states have a deep ethically-based duty to prevent and identify child sexual abuse, and to respond appropriately to it after it occurs. These ethical duties are consistent with bodies of political and public health theory, the Capabilities Approach, and human dignity informing the book’s entire conceptual approach