Abstract,32-Microglobulin (jB2M) is a major constituent of amyloid fibrils in hemodialysis-associated amyloidosis (HAA), a complication of long-term hemodialysis. However, the pathological role of 62M in HAA remains to be determined. Recently, we demonstrated that ,62M in the amyloid deposits ofHAA is modified with advanced glycation end products (AGEs) of the Maillard reaction. Since AGEs have been implicated in tissue damage associated with diabetic complications and aging, we investigated the possible involvement of AGE-modified j82M (AGE-Ii2M) in the pathogenesis of HAA. AGE-and normalf32M were purified from urine of long-term hemodialysis patients. AGE-,2M enhanced directed migration (chemotaxis) and random cell migration (chemokinesis) of human monocytes in a dose-dependent manner. However, normal-,62M did not enhance any migratory activity. AGE-lB2M, but not normal-#2M, increased the secretion of TNF-a and IL-1,B from macrophages. Similar effects were also induced by in vitro prepared AGE-,32M (normal-B62M incubated with glucose in vitro for 30 d). When TNF-a or IL-1,6 was added to cultured human synovial cells in an amount equivalent to that secreted from macrophages in the presence of AGE-,02M, a significant increase in the synthesis of collagenase and morphological changes in cell shape were observed. These findings suggested that AGE-182M, a major component in amyloid deposits, participates in the pathogenesis of HAA as foci where monocyte /macrophage accumulate and initiate an inflammatory response that leads to bone/joint destruction. (J. Clin. Invest. 1994. 93:521-528.)

No abstract

No abstract

Aging is associated with decreased skeletal muscle function. Increased levels of advanced glycation end products (AGEs) in skeletal muscle tissue are observed with advancing age and in diabetes. Although serum AGE level is negatively associated with grip strength in elderly people, it is unknown whether this association is present in adult males. To determine the relationship between AGE accumulation in tissue and muscle strength and power among Japanese adult men. Skin autofluorescence (AF) (a noninvasive method for measuring tissue AGEs), grip strength (n = 232), and leg extension power (n = 138) were measured in Japanese adult men [median (interquartile range) age, 46.0 (37.0, 56.0) years]. After adjustment for potential confounders, the adjusted means [95% confidence interval (CI)] for grip strength across the tertiles of skin AF were 44.5 (43.2, 45.9) kg for the lowest tertile, 42.0 (40.6, 43.3) kg for the middle tertile, and 41.7 (40.3, 43.1) kg for the highest tertile (P for trend < 0.01). Moreover, the adjusted geometric means (95% CI) of leg extension power across the tertiles of skin AF were 17.8 (16.6, 19.1) W/kg for the lowest tertile, 17.5 (16.4, 18.7) W/kg for the middle tertile, and 16.0 (14.9, 17.1) W/kg for the highest tertile (P for trend = 0.04). Among Japanese adult men, participants with higher skin AF had lower muscle strength and power, indicating a relationship between AGE accumulation and muscle strength and power. A long-term prospective study is required to clarify the causality.

1. Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor. 2. The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50 μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600 mg oral dose of alectinib in the first period, and a single 600 mg/67 μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects. 3. The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5 L/h, volume of distribution was 475 L and the hepatic extraction ratio was low (0.14). 4. Near-complete recovery of administered radioactivity was achieved within 168 h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively. 5. This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.