Circulating Interleukin-6 Is Associated with Skeletal Muscle Strength, Quality, and Functional Adaptation with Exercise Training in Mobility-Limited Older Adults.

BACKGROUND: Human aging is characterized by a chronic, low-grade inflammation suspected to contribute to reductions in skeletal muscle size, strength, and function. Inflammatory cytokines, such as interleukin-6 (IL-6), may play a role in the reduced skeletal muscle adaptive response seen in older individuals. OBJECTIVES: To investigate relationships between circulating IL-6, skeletal muscle health and exercise adaptation in mobility-limited older adults. DESIGN: Randomized controlled trial. SETTING: Exercise laboratory on the Health Sciences campus of an urban university. PARTICIPANTS: 99 mobility-limited (Short Physical Performance Battery (SPPB) ≤9) older adults. INTERVENTION: 6-month structured physical activity with or without a protein and vitamin D nutritional supplement. MEASUREMENTS: Circulating IL-6, skeletal muscle size, composition (percent normal density muscle tissue), strength, power, and specific force (strength/CSA) as well as physical function (gait speed, stair climb time, SPPB-score) were measured pre- and post-intervention. RESULTS: At baseline, Spearman's correlations demonstrated an inverse relationship (P<0.05) between circulating IL-6 and thigh muscle composition (r = -0.201), strength (r = -0.311), power (r = -0.210), and specific force (r = -0.248), and positive association between IL-6 and stair climb time (r = 0.256; P<0.05). Although the training program did not affect circulating IL-6 levels (P=0.69), reductions in IL-6 were associated with gait speed improvements (r = -0.487; P<0.05) in "higher" IL-6 individuals (>1.36 pg/ml). Moreover, baseline IL-6 was inversely associated (P<0.05) with gains in appendicular lean mass and improvements in SPPB score (r = -0.211 and -0.237, respectively). CONCLUSIONS: These findings implicate age-related increases in circulating IL-6 as an important contributor to declines in skeletal muscle strength, quality, function, and training-mediated adaptation. Given the pervasive nature of inflammation among older adults, novel therapeutic strategies to reduce IL-6 as a means of preserving skeletal muscle health are enticing.

Characterization of reactions after transfusion of cellular blood components that are white cell reduced before storage.

BACKGROUND: During the storage of cellular components before transfusion, cytokines that may mediate transfusion reactions are released from white cells (WBCs). Adverse effects of transfused cellular blood components therefore depend not only on the number of residual WBCs in blood components, but also on the timing of WBC reduction. STUDY DESIGN AND METHODS: Febrile nonhemolytic transfusion reactions (FNHTRs), allergic reactions, and other reactions were characterized in recipients of 4728 units of red cells (RBCs) and 3405 bags of single-donor apheresis platelets (SDAPs), all of which underwent prestorage WBC reduction. To delineate the impact of prestorage versus poststorage WBC reduction of RBCs on transfusion reactions, these results were compared with reactions occurring after the transfusion to similar recipients of 6447 bags of RBCs that underwent poststorage WBC reduction by bedside filtration and 5197 units of SDAPs that underwent prestorage WBC reduction. The levels of interleukin (IL) 1 beta, IL-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha) were measured in a subset of 20 implicated cellular blood components at the time of transfusion reactions and correlated with the duration of storage before transfusion. RESULTS: The incidence of reactions was greater after transfusions of SDAPs (5.49%) than of RBCs (1.63%). The incidence of FNHTRs after transfusion of RBCs that were WBC reduced before storage (1.1%) was significantly lower (p = 0.0045) than that after transfusion of RBCs that were WBC reduced after storage (2.15%). Although allergic reactions to RBCs that were WBC reduced before storage were also less common (0.41%) than those to RBCs that were WBC reduced after storage (0.51%), the difference was not significant (p = 0.067). At the time of reactions to RBCs and SDAPs that were reduced before storage, the level of IL-6 was negatively correlated (r = -0.54, p = 0.014) with the duration of storage before transfusion, and there was no correlation between the level of either IL-1 beta or IL-8 and the interval before transfusion. TNF-alpha was not detectable in any implicated component. CONCLUSION: FNHTRs, but not allergic reactions, were less common after transfusion of RBCs that were WBC reduced before storage than after the transfusion of those WBC reduced after storage at the bedside by filtration. The level of IL-6 in implicated cellular blood components that were WBC reduced before storage was inversely correlated with the length of storage before transfusion. Further studies are needed to determine whether the transfusion of cellular blood components that were WBC reduced before storage can both diminish the incidence of adverse reactions and improve outcome.

Characterization of reactions after exclusive transfusion of white cell-reduced cellular blood components.

BACKGROUND: Potential adverse effects of white cells (WBCs) within transfused cellular blood components include febrile nonhemolytic transfusion reactions (FNHTRs), alloimmunization, transmission of infectious diseases, transfusion-related acute lung injury, and immunomodulation. Although exclusive use of WBC-reduced components to prevent alloimmunization and cytomegalovirus transmission has been studied, the use of these components to avert FNHTR has not been examined. STUDY DESIGN AND METHODS: Transfusion reactions (FNHTRs, allergic reactions, and others) were characterized in recipients of 12,277 WBC-reduced single-donor apheresis platelets (SDAPs) and/or red cells (RBCs). Medical and laboratory evaluations for possible infectious and immunologic (alloimmunization) causes of each reaction were undertaken, and the benefit of further modification of components for the prevention of subsequent reactions was also evaluated. RESULTS: Transfusion reactions occurred after 481 (3.92%) of 12,277 transfusions. Allergic reactions occurred more commonly after transfusion of SDAPs (3.69%) than of RBCs (0.51%). Conversely, FNHTRs occurred more commonly after transfusion of RBCs (2.15%) than of SDAPs (1.58%). HLA antibodies were present in a posttransfusion sample from 27 (10.6%) of 255 patients; bacterial contamination was a possible cause of only 2 (0.42%) of 481 reactions. In patients with recurrent FNHTRs, further WBC reduction in components did not wholly prevent further FNHTRs. CONCLUSION: The incidence of FNHTRs and alloimmunization after exclusive transfusion of WBC-reduced RBCs and SDAPs was low. Further WBC reduction in components transfused to patients with a history of recurrent FNHTRs does not completely prevent subsequent reactions.

Strategies for the avoidance of bacterial contamination of blood components.

Gram staining and bacterial culturing methods were used to determine the incidence of bacterial contamination of cellular blood components at the time of transfusion reactions. Over a 5-year period, 2208 (4.3%) of 51,278 transfusions were complicated by reactions. Overall bacterial contamination occurred in 5 (0.03%) of 17,928 transfusions of single-donor apheresis platelets, 1 (0.14%) of 712 transfusions of pooled random-donor platelet concentrates, 1 (0.003%) of 31,385 transfusions of red cells, and 0 of 1253 transfusions of fresh-frozen plasma. Gram staining done at the time of positive cultures was positive in three of six cases. Although six of seven recipients of contaminated components suffered no clinical sequelae, contaminated transfusions may have been a contributing cause of death in one case. Attempts were made to avoid the transfusion of contaminated cellular blood components by performing routine bacterial cultures: 0 of 341 quality control cultures were positive. To avoid the transfusion of contaminated platelets by identifying bacteria, Gram staining was performed in all single-donor apheresis platelet units collected on open systems and daily in platelets stored > 48 hours: 8 (0.15%) of 5334 smears done on 3829 platelet units were interpreted as positive, and those units were not transfused, but only two of eight units were culture positive. These studies suggest that bacterial contamination can result in adverse clinical sequelae in transfusion recipients and that both culturing and Gram staining are poor methods of screening for contaminated units. More sensitive and specific methods of generalized screening for bacterial contamination are needed.

The inhibition of fibroblast proliferation by a novel monokine: an in vitro and in vivo study.

We have identified a product of rabbit macrophages that inhibits fibroblast proliferation. Tested in vitro against several fibroblast populations, this monokine inhibited rabbit conjunctival fibroblast proliferation by 85% (p = 0.005), human conjunctival fibroblast proliferation by 88% (p = 0.005), human hypertrophic scar fibroblast proliferation by 85% (p = 0.005), and human keloid fibroblast proliferation by 79% (p = 0.005). Additionally (in an in vivo model), this monokine was injected into healing rabbit wounds and inhibited fibroblast proliferation by 33% after 7 days (p = 0.0001) and by 27% after 2 weeks (p < 0.0001). Preliminary analysis of the active factor demonstrates that it is not species-specific, has a molecular weight less than 3000 d, is resistant to degradation by trypsin and carboxypeptidase A, is heat-stable, and is produced by macrophages largely in the first 3 days of culture.

Identification of the metabolites of di-(2-ethylhexyl) phthalate in urine from the African green monkey.

The metabolites of di-(2-ethylhexyl) phthalate (DEHP) found in urine from African Green monkeys after intravenous administration of the 14C-labeled parent compound were isolated and identified. Criteria of identification included cochromatography with rat-derived standards on direct-phase HPLC and a variety of gas-chromatographic columns, as well as correspondence of mass spectra (70-eV electron impact and methane positive chemical ionization) with those of known standards. Approximately 80% of the urinary metabolites were excreted in the form of glucuronide conjugates. This is analogous to what has been reported for the urinary metabolites of DEHP from humans, but in clear contrast to the metabolites found in rat urine. Rat urinary metabolites of DEHP are excreted unconjugated, and consist primarily of derivatives more highly oxidized than the major metabolites produced by monkey or human. It is suggested that the African Green monkey may be a better model for human metabolism of DEHP than is the rat.

Effect of heat on the conversion of di-2-ethylhexyl phthalate to mono-2-ethylhexyl phthalate in human plasma.

Plasma di-2-ethylhexyl phthalate (DEHP), which accumulates during blood storage in plastic bags, gives rise to plasma mono-2-ethylhexyl phthalate (MEHP). This also in plasma samples awaiting analysis, which are no longer stored in plastic bags. Heating plasma samples at 60 C for 25 to 30 minutes in a water bath effectively halts conversion of DEHP to MEHP during subsequent room temperature storage for at least 100 hours. This result is consistent with the view that MEHP accumulation in plasma is due to enzymatic hydrolysis of DEHP by esterase (s) which can be heat-inactivated.

Nonlinear least-squares regression programs for microcomputers.

Nonlinear least-squares regression can be performed on a microcomputer with BASIC language capability and 8K or more bytes of random access memory. At least five nonlinear regression programs written in BASIC exist, two of which have been implemented on microcomputers. These programs and some of their characteriscics are described. Advantages and disadvantages of performing nonlinear regression on microcomputers are contrasted with use of nonlinear regression programs requiring large computers.

Chromatographic studies of sera from calves vaccinated with brucella abortus, strain 19.

The presence of antibody was detected by agglutination tests in the serum of calves four days after vaccination with Brucella abortus strain 19. Titres had reached a maximum by seven to ten days post-vaccination. Sucrose density-gradient ultracentrifugation demonstrated that the earliest antibodies were macroglobulins, IgM (19Sgamma; gammaM)-globulins. Lighter antibodies, IgG (7Sgamma(2); gammaG)-globulins, appeared a few days later. With time, antibody titres fell, IgM declining somewhat more quickly than IgG. After revaccination some seven months later, there was a rapid rise in both IgM and IgG.Anion-exchange column chromatography (DEAE-cellulose) and gel filtration (Sephadex G-200) were applied in separating the two forms of antibody. The former method, in which a gradient buffer system was used, proved to be the more efficient; the IgG antibodies apeared in early eluates at pH 7.8 to 8.0 and low ionic strength, 0.03M, whereas IgM was eluted late when the pH had fallen below 6.0 and the molarity had increased to beyond 0.2. DEAE cellulose chromatography detected IgG as well as IgM sera collected as early as five days after vaccination.

Anaplasmosis: comparison of complement fixation methods and study of the cattle population of southern Alberta.

The standard procedure for the complement-fixation test adopted in 1958 by the Animal Disease Eradication Division of the U.S. Department of Agriculture for testing of anaplasmosis was compared with the routine method used in our laboratory. In general a good agreement was observed between the two methods, although some standard control sera having a low titre in the U.S.D.A. test gave a slightly higher reaction in the A.D.R.I. test, whereas the reverse was observed with certain high titre control sera. None of the differences in titre were sufficient to change the interpretation of the tests.A survey of 3090 field samples collected from southern Alberta close to United States border detected 3 serological reactions in 3 different herds. In one of these, the animal was negative when retested 3 months later. In a second animal the serum titre was still present 11 weeks later but the blood from this animal failed to transmit infection to a susceptible splenectomized calf. In the case of the third herd the animal had been disposed of at the time of retest but all other animals in this herd at the time the reacting animal was examined were still serologically negative. This survey failed to reveal the presence of anaplasmosis in the Canadian animals investigated.