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Objectives: To examine the frequency and severity of pain and use of pain therapies among long-term care residents with moderate to severe dementia and to explore the factors associated with increased pain severity., Design: Prospective individual data were collected over 1 to 3 days for each participant., Setting: Sixteen long-term care facilities in Alabama, Georgia, Pennsylvania, and New Jersey., Participants: Residents with moderate to severe cognitive impairment residing in a long-term care facility for at least 7 days were enrolled (N = 205). Residents were 47% female, predominantly white (69%), and 84 years old, on average (SD = 10 years)., Measurements: A comprehensive pain assessment protocol was used to evaluate pain severity and characteristics through medical record review, interviews with nursing home staff, physical examinations, as well as pain observation tools (Mobilization-Observation-Behavior-Intensity-Dementia Pain Scale and Pain Intensity Measure for Persons With Dementia). Known correlates were also assessed (agitation, depression, and sleep)., Results: Experts' pain evaluations indicated that residents' usual pain was mild (mean = 1.6/10), and most experienced only intermittent pain (70%). However, 45% of residents experienced moderate to severe worst pain. Of residents, 90% received a pain therapy, with acetaminophen (87%) and opioids (32%) commonly utilized. Only 3% had a nondrug therapy documented in the medical record. The only resident characteristic that was significantly associated with pain severity was receipt of an opioid in the past week., Conclusion: Using a comprehensive pain assessment protocol, we found that most nursing home residents with moderate to severe dementia had mild usual, intermittent pain and the vast majority received at least one pain therapy in the previous week. Although these findings reflect improvements in pain management compared with older studies, there is still room for improvement in that 45% of the sample experienced moderate to severe pain at some point in the previous week. J Am Geriatr Soc 68:794-802, 2020., (© 2019 The American Geriatrics Society.)

T lymphocytes are activated by a complex series of events, but the mechanisms remain unclear. One uncertainty is the time of receptor-ligand interaction necessary for commitment to DNA synthesis and proliferation. Although this issue has broad implications for the interpretation of T cell activation data, it remains unresolved. Therefore, we examined the temporal activation requirements of rat splenocytes stimulated with concanavalin A (Con A) by measuring proliferation, as well as interleukin-2 (IL-2) production and IL-2 receptor IL-2R) expression. Splenocytes stimulated with various Con A concentrations for 3 h did not incorporate significantly more [3H]thymidine than unstimulated splenocytes. Some increase occurred after 6 h of lectin exposure but maximum proliferation occurred only after the 52-h stimulation. Furthermore, Con A incubations of 6 h or more were required for significant increases in IL-2 or IL-2R. Maximum lymphokine production and receptor expression were observed after the 52-h stimulation. Thus, activation of some primary lymphocytes required only 6 h of stimulation, but much longer mitogen contact was necessary for maximum recruitment.

Most studies of human blood lymphocyte function following space flight have indicated that microgravity suppresses T cell proliferation. However, several other postflight experiments with animals have shown no decrease in proliferation of lymphocytes from peripheral lymphatic tissues, suggesting that different tissues may be variably affected by microgravity. Therefore, we examined the proliferation of lymphocytes from both spleen and lymph nodes of rats following a 4-day flight aboard the Space Shuttle. The experiments were designed to investigate tissue variability as well as potential mechanisms involved in suppressing proliferation. We found that proliferation of lymph node lymphocytes (LNL) from flight (FLT) animals stimulated with the antigen receptor-dependent T cell mitogen concanavalin A was depressed and could not be restored by supplementing cultures with interleukin 1 or interleukin 2 (IL-2). Response to another receptor-dependent mitogen, phytohemagglutinin, was not decreased. However, proliferation of FLT LNL following stimulation with the receptor-independent, mitogenic combination of phorbol ester and ionomycin was depressed. LNL IL-2 activity, cell surface marker expression, and B cell responses to mitogen were normal. Thus, deficits in antigen receptor/ligand interactions, cell surface marker expression, or IL-2 did not account for the suppressed lymphocyte proliferation observed postflight. In contrast to LNL, FLT splenocyte proliferation was not depressed. Assayable IL-2, IL-2 receptor expression, and cell surface marker expression likewise were unaffected by space flight. The differences between lymph node and splenic responses demonstrate the tissue-specific nature of microgravity effects on individual lymphatic tissues.

Studies of peripheral blood lymphocytes from astronauts indicate that microgravity depresses T-cell responsiveness. However, this effect has not been examined in cells of peripheral lymphatic tissue, where most lymphocytes are located. In this study, inguinal lymph node lymphocytes from rats flown on the COSMOS 2044 mission were tested for proliferation and interleukin-2 (IL-2) production. Cells cultured with mitogenic lectins, phorbol ester, and calcium ionophore, or T-cell mitogen and lymphokine, were assayed for DNA synthesis by [3H]thymidine incorporation. Lymphocytes incubated with a T-cell mitogen alone also were tested for IL-2 production. Proliferation of lymphocytes from flight rats was not significantly different from controls for any of the mitogens tested. Furthermore, lymph node lymphocytes from flight rats was not significantly different from controls for any of the mitogens tested. Furthermore, lymph node lymphocytes from control and flown rats produced similar amounts of IL-2. Thus microgravity may act on lymphocytes in a tissue-specific manner, a new finding that could impact on the evaluation of spaceflight effects on immunocompetence.

The effects of microgravity on the immune system are largely unknown, but understanding such effects becomes increasingly important as space exploration continues and mission duration increases. Reductions in postflight human T cell reactivity to mitogens is well documented. Similar results have been obtained using a clinostat as an in vitro model of microgravity. In this study, a rat tail suspension model of weightlessness was used to examine in vitro lymphocyte proliferation in response to mitogens. Experiments were designed to uncover potential deficits in events related to proliferation including cell surface protein and IL-2 receptor (IL-2R) expression, interleukin-2 (IL-2) production, and accessory cells. Suspension of rats for 1 week led to a significant depression in [3H]thymidine incorporation by mitogen-stimulated peripheral blood lymphocytes (PBL) but only a small decrease in the proliferation of lymph node lymphocytes and splenocytes. There were no changes in the percentages of cells expressing CD4, CD5, CD8 or immunoglobulin. Moreover, no changes in IL-2 production or IL-2R expression were observed. More esterase-positive macrophages were detected in all lymphatic tissues of suspended rats, but there was no corresponding increase in the percentage of cells bearing the macrophage markers OX41 or OX42. This increase in the number of macrophages may be related to the observed suppression of lymphocyte proliferation. The tissue specificity of the decrease in mitogen activation indicates that there may be a compartmentalized response in the rats tested in the hindlimb suspension model.

Multiple blood samples were collected over the first 15 min after an i.v. injection of 25 units/kg of heparin in four healthy subjects. Plasma heparin activity in each sample was determined by a chemical neutralization assay using polybrene and a bioassay based on activated partial thromboplastin time. Chemically assayed heparin declined much more rapidly than bioassayed heparin over the first 5-7 min after the dose. Subsequently, both heparin activity vs time curves declined with a similar terminal half-life. Slopes of the in vivo 1n APTT vs plasma heparin activity (determined by chemical neutralization) relationships were significantly greater than those of the corresponding in vitro relationships between 1n APTT vs heparin activity added to plasma. A possible explanation for these heparin assay differences is a rapid in vivo enhancement of the anticoagulant effect of heparin. How such enhancement may occur, however, is presently unclear.

A method for determining heparin activity (in unit/ml) in human plasma is described. The method is based on neutralization of heparin by Polybrene , a polymerized quaternary ammonium salt. It uses serial incubations of plasma with increasing amounts of Polybrene in conjunction with thrombin-induced coagulation times to define the amount of Polybrene required to neutralize heparin in the sample. Reference curves involve linear relationships between amounts of Polybrene required to neutralize known amounts of heparin. Coefficients of variation for the assay vary from 4 to 10% over the range of 0.05 to 1.0 unit/ml.

Six normal subjects (three men and three women) took 200 mg sulfinpyrazone in two oral preparations, a capsule and a suspension. Plasma and urine levels of sulfinpyrazone and the sulfide, p-hydroxy, and sulfone metabolites were measured over three days. The plasma sulfinpyrazone/time concentration profiles indicated a postabsorptive biexponential decline with a mean terminal half life (t1/2) of 299 +/- 107 min. There was intersubject variation in the formation of the metabolites, the greatest being with the sulfide metabolite. Mean t1/2 of the sulfide metabolite was 659 +/- 192 min. The apparent fraction of sulfinpyrazone absorbed was 0.93 +/- 0.24 and the free fraction in plasma was 1.26 +/- 0.04%. Since the sulfide metabolite has a more potent antiplatelet effect and its formation in normal subjects is variable, direct administration of the sulfide may provide a more predictable antithrombotic effect in patients.

Activated partial thromboplastin time (APTT) is the most widely used coagulation test for monitoring heparin therapy. This study quantitates the differences in heparin sensitivity of seven commercially available APTT reagents, using plasma samples obtained from 20 subjects. The reagents studied were Actin, Actin FS, Automated APTT, Cephotest, Coagachek KAPTT, Platelin plus activator, and Activated Thrombofax. The relationship between plasma heparin and APTT was established for all reagents in each subject. For each reagent studied there was a marked intersubject variability in heparin sensitivity. There was also a marked difference in heparin sensitivity among the different reagents. The average plasma heparin activities required to double baseline APTT values ranged from 0.19 +/- 0.04 (mean +/- SD) unit/mL for the most sensitive reagents (Platelin and Actin FS) to 0.43 +/- 0.12 unit/mL for the least sensitive reagent (Actin). It is concluded that reagent variability may significantly contribute to overdosage and under dosage of heparin in the individual patient. These results stress that a standard APTT reagent be developed.

Chondroitin-4-sulfate (chondroitin sulfate A, CSA) is a natural glycosaminoglycan which has been shown to have antithrombotic effects in vivo. This study investigates its anticoagulant effect in vitro. CSA was added to citrated plasma obtained from 16 human volunteers to yield concentrations ranging from 25 to 500 micrograms/ml. The anticoagulant effect of CSA was determined by activated partial thromboplastin time (APTT). The average baseline APTT was 32.5 +/- 3.4 sec. An excellent linear relationship was observed between the natural logarithms of APTT and plasma CSA concentrations; the slopes of these relationships (APTT-CSA slopes) were determined by linear regression. The average APTT-CSA slope was 0.986 +/- 0.145 ml/mg. Plasma concentrations of antithrombin III, alpha 1 antitrypsin, alpha 2 macroglobulin, fibrinogen, and alpha 1 acid glycoprotein were normal. There were no statistically significant correlations between baseline APTT and APTT-CSA slope values or between either of these parameters and plasma concentrations of any of the measured plasma proteins. Additional in vitro studies showed that the anticoagulant effect of CSA is only in part mediated by antithrombin III. The results of this study suggest that the antithrombotic effect of this biologically active substance are at least in part due to its anticoagulant effect.

B-cell responses of 3 immunoglobulin isotypes (IgA, IgG, and IgM) were investigated in the large intestine and mesenteric lymph nodes (MLN) of naive or immune mice after inoculation of oocysts of Eimeria falciformis. Primary and anamnestic IgA and IgG lymphocyte responses to E. falciformis occurred in the large intestine of nonimmune and immune mice, respectively. IgA-containing lymphocytes (IgAc) were the largest population of responding B cells in the large intestine. In infected mice, IgAc accumulated in the apical portion of the lamina propria, whereas IgG-containing lymphocytes (IgGc) were more numerous at the base of the lamina propria. No significant increase in the number of IgM-containing lymphocytes (IgMc) was observed in the lamina propria of the large intestine. Primary but no anamnestic B-cell responses occurred in the MLN, and immune mice actually had reduced numbers of IgAc and IgGc in the MLN when compared with naive mice. IgGc were the largest population of responding B cells in the MLN. Thus, IgAc appear to accumulate preferentially at the site of parasite development, whereas IgGc are primarily localized deeper in the lamina propria of the large intestine and in the draining lymph nodes of mice infected with E. falciformis.