How much do we understand about the effects of ageing on healing?

Poor experimental design has contributed to a perceived association of ageing with delayed wound healing. Continuing research on the influence of ageing will allow more focused therapeutic strategies.

Matrix metalloproteinases: their function in tissue repair.

Matrix metalloproteinases are involved in all stages of cutaneous wound repair and play a key role in regulating the balance between tissue synthesis and tissue destruction. Greater understanding of this may result in better treatment options.

A non-class I MHC intestinal epithelial surface glycoprotein, gp180, binds to CD8.

The activation of CD8(+) T cells by normal intestinal epithelial cells in antigen-specific or allogeneic mixed cell culture systems has significant implications for the modulation of mucosal immune responses due to the fact that these T cells appear to have regulatory rather than cytolytic activity. A 180-kDa glycoprotein (gp180) has been identified and shown to be important in CD8(+) T cell activation by intestinal epithelial cells. In this study, we examine, in further detail, the role that the CD8 molecule plays in this interaction. It has been previously shown that monoclonal antibodies against gp180 inhibited the activation of CD8-associated p56(lck) in T cells. Although indirectly suggested by these data, there was no evidence that the activation of this protein tyrosine kinase was a direct result of gp180 interacting with the CD8 molecule. In this study, we document that soluble gp180 is able to bind to CD8-Fc fusion proteins and is absorbed by human CD8 alpha but not CD4 transfected murine T cells and that this interaction is dependent upon carbohydrate on the gp180 molecule. Furthermore, the sites used for binding by gp180 are distinct from those used by the conventional CD8 ligand, class I MHC. Thus, gp180 appears to be a novel CD8 ligand that plays an important role in the activation of CD8-associated kinases and of CD8(+) T cells.

Oral tolerance to protein antigens.

Oral tolerance is an active non-response to antigens delivered via the oral route. Mechanisms governing tolerance induction have been well characterized in mouse. Similar studies in man are lacking, although there is evidence that tolerance can be induced. In disease states, tolerance is altered and this may account for the presence of mucosal inflammation. In food hypersensitivity there is evidence that allergens may be handled differently and this may play a role in disease expression.

Defective expression of gp180, a novel CD8 ligand on intestinal epithelial cells, in inflammatory bowel disease.

Previous studies support a role for intestinal epithelial cells (IEC) as antigen-presenting cells in mucosal immune responses. T cells activated by IEC are CD8+, suppressor in function, and dependent upon CD8-associated p56lck activation. A 180-kD glycoprotein (gp180) recognized by mAbs B9 and L12 has been identified and shown to be important in CD8+ T cell activation by IEC. Since IEC derived from patients with inflammatory bowel disease (IBD) are incapable of activating CD8+ T cells, we asked whether this correlated with gp180 expression. While frozen sections of normal bowel revealed bright gp180 staining on all IEC, both inflamed and uninflamed ulcerative colitis (UC) specimens showed patchy staining. In Crohn's disease (CD), staining was faint to absent. Flow cytometry confirmed immunohistochemical data. The staining patterns correlated with the ability of IEC to activate CD8-associated p56lck. Normal IEC induced phosphorylation of p56lck in CD8alpha but not CD4+ transfectants. In contrast, both UC and CD IEC activated CD4 and, to a much lesser extent, CD8-associated p56lck. Thus, gp180 expression by IBD IEC appears to be altered, and correlates with a functional alteration of lck activation. This defect may reflect a more proximal event in the pathogenesis of IBD.

Basic and clinical overview of the mucosal immune system.

What is clearly evolving today is the concept of mucosal immunity as a discrete system that performs novel immunologic tasks and is uniquely regulated. Although many of the same factors exist in both the systemic and the mucosal immune systems, their structural and functional properties are tailored to different microenvironments. Because it is persistently flooded by a massive antigen load from the environment, the gut-associated lymphoid tissue must continually maintain a delicate balance between active immunity, tolerance, and suppression of immune responses. Homeostasis is essential. Dysfunction of the mucosa's complex immunoregulatory mechanisms may give rise to a diverse panoply of illnesses, including inflammatory bowel disease and celiac sprue. Current research on mucosal interactions at the molecular and cellular level is revolutionizing our understanding of the underlying pathophysiology of these diseases, and may guide their future diagnosis, therapy, and prevention. Indeed, the current wave of investigation has carried the field beyond the realm of mucosal disease, allowing for the harnessing of special mucosal phenomena in the development of new therapeutic modalities and in the treatment of an even wider array of systemic disorders.

Treatment of central venous catheter occlusions with ethanol and hydrochloric acid.

BACKGROUND: Occluded central venous lines (CVLs) is a major problem in pediatric patients. METHODS: To relieve obstructed catheters, infusions of ethanol (up to 3 mL of a 70% solution) for presumed lipid occlusions and hydrochloric acid (HCl, 0.1 N, up to 3 mL) for presumed mineral and drug precipitates were given in an attempt to relieve obstructed catheters. RESULTS: Patency was restored in 34 of 39 occluded catheters over an 18-month period. CONCLUSIONS: Clearing occluded CVLs with ethanol and HCl is not only beneficial to the patient but also offers considerable cost savings compared to CVL replacement.

L-deprenyl (selegiline) added to Sinemet CR in the management of Parkinson's disease patients with motor response fluctuations.

L-deprenyl (Eldepryl) added to Sinemet CR in the treatment regimens of seven patients with Parkinson's disease (PD) and therapeutic response fluctuations (RF) allowed a statistically significant reduction in total daily levodopa intake and an increase in the mean interdose interval. Trends were noted towards a reduction in the number of daily "off" periods and an increase in the portion of the waking day spent "on." Three patients suffered an increase in the intensity of their dyskinesias, and discontinued taking deprenyl. Four patients, all of whom reported improved functioning during "off" periods, have continued taking the combination. Sinemet CR and deprenyl can safely be used together in patients with advanced PD, and the combination may result in improved control of motor fluctuations in selected patients.

Results of long-term treatment with controlled-release levodopa/carbidopa (Sinemet CR).

35 Parkinson's disease patients with motor response fluctuations (RF) participated in controlled clinical trials comparing Sinemet CR to Standard Sinemet (STD) at our institutions. 13 of 25 eligible patients continued to two years (the longest possible follow-up from the second study), and 5 of 11 have continued taking CR up to 4 years. At the end of both two and four years, patients were taking significantly fewer medication doses, with a significantly longer interdose interval, and up to two years, experienced fewer "off" periods than when on Standard Sinemet (STD) alone. Most patients required STD at at least one dose each day to hasten to onset of antiparkinson effect. Sinemet CR is a useful adjunct in the long-term management of motor response fluctuations in Parkinson's disease.

Sustained-release (+)-PHNO [MK-458 (HPMC)] in the treatment of Parkinson's disease: evidence for tolerance to a selective D2-receptor agonist administered as a long-acting formulation.

4-Propyl-9-hydroxynaphthoxazine, or MK-458 (HPMC), a selective, nonergot D2 agonist administered orally twice a day in sustained-release form, was studied as adjunctive therapy with carbidopa-levodopa (Sinemet) in 12 Parkinson's disease patients with motor response fluctuations. The dosage of agonist was gradually increased over 12 weeks to a maximum tolerated level of up to 60 mg/day, and that of Sinemet was reduced concurrently. After 8 weeks, reduction of Sinemet averaged 45.1%, but over the next 4 weeks, despite a continued increase in dosage of the agonist, patients were unable to decrease their Sinemet further, and by 12 weeks mean reduction in Sinemet was only 32%. Only five patients completed the planned 24-week study, mostly due to progressive loss of efficacy. The MK-458 is capable of partially substituting for Sinemet in dosages employed in this study. Reduced sensitivity to the drug can appear over a relatively short time, perhaps as a result of down-regulation of postsynaptic dopamine receptors.

Ascorbic acid, vitamin A, folic acid, and amino acids in blood of patients with hemophilia.

Blood levels of ascorbic acid, vitamin A, folic acid, and amino acids were studied in patients at the South Texas Comprehensive Hemophilia Center, San Antonio, TX. The mean plasma ascorbic acid level in hemophiliacs was significantly lower than controls (p less than 0.0001). This was observed despite a dietary ascorbic acid intake in excess of 66% of the Recommended Dietary Allowances (RDA). However, those subjects receiving specific factor replacement therapy at home and consuming at least 66% RDA of ascorbic acid maintained a mean plasma ascorbic acid level not significantly less than controls. Hemophilic subjects not on home therapy, on the other hand, had a mean plasma ascorbic acid level significantly below that of controls while receiving optimal dietary ascorbic acid. With prompt adequate medical care of bleeding episodes and with optimal nutrition, the demand for ascorbic acid needed for tissue repair in hemophilic patients may be lessened. Hemophiliacs had mean serum vitamin A, mean serum folate, and mean red cell folate levels that were not significantly different from controls. Significantly higher mean plasma arginine and lower, but not significantly lower, mean plasma ornithine levels were found in hemophilic subjects, suggesting altered arginase activity.

Nutritional status of patients with hemophilia.

The nutritional status of 57 patients with hemophilia was studied at the South Texas Comprehensive Hemophilia Center, San Antonio. Dietary and anthropometric analyses were assessed as part of the nutrition evaluation. Calcium and vitamin A were two nutrients whose consumption was most often reported to be below one-half of the RDA. No statistically significant difference in caloric or nutrient intake was found between below-poverty income level groups. Participation in supplemental food programs produced some improvement in dietary intake. Some patients with hemophilia were overweight and some were underweight for their heights. When the weights of patients with hemophilia were compared to standards for age-adjusted ideal, desirable body weight, more than one-half of the subjects 25 years old or older exceeded the weight range for large frame men. Weight control should be emphasized for the patients who lead a sedentary life because of the physical limitations imposed by the complications of hemophilia.