Reduced opioid requirements following unicompartmental knee arthroplasty compared with total knee arthroplasty.

AIMS: Unicompartmental knee arthroplasty (UKA) provides improved early functional outcomes and less postoperative morbidity and pain compared with total knee arthroplasty (TKA). Opioid prescribing has increased in the last two decades, and recently states in the USA have developed online Prescription Drug Monitoring Programs to prevent overprescribing of controlled substances. This study evaluates differences in opioid requirements between patients undergoing TKA and UKA. PATIENTS AND METHODS: We retrospectively reviewed 676 consecutive TKAs and 241 UKAs. Opioid prescriptions in morphine milligram equivalents (MMEs), sedatives, benzodiazepines, and stimulants were collected from State Controlled Substance Monitoring websites six months before and nine months after the initial procedures. Bivariate and multivariate analysis were performed for patients who had a second prescription and continued use. RESULTS: Patients undergoing UKA had a second opioid prescription filled 50.2% of the time, compared with 60.5% for TKA (p = 0.006). After controlling for potential confounders, patients undergoing UKA were still less likely to require a second prescription than those undergoing TKA (adjusted odds ratio (OR) 0.58, 95% confidence interval (CI) 0.42 to 0.81; p = 0.001). Continued opioid use requiring more than five prescriptions occurred in 13.7% of those undergoing TKA and 5.8% for those undergoing UKA (p = 0.001), and was also reduced in UKA patients compared with TKA patients (adjusted OR 0.33, 95% CI 0.16 to 0.67; p = 0.022) in multivariate analysis. The continued use of opioids after six months was 11.8% in those undergoing TKA and 8.3% in those undergoing UKA (p = 0.149). The multivariate models for second prescriptions, continued use with more than five, and continued use beyond six months yielded concordance scores of 0.70, 0.86, and 0.83, respectively. CONCLUSION: Compared with TKA, patients undergoing UKA are less likely to require a second opioid prescription and use significantly fewer opioid prescriptions. Thus, orthopaedic surgeons should adjust their patterns of prescription and educate patients about the reduced expected analgesic requirements after UKA compared with TKA. Cite this article: Bone Joint J 2019;101-B(7 Supple C):22-27.

Intermediate or chronic cutaneous leishmaniasis: leukocyte immunophenotypes and cytokine characterisation of the lesion.

The American cutaneous forms of leishmaniasis include immune-responder individuals with localised cutaneous leishmaniasis (LCL) and non-responder individuals with diffuse cutaneous leishmaniasis (DCL). Patients with intermediate or chronic cutaneous leishmaniasis (ICL) have increased morbidity due to the length of their illness, atypical forms and areas of compromise. In the present study, we evaluated the expression of the leukocyte antigens (CD4, CD8, CLA: cutaneous lymphocyte antigen, CD69, CD83 and CD1a) and cytokines (IFN-gamma, IL-4, IL-10 and TGF-beta 1) in the lesions of patients with ICL (n = 18) using an immunocytochemical procedure. ICL results were compared with the information for LCL (n = 19) and DCL (n = 4). The numbers of CD4+ and CD8+ T cells in ICL were similar to those of LCL lesions, but significantly different (P < or = 0.05) from DCL lesions. LCL lesions have about half the numbers of early activated CD69+ cells as ICL, but most are CLA+ skin homing memory T cells, whereas ICL lesions have the highest number of CD69+ T cells, but about one-third of these cells expressed CLA. This suggests that the granuloma of ICL patients contains many activated T cells that are unprimed to cutaneous-launched antigens, thus contributing to an aberrant immune response. In contrast, DCL granulomas presented the lowest numbers of activated CD69+ and CLA+ cells, associated with the characteristic tolerogenic state of these patients. The immunolocalisation of cytokines showed a mixed cytokine pattern in ICL lesions with many positive cells for IL-10, TGF-beta 1, IL-4 and IFN-gamma, with a preponderance of the first two, and different from the prevalent Th1 and Th2 responses associated with LCL and DCL lesions, respectively. CD1a+ Langerhans cells were decreased (P < or = 0.05) in both ICL (271 +/- 15 cells/mm2) and DCL (245 +/- 19 cells/mm2) as compared to LCL (527 +/- 54 cells/mm2) epidermis. The percentage of IL-10+ epidermal Langerhans cells in ICL (33.69), from the total CD1a+ population, was higher than in LCL (17.45). In addition, fewer CD83+ primed Langerhans cells were present in ICL epidermis. The diminished participation of epidermal Langerhans cells, causing a defective signalling by the epidermis, in ICL lesions may account for the tissue-damaging state observed in these patients.

Adhesion molecules in lesions of American cutaneous leishmaniasis.

Accessory signals, which include adhesion molecules, MHC-II molecules and cytokines, are necessary to foster the interaction between memory T cells and epidermal cells, that is required to promote cutaneous inflammatory responses. American cutaneous leishmaniasis (ACL) is characterized by a spectrum of immunological manifestations, and is a prototype disease for the study of regulatory mechanisms involved in immune protection against protozoal infection. In the present study, we show that diffuse cutaneous leishmaniasis (DCL) epidermis contains keratinocytes that do not express ICAM-1 and HLA-DR molecules. Langerhans cells (LC) are within normal values or somewhat lower, and a very few cells expressing the HB15 molecule--a new described member of the Ig superfamily--are found in such lesions. Mucocutaneous leishmaniasis (MCL) epithelium shows an increased expression of ICAM-1 and HLA-DR molecules, few HB15+ cells, and an absence of epithelial LC. Localized cutaneous leishmaniasis (LCL) epidermis displays ICAM-1+ keratinocytes organized in patches, a uniform expression of HLA-DR, hyperplasia of LC, and numerous HB15+ cells. In all forms of the disease, infiltrating T cells express more LFA-1 beta than LFA-1 alpha, but LFA-1 beta+ T cells are more abundant in LCL granulomas. In contrast, there are more LFA-1 alpha+ T cells in DCL and MCL than in LCL granulomas. LCL lesions also show the highest numbers of HB15+ cells within the granuloma. These results indicate the importance of adhesion molecules in ACL lesions, and open new possibilities for therapeutic schemes oriented towards the control of cell migration.

The clinical and immunological spectrum of American cutaneous leishmaniasis.

American cutaneous leishmaniasis is characterized by a spectrum of clinical manifestations. These include localized, often self-healing single lesions, intermediate forms which frequently produce mucosal lesions and often show exaggerated delayed-type hypersensitivity (DTH), and the rare diffuse cutaneous leishmaniasis in which no reaction of protective cell-mediated immunity or DTH can be demonstrated. Clinical, pathological and immunological studies have begun to unravel some of the mechanisms associated with different disease manifestations, dependent on complex interactions between the host immune response, measured in terms of indices including lymphocyte subsets and lymphokines in vitro and within active lesions, and different species of Leishmania.

Cell-mediated immunity in localized cutaneous leishmaniasis patients before and after treatment with immunotherapy or chemotherapy.

In previous studies of the treatment of localized cutaneous leishmaniasis (LCL) we demonstrated that the therapeutic efficiency of immunotherapy (BCG plus promastigotes of Leishmania mexicana) is equal to that of chemotherapy (Glucantime), without causing the serious side-effects of the drug treatment. In the present study, various aspects of cell-mediated immunity, including the lymphoproliferative response, and leucocyte subpopulations were evaluated both before treatment and after cure in 39 LCL patients who had received immunotherapy (IT), in 34 submitted to chemotherapy (CT), and in 14 patients cured by the administration of BCG alone. We demonstrated evident signs of T-cell activation in cured patients who had received either CT or IT. For example, an increased expression of IL-2 receptors was observed in such patients, compared to their pretreatment values. Also, a significant percentage of patients showed augmented in-vitro responses to mitogen, and both in-vitro and in-vivo reactivity to leishmanial antigen. No evidence was found for the development of an exaggerated immune response to Leishmania parasites in the IT group, because the final level of immunological reactivity was comparable to the CT group. Neither was there any difference in terms of the final immune response between the patients cured by BCG treatment alone and the other groups. However, the therapeutic efficiency of BCG was lower and the mean cure time was longer. We conclude that IT is very useful in the treatment of LCL patients because of its high efficiency, low propensity to produce side-effects, and the fact that it does not induce a state of hyper-reactivity.

Situación actual en inmunoterapia de Leishmania / Current situation in inmunotherapy of the Leishmaniasis

En un ensayo clínico controlado, con evaluación a ciegas y asignación al azar, se ha evaluado la eficacia terapéutica de una combinación de B.C.G. con promastigotes de L.Mexicana amazonensis muertos por calor (Inmunoterapia) en comparación con Antimoniaco de Meglumine (Quimioterapia) y un tercer grupo vacunado con B.C.G. solamente, con un total de 171 pacientes de Leishmaniasis Cutánea localizada (99 Inmunoterapia, 46 Quimioterapia y 26 con BCG). Los resultados obtenidos son comparables en los dos primeros grupos, tanto en el porcentaje de curación (más del 95% a las 32 semanas) como en el tiempo promedio de curación (alrededor de 17 semanas, en cambio en el grupo con BCG solamente los porcentajes de curación son muy bajos (38,5% a las 32 semanas) y el tiempo promedio de curación mucho más prolongado (26 semanas). Los efectos secundarios fueron leves e infrecuentes (menos del 5%) en inmunoterapia y con BCG solo, pero muy frecuente (48%) y severos en quimioterapia. Resultados preliminares indican así mismo buena eficacia terapéutica de la inmunoterapia en pacientes cutáneos y mucosos del área intermedia del espectro clínico-inmunológico y en pacientes con L.Cutánea Difusa (LCD). en este trabajo se discuten los fundamentos de la inmunoterapia en Leishmaniasis en base al espectro de deficiencias de inmunidad celular y se plantean las perspectivas de la inmunoprofilaxis en base a estos conceptos

Demonstration of an indomethacin-sensitive mechanism regulating immune reactivity in American cutaneous leishmaniasis patients.

We investigated some aspects of the regulation of the immune response that were sensitive to the effect of indomethacin (INDO), an inhibitor of prostaglandin synthesis, in 84 patients with American cutaneous leishmaniasis (ACL), and in normal controls. The patients were classified on the basis of clinical and histopathological criteria as suffering localized (LCL), mucocutaneous (MCL) or diffuse (DCL) forms of the disease. The responses in vitro to mitogens (PHA and Con A) and leishmanial antigens were evaluated in the presence or absence of INDO. It was found that the drug significantly increased in vitro the mitogenic stimulation by PHA of peripheral blood mononuclear cells from LCL, MCL and DCL patients, but the effect was less evident in the controls. Considering specific responses to leishmanial antigens, we showed that in the presence of INDO, these were significantly increased in LCL patients, but not in MCL or DCL. Also, only in LCL was an inverse correlation found between the initial response to leishmanial antigen and the increase caused by INDO. Significant correlations were found between the INDO-induced enhancement of PHA and Con A responses in the patient groups, but not in the controls. In LCL patients there was a significant correlation between the increases caused by INDO of the mitogen and antigen responses. It can be suggested that an indomethacin-sensitive (prostaglandin dependent) suppressor mechanism operates in LCL patients, that is possibly responsible for the modulation of the immune response against the parasite. In MCL, where this suppressive mechanism is apparently not functional, the response to the parasite is intense, and a possible consequence of this could be tissue damage. Our results indicate, however, that the anergy observed in DCL patients is not due to an involvement of prostaglandins in the suppression of the specific immune response.

New projections in the development of a vaccination model using two microorganisms and its application in leishmaniasis and leprosy

Conventional vaccination is oriented toward the prevention of disease in individuals capable of developing normal immune responses. A new model of vaccination employing two microorganisms has been described for the correction of variable degrees of antigen-specifit deficiency in the development of effective cell-mediated immunity in two diseases, leprosy and cutaneous leishmaniasis, both of which are characterized by a spectrum of clinical manifestations. A schematic representation of the immunologic defect in the severe and progressive forms of these diseases and a possible mechanism for its correction using this vaccine model are presented. Immunotherapeutic and immunoprophylactic applications of the model are described, with particular reference to recent experience in the immunotherapy of localized cutaneous leishmaniasis. The efficacy, virtual absence of secondary effects, ease of administration and low cost of this therapeutic modality indicate that it offers an important option or field use in endemic of leishmaniasis

An unusual case of hyper-production of IgE, treated by plasmapheresis.

A 15-year-old boy with severe inflammatory skin lesions from an early age was found to have extremely elevated serum IgE levels (up to 376.000 IU/ml). His skin showed positive direct immunofluorescence for IgE and he had peripheral and bone marrow eosinophilia. No evidence for atopic disease was found, but he suffered intestinal helminthic infection of moderate intensity. He showed a somewhat depressed cell mediated immune response but a normal polymorphonuclear function. Various treatments that included anti-inflammatory, anti-allergic, anti-parasitic, anti-mycotic and PUVA therapy did not significantly improve his condition A therapeutic test using plasmapheresis produced marked, though short-lived clinical improvement. We believe that this case might result from the superimposition of the stimulatory effects of intestinal helminthiasis on a background of intrinsic hyper-production of IgE.

In situ characterization of the cellular immune response in American cutaneous leishmaniasis.

American cutaneous leishmaniasis is a spectrum of granulomatous disease caused by related species of an intracellular parasite. The host response in localized cutaneous leishmaniasis (LCL) is effective in that few organisms can be found in tissue lesions. In contrast, diffuse cutaneous leishmaniasis (DCL) patients mount a poor response with numerous parasites present in multiple skin lesions. Immunopathological correlates were sought in LCL and DCL with immunoperoxidase techniques using monoclonal antibodies directed against T lymphocyte subpopulations and interleukin-2 in tissue lesions. Both LCL and DCL granulomas showed a mixture of T lymphocyte subpopulations with the ratio of helper:suppressor phenotypes less than one. This ratio and localization of cells is more similar to the ineffective lepromatous leprosy granuloma than the effective tuberculoid leprosy granuloma. In contrast, interleukin-2 was identified in equivalent numbers of cells in LCL and tuberculoid leprosy, an order of magnitude greater than DCL and lepromatous leprosy lesions. Cells expressing Tac, the receptor for interleukin-2, were present in approximately equal numbers in all disorders. The immunological effectiveness of granulomas appear to related less to the numbers and location of T cell phenotypes than to the functional aspects of these cells, particularly the ability to generate lymphokines.

Mechanisms associated with immunoregulation in human American cutaneous leishmaniasis.

Mechanisms possibly involved in the regulation of the immune response were evaluated in 49 patients with American cutaneous leishmaniasis (ACL). The patients were classified on the basis of clinical and histopathological criteria as suffering localized (LCL), mucocutaneous (MCL) or diffuse (DCL) forms of the disease. A significant leishmanial antigen-induced suppression of in vitro mitogen responsiveness was demonstrated in the DCL group, but not in the other two diseases states. Lack of suppressive activity was particularly evident in MCL, this being the group that presented the highest in vivo and in vitro reactivity to the parasite antigens. In fact, a significant inverse correlation was found between the degree of suppression and the antigen-induced lymphocyte proliferative response. In contrast, a mixture of mononuclear cells from MCL patients and normal subjects showed higher that expected responses to mitogen, while this increase was not observed in co-cultures of DCL and normal mononuclear cells. Due to their possible modulatory influences, circulating immune complexes were also evaluated in these patient groups, higher levels being found in MCL and DCL patients than in either LCL or controls. The possible mechanisms involved in the regulation of the immune response to the protozoan in the complex disease spectrum of ACL are discussed in relation to anergy in DCL and hyperresponsiveness in MCL.

Leishmania species: comparative ultrastructure of experimental nodules and diffuse human cutaneous lesions in American leishmaniases.

Experimental nodules of American leishmaniases were obtained by inoculating 0.1-1 x 10(5) amastigotes into the dorsum of the hindpaws of golden hamsters and of C57Bl/6J mice. The amastigotes were obtained by biopsy of lesions in six human cases of cutaneous leishmaniases and were serially maintained in golden hamsters and in a fetal calf serum-containing medium. Human nodules were obtained by biopsy from several patients with diffuse cutaneous leishmaniases, always prior to treatment. Within the same host species, no ultrastructural differences were seen in the tissue response to isolates of Leishmania mexicana, L. brasiliensis, or L. garnhami, nor were there differences between the host species in response to a particular isolate of the genus Leishmania. The typical inflammatory response was a macrophage granuloma with abundant polymorphonuclear neutrophils, some eosinophils, and plasma cells. Simple human cutaneous leishmanial lesions, as well as experimental nodules in regression, show many fibroblasts, much collagen fiber, but very few parasites. In typical lesions, parasites occurred within macrophage phagolysosomes, within distended lacunar cells, and in the intercellular spaces. Leishmaniae strongly adhered to parasitophorous vacuoles by a site of their plasma membrane directly opposite the flagellum, and the host cell cytoplasm close to the adherence site became highly vacuolated. In most cases the intra- and extracellular parasites show normal morphology, which suggest the inability of phagocytic cells to attack them.

Characterization of the cellular immune response in American cutaneous leishmaniasis.

The in vitro and in vivo cellular immune reactivity of 49 patients with American cutaneous leishmaniasis (ACL) was evaluated using mitogens and parasite antigens. Patients were examined before treatment and were classified on the basis of clinical and histopathological criteria as suffering localized cutaneous leishmaniasis (LCL, 32 patients) or mucocutaneous leishmaniasis (MCL, 11 patients). A small group (6 patients) of treated diffuse cutaneous leishmaniasis (DCL) patients was also examined. The lymphocyte proliferative responses to PHA were significantly lower than those of controls (87 individuals, from either endemic or nonendemic zones) in LCL, and particularly MCL. Con A responses were, however, effectively normal in these patients. Both in vivo and in vitro cellular immune responses to leishmanial antigens were significantly greater in MCL and LCL patients than in the controls, the intensity of the reactions being by far the greatest in MCL. DCL patients demonstrated a complete absence of specific immune responsiveness both in vivo and in vitro. The significance of these results in the mechanisms leading to the resolution of the infection or production of pathologic lesions is discussed.