Abnormal clonogenic potential of T cells from multiple myeloma patients

Peripheral blood lymphocytes (PBLs) from multiple myeloma patients are defective in both proportion and absolute numbers of OKT4+ cells and have a normal proportion but reduced absolute number of OKT8+ cells. To assess the functional capabilities of the T cells in myeloma patients, we cloned the T cells in PBLs using limiting dilution conditions in which 100% of OKT4+ and OKT8+ T cells in normal PBLs are able to form a clone. In contrast, the OKT8+ cells from PBLs of five of seven multiple myeloma patients were severely compromised in their clonogenic potential; only 7% to 25% of OKT8+ T cells appeared to give rise to a clone. Clonogenic potential of the OKT4+ cells in patients was more nearly normal. Analysis of two multiple myeloma patients with abnormally low numbers of T cells in PBLs revealed the existence of abnormalities in the progenitors of T cell clones. In both patients, two to three times as many T cell clones were observed as would have been expected based on the number of PBLs cultured at limiting dilution, indicating that OKT4-8- cells in PBLs are capable of giving rise to OKT4+ and, at lower frequency, to OKT8+ clonal progeny in vitro. We conclude that purely quantitative assessment of T cell subsets should be interpreted with caution, since proportionately normal numbers of OKT8+ cells in patient PBLs are seriously compromised in their ability to give rise to clonal progeny in vitro, and since there appears to be a OKT4-8- population of T cells in PBLs that are committed to become OKT4+ or OKT8+ T cells, but are unable to do so in vivo.     

Increased apoptosis of immunoreactive host cells and augmented donor leukocyte chimerism, not sustained inhibition of B7 molecule expression are associated with prolonged cardiac allograft survival in mice preconditioned with immature donor dendritic cells plus anti-CD40L mAb.

BACKGROUND: We previously reported the association among donor leukocyte chimerism, apoptosis of presumedly IL-2-deficient graft-infiltrating host cells, and the spontaneous donor-specific tolerance induced by liver but not heart allografts in mice. Survival of the rejection-prone heart allografts in the same strain combination is modestly prolonged by the pretransplant infusion of immature, costimulatory molecule-(CM) deficient donor dendritic cells (DC), an effect that is markedly potentiated by concomitant CM blockade with anti-CD40L (CD154) monoclonal antibody (mAb). We investigated whether the long survival of the heart allografts in the pretreated mice was associated with donor leukocyte chimerism and apoptosis of graft-infiltrating cells, if these end points were similar to those in the spontaneously tolerant liver transplant model, and whether the pretreatment effect was dependent on sustained inhibition of CM expression of the infused immature donor DC. In addition, apoptosis was assessed in the host spleen and lymph nodes, a critical determination not reported in previous studies of either spontaneous or "treatment-aided" organ tolerance models. METHODS: Seven days before transplantation of hearts from B10 (H-2b) donors, 2x10(6) donor-derived immature DC were infused i.v. into C3H (H-2k) recipient mice with or without a concomitant i.p. injection of anti-CD40L mAb. Donor cells were detected posttransplantation by immunohistochemical staining for major histocompatibility complex class II (I-Ab) in the cells of recipient lymphoid tissue. CM expression was determined by two-color labeling. Host responses to donor alloantigen were quantified by mixed leukocyte reaction, and cytotoxic T lymphocyte (CTL) assays. Apoptotic death in graft-infiltrating cells and in areas of T-dependent lymphoid tissue was visualized by terminal deoxynucleotidyltransferase-catalyzed dUTP-digoxigenin nick-end labeling and quantitative spectrofluorometry. Interleukin-2 production and localization were estimated by immunohistochemistry. RESULTS: Compared with control heart transplantation or heart transplantation after only DC administration, concomitant pretreatment with immature donor DC and anti-CD40L mAb caused sustained elevation of donor (I-Ab+) cells (microchimerism) in the spleen including T cell areas. More than 80% of the I-Ab+ cells in combined treatment animals also were CD86+, reflecting failure of the mAb to inhibit CD40/ CD80/CD86 up-regulation on immature DC in vitro after their interaction with host T cells. Donor-specific CTL activity in graft-infiltrating cells and spleen cell populations of these animals was present on day 8, but decreased strikingly to normal control levels by day 14. The decrease was associated with enhanced apoptosis of graft-infiltrating cells and of cells in the spleen where interleukin-2 production was inhibited. The highest levels of splenic microchimerism were found in mice with long surviving grafts (>100 days). In contrast, CTL activity was persistently elevated in control heart graft recipients with comparatively low levels of apoptotic activity and high levels of interleukin-2. CONCLUSION: The donor-specific acceptance of rejection-prone heart allografts by recipients pretreated with immature donor DC and anti-CD40L mAb is not dependent on sustained inhibition of donor DC CM (CD86) expression. Instead, the pretreatment facilitates a tolerogenic cascade similar to that in spontaneously tolerant liver recipients that involves: (1) chimerism-driven immune activation, succeeded by deletion of host immune responder cells by apoptosis in the spleen and allograft that is linked to interleukin-2 deficiency in both locations and (2) persistence of comparatively large numbers of donor-derived leukocytes. These tolerogenic mechanisms are thought to be generic, explaining the tolerance induced by allografts spontaneously, or with the aid of various kinds of immunosuppression.     

Primary adult liver transplantation under tacrolimus: more than 90 months actual follow-up survival and adverse events.

The introduction of tacrolimus has shown decreased rates of acute and steroid-resistant rejection after liver transplantation (LTx). The aim of the present study is to examine the long-term efficacy and safety of tacrolimus in primary liver transplant recipients. The first 121 consecutive adults (aged >16 years) who underwent primary LTx at a single center from August 1989 to February 1990 were followed up until August 1997. The mean follow-up was 93.2 +/- 1.2 months (range, 90.5 to 96.5 months). Patient survival, graft survival, rate of rejection, and adverse events were examined. The actual 7-year patient survival rate was 67.8%, and the graft survival rate was 63.6%. Infections, recurrence of disease, de novo malignancies, and cardiovascular events constituted the main causes of graft loss and death in the long term. Graft loss related to acute or chronic rejection was rare. The rate of acute rejection beyond 2 years was approximately 3% per year, and most rejections were steroid responsive. Approximately 70% of the patients received only tacrolimus after 1 year. Four patients developed end-stage renal disease, and 2 patients underwent kidney transplantation. Hyperkalemia and hypertension were observed in one third of the patients. New-onset insulin-dependent diabetes mellitus was observed in 9% and 13% of the patients at the 1-year and 7-year follow-up, respectively. Seven patients developed de novo malignancies, including two skin malignancies. Six patients developed posttransplantation lymphoproliferative disorder during the entire follow-up period. Actual patient and graft survival at 7 years was excellent, and few adverse events developed after the first year. Graft loss from acute or chronic rejection was rare under tacrolimus, and approximately 70% of the patients were steroid free on tacrolimus monotherapy after the first year after LTx.     

Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion

Chronic rejection accounts for most renal allograft losses after the first year posttransplantation. On March 24 and 25, 1997, a roundtable of five transplant surgeons, two nephrologists, and one pathologist assembled in Dallas, Texas, to review critical issues surrounding chronic renal allograft rejection. This article summarizes the presentations and relevant discussions of this meeting regarding the cause of chronic rejection, clinical diagnoses, risk factors, future prospects for intervention strategies, and general recommendations for the transplant community. Growing evidence indicates that chronic rejection is the aggregate sum of irreversible immunologic and nonimmunologic injuries to the renal graft over time. A history of acute rejection episodes and inadequate immunosuppression, likely attributable to inconsistent cyclosporine exposure or poor patient compliance, are among the most recognizable immunologic risk factors for chronic rejection. Donor organ quality, delayed graft function, and other donor and recipient variables leading to reduced nephron mass are nonimmunologic factors that contribute to the progressive deterioration of renal graft function. Clinical management of renal transplant recipients should incorporate both immunologic- and nonimmunologic-based intervention strategies aimed at minimizing risk factors to thwart the progression of chronic rejection and improve long-term allograft and patient survival.     

Computed tomography of Paget disease of the skull versus fibrous dysplasia

Objective. Radiologists are often challenged to review CT examinations of the skull without pertinent clinical information or plain radiographs. Skull lesions of fibrous dysplasia (FD) may often be confused with Paget disease (PD). The purpose of this article is to evaluate radiographic similarities and to find the signs that can differentiate PD from FD of the skull on head CT and to describe the CT imaging features of PD and FD. Design and patients. CT scans of the skull in eight cases of PD, 18 cases of FD (13 cases of skull and facial bones, five cases of only facial bones) and 10 normals were studied retrospectively. Results. Ten features were found to be similar in PD and FD and 10 other features were found to be dissimilar. The frequency of the 10 differentiating features was evaluated to determine their reliability in distinguishing one disorder from the other. The differentiating features in order of significance include: (1) “groundglass” appearance, (2) symmetry, (3) involvement of the paranasal sinuses, (4) thickness of the cranial cortices, (5) involvement of the sphenoid bone, (6) orbital involvement, (7) nasal cavity involvement, (8) presence of a soft tissue mass, (9) maxillary involvement, and (10) the presence of cyst-like changes. Conclusion. These 10 signs improve the radiologist’s skill in differentiating FD and PD.     

Who needs a fine-needle biopsy? A comparison of the ATA and ACR TI-RADS guidelines in a single-centre retrospective study

The 2015 American Thyroid Association (ATA) and 2017 American College of Radiology: Thyroid Imaging, Reporting and Data System (ACR TI-RADS) guidelines are two popular guidelines adopted to stratify sonographic risk of malignancy for thyroid nodules, and to select cases for fine-needle aspiration (FNA). To understand the test performance of the two systems in predicting thyroid malignancy, 164 thyroidectomy cases performed in a regional hospital in Hong Kong between January 2021 and June 2022 were reviewed. Sonographic images of the index nodule in each case were retrospectively classified into different risk categories using the ATA and ACR TI-RADS guidelines, respectively, followed by retrieval of cytological and pathological results, for comparison. The index nodule was proven malignant in 26.8% of cases in the final pathology. There was a strong and positive correlation between the ATA and ACR TI-RADS risk categories assignment (r_s = .931, p < .001). Recommending FNA according to the ATA had a better sensitivity for malignancy than using the ACR TI-RADS (81.8% vs 72.7%), at the expense of a lower specificity (10.8% vs 40.8%). The sensitivity for malignancy of both systems could be further improved if all fluorodeoxyglucose (FDG)-avid nodules were investigated with FNA regardless of sonographic features and size. There was a statistically significant association between “nodules with FDG avidity and nodules recommended for FNA by the ACR TI-RADS guideline” and an eventual malignant thyroid nodule (p = .002).     

Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery

BACKGROUND: Morphine-6-glucuronide (M6G) has promising preclinical characteristics and encouraging pharmacokinetic features for acute nociceptive pain. Early studies have produced a good safety profile when compared to morphine sulfate, although in surrogate pain models studies, a mixed picture emerged. A study to evaluate the efficacy and safety profile in a clinical setting was designed. METHODS: The authors conducted a double-blind, randomized, dose-finding study of patients scheduled to undergo major joint replacement. One hundred patients of both sexes were included, with 50 patients in each group. A loading dose of 10 mg of study medication was given intravenously at induction of anesthesia, and two further doses were allowed during surgery if required. Bolus doses via a patient-controlled analgesia system were given subcutaneously at 2 mg/dose and set at a 10-min lockout. Assessments of pain intensity and relief were recorded during the 24-h period. RESULTS: There were no statistically significant differences between the treatments for 24-h mean pain intensity. However, pain intensity was significantly higher in the M6G group than in the morphine group at 30 min and 1 h. There was no statistical difference in 24-h mean pain relief or retrospective pain scores at any time point during the 24-h period. The severity of sedation was significantly greater in the morphine group than in the M6G group at 30 min, 1 h, 2 h, and 24 h. Respiratory depression was greater in the morphine group than in the M6G group, and more patients in the morphine group withdrew from the study because of respiratory depression. CONCLUSIONS: Overall, M6G has an analgesic effect similar to that of morphine over the first 24 h postoperatively. However, M6G may be slower onset initially than morphine; therefore, a larger initial dose may be required.     

Tobacco use following liver transplantation for alcoholic liver disease: an underestimated problem.

Alcohol and tobacco use commonly co-occur, with at least 90% of those with an alcohol problem also using tobacco. Thus, 3 years ago when we discovered higher rate of late deaths due to lung and oropharyngeal cancer in patients who had received a transplant for alcoholic liver disease (ALD), we hypothesized that these patients were continuing to expose themselves to tobacco after liver transplantation (post-LTX) and that this behavior was increasing their risk for cancer. We subsequently began a prospective investigation of post-LTX tobacco use in patients having undergone LTX for ALD (n = 172). For 33 recipients we had data starting from our first assessment at 3 months post-LTX and for this subgroup we report on the details of the timing of tobacco use resumption and the redevelopment of nicotine addiction. We found that on average more than 40% are smoking across all time periods. ALD recipients resume smoking early post-LTX, increase their consumption over time, and quickly become tobacco dependent. These data highlight an underrecognized serious health risk for these patients and demonstrate our need for more stringent clinical monitoring and intervention for tobacco use in the pre- and post-LTX periods.     

Subrupture tendon fatigue damage

The mechanical and microstructural bases of tendon fatigue, by which damage accumulates and contributes to degradation, are poorly understood. To investigate the tendon fatigue process, rat flexor digitorum longus tendons were cyclically loaded (1–16 N) until reaching one of three levels of fatigue damage, defined as peak clamp‐to‐clamp strain magnitudes representing key intervals in the fatigue life: i) Low (6.0%–7.0%); ii) Moderate (8.5%–9.5%); and iii) High (11.0%–12.0%). Stiffness, hysteresis, and clamp‐to‐clamp strain were assessed diagnostically (by cyclic loading at 1–8 N) before and after fatigue loading and following an unloaded recovery period to identify mechanical parameters as measures of damage. Results showed that tendon clamp‐to‐clamp strain increased from pre‐ to post‐fatigue loading significantly and progressively with the fatigue damage level (p ≤ 0.010). In contrast, changes in both stiffness and hysteresis were significant only at the High fatigue level (p ≤ 0.043). Correlative microstructural analyses showed that Low level of fatigue was characterized by isolated, transverse patterns of kinked fiber deformations. At higher fatigue levels, tendons exhibited fiber dissociation and localized ruptures of the fibers. Histomorphometric analysis showed that damage area fraction increased significantly with fatigue level (p ≤ 0.048). The current findings characterized the sequential, microstructural events that underlie the tendon fatigue process and indicate that tendon deformation can be used to accurately assess the progression of damage accumulation in tendons. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:264–273, 2009