Inhibition of concanavalin A-induced acute T cell dependent hepatic damage in mice by hypothyroidism

Abstract: Aims/Background: Concanavalin A (Con A) activates T lymphocytes and causes acute T-cell-mediated hepatic injury in mice. Decreased thyroid hormonal production is associated with a variety of immunological manifestations, including inactivation of macrophages with reduced TNF production and reduced soluble IL-2 receptors in the serum. We have recently shown that hypothyroidism prevents the development of cirrhosis and also minimizes hepatic damage in rats with fulminant hepatic failure. In the present study we examined the effects of hypothyroidism on a mouse model of Con A induced T cell-mediated acute hepatitis. Methods: Hypothyroidism was induced both medically (MMI, PTU) and surgically. Eight groups of 10 mice each were studied: euthyroid controls (2 groups: water, Con A) and hypothyroid (6 groups: MMI, PTU, Surgical, MMI-Con A, PTU-Con A, Surgical-Con A). Results: Hepatic inflammation was significantly decreased in each of the Con A treated hypothyroid groups of mice. The serum transaminases, TNF-α and IL-6 levels were significantly elevated in the Con A treated group while near normal levels were found in the hypothyroid Con A treated groups (mean±SE AST: 1499±18 vs 78±10 IU/1, p<0.001; TNF: 2500±250 vs 135± 15 pg/ml. p<0.001, IL-6: 12,200±300 vs 1260±140 pg/ml, p<0.001, respectively). Conclusions: Hypothyroidism, independent of the mode of induction, can effectively inhibit the development of acute T cell-mediated liver damage in mice. These results suggest that some decrease in thyroid function might have a role in the prevention of immune mediated liver diseases.     

Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia

Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.     

Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice

OBJECTIVE: Azathioprine and 6-mercaptopurine interact in purine metabolism and DNA synthesis, thus their potential mutagenic effects have been of concern in the management of inflammatory bowel disease (IBD), especially in patients of childbearing age. Although several clinical studies have indicated their safety in both reproduction and pregnancy, in a recent large epidemiological study concerns were raised about their adverse effects in pregnant patients with IBD, and experimental or basic data on this subject are limited. The aim of this study was to investigate sperm production, sperm quality, and reproductive outcome following prolonged 6-MP administration to male mice. MATERIAL AND METHODS: Highly inbred Balb/c adult male mice were used. 6-MP at doses of 2, 5, and 8 mg/kg (n = 9 for each group) was given daily for 51 days and the treatment group was compared with controls. After 45 days of treatment, the mice were mated with females. Following 13 days of pregnancy, the products of conception were evaluated and live fetuses were examined for gross malformations. Sperm production and morphology were examined after 51 days of 6-MP administration. RESULTS: Treatment with 6-MP at all doses did not affect sperm morphology and sperm production in the testicular tubules, as compared with controls (70% normal sperm). However, pregnancy rates were inversely related to escalating doses of 6-MP: 55%, 41%, 28%, and 16% for control, 2, 5, and 8 mg/kg groups, respectively. Resorption rates (abortions) were 21% in the control group as compared with 45-50% in all the treatment groups, but the incidence of major congenital malformations was not increased. CONCLUSIONS: Long-term 6-MP treatment in male mice did not impair sperm production and sperm morphology. However, a significantly high rate of embryonic resorption indicated occult sperm damage. Thus, normal sperm analysis does not necessarily imply that sperm damage at genetic level did not occur. It is difficult to extrapolate from these results to the clinical use of 6-MP/azathioprine in IBD patients; however, further basic genetic testing for DNA damage and clinical follow-up are warranted.     

Erythropoietin has an anti-myeloma effect - a hypothesis based on a clinical observation supported by animal studies

Recombinant human erythropoietin (rHuEpo) was introduced into clinical practice more than a decade ago, and has been found to be effective in the treatment of several types of anemia, including anemia of end-stage renal failure and cancer-related anemia. No study has suggested that Epo might have an effect on the biology of the disease, nor any survival advantage to cancer patients treated with Epo for anemia has been reported. Here we report six patients with advanced multiple myeloma (MM) with very poor prognostic features, whose expected survival was <6 months. All six patients were treated with rHuEpo for their anemia, either without any chemotherapy or very mild chemotherapy for a short time. Yet, surprisingly they lived for 45-133 months totally from MM diagnosis and 38-94 months with rHuEpo (with a good quality of life). In fact, one patient, is still alive and well, more than 8 yr after chemotherapy was discontinued because of a resistant aggressive disease. The course in these six MM patients led us to hypothesize that Epo might have an antineoplastic or antimyeloma effect. We proceeded and tested that hypothesis in mouse models of myeloma (Mittelman M et al., Proc Natl Acad Sci USA 98:5181,2001). In these models we confirmed that rHuEpo induced tumor regression in about 50% of the BALB/c mice inoculated with MOPC-315 myeloma cells. We then presented evidence that the mechanism is a new immune-mediated phenomenon, via activation of CD8+ T cells. Furthermore, evidence from the literature supports the antineoplastic effect of Epo. Epo might be used as an adjunct immune treatment in various malignant diseases, in addition to the current regimens and chemotherapeutic protocols. Future trials should determine the role of Epo in myeloma and cancer treatment, besides clarifying concerns about the presence of Epo receptors on some tumor cells.     

Clinical aspects of ballistic peripheral nerve injury: shrapnel versus gunshot

Objectives

Ballistic injuries to peripheral nerves pose special challenges in terms of indications, timing and type of surgical intervention. The aim of the present work was to analyze our experience in the surgical treatment of peripheral nerve ballistic injuries with respect to the mechanism of injury (gunshot versus shrapnel), and identify common and dissimilar prognostic factors in both types of injury.

Methods

This study was conducted on 42 patients totaling 58 nerves. Twenty-two patients (32 nerves) were injured by gunshot and 20 patients (26 nerves) by shrapnel. Median postoperative follow-up was 33 months (range 12 months to 14 years).

Results

Overall postoperative outcome appears to be more favorable for gunshot-wound (GSW) patients than shrapnel-injured patients, especially in terms of neuropathic pain relief (75 % vs. 58 % respectively, p < 0.05). Presence of foreign particles in shrapnel injured patients has a negative impact on the surgical outcome in terms of rate of pain improvement (28 % compared to 67 % in patients with and without foreign particles, respectively). Nerve graft reconstruction, rather than neurolysis, seems to be the more beneficial treatment for shrapnel-induced neuropathic pain (100 % vs. 47 % in improvement rate, respectively). Early surgical intervention (median 2 months after injury) significantly relieved neuropathic pain in 83 % of shrapnel-injured patients compared to 58 % in patients operated later.

Conclusions

This study suggests that shrapnel injury is more destructive for nerve tissue than gunshot injury. Our impression is that early surgical intervention in shrapnel injuries and split nerve grafting (especially when small fragments are recognized in the nerve) significantly improve the patient’s functional activity and quality of life.     

Predictive factors for latency period and a prognostic model for survival in patients with therapy‐related acute myeloid leukemia

Therapy‐related acute myeloid leukemia (t‐AML) is an increasingly recognized sequela in patients receiving chemotherapy or radiotherapy for a primary malignancy or autoimmune disease. This study assessed factors related to the latency period (LP) between the antecedent disorder (AD) and t‐AML diagnosis and developed a comprehensive prognostic model to predict overall survival (OS). We evaluated a cohort of newly diagnosed t‐AML patients treated with cytarabine‐based induction therapy from 2001 to 2011. Multivariable linear and proportional hazards models were used to assess the impact of different classes of chemotherapy on the LP and to identify independent prognostic factors for OS. Of 730 treated AML patients, 58 (7.9%) had t‐AML. Median LP to t‐AML was 5.6 years (range, 0.5–38.4). 64% of patients achieved CR and median OS was 10.7 months. Independent prognostic factors of short LP were age at AD (P < 0.0001) and prior treatment with mitotic inhibitors (P = 0.05). Unfavorable cytogenetics (P = 0.004), antecedent hematologic or autoimmune disease (P = 0.01), age >60 (P = 0.03), and platelet count <30,000 μL (P = 0.04) at the time of t‐AML diagnosis were prognostic for inferior OS. A prognostic model using these factors was developed that risk stratified t‐AML patients into two groups: favorable and unfavorable. Patients in the favorable group had a median OS of 37.6 months compared with 6.4 months in patients comprising the unfavorable group (P < 0.0001). Multicomponent prognostic models integrating disease or treatment‐related covariates can help better understand how t‐AML evolves; and can be clinically useful in risk stratifying t‐AML patients undergoing induction therapy. Am. J. Hematol. 89:168–173, 2014. © 2013 Wiley Periodicals, Inc.     

Pneumococcal vaccine targeting strategy for older adults: Customized risk profiling

Background

Current pneumococcal vaccine campaigns take a broad, primarily age-based approach to immunization targeting, overlooking many clinical and administrative considerations necessary in disease prevention and resource planning for specific patient populations. We aim to demonstrate the utility of a population-specific predictive model for hospital-treated pneumonia to direct effective vaccine targeting.

Methods

Data was extracted for 1,053,435 members of an Israeli HMO, age 50 and older, during the study period 2008–2010. We developed and validated a logistic regression model to predict hospital-treated pneumonia using training and test samples, including a set of standard and population-specific risk factors. The model's predictive value was tested for prospectively identifying cases of pneumonia and invasive pneumococcal disease (IPD), and was compared to the existing international paradigm for patient immunization targeting.

Results

In a multivariate regression, age, co-morbidity burden and previous pneumonia events were most strongly positively associated with hospital-treated pneumonia. The model predicting hospital-treated pneumonia yielded a c-statistic of 0.80. Utilizing the predictive model, the top 17% highest-risk within the study validation population were targeted to detect 54% of those members who were subsequently treated for hospitalized pneumonia in the follow up period. The high-risk population identified through this model included 46% of the follow-up year's IPD cases, and 27% of community-treated pneumonia cases. These outcomes were compared with international guidelines for risk for pneumococcal diseases that accurately identified only 35% of hospitalized pneumonia, 41% of IPD cases and 21% of community-treated pneumonia.

Conclusions

We demonstrate that a customized model for vaccine targeting performs better than international guidelines, and therefore, risk modeling may allow for more precise vaccine targeting and resource allocation than current national and international guidelines. Health care managers and policy-makers may consider the strategic potential of utilizing clinical and administrative databases for creating population-specific risk prediction models to inform vaccination campaigns.     

The weight of MMRV-related febrile convulsions among other clinical factors contributing to febrile convulsions in children

Background

It was previously demonstrated that MMRV vaccine causes a higher rate of febrile convulsions (FC) compared to the MMR vaccine. Additional risk factors for FC include age, familial tendency, day care attendance, viral diseases, complications at birth and developmental delay.

Objective

We evaluated the relative and attributable risk of FC for vaccinees’ age, ethnicity, low birth weight, preterm birth and MMRV vaccination in 10–24 months old children.

Methods

Data on medical history and vaccination were extracted from data warehouses of Clalit Health Services and Israel's Ministry of Health and linked on an individual record level for 90,294 MMR- and 8344 MMRV-vaccinees. A retrospective study design was used to reveal the risk factors associated with FC in study participants.

Results

During the second week after immunization, an elevated relative risk of FC was demonstrated in MMRV-recipients (adjusted RR = 2.16 (95%CI: 1.01; 4.64)). However, the cumulative incidence of FC during the entire 40-day observation period did not differ between the MMR and MMRV vaccinees. The MMRV-specific attributable risk of FC was not statistically significant at any point of observation period and was exceedingly low compared to other risk factors, equaling 5.3 FC cases per 10,000 vaccinees (95%CI: −1.4; 12.2).

Discussion

Our findings demonstrate that MMRV-associated FC in 10–24 months old contributes very marginally to the overall rate of FC in this population.

Conclusion

Given the low number of MMRV-specific FC cases, their transient nature and the benefit of vaccination, the overall benefit-risk of the vaccine can be considered favourable. Nonetheless, the option of separate immunization with MMR + V should be offered to parents, in order to maintain sufficient vaccine uptake in the population.