Factors affecting patient safety culture in a university hospital under the universal health insurance system: A cross-sectional study from Japan.

We conducted a cross-sectional study of patient safety culture aimed at examining the factors that influence patient safety culture in university hospitals under a universal health insurance system. The Hospital Survey on Patient Safety Culture developed by the Agency for Healthcare Research and Quality was used. The survey was distributed to 1066 hospital employees, and 864 responded. The confirmatory factor analysis showed a good fit of the results to the 12-composites model. The highest positive response rates were for "(1) Teamwork within units" (81%) and "(2) Supervisor/manager expectations and actions promoting patient safety" (80%), and the lowest was for "(10) Staffing" (36%). Hayashi's quantification theory type 2 revealed that working hours per week had the greatest negative impact on patient safety culture. Under a universal health insurance system, workload and human resources might have a significant impact on the patient safety culture.

The Relationship Between Duration of General Anesthesia and Postoperative Fall Risk During Hospital Stay in Orthopedic Patients.

OBJECTIVES: We performed a retrospective observational study to investigate the relationship between general anesthesia duration and postoperative falls of hospitalized patients who underwent orthopedic surgery. METHODS: We used electronic medical record data and incident report data from the Osaka Medical and Pharmaceutical University Hospital. The study included 4,042 patients admitted to the Department of Orthopedic Surgery from 2014 to 2018, and the following exclusion criteria were applied: no surgery, less than 18 years of age, and fall between admission and surgery. This study only considered falls that occurred within 21 days of surgery. The multivariate logistic regression model adjusted for patient background was used to determine the risk of falling according to the duration of general anesthesia. RESULTS: After exclusions, 3,398 patients were included in the analysis. Among them, 45 patients (1.32%) had fallen, of whom 7 (15.6%) were injured and 2 (4.4%) experienced fractures. Multivariate logistic regression analysis to determine the adjusted odds ratio showed that longer general anesthesia duration was an independent risk factor for postoperative falls. In addition, cardiovascular disease had significantly higher associations with postoperative falls. CONCLUSIONS: In the postoperative care of orthopedic patients, the risk of falling should be assessed by considering the duration of general anesthesia in addition to the traditional fall risk factors. Furthermore, falls could be prevented by educating patients and their caregivers about the risk and mobilizing staff to support postoperative patients at a higher risk of falls when they walk in the hospital.

Farnesol activates the intrinsic pathway of apoptosis and the ATF4-ATF3-CHOP cascade of ER stress in human T lymphoblastic leukemia Molt4 cells.

In this study, we demonstrate that treatment of T lymphoblastic leukemic Molt4 cells with farnesol activates the apoptosome via the intrinsic pathway of apoptosis. This induction was associated with changes in the level of intracellular potassium and calcium, the dissipation of the mitochondrial and plasma membrane potential, release of cytochrome c, activation of several caspases, and PARP cleavage. The induction of apoptosis by farnesol was inhibited by the addition of the pan-caspase inhibitor Z-VAD-fmk and by the exogenous expression of the anti-apoptotic protein Bcl2. Analysis of the gene expression profiles by microarray analysis revealed that farnesol increased the expression of several genes related to the unfolded protein response (UPR), including CHOP and CHAC1. This induction was associated with the activation of the PERK-eIF2α-ATF3/4 cascade, but not the XBP-1 branch of the UPR. Although farnesol induced activation of the ERK1/2, p38, and JNK pathways, inhibition of these MAPKs had little effect on farnesol-induced apoptosis or the induction of UPR-related genes. Our data indicate that the induction of apoptosis in leukemic cells by farnesol is mediated through a pathway that involves activation of the apoptosome via the intrinsic pathway and induction of the PERK-eIF2α-ATF3/4 cascade in a manner that is independent of the farnesol-induced activation of MAPKs.

[Hypereosinophilic syndrome accompanied with digital gangrene: efficacy of therapeutic angiogenesis by autologous bone marrow mononuclear cells transplantaion].

A 62-year-old-man presented to our hospital with complaints of coldness, numbness, pain, weakness and cyanosis on the fingers and toes in March 2010. Laboratory findings revealed marked eosinophilia (46.6%; WBC 20600/µl), an elevation of serum creatine kinase, proteinuria and hematuria. He was diagnosed as hypereosinophilic syndrome (HES) without evidence to support a diagnosis of underlying diseases causing eosinophilia. After the initiation of corticosteroid therapy, peripheral eosinophil count was dramatically decreased, and both serum CK value and urinary findings became normalized. However, his symptoms persisted and digital necrotic changes developed. Angiography of the bilateral upper and lower extremities showed multiple arterial occlusions with poor collaterals. The digital gangrenes were unresponsive to peripheral circulation ameliorators and gradually progressed. In July 2010, autologous transplantation of bone marrow mononuclear cells was performed for achievement of therapeutic angiogenesis. His digital skin color was ameliorated by the angiogenic therapy in two weeks, and digital gangrenes did not progress after that. After amputation of his fingers and toe, cut surfaces healed with favorable epithelization, and the symptoms were subsequently eliminated. Moreover, during three years after the therapy, as well as the effect on the skin lesion, the significant improvement in peripheral circulation was observed. Therefore, we proposed that therapeutic angiogenesis by autologous bone marrow mononuclear cells transplantation was a novel and effective treatment for intractable digital gangrene associated with HES.

Double cancer of plantar malignant melanoma and vulvar extramammary Paget's disease.

A 75-year-old woman presented with a 2-year history of a pigmented nodular lesion on her left sole and a 9-year history of a red infiltrative plaque on the vulva. The plantar lesion was a 15-mm ulcerated nodule located at the center of a 25-mm atypical pigmentation region; the nodule was clinically suspected to be a malignant melanoma. Histopathological analysis of the vulvar lesion biopsy sample indicated extramammary Paget's disease (EMPD). There was no evidence of metastasis in the computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography scans. We simultaneously performed a wide excision of both lesions and a left inguinal sentinel lymph node biopsy. Melanoma cells were identified in the sentinel lymph nodes, and left radical lymph node dissection was performed after a course of neoadjuvant chemotherapy. All the lymph nodes that were resected during the second operation tested negative for melanomas, and the plantar lesion was diagnosed as a stage IIIB malignant melanoma (pT4b, Na2, M0). Thereafter, we administrated four courses of chemotherapy, and 8 months after the operation, there was no evidence of recurrence or metastatic lesions. We present a case report of double cancer: a plantar malignant melanoma and vulvar EMPD, and also discuss the possible genetic mutations responsible for these two tumors.

The role of interleukin-33 in chronic allergic conjunctivitis.

PURPOSE: The authors discovered a genetic association between the ST2L gene and atopy. The ST2L gene encodes a membrane-bound functional marker for Th2 cells. Recently, a novel Th2 cytokine, interleukin-33 (IL-33), was discovered to be a specific ligand for ST2L. The authors investigated the role of IL-33 in chronic allergic conjunctivitis. METHODS: Immunohistochemical analysis was carried out using giant papillae samples obtained from patients with atopic keratoconjunctivitis. The authors used proinflammatory stimuli to clarify IL-33 mRNA/protein-inducing signals with cultured human conjunctival epithelial cells, fibroblasts, human umbilical vascular endothelial cells, and mast cells. These cells were also used to examine the expression of ST2L (IL-33R). Finally, cultured mast cells were stimulated with recombinant IL-33 (rIL-33) to examine the downstream signals. RESULTS: The authors found IL-33 protein expression in human vascular endothelial cells in the giant papillae and in the control conjunctivae. IL-33 expression was also observed in conjunctival epithelium of the giant papillae but not in the control conjunctivae. IL-1 beta stimulation upregulated IL-33 mRNA expression in conjunctival fibroblasts. The authors also confirmed mature IL-33 protein expression in ocular resident cells by Western blot analysis. Preferential ST2L expression was observed in human mast cells, and phosphorylation of p38 MAPK and IL-13 mRNA induction was observed in human cultured mast cells after rIL-33 stimulation. Phosphorylation of p38 MAPK was inhibited by soluble ST2 protein. CONCLUSIONS: The IL-33-ST2 signaling cascade plays some roles in the pathophysiology of chronic allergic conjunctivitis through the activation of mast cells.

Successful treatment of Stevens-Johnson syndrome with steroid pulse therapy at disease onset.

PURPOSE: To evaluate the visual prognosis of patients with Stevens-Johnson syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), followed by general and topical high-dose corticosteroids administration from disease onset. DESIGN: Prospective, observational case series. METHODS: Between May 1, 2003 and June 30, 2005, we enrolled 5 patients with SJS or TEN with ocular complications at the acute stage. Intravenous pulse therapy with methylprednisolone (steroid pulse therapy; 500 or 1000 mg/day for 3 to 4 days) was initiated within 4 days from disease onset. Topically, 0.1% betamethasone was applied over 5 times daily for at least 2 weeks. Visual acuity (VA) and slit-lamp microscopic appearance 1 year from disease onset were evaluated. RESULTS: At the first examination, corneal or conjunctival epithelial defects and pseudomembranous conjunctivitis were present in all cases. Skin eruptions dramatically improved after steroid pulse therapy. Although ocular inflammation increased for several days, pseudomembranes disappeared and corneal and conjunctival epithelium regenerated within 6 weeks. At the chronic stage, all eyes had clear corneas with the palisades of Vogt (POV), implying the presence of corneal epithelial stem cells. Best-corrected VA was 20/20 or better in all eyes. Five eyes showed superficial punctate keratopathy. No eye had cicatricial changes except for 1 with slight fornix shortening. No significant adverse effects of steroid occurred during all clinical courses. CONCLUSIONS: Steroid pulse therapy at disease onset is of great therapeutic importance in preventing ocular complications. Topical betamethasone also shows great promise for preventing corneal epithelial stem cell loss in the limbal region and cicatricial changes.

Platelet-derived microparticles and soluble P-selectin as platelet activation markers in patients with atopic dermatitis.

Plasma levels of platelet-derived microparticles (PDMPs) and soluble P-selectin (sP-selectin) were investigated as markers of platelet activation in 46 atopic dermatitis (AD) patients, 20 non-atopic urticaria patients and 22 healthy controls. The relationships between these markers and the scoring AD (SCORAD) index, blood eosinophil number, serum IgE, and serum lactate dehydrogenase were also investigated in AD patients. Plasma PDMPs and sP-selectin levels were significantly higher in AD patients compared with the other two groups. In multiple regression analysis, the SCORAD index was the most significant factor associated with the platelet activation markers. Among the SCORAD index components, excoriations were most closely related to the markers. The elevated levels of PDMPs and sP-selectin were significantly reduced following skin lesion improvement by drug treatment. Our results show that blood platelets are activated in AD patients upon aggravation of eruption, suggesting that activated platelets may be involved in the pathomechanism of AD.

Immunoregulatory T cells in the peripheral blood of melanoma patients treated with melanoma antigen-pulsed mature monocyte-derived dendritic cell vaccination.

BACKGROUND: Regulatory T cells (Treg) may inhibit monocyte-derived melanoma antigen-pulsed dendritic cells (DC) vaccination in treatment of melanoma. However, the Treg level in peripheral blood mononuclear cells (PBMCs) following DC vaccination has not been examined in melanoma patients in Japan. OBJECTIVE: To evaluate differences in the helper T cell and Treg population and mRNA levels of Treg in pre- and post-DC vaccination PBMCs obtained from melanoma patients. METHODS: Levels of intracellular forkhead box protein 3 (Foxp3) mRNA as well as levels of CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(+) T cells were examined by real-time PCR and flow cytometry using PBMCs from 9 patients who received DC vaccination. RESULTS: Eight of the 9 cases and 7 of the 9 cases showed increased populations of CD4(+)CD25(+) T cells and CD4(+)CD25(+)Foxp3(+) T cells, respectively after repeated DC vaccination. Five of 8 cases showed an increase of Foxp3 mRNA after treatment. Four of these 5 cases also had increased CD4(+)CD25(+) and CD4(+)CD25(+)Foxp3(+) T cells, but the fifth case showed a decrease in CD4(+)CD25(+)Foxp3(+) T cells. Three cases showed a decrease of Foxp3 mRNA. One of these 3 cases showed decreased population of CD4(+)CD25(+)Foxp3(+) T cells, but two cases showed increased population of CD4(+)CD25(+)Foxp3(+) T cells. In 3 of 8 cases Foxp3 expression at the cellular (protein) and mRNA level were inconsistent. CONCLUSION: Repeated DC vaccination may commonly induce Treg and helper T cells at the cellular level. However, there are a few discrepancies of Treg expression at cellular and mRNA level.

Immunohistological analysis of peptide-induced delayed-type hypersensitivity in advanced melanoma patients treated with melanoma antigen-pulsed mature monocyte-derived dendritic cell vaccination.

BACKGROUND: In melanoma patients vaccinated with monocyte-derived melanoma peptide-pulsed dendritic cells (DC), the delayed-type hypersensitivity (DTH) reactions have been examined as a surrogate marker to determine if acquired immunity is induced by DC vaccination. To date, however, only limited information has been reported as for histopathological analyses of DTH. OBJECTIVE: To evaluate tumor-specific immunomonitoring histopathologically after DC vaccination in melanoma patients. METHODS: Seven patients previously vaccinated with monocyte-derived melanoma peptide-pulsed DCs were challenged with recall antigenic peptide injection in the skin of the forearm. Using immunohistochemical techniques, the presence of immune cells and the expression of CD4, CD8, interleukin (IL)-2, IL-4, IL-10, Foxp3, CD1a, CD1d, and interferon (IFN)-gamma was investigated at the site of injection where a DTH reaction developed. RESULTS: Strong DTH reactions from infiltrated erythema to bullae formation were detected in all 7 cases. Biopsies taken from the DTH site revealed heavy infiltration of mononuclear cells and eosinophils in the dermis and subcutaneous tissue. Cells staining positively for CD4, CD8, IL-2, IL-4, Foxp3, CD1d, and IFN-gamma were increased at the site 48h after antigen injection in all cases. Cells positive for IL-10 were never found in any patient. Regulatory T cells appeared 6h after injection and reached their maximum at day 7. CONCLUSIONS: The significant induction of CD8(+)T cells as well as both Th1 and Th2-type cells at the site of DTH suggests that effective antigen presentation leading to anti-tumor immune responses has taken place. Inhibitory mechanisms may also develop as the disappearance of the DTH response could be related to an increase in Foxp3+ cells.

Elevated platelet activation in patients with atopic dermatitis and psoriasis: increased plasma levels of beta-thromboglobulin and platelet factor 4.

BACKGROUND: Beyond their role in hemostasis and thrombosis, platelets are important for modulating inflammatory reactions. Activated platelets play a role in the pathomechanism of inflammatory diseases such as asthma, but little is known about platelet activation in chronic skin inflammation, including atopic dermatitis (AD) and psoriasis. Furthermore, the relationship between platelet activation and disease severity is not understood. This work was performed to investigate plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) as platelet activation markers in patients with AD or psoriasis, and to determine the relationships between these markers and disease severity. METHODS: Plasma levels of beta-TG and PF4 were measured by enzyme-linked immunoassay in 22 healthy controls, 44 patients with AD, and 16 patients with psoriasis. The relationships between these markers and the scoring AD (SCORAD) index, blood eosinophilia, serum IgE and serum lactate dehydrogenase were investigated in AD patients, and relationships with the psoriasis area and severity index (PASI) score were examined in psoriatic patients. RESULTS: Plasma beta-TG and PF4 levels were significantly higher in patients with AD or psoriasis compared with healthy controls. beta-TG and PF4 levels correlated with the SCORAD index, and PF4 levels correlated with PASI scores. Elevated beta-TG and PF4 levels were significantly reduced after treatments. CONCLUSIONS: Our results show that blood platelets are activated in patients with AD or psoriasis, suggesting that activated platelets play a role in the pathomechanism of chronic skin inflammation. Furthermore, plasma beta-TG and PF4 may be markers for the severity of AD and psoriasis.

Stat6-independent tissue inflammation occurs selectively on the ocular surface and perioral skin of IkappaBzeta-/- mice.

PURPOSE: IkappaBzeta(-/-) mice have been reported to be affected by allergic dermatitis. This study was conducted to analyze the pathophysiological role of IkappaBzeta and to address the functional relevance of Th2-mediated immune responses in the development of ocular surface inflammation and dermatitis by IkappaBzeta(-/-) mice. METHODS: BALB/c background IkappaBzeta(-/-) mice were established without individual differences; IkappaBzeta/Stat6 double-knockout (WKO) mice unable to produce Th2 cytokine were created; and microscopic-, histologic-, and immunochemical studies were performed. In IkappaBzeta(-/-) mice the serum IgE levels were examined by ELISA, and quantitative PCR was used to study the gene expression of IFN-gamma, IL4, IL10, TNFalpha, IL6, IL17alpha, and CCL11 in eyelid tissue. RESULTS: IkappaBzeta(-/-) mice exhibited a severe inflammatory phenotype on the ocular surface and perioral skin. The inflammatory infiltrates in the perioral skin consisted primarily of CD4(+) and CD8(+) cells; CD4(+) and CD45R/B220(+) cells were mainly detected in the conjunctiva. In eyelid and perioral skin tissue, the expression of IL-17alpha and of Th1 and Th2 cytokines, but not of CCL11, was augmented. IkappaBzeta(-/-) and IkappaBzeta(+/-) mice did not differ significantly in their serum total IgE levels before, 0 to 4 weeks, and 5 to 9 weeks after disease onset. IkappaBzeta/Stat6 WKO mice showed the same or slightly more severe inflammation than did IkappaBzeta(-/-) mice. CONCLUSIONS: IgE and Stat6 are not responsible for the immune pathologic response leading to the development of ocular surface and perioral skin inflammation in IkappaBzeta(-/-) mice. IkappaBzeta(-/-) mice may be a suitable model for Stevens-Johnson syndrome, but not for atopic dermatitis.

Narrow-band ultraviolet B phototherapy in patients with recalcitrant nodular prurigo.

Management of nodular prurigo has been less than satisfactory. Conventional therapies such as systemic antihistamines and topical steroids have not been particularly successful. The effects of narrow-band ultraviolet B (NB-UVB) phototherapy in the treatment of various inflammatory dermatoses have been proven, however, no data exist on the efficacy and the duration of remission in NB-UVB monotherapy for nodular prurigo. The aim of this study was to evaluate the effect of NB-UVB phototherapy on recalcitrant nodular prurigo. NB-UVB phototherapy was performed once a week on 10 patients with recalcitrant nodular prurigo. The initial dose was 0.4 J/cm(2), and the dose was increased by 0.1 J/cm(2) for each treatment. The treatment was performed until the eruption was almost clear. In each patient, a mean cumulative dose of 23.88 J/cm(2) was applied over a mean of 24.3 irradiations. The mean maximum daily dose of ultraviolet B was 1.2 +/- 0.4 J/cm(2). NB-UVB phototherapy notably improved the eruption of nodular prurigo in all patients. Follow up at 1 year revealed that only one patient had relapsed. The remaining nine patients continued to derive long-term benefits. NB-UVB phototherapy appears to be an effective treatment for recalcitrant nodular prurigo, offering long-term benefits in the majority of those treated.

The role of platelets in leukocyte recruitment in chronic contact hypersensitivity induced by repeated elicitation.

Platelets have been shown to be important in inflammation, but their role in chronic allergic dermatitis remains unclear. To investigate the role of platelets in a mouse model of chronic contact hypersensitivity induced by repeated elicitation, mice were sensitized and repeatedly elicited in ears with hapten, with or without platelet depletion, by administering antiplatelet antibody or busulfan. Ear thickness, leukocyte infiltration, serum IgE, and scratching behavior significantly decreased in thrombocytopenic mice. cDNA microarray of ear tissue showed reduced gene expression associated with Th2 lymphocytes. Flow cytometry showed increased P-selectin expression on platelets and an increased number of platelet-leukocyte aggregates in blood of repeatedly elicited mice, compared with sham-sensitized mice. In thrombocytopenic mice, inflammation was restored by platelet infusion, which was blocked by platelets from P-selectin-deficient mice or by pretreating platelets with anti-P-selectin antibody. Moreover, injection of activated platelet supernatant into ears led to increased leukocyte infiltration, which was blocked by pretreating platelets with antiplatelet compounds or neutralizing several chemokines in the platelet supernatant. These results suggest that platelets induce leukocyte recruitment into skin by forming platelet-leukocyte aggregates via P-selectin in blood and secreting chemokines at inflamed sites. Therefore, controlling platelet activity may be useful for treatment of chronic allergic dermatitis.

Vaccination of Japanese patients with advanced melanoma with peptide, tumor lysate or both peptide and tumor lysate-pulsed mature, monocyte-derived dendritic cells.

We performed a clinical trial to assess the feasibility and efficacy of immunotherapy with peptides, tumor lysate or both peptides and tumor lysate-pulsed mature, monocyte-derived dendritic cells (DC) for advanced malignant melanoma patients that are resistant to conventional therapies. Sixteen patients were enrolled in this trial. All patients received DC vaccines i.d. in the proximal thigh, close to the inguinal lymph nodes, one treatment per week or 2 weeks. Several factors such as clinical findings, computed tomography (CT) images, delayed type hypersensitivity (DTH) response, enzyme-linked immunosorbent spot (ELISPOT) assay, and immunohistochemistry in primary, metastatic lesions and the DTH site were evaluated. Clinical results through DC vaccination were as follows: in 11 evaluable cases, three stable disease, six progression of disease and two disease-free from the time of study entry to the completion of one vaccination course. One patient showed reduction of the tumors in the metastases on chest CT during the first and second course of DC vaccination. Ten out of 14 evaluable cases showed positive DTH responses to more than one treatment with melanoma peptides or tumor lysate. Eight out of 13 evaluable cases showed positive immunological responses to more than one treatment with melanoma peptides or tumor lysate in an ELISPOT assay. As for the experiences with toxicity and adverse reactions, autosensitization dermatitis-like eruptions appeared in five cases during DC vaccination. No severe adverse effects were seen in any of the patients. In our study, the clinical efficacy in prolongation of the patients' survival was confirmed. At the same time, cancer immunoediting of the tumor was also found. It will be necessary to improve the tumor-specificity of this therapeutic approach and to analyze the mechanism(s) of tumor escape from immunosurveillance in melanoma.

Successful treatment of diabetic gangrene with topical application of a mixture of peripheral blood mononuclear cells and basic fibroblast growth factor.

Diabetic gangrene is a non-healing skin ulcer that is often resistant to most common treatments. It is caused by microvascular disorders and an immunocompromised state which are induced by diabetes mellitus. We report a 65-year-old man with an aggressive, refractory diabetic gangrene on his left foot. Treatment of his diabetic gangrene with topical application of a mixture of peripheral blood mononuclear cells (PBMC) and basic fibroblast growth factor (bFGF) resulted in a dramatic improvement in a short time. The ulcer was completely closed and, in the past 6 months, no new ulceration has been observed. The patient is able to stand and walk by himself. Topical application of a mixture of PBMC and bFGF appears to be a useful, non-invasive and convenient method for the treatment of diabetic gangrene.

High incidence of T-cell lymphomas in mice deficient in the retinoid-related orphan receptor RORgamma.

Nuclear receptors are critical regulators of many physiological processes and have been shown to be involved in a variety of disease processes, including malignant neoplasms. Our laboratory is investigating the function of the retinoid-related orphan receptor gamma (RORgamma) and its possible role in disease. Studies of mice deficient in the expression of RORgamma demonstrated that this receptor plays a crucial role in the regulation of thymopoiesis and lymph node organogenesis. In this study, we show that changes in homeostasis in the thymus of RORgamma-/- mice are associated with a high incidence of T-cell lymphomas. Over 50% of the deficient mice of mixed genetic background die within the first 4 months as a result of thymic lymphomas. A high incidence of lymphomas was also observed in RORgamma-/- 129/SvEv mice. The lymphoblastic cells metastasized frequently to spleen and liver. No other tumor types were detected in any of RORgamma-/- mice that died during the course of the experiment, and none of the heterozygous mice developed thymic lymphomas. Lymphoma formation was associated with increased cellular proliferation and an increase in the number of apoptotic cells. When placed in culture, the RORgamma-/- lymphoblastic cells underwent accelerated "spontaneous" apoptosis at a rate similar to that of RORgamma-/- thymocytes. Upon prolonged culture, several lymphoblastic cell lines could be established. Analysis of the immunophenotype of the lymphoblastic cells showed that the CD4 and CD8 subpopulations varied substantially among different lymphomas. The established cell lines consisted mostly of CD44-CD25+CD4-CD8- cells. Our studies indicate that loss of RORgamma disturbs homeostasis in the thymus by enhancing apoptosis and cellular proliferation. The latter may enhance the probability of individual cells to acquire genetic alterations that make them escape negative selection and normal differentiation programs and as a consequence lead to increased susceptibility to the development of T-cell lymphoma.