Regulatory T cells: prospective for clinical application in hematopoietic stem cell transplantation

PURPOSE OF REVIEW: Regulatory T cells exert a dominant effect in controlling autoimmunity and maintaining peripheral tolerance. Regulatory T cells are also involved in preventing allograft rejection and graft versus host disease. Cellular therapy with expanded regulatory T cells represents a promising approach to control T-cell mediated pathology. In this review we will summarize the efforts to design new methods for expanding regulatory T cells and exploit their regulatory function as cellular therapy for the treatment of graft versus host disease after hematopoietic stem cell transplantation. RECENT FINDINGS: Among CD4+ T cells, the best described are the naturally occurring CD4+CD25+ regulatory T cells and type 1 regulatory T cells. Recent progress has been made in the characterization of both subsets in terms of isolation and induction, respectively. However, a clear definition of their mechanisms of action has still to be achieved. SUMMARY: Better understanding of the mechanisms of suppression mediated by regulatory T cells might enable their use to modulate specific immune responses. Moreover, the recent development of methods allowing the ex-vivo expansion of regulatory T cells, to provide sufficient number of cells for in-vivo infusion, represents the first step toward the use of these cells as cellular therapy for the treatment of immunologic and hematological diseases.     

Primary mediastinal choriocarcinoma in a male metastatic to the choroid

Summary A rare metastatic choroidal tumor from primary mediastinal choriocarcinoma in a male is described. This tumor secreted gonadotrophins and showed the histopathologic characteristics of cytotrophoblast and syncytiotrophoblast cells. Early metastatic disease resulted in rapid death; the development of the choroidal metastatic lesion was diagnosed at autopsy.     

Spiromustine: a new agent entering clinical trials

Investigational New Drugs - Spiromustine is a new alkylating agent, of interest since it was rationally designed as a lipophilic compound capable of penetrating the CNS. This lipophilicity may also...     

Synovial cysts of the hip joint and iliopsoas bursitis: A spectrum of imaging abnormalities

Synovium-related soft tissue disease around the hip constitutes a spectrum ranging from isolated iliopsoas bursitis to pure articular synovial herniations without bursal involvement. The clinical, pathologic, and radiographic features of these entities are discussed as they pertain to the variety of underlying disorders which predispose to their occurrence. Nine case reports are utilized to illustrate the variable clinical and radiographic presentations which may be encountered. Based upon these cases as well as those in the literature, an imaging algorithm has been developed which should eliminate unnecessary studies and allow prompt and accurate diagnosis.     

Sudden sensorineural hearing loss: our experience in diagnosis, treatment, and outcome

OBJECTIVES: To describe our experience concerning sudden sensorineural hearing loss (SSNHL) in a large single-institution series of SSNHL patients and to discuss the results. METHOD: This was a retrospective study, and the charts of 156 consecutive inpatients (65 males, mean age 44 years, range 10-74 years; 91 females, mean age 46 years, range 15-75 years) with the diagnosis of SSNHL from 1987 to 2000 were reviewed. One hundred forty-three of 156 patients received multidrug therapy (plasma expanders, antiaggregants, steroids), whereas only 13 SSNHL patients received hyperbaric oxygen therapy. RESULTS: Old age, vascular and metabolic risk factors, and cigarette smoking do not a have a high prevalence in the SSNHL population. An etiologic factor was detected in 23 of 156 (15%) cases (16 cases of acute infection, 4 cases of neurovascular conflicts, 2 cases of cerebellar angiomas, 1 case of cochleovestibular schwannoma). The outcome was not related to the laterality, age, or hearing loss type. On the contrary, a statistically significant association between poor recovery and male sex, both tinnitus and vertigo, and the initial severity of the hearing loss was observed. CONCLUSIONS: Mostly, SSNHL results in idiopathic disease. At present, diagnostic and therapeutic efforts appear to be inadequate to improve the prognosis of SSNHL. Further studies are needed to obtain better knowledge about the etiopathogenesis of SSNHL so that new therapeutic strategies can be considered in the treatment of this challenging ear disease.     

Fluconazole prophylaxis prevents invasive fungal infection in high-risk, very low birth weight infants

OBJECTIVES: To evaluate the benefit of fluconazole prophylaxis in preventing invasive fungal infection in very low birth weight (VLBW) infants with central vascular access. STUDY DESIGN: A 3-year baseline period (1998 to 2000) was compared with a subsequent 3-year period (2001 to 2003) during which a different protocol for preventing invasive fungal infection was used. All infants with a birth weight < 1500 g and with central vascular access were eligible for the study. Fluconazole (Diflucan R) was administered for 28 days at a dose of 6 mg/kg every third day during the first week and daily after the first week. RESULTS: There were no significant differences between the baseline and the fluconazole groups in demographic characteristics or risk factors for fungal infection. Fungal infection developed in 9 of the infants in the baseline group and in none of those in the fluconazole group (P=.003). A trend of decreasing mortality rate between the 2 groups (12.6% vs 8.1%; P=.32) was observed but was not statistically significant. No adverse effects of fluconazole therapy were documented. CONCLUSIONS: Fluconazole prophylaxis appeared to be beneficial in preventing invasive fungal infection in VLBW infants.     

Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

OBJECTIVE: To develop diagnostic guidelines for macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (S-JIA). STUDY DESIGN: We followed the classification criteria approach that is based on the comparison of patients with the index disease with patients with a "confusable" disease. The former group included 74 patients with S-JIA-associated MAS reported in the literature or seen by the authors; the latter group included 37 patients with S-JIA who had 51 instances of "high disease activity" seen by the authors. The relative power of clinical, laboratory, and histopathologic variables in discriminating patients with MAS from patients with high disease activity was evaluated by calculating the sensitivity rate, specificity rate, area under the receiver operating characteristic curve, and diagnostic odds ratio (DOR). The combinations of variables that led to best separation between patients and control subjects were identified through "the number of criteria present" method. RESULTS: The strongest clinical discriminators were hemorrhages (DOR = 67) and central nervous system dysfunction (DOR = 63); the strongest laboratory discriminators were decreased platelet count (DOR = 1092), increased aspartate aminotransferase (DOR = 247), leukopenia (DOR = 70), and hypofibrinogenemia (DOR = 165). The best separation between patients and control subjects occurred when any 2 or more laboratory criteria (DOR = 1309) were simultaneously present; the second best performance was provided by the presence of any 2, 3, or more clinical and/or laboratory criteria (DOR = 765 and 743, respectively). CONCLUSION: We identified preliminary diagnostic guidelines for MAS complicating S-JIA. These guidelines deserve prospective validation.     

Glutamine amidotransferase activity of NAD+ synthetase from Mycobacterium tuberculosis depends on an amino-terminal nitrilase domain

NAD(+) synthetase (NadE; E.C. 6.3.5.1) from Mycobacterium tuberculosis utilizes both glutamine and ammonia to catalyze NAD(+) production, in contrast to the corresponding NH(3)-dependent enzymes from other prokaryotes. Here we report the site-directed mutagenesis of amino acids located in the N-terminal domain and predicted to be essential for glutamine hydrolysis. The residues forming the putative catalytic triad (Cys176, Glu52 and Lys121) were replaced by alanine; the mutated enzymes were expressed in the Escherichia coli Origami (DE3) strain and purified. The three mutants completely lost their glutamine-dependent activity, clearly indicating that Cys176, Glu52 and Lys121 are crucial for this activity. In contrast, the C176A and E52A variants, respectively, retained 90 and 30% of the original NH(3)-dependent specific activity, while the K121A mutant lost this activity. The results show that glutamine-amidotransferase activity is mediated by an N-terminal domain belonging to the superfamily of nitrilases. This domain, a new type of glutamine amide transfer (GAT) domain, is the first to be characterized in bacterial NAD(+) synthetases.     

Endogenous leukemia inhibitory factor attenuates endotoxin response

Leukemia inhibitory factor (LIF) is induced in inflammation and likely plays a regulatory role. Using LIF-deficient mice (LIF-/-), we report here that endogenous LIF has a protective role in endotoxic shock and host defence. LIF-/- mice have heightened sensitivity to LPS in a LPS/D-galactosamine (D-Gal) sensitization model compared to wild-type mice (LIF+/+), enhanced thrombocytopenia and leukopenia, with increased hepatic necrosis, neutrophil sequestration in the lung and accelerated mortality. These findings correlated with 10-fold higher tumour necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6) serum levels and reduced IL-10 production in LIF-/- mice in response to LPS. Therefore, endogenous LIF attenuates the endotoxic shock response, enhances the expression of basal acute phase proteins and IL-10 production, which downregulates TNFalpha synthesis and release and thereby confers partial protection to endotoxemia.