CXCR4 regulates migration and development of human acute myelogenous leukemia stem cells in transplanted NOD/SCID mice

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 participate in the retention of normal hematopoietic stem cells within the bone marrow (BM) and their release into the circulation. Homing and engraftment of human stem cells in immunodeficient mice are dependent on cell surface CXCR4 expression and the production of BM SDF-1, which acts also as a survival factor for both human and murine stem cells. However, the role of SDF-1/CXCR4 interactions in the control of human acute myelogenous leukemia (AML) cell trafficking and disease progression is poorly understood. In this study, we report that although some AML cells do not express surface CXCR4, all AML cells tested express internal CXCR4 and SDF-1. Culture of AML cells with SDF-1 promoted their survival, whereas addition of neutralizing CXCR4 antibodies, SDF-1 antibodies, or AMD3100 significantly decreased it. Pretreatment of primary human AML cells with neutralizing CXCR4 antibodies blocked their homing into the BM and spleen of transplanted NOD/SCID/B2m(null) mice. Furthermore, weekly administrations of antihuman CXCR4 to mice previously engrafted with primary AML cells led to a dramatic decrease in the levels of human AML cells in the BM, blood, and spleen in a dose- and time-dependent manner. Interestingly, the same treatment did not affect significantly the levels of normal human progenitors engrafted into NOD/SCID mice. Taken together, our findings demonstrated the importance of the SDF-1/CXCR4 axis in the regulation of in vivo motility and development of human AML stem cells and identified CXCR4 neutralization as a potential treatment for AML.     

Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-gamma production of CD8+ T cells in secondary progressive multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system considered to be mediated by T helper type-1 cells. Several agents have been found to modify the disease course of MS, including interferon-beta1 (IFN-beta1), glatiramer acetate mitoxantrone. We have employed pulse therapy with cyclophosphamide in a selected group of patients with actively progressive disease. Chemokine receptors have been found to differentiate between polarized T helper type-1 (Th1) and type-2 (Th2) lymphocytes. The chemokine receptors CCR5 and CXCR3 are expressed primarily on Th1 cells and CCR3, CCR4 and CCR8 on Th2 cells. Previous studies of the expression of chemokine receptors in MS have shown that active MS plaques are infiltrated by CCR5(+) and CXCR3(+) T cells. Some of these T cells may express both CCR5 and CXCR3. These T cells are major producers of IFN-gamma, which worsens the clinical condition of patients with MS. We previously found that patients with MS had a high proportion of CXCR3(+) T cells and that those with chronic progressive MS had a high proportion of CCR5(+) T cells in their peripheral blood. We report here that in patients with secondary progressive MS, cyclophosphamide induces a marked increase in the percentage of CCR4(+) T cells that produce high levels of IL-4 and reverses the increase in the percentages of IFN-gamma-producing CCR5(+) and CXCR3(+) CD8(+) T cells. Furthermore, therapy with cyclophosphamide increases IL-4-producing CD4(+) T cells and reverses the increase in IFN-gamma-producing CD8(+) T cells. Our study shows that cyclophosphamide has immunomodulatory properties besides its suppressive effects, and that chemokine receptors can be important tools both for understanding the immune dysregulation in MS and for monitoring response to therapy.     

Rehabilitation of the disabled mentally III in the community

The purpose of this article is to review the latest developments in the area of rehabilitation of disabled mentally ill patients. Rehabilitation is a comprehensive and multi-disciplinary treatment. It involves a wide variety of interventions. These interventions are designed to enable the client to integrate into the normal life of the community and to improve his quality of life. This review discusses the different approaches and their effectiveness. The approaches that are described include comprehensive psychiatric, psycho-social and psycho-educational interventions including family therapy, training in social skills, and vocational intervention in programs and services in the community. The approaches that have been shown to be the most effective in controlled studies include: follow-up psychiatric drug treatment, individual and family psycho-educational treatment; social skills training; community sheltered-housing facilities and vocational rehabilitation programs. It has been emphasized that the effectiveness of treatment is conditional not only on the client's resilience and a comprehensive and multidisciplinary treatment approach, but also on the community financial resources and the level of training of the professionals.     

Urinary tract infection in very low birth weight preterm infants

BACKGROUND: The prevalence of urinary tract infection (UTI) in preterm neonates ranges between 4 and 25%. The need for a radiologic investigation has not yet been established in very low birth weight premature newborns (<1500 g birth weight). PATIENTS AND METHODS: For an 11-year period (1990 to 2001), medical records of 62 very low birth weight premature infants admitted to a Level III neonatal intensive care unit and who developed UTI were reviewed retrospectively. Results of renal ultrasound and voiding cystourethrograms were compared between extremely low birth weight infants (birth weight, <1000 g) (Group A, Patient 34) and premature infants with birth weight between 1001 and 1500 g (Group B, Patient 28). RESULTS: UTI was more common in Group A (12.2%) than in Group B (5.7%) infants. Renal ultrasound detected mild renal pelvic dilatation (unilateral or bilateral) in 9 infants in Group A (26%) and in 1 infant in Group B (3.5%). Voiding cystourethrograms were performed in 26 of 34 (76%) infants in Group A and in 17 of the 28 (61%) premature infants in Group B. Vesicourethral reflux (VUR) was observed in 6 infants, 2 in group A (7.7%) and 4 in Group B (23%). CONCLUSIONS: We found that the rate of VUR was lower in very low birth weight premature newborns than that reported in the medical literature among term newborns who developed UTI. VUR was less frequent in extremely low birth weight infants who developed UTI than in infants weighing 1001 to 1500 g.     

Neonatologists are using much less dexamethasone

Two historical cohorts (1993-1994 and 2001) of preterm infants ventilated for respiratory distress syndrome were compared. Dexamethasone administration fell from 22% to 6%. Chronic lung disease in survivors rose slightly from 13% to 17%, and mortality fell from 21% to 15% (other causes). The effect of restriction of dexamethasone use on chronic lung disease and mortality remains to be seen.     

The pathophysiology of the fetus of the diabetic mother

The metabolic processes that are responsible for the pathophysiology of the fetus of the diabetic mother have been elucidated in recent years and include maternal hyperglycinemia, fetal hyperglycinemia, fetal hyperinsulinemia, and increased levels of maternal, placental, and fetal insulin-like growth factors. Counter-regulatory mechanisms, such as insulin-like growth factors binding proteins and leptin also play a role. The fetal hypermetabolic state leads to increased somatic growth, obesity, and metabolic disturbances with short- and long-term consequences.     

Successful major surgical recovery of a patient following haploidentical stem cell transplantation for chronic myeloid leukemia in blast crisis and aspergillosis

A 44-year-old woman who underwent haploidentical stem cell transplantation (haplo SCT) for chronic myeloid leukemia in blast crisis and aspergillosis was admitted to the emergency room 7 months later because of severe right upper quadrant abdominal pain, fever, leukocytosis and peritoneal signs. Computer tomography disclosed cholecystitis and gallbladder perforation. Within hours, she underwent urgent open laparatomy and cholecystectomy. The postoperative period was uneventful and she was discharged 10 days later without any complications. Currently, she is 2(1/2) years posttransplantation in full hematological, cytogenetic and molecular remission with 100% Karnofsky performance status. Most notably, normal and fast recovery was observed following major surgery 7 months post-haplo SCT which is usually considered to result in long-lasting immunosuppression and malfunction of the immune system.     

Tracheobronchial stenosis from acid aspiration presenting as asthma

We report a case of a 42-year-old man who fell in a vat of hydrochloric acid, resulting in ingestion and aspiration of acid. Initially, he suffered from a chemical pneumonitis and GI burns. He was released from the hospital without complications, only to return with signs and symptoms consistent with asthma. Evaluation revealed multiple areas of large airway stenosis, resulting from the chemical burns. The stenoses were treated with multiple stents.     

Immunomodulation of experimental autoimmune encephalomyelitis by oral administration of copolymer 1

The activity of copolymer 1 (Cop 1, Copaxone, glatiramer acetate) in suppressing experimental autoimmune encephalomyelitis (EAE) and in the treatment of multiple sclerosis patients when injected parenterally has been extensively demonstrated. In the present study we addressed the question of whether Cop 1 can induce oral tolerance to EAE similar to myelin basic protein (MBP). We now have demonstrated that oral Cop 1 inhibited EAE induction in both rats and mice. Furthermore, oral Cop 1 was more effective than oral MBP in suppressing EAE in rats. The beneficial effect of oral Cop 1 was found to be associated with specific inhibition of the proliferative and Th1 cytokine secretion responses to MBP of spleen cells from Cop 1-fed mice and rats. In all of these assays, oral Cop 1 was more effective than oral MBP. The tolerance induced by Cop 1 could be adoptively transferred with spleen cells from Cop 1-fed animals. Furthermore, Cop 1-specific T cell lines, which inhibit EAE induction in vivo, could be isolated from the above spleen cells. These T cell lines secrete the anti-inflammatory cytokines IL-10 and transforming growth factor type beta, but not IL-4, in response to both Cop 1 and MBP. In conclusion, oral Cop 1 has a beneficial effect on the development of EAE that is associated with down-regulation of T cell immune responses to MBP and is mediated by Th2/3 type regulatory cells. These results suggest that oral administration of Cop 1 may modulate multiple sclerosis as well.