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.     

Coronavirus-induced demyelination occurs in the absence of CD28 costimulatory signals

Infection of mice with mouse hepatitis virus (MHV) strain A59 results in acute encephalitis, hepatitis, and chronic demyelinating disease. T lymphocytes play an important role in MHV infection, and costimulatory signals are an important component of T cell function. To elucidate the role of the main costimulatory molecule, CD28, in MHV pathogenesis and demyelination, we examined the kinetics of MHV-A59 infection in CD28 knockout mice. MHV-A59-infected CD28 knockout mice developed acute encephalitis and hepatitis, and the same degree of chronic demyelination as normal C57Bl/6 (B6) mice. Thus, CD28, the costimulatory T cell molecule, is not required for MHV infection and MHV-induced demyelination.     

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.     

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.     

CT assessment of bone marrow transplant patients with rhinocerebral aspergillosis

PURPOSE: Invasive rhinocerebral aspergillosis is a hazardous complication of bone marrow transplantation. A study was conducted to describe the computed tomography (CT) features of this disease. MATERIALS AND METHODS: Charts and CT scans of bone marrow transplant patients with invasive rhinocerebral aspergillosis were reviewed. The diagnosis was confirmed by otolaryngologic examination and biopsy of suspected lesions. Sinus CT scans were conducted without contrast material. They were repeated with contrast if intracranial or intraorbital extension was suspected. CT scans were correlated with physical examination, history of disease, and histology. RESULTS: Of 1,013 bone marrow transplantations carried out over a 10-year period, 21 patients (2.07%) developed invasive rhinocerebral aspergillosis. In most cases the infection was unilateral. Air-fluid levels and calcifications were rarely encountered. Mucosal thickening, soft tissue hyperdense masses in the nasal cavity and/or sinuses, and clear (uninvolved) ethmoid cells amid diseased cells, were significant CT features that characterized invasive fungal infection. Opacification of the sinus represented extensive disease with tissue necrosis. When bone destruction was encountered, fulminant infection was already present, usually with significant orbital and/or brain invasion. CONCLUSIONS: When correlated with clinical findings and histologic results, the above CT features can help identify early infection so that appropriate medical and surgical treatment can be instituted.     

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.     

The classic approach to diagnosis of vulvovaginitis: a critical analysis

OBJECTIVE: To correlate the symptoms, signs and clinical diagnosis in women with vaginal discharge, based on the combined weight of the character of the vaginal discharge and bedside tests, with the laboratory diagnosis. METHODS: Women presenting consecutively to the women's health center with vaginal discharge were interviewed and examined for assessment of the quantity and color of the discharge. One drop of the material was then examined for pH and the whiff test was done; a wet mount in saline and in 10% KOH was examined microscopically. The clinical diagnosis was based on the results of these assessments. Gram stain and cultures of the discharge were sent to the microbiology laboratory. RESULTS: One hundred and fifty-three women with vaginal discharge with a clinical diagnosis of vulvovaginitis participated in the study. Fifty-five (35.9%) had normal flora and the other 98 (64.1%) had true infectious vulvovaginitis (kappa agreement = 18%). According to the laboratory, the principal infectious micro-organism causing the vulvovaginitis was Candida species. Candida infection was associated with pH levels of less than 4.5 (p < 0.0001, odds ratio = 4.74, 95% confidence interval: 2.35-9.5, positive predictive value 68.4%). The whiff test was positive in only a small percentage of bacterial vaginosis (BV) (p = not significant (NS)). Clue cells were documented in 53.3% of patients with a laboratory diagnosis of BV (p < 0.02, positive predictive value 26.7%). CONCLUSIONS: The current approach to the diagnosis of vulvovaginitis should be further studied. The classical and time-consuming assessments were shown not to be reliable diagnostic measures.     

July 2000: A 70 year old with rigidity, decreased ocular movements, and dementia

The July Case of the Month (COM): A 70 year old male presented with a four year history of cognitive decline, difficulty expressing himself, and an increasingly unsteady gait with numerous falls. At presentation he was wheel-chair bound. Examination showed some slowing of speech, mild memory impairment, but normal cranial nerves. Spastic weakness and brisk reflexes were also noted, with bilateral ankle clonus. MRI scans were normal. Four years later he was admitted with a urinary tract infection and was mute with severely impaired ocular motility. He died 18 months later and autopsy showed the classic neuropathological findings of typical Progressive supranuclear palsy, including tau-positive glial inclusions.