Bone marrow transplantation depleted of T cells followed by repletion with incremental doses of donor lymphocytes for relapsing patients with chronic myeloid leukemia: a therapeutic strategy

BACKGROUND: For patients with chronic myeloid leukemia (CML), long-term survival after stem cell transplantation requires adequate control of graft-versus-host disease (GVHD) and disease recurrence. Relapsing patients respond to donor lymphocyte infusion (DLI) but develop life-threatening complications. METHODS: Patients with CML in first chronic phase received bone marrow (n = 14) or peripheral blood progenitor cell transplants (n = 4) from HLA-identical siblings. GVHD prophylaxis was by ex vivo T-cell depletion with CAMPATH 1G. If disease recurred, donors' mononuclear cells were collected by apheresis, the CD3 samples commencing at 10(6)/kg were aliquoted at half-log increment intervals, cryopreserved, and infused until disease clearance. RESULTS: Eighteen patients (median age: 32.5 years) received transplants. All engrafted without procedure-related mortality. Fourteen patients relapsed, and 13 entered the DLI program. Two developed extensive GVHD after single schedule infusions ranging from 89x10(6) to 670x10(6) mononuclear cells/kg, and one survives in complete remission (CR). The rest, treated with incremental dose DLI, experienced no acute toxicities. One, who had developed grade III steroid-responsive GVHD, died in CR2 from opportunistic infections. Steroids reversed limited cutaneous GVHD and elevated liver enzymes in five patients. Three others developed pancytopenia, and two restored blood counts only after donor peripheral blood progenitor cell infusions. Molecular CR2 was established in 12/13 patients, occurring in 10/11 (91%) on the incremental program at a median accumulation of 67 (range: 5-166) x10(6) CD3 cells/kg. Sixteen of 18 (89%) survive at median of 854.5 days from bone marrow transplantation, 4 in CR1 and 10 in CR2 at a median disease-free survival (for remission 2) duration of 341 days. The median combined disease-free survival of the 14 patients in CR 1+2 is 660 days, with 99% average performance status. CONCLUSIONS: Escalating DLI leads to safe new molecular CR in most CML relapse patients. These results raise the possibility of using "safe" transplantation programs of T-cell depletion, that include graded DLI as prevention against disease recurrence.     

Imaging in isolated sacral tuberculosis: a review of 15 cases

Objective. To review imaging studies of isolated involvement of the sacrum due to tuberculosis and determine the role of imaging in the diagnosis and management of these patients. Design and patients. A retrospective analysis of 15 cases of isolated sacral tuberculosis imaged with MR imaging was performed. The CT images were also reviewed where available, and the various lesion characteristics were identified. We also reviewed the medical records in an attempt to determine the impact of the imaging studies on the management of these patients. Results. Fifteen patients (5 male, 10 female) presented with symptoms of 3–15 months’ duration. Chronic localized backache with muscle spasm was the commonest presenting symptom; discharging sinuses with abscess formation was found in six patients, five of whom were children. MR imaging of the sacrum revealed a hypointense marrow signal on T1-weighted images and hyperintense signal on T2-weighted images in 14 of 15 patients, the S2 vertebra being always involved. CT revealed osteolytic changes in the sacrum in all the five patients in whom CT was performed. All patients showed marked clinical improvement within 1 year of anti-tuberculous chemotherapy. Conclusion. Isolated tuberculosis of the sacrum is uncommon but should be suspected in patients presenting with chronic low backache or children with discharging sinuses/abscesses and showing sacral destruction on CT or MR imaging. MR imaging can identify cases and enables early institution of anti- tuberculous chemotherapy. Received: 31 August 1999 Revision requested: 1 November 1999 Revision received: 27 March 2000 Accepted: 14 April 2000     

An evaluation of the use of the transdermal contraceptive patch in adolescents.

PURPOSE: To evaluate the acceptability and feasibility of using the new transdermal contraceptive patch in adolescents. METHODS: A 3-month longitudinal trial using the Ortho Evra transdermal contraceptive patch in 50 adolescent girls. All healthy girls aged 15-18 years were invited to participate from two San Francisco Bay Area teen clinics. Participants were followed after 1 month and 3 months of treatment. Data were collected on patch detachments, perceived advantages and disadvantages, side effects, and compliance. Data were analyzed using Student's t-test (SPSS). RESULTS: Forty participants (80%) completed 1 month of treatment and 31 (62%) completed all 3 months of the study. There were no pregnancies during treatment. At the 3-month follow-up, 87.1% of participants reported perfect compliance. Ease of use, the fact that it does not require daily attention, and the ease of concealment were among the main reported advantages. Roughly 77% of participants who completed the study were planning to continue using the patch. The 35.5% rate of complete or partial detachment of at least one patch was considerably higher than reported in previous studies of adults. As in adults, the most commonly reported complaints were application site reactions and breast discomfort. CONCLUSIONS: This evaluation found an overall positive impression of the new transdermal contraceptive patch, with good rates of short-term compliance and few side effects among adolescents. However, the high degree of detachment unique to this sample of adolescents is concerning and requires further evaluation.     

Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease

In 1967, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a “peribronchiolar monocytic infiltration with some excess in eosinophils.” Decades of research defined enhanced RSV disease (ERD) as the result of immunization with antigens not processed in the cytoplasm, resulting in a nonprotective antibody response and CD4⁺ T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection. In recent years, the field of RSV experienced significant changes. Numerous vaccine candidates with novel designs and formulations are approaching clinical trials, defying our previous understanding of favorable parameters for ERD. This review provides a succinct analysis of these parameters and explores criteria for assessing the risk of ERD in new vaccine candidates.     

Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model

Oral squamous cell carcinoma (OSCC) is a lethal disease whose incidence is increasing. Epidemiologic studies demonstrate an association between periodontitis and oral cancer, and periodontal pathogens are implicated in the pathogenesis of numerous disorders, including rheumatoid arthritis, cardiovascular diseases, diabetes and gastrointestinal malignancies. Nevertheless, a causal role for periodontal pathogens in OSCC has not been shown, partly due to the lack of an appropriate animal model. Here, utilizing a newly-established murine model of periodontitis-associated oral tumorigenesis, we report that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect. Our results indicate that periodontal pathogens P. gingivalis and F. nucleatum stimulate tumorigenesis via direct interaction with oral epithelial cells through Toll-like receptors. Furthermore, oral pathogens stimulate human OSCC proliferation and induce expression of key molecules implicated in tumorigenesis. To the best of our knowledge, these findings represent the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis. These results are highly relevant for the design of effective prevention and treatment strategies for OSCC.     

Loss of Afferent Vestibular Input Produces Central Adaptation and Increased Gain of Vestibular Prosthetic Stimulation

Implanted vestibular neurostimulators are effective in driving slow phase eye movements in monkeys and humans. Furthermore, increases in slow phase velocity and electrically evoked compound action potential (vECAP) amplitudes occur with increasing current amplitude of electrical stimulation. In intact monkeys, protracted intermittent stimulation continues to produce robust behavioral responses and preserved vECAPs. In lesioned monkeys, shorter duration studies show preserved but with somewhat lower or higher velocity behavioral responses. It has been proposed that such changes are due to central adaptive changes in the electrically elicited vestibulo-ocular reflex (VOR). It is equally possible that these differences are due to changes in the vestibular periphery in response to activation of the vestibular efferent system. In order to investigate the site of adaptive change in response to electrical stimulation, we performed transtympanic gentamicin perfusions to induce rapid changes in vestibular input in monkeys with long-standing stably functioning vestibular neurostimulators, disambiguating the effects of implantation from the effects of ototoxic lesion. Gentamicin injection was effective in producing a large reduction in natural VOR only when it was performed in the non-implanted ear, suggesting that the implanted ear contributed little to the natural rotational response before injection. Injection of the implanted ear produced a reduction in the vECAP responses in that ear, suggesting that the intact hair cells in the non-functional ipsilateral ear were successfully lesioned by gentamicin, reducing the efficacy of stimulation in that ear. Despite this, injection of both ears produced central plastic changes that resulted in a dramatically increased slow phase velocity nystagmus elicited by electrical stimulation. These results suggest that loss of vestibular afferent activity, and a concurrent loss of electrically elicited vestibular input, produces an increase in the efficacy of a vestibular neurostimulator by eliciting centrally adapted behavioral responses without concurrent adaptive increase of galvanic afferent activation in the periphery.     

Lice infestation in goats in western Santa Catarina,Brazil

Parasitic diseases affecting goats are able to cause major economic losses, standing out, among them, the lice infestation. According to the literature, lice can act as vectors of other diseases, including the ones caused by blood protozoan. In this sense, this survey study aimed to assess the ectoparasites of goats in the west region of Santa Catarina (SC). Two hundred seventeen goats from 24 different rural properties located in 17 towns in SC were examined. From them, ectoparasites were collected and evaluated in laboratory, where the parasitological classification was performed. In 13 properties, it was possible to identify ectoparasites. Damalinia caprae lice were observed in 126 animals (58 %), while Linognathus stenopsis were found in 10 animals (4.6 %). It is noteworthy that, in these properties, all the animals were under lice parasitism, independent of sex or age. The goats had peeling skin, particularly in the back region (lumbar). All of the 24 properties evaluated were reported having problems with lice in different seasons of the year, even under regular treatment with cypermethrin (spraying). Based on our findings, it was possible to conclude that D. caprae is the major ectoparasite of goats in the investigated area.