A 5-drug regimen maximizing the dose of cyclophosphamide is effective therapy for adult Burkitt or Burkitt-like lymphomas

Burkitt lymphoma (BL) and Burkitt-like lymphomas (BLL) are clinically and biologically aggressive B-cell malignancies. Brief-duration, high intensity multidrug regimens with central nervous system (CNS) prophylaxis have proven to be effective, with published series of adult patients documenting complete response (CR) rates of 80 to 100 percent and 2-year event-free survival (EFS) rates ranging from 60 to 90 percent. Based upon the known sensitivity of BL to cyclophosphamide and favorable results reported from the Dana Farber Cancer Center using high-dose CHOP in diffuse aggressive lymphomas, we tested a regimen designed to maximize the administered dose of cyclophosphamide while eliminating other agents commonly used in BL protocols. Eleven patients with Burkitt or Burkitt-like lymphoma were treated with 4 cycles of a 5-drug regimen, called high-dose CHOP, which contains a cyclophosphamide dose of 4 gm/m2 with each cycle. Intrathecal methotrexate and midcycle high-dose methotrexate were added as CNS prophylaxis. Ten patients achieved a complete response (91 percent) and with a median follow up of 38 months, the 3-year EFS is 64 percent and the 3-year overall survival (OS) is 72 percent. Three patients recurred after the achievement of a CR. Treatment-related toxicities included myelosuppression, neutropenic fevers/infections, and tumor lysis syndrome requiring hemodialysis in 2 patients. There were no treatment-related deaths and none of the patients had to discontinue therapy secondary to toxicity. In conclusion, the high-dose CHOP with midcycle methotrexate regimen produces response rates and EFS rates comparable to other regimens, with an acceptable toxicity profile. Utilization of high dose cyclophosphamide may eliminate the need for several other agents in Burkitt lymphoma regimens.     

Removal of Species Constraints in Antibody Detection

Serum antibodies from myriad species, particularly birds, can provide key information regarding the transmission and the expansion of the territory of emerging pathogens. Expedient antibody analysis is constrained by a lack of species-specific reagents, a deficiency potentially highlighted by the recent swine-origin influenza A virus (H1N1) outbreak. Available methodologies present difficulties that discourage thorough serologic monitoring of potential disease vectors or hosts. Rapid high-throughput procedures that combined serum amine labeling via biotinylation, contaminant removal, and microsphere-based immunoassays for antibodies to three arboviruses were developed. Agent-specific adaptations of this simple format should facilitate expanded surveillance and diagnostic capabilities regarding pathogens of human and veterinary importance.Serologic analysis of samples obtained from nondomestic animals, birds in particular, can provide key information regarding the transmission and the expansion of the territory of emerging pathogens (1). Unfortunately, species-specific reagents such as antispecies capture antibodies and detection conjugates, necessary for most rapid diagnostic methods, are frequently unavailable due to a lack of commercial interest. Traditional methods for circumventing species constraints often use live pathogens, are technically challenging, or are so time-consuming that large-scale testing becomes impractical (2). Methods that utilize protein G (4) are able to capture and detect mammalian IgG but cannot be used when the antibodies of interest are IgM and IgY, the former being the first of the Igs to be generated after infection and the latter being the avian and reptilian equivalent of IgG. The results of blocking enzyme-linked immunosorbent assay (ELISAs) (3) are sometimes inconsistent, and test sensitivities are dependent on the relative affinities of the competing monoclonal and serum antibodies to the antigens. Disease surveillance that involves the analysis of antibodies in nondomestic species is thus limited.The ideal method for the detection of antibodies in a range of species would be rapid, be capable of high throughput, provide a positive signal (as opposed to a signal reduction via competition), and require a small sample volume. Total antibody measurement would be advantageous, because surveillance is usually conducted without knowledge of the timing of infection. Biotin (vitamin H) is well-known to react with free amine groups on proteins (18). We determined that virus-specific serum antibodies independent of the species of origin could be biotinylated and directly detected in microsphere immunoassays (biotin-MIAs) that were modified from established protocols (11). Here we describe the development of two species-independent antibody detection methods for use with arboviruses, which involve animals as vectors or hosts. The first is a duplex procedure for the detection of antibodies to West Nile (WN) and St. Louis encephalitis (SLE) viruses, and the second is a procedure for the identification of anti-eastern equine encephalitis (anti-EEE) virus antibodies.     

Kawasaki disease: role of coronary CT angiography

Invasive coronary angiography is considered to be the gold standard for diagnosis and follow-up of coronary artery aneurysms, thrombosis and stenosis in patients with Kawasaki Disease. However, the availability of multi-detector CT coronary angiography provides a viable alternative as a non-invasive imaging modality for sequential follow-up of patients with Kawasaki disease. High quality multidetector CT angiography images of coronary arterial anatomy can be obtained after adequate heart rate control using beta blockers.     

Study of coagulation factor activities in apheresed thawed fresh frozen plasma at 1-6 degrees C for five days

The concern for the loss of activities of coagulation factors in thawed fresh frozen plasma kept at 1-6 degrees C for long periods has prevented transfusion services from using thawed plasma beyond 24 hours of storage. There is no mention of the method of collection of the plasma and/or the study of the bacterial growth in the studies reported in the literature. The present project was undertaken to investigate coagulation factor activities and bacterial growth in apheresed fresh plasma. Twenty apheresed plasma units from different blood groups were used. After the 24-hour expiration time of the thawed plasma kept at 1-6 degrees C, aliquots were taken at day 1, day 3, and day 5 of expiration time and were immediately frozen at -70 degrees C. Samples were assayed for activities of coagulation factors II, V, VII, VIII, X, XI, and fibrinogen (Fib). Our study reveals no statistically significant change in activities of coagulation factors II, VII, X, XI, and fibrinogen from day 1 to day 5 storage of plasma at 1-6 degrees C; however, there is a mean decrease of 8.8 and 14.3% in activities of factors V and VIII, respectively. All culture samples taken on day 5 storage were negative at 7 days. In conclusion, our results do not show a significant change in the activity of most coagulation factors in the thawed apheresis plasma stored at 1-6 degrees C over a 5-day period. Hence, it is feasible to transfuse the plasma beyond the 24-hour period without compromising the clinical outcome of patients with coagulopathy.     

IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction

BACKGROUND & AIMS: Tumor necrosis factor (TNF) plays a critical role in intestinal disease. In intestinal epithelia, TNF causes tight junction disruption and epithelial barrier loss by up-regulating myosin light chain kinase (MLCK) activity and expression. The aim of this study was to determine the signaling pathways by which TNF causes intestinal epithelial barrier loss. METHODS: Caco-2 cells that were either nontransfected or stably transfected with human TNF receptor 1 (TNFR1) or TNFR2 and mouse colonocytes were used for physiologic, morphologic, and biochemical analyses. RESULTS: Colitis induced in vivo by adoptive transfer of CD4(+)CD45RB(hi) T cells was associated with increased epithelial MLCK expression and myosin II regulatory light chain (MLC) phosphorylation as well as morphologic tight junction disruption. In vitro studies showed that TNF caused similar increases in MLCK expression and MLC phosphorylation, as well as barrier dysfunction, in Caco-2 monolayers only after interferon (IFN)-gamma pretreatment. This reductionist model was therefore used to determine the molecular mechanism by which IFN-gamma and TNF synergize to cause intestinal epithelial barrier loss. IFN-gamma priming increased TNFR1 and TNFR2 expression, and blocking antibody studies showed that TNFR2, but not TNFR1, was required for TNF-induced barrier dysfunction. Transgenic TNFR2, but not TNFR1, expression allowed IFN-gamma-independent TNF responses. CONCLUSIONS: IFN-gamma primes intestinal epithelia to respond to TNF by inducing TNFR2 expression, which in turn mediates TNF-induced MLCK-dependent barrier dysfunction. The data further suggest that epithelial TNFR2 blockade may be a novel approach to restore barrier function in intestinal disease.     

Decreased neural specialization in old adults on a working memory task

Compelling evidence shows that there is decreased neural specialization in the ventral visual cortex in older adults under passive viewing conditions. We assessed whether such specialization would be maintained on a working memory task and whether decreased specialization co-occurred with increased prefrontal activations. Participants encoded three faces or houses and maintained the set across an 8-s interval. Results provided evidence for less specialization of faces and houses in older adults than in younger adults, while the middle and inferior frontal cortex showed increased activation in elders compared with the young.     

Limits to fast-conducting somatosensory feedback in movement control

Somatosensory feedback occurs during every movement performed. The transmission of this feedback is dynamically regulated during movement. This review addresses the limits of somatosensory feedback control of human movement and proposes that dynamic modification of feedback inflow requires an increased reliance on internal models for movement control.