Impact of intra-abdominal drains in emergency gastrointestinal surgery: a scoping review.

INTRODUCTION: Intra-abdominal drains are often placed in emergency gastrointestinal surgery procedures with the aim to prevent the formation of intra-abdominal collections (IAC) and aid in their early detection. However, the evidence for this is debated. This scoping review aims to evaluate the current evidence for their use in this setting. METHODS: A literature search was performed using MEDLINE via PubMed, Scopus, Web of Science, Cochrane Library, and ClinicalTrials.gov. Primary studies published between January 2000 and September 2023 that assessed intra-abdominal drain placement and post-operative IAC formation in emergency gastrointestinal surgery were included. RESULTS: A total of 26 articles were identified. There was no strong evidence to suggest that prophylactic intra-abdominal drain placement influences the formation of IAC in emergency gastrointestinal procedures. There was a suggestion that drain placement may increase the rate of surgical site infection and length of hospital stay. However, current studies on the topic are of poor quality and high risk of bias. CONCLUSION: The undifferentiated use of drains in emergency gastrointestinal surgery should not be encouraged. Drain placement should be specific to the clinical context. Higher quality research is warranted to better understand the influence drain placement has on post-operative outcomes.

Natural pet food: a review of natural diets and their impact on canine and feline physiology.

The purpose of this review is to clarify the definition of "natural" as it pertains to commercial pet food and to summarize the scientific findings related to natural ingredients in pet foods and natural diets on the impact of pet health and physiology. The term "natural," when used to market commercial pet foods or pet food ingredients in the United States, has been defined by the Association of American Feed Control Officials and requires, at minimum, that the pet food be preserved with natural preservatives. However, pet owners may consider natural as something different than the regulatory definition. The natural pet food trend has focused on the inclusion of whole ingredients, including meats, fruits, and vegetables; avoiding ingredients perceived as heavily processed, including refined grains, fiber sources, and byproducts; and feeding according to ancestral or instinctual nutritional philosophies. Current scientific evidence supporting nutritional benefits of natural pet food products is limited to evaluations of dietary macronutrient profiles, fractionation of ingredients, and the processing of ingredients and final product. Domestic cats select a macronutrient profile (52% of ME from protein) similar to the diet of wild cats. Dogs have evolved much differently in their ability to metabolize carbohydrates and select a diet lower in protein (30% of ME from protein) than the diet of wild wolves. The inclusion of whole food ingredients in natural pet foods as opposed to fractionated ingredients may result in higher nutrient concentrations, including phytonutrients. Additionally, the processing of commercial pet food can impact digestibility, nutrient bioavailability, and safety, which are particularly important considerations with new product formats in the natural pet food category. Future opportunities exist to better understand the effect of natural diets on health and nutrition outcomes and to better integrate sustainable practices in the production of natural pet foods.

Fabry disease in children: correlation between ocular manifestations, genotype and systemic clinical severity.

BACKGROUND/AIMS: Fabry disease is an X linked lysosomal disorder associated with severe multiorgan failure and premature death. This study aims to determine the prevalence of ophthalmic manifestations in children with the condition and investigate the correlation with genotype and systemic disease severity. METHODS: The records of 26 children from 18 pedigrees with Fabry disease undergoing regular ophthalmic and systemic examination were reviewed. All pedigrees underwent GLA gene sequencing to determine genotype. Correlations between ocular and systemic phenotype and genotype were investigated. RESULTS: Corneal verticillata occurred in 50% of the children in this study (95% CI, 29% to 79%). Children with ophthalmic manifestations were more likely to have loss-of-function GLA mutations (p=0.003). Retinal vascular tortuosity was seen in seven children (27%), all of whom had systemic symptoms suggestive of autonomic neuropathy, such as diarrhoea and syncope. These symptoms seemed less prevalent in children without retinal vascular changes, although this did not reach statistical significance (p=0.134). CONCLUSION: Ophthalmic manifestations of Fabry disease are common even in young children with loss-of-function GLA gene mutations. Although the limited sample size possibly prevented statistical significance, systemic symptoms of autonomic neuropathy often coexist with retinal vascular changes and may share the same pathogenesis.

The effect of travoprost on daytime intraocular pressure in normal tension glaucoma: a randomised controlled trial.

BACKGROUND/AIMS: To determine the medium-term effect of travoprost on the daytime intraocular pressure (IOP) of patients with normal tension glaucoma (NTG) METHODS: Newly diagnosed NTG patients underwent baseline, daytime, hourly IOP phasing. Patients were randomised to either treatment or no treatment (control). Treatment comprised once daily topical travoprost 0.004%. After 6 months, the participants underwent their second IOP phasing. RESULTS: Data from 88 participants were analysed-54 were randomised to treatment and 34 to the control group. The mean duration of treatment was 6 months. The average, maximum and minimum diurnal IOPs for treated patients were statistically significantly lower than for control patients at follow-up (p<0.001). When compared with baseline IOP, the travoprost treated group demonstrated a decrease of 16.1%, 13.5% and 16.7% in the average IOP, maximum IOP, and minimum IOP respectively. Of those treated, about one-third achieved a decrease in average IOP of at least 20%; only about one-tenth achieved a reduction of at least 30%. CONCLUSION: Travoprost monotherapy had a sustained hypotensive effect in NTG and achieved a reasonable or good response (>20% reduction in average IOP) in 32.9% of treated eyes. However, in the majority of eyes with NTG, travoprost monotherapy appeared unable to produce the desirable 30% reduction in average IOP.

Diplopia following cataract surgery: a review of 150 patients.

AIM: To study the motility pattern, underlying mechanism, and management of patients who complained of double vision after cataract surgery. METHODS: A retrospective case note analysis of 150 patients presenting with diplopia after cataract surgery to an orthoptic clinic over a 70-month period. Information was retrieved from orthoptic, ophthalmological, and operating room records. RESULTS: A total of 3% of patients presenting to the orthoptic clinic had diplopia after cataract surgery. We grouped these according to the underlying mechanisms which were: (1) decompensating pre-existing strabismus (34%), (2) extraocular muscle restriction/paresis (25%), (3) refractive (8.5%), (4) concurrent onset of systemic disease (5%), (5) central fusion disruption (5%), and (6) monocular diplopia (2.5%). Twenty per cent of the patients could not be categorised with certainty. After infiltrational anaesthesia, extraocular muscle restriction/paresis was the commonest presentation, while decompensation of preexisting strabismus was commonest with topical anaesthesia.For the 150 patients seen, prisms were the commonest form of treatment prescribed (64%) either in isolation or in combination with other treatment, including surgery (19%). Convergence and divergence insufficiency/paresis patterns were also common. A changing motility pattern was noted in some patients who had early documentation, with increasing comitance over time (spread of comitance). Partial resolution made it difficult to clearly identify the underlying mechanism in patients with late documentation. CONCLUSION: Double vision is a troublesome complication of otherwise successful cataract surgery. The use of topical anaesthesia does not abolish this surgical risk.

Corticosteroid-induced glaucoma: a review of the literature.

The intraocular pressure rise that can complicate the use of topical or systemic corticosteroid has been recognised for 50 years. More recently, following isolation of the myocilin gene (previously known as the trabecular meshwork inducible glucocorticoid response or TIGR gene), there has been renewed interest in this steroid-responsive phenomenon. Furthermore, the currently fashionable use of injectable intraocular steroids in the management of clinically significant subretinal fluid and macular oedema has resulted in an increased incidence. Animal studies, cell biology, molecular biology, and an improved knowledge of genetics have provided a better understanding of the mechanisms behind the response. The purpose of this review is to describe the risk factors for developing corticosteroid-induced glaucoma, to discuss the underlying mechanisms and genetics of the condition and to present management options.

Human leukemias with mutated FLT3 kinase are synergistically sensitive to FLT3 and Hsp90 inhibitors: the key role of the STAT5 signal transduction pathway.

17-allylamino-17-demethoxygeldanamycin (17-AAG), an inhibitor of the molecular chaperone heat shock protein 90, results in cell type-specific inhibition of proliferation of leukemic cells. GTP14564 is a tyrosine kinase inhibitor actively against FLT3. The current study evaluated the single and combined effects of 17-AAG and GTP14564, and the role of FLT3 in their inhibitory effects. The importance of FLT3 mutations was demonstrated using small interfering RNA (siRNA) targeted to FLT3. Similar to FLT3 siRNA, GTP14564 inhibited FLT3 internal tandem duplication (ITD) cells (MV4;11) and FLT3 amplified wild-type cells (SEMK2-M1), but not wild-type FLT3 cells (RS4;11). However, when RS4;11 cells were stimulated with FLT3-ligand, phosphorylation of STAT5 and GTP14564 inhibition were observed. Responses to GTP14564 in all cell types were directly related to the level of STAT5 phosphorylation in the cells. We observed synergistic effects of combined 17-AAG and GTP14564 in cell lines with FLT3-ITD and amplified wild-type FLT3. Combined treatment with 17-AAG and GTP14564 reduced the levels of p-FLT3 and p-STAT5, enhanced G0/G1 arrest and apoptosis in FLT3-ITD and amplified wild-type FLT3. The combination of 17-AAG with FLT3 kinase inhibitors can enhance targeted therapy in leukemias with FLT3 mutations, such as MLL fusion gene leukemias.

Are we training junior doctors to respond to major incidents? A survey of doctors in the Wessex region.

OBJECTIVE: To assess the current status of awareness and training of junior medical staff in the Wessex region in the event of a "conventional" major incident. METHODS: A telephone questionnaire of specialist registrars (SpRs) (or equivalent, for example, staff grade) in six core specialties was performed in all the 11 acute hospitals in the Wessex region on the same evening. This group was selected to represent a sample of the most senior medical staff "on site" at each hospital. RESULTS: 56 of 64 (87.5%) SpRs participated. Nine of the 56 (16%) SpRs questioned had previously been involved in a major incident, and 18 (32%) had experienced some form of major incident training exercise. Subgroup analysis of the specialties showed that although there were no significant differences in numbers of training experiences between specialties, only one of nine (11%) orthopaedic SpRs had ever been involved in a training exercise. Twenty five of the 56 (45%) SpRs felt that they were confident of their role in the event of an incident. CONCLUSION: Most middle grade staff in Wessex were not confident of their role in the event of a major incident. Most SpRs questioned had never attended a major incident training exercise.

Preclinical studies targeting normal and leukemic hematopoietic cells with Yttrium-90-labeled anti-CD45 antibody in vitro and in vivo in nude mice.

A study was undertaken to investigate the suitability of using a high affinity (Kd = 1.1 nM) anti-CD45 monoclonal antibody for delivering the high energy beta-particle emitting isotope (90)Y to lymphohematopoietic target cells in vivo. The antibody, AHN-12, recognized the tyrosine phosphatase CD45 expressed on the surface of normal and malignant hematopoietic cells and studies showed that it reacted with both CD45-expressing normal peripheral blood cells and leukemia cells from patients. The antibody was readily labeled with (90)Y using the highly stable chelate 1B4M-DTPA and the radioimmunoconjugate was designated (90)Y-anti-CD45. The agent selectively bound to CD45(+) B cell line Daudi, but not CD45(-) control cells and significantly (p = 0.007) more bound to Daudi tumors growing in athymic nude mice than did a control non-reactive antibody. Moreover, biodistribution data correlated well to an anti-Daudi effect observed against established tumors in nude mice. The effect was dose dependent and irreversible with the best results in mice receiving a single dose of 137 microCi (90)Y-anti-CD45. These mice displayed a significantly (p < 0.0095) better anti-tumor effect than a control (90)Y-labeled antibody and survived over 135 days with no evidence of tumor. Histology studies showed no significant injury to kidney, liver, or small intestine even at 254 microCi, the highest dose tested. Because radiolabeled anti-CD45 antibody can be used to deliver radiation selectively to lymphohematopoietic tissue, these data indicate that this agent may be used to improve treatment of hematopoietic malignancies, particularly leukemia and lymphoma, when combined with hematopoietic stem cell transplantation in a future clinical trial.

Phosphorus requirements of broiler chicks six to nine weeks of age as influenced by phytase supplementation.

Two trials of similar design were conducted to determine the nonphytate phosphorus (NPP) requirements for broilers from 42 to 63 d of age in diets with or without phytase supplementation. Male broilers of a commercial strain were grown to 42 d on nutritionally complete diets with NRC (1994) recommended levels of Ca and NPP. At 42 d, the birds were placed on experimental diets and fed to 63 d. The experimental treatments consisted of a 2 x 6 factorial arrangement with two levels of phytase (0 or 800 U/kg) and six levels of NPP (0.10 to 0.35% in 0.05% increments). Body weight gain, feed conversion, and mortality were determined during the period. At 49, 56, and 63 d, excreta samples were taken, and samples of birds were killed for tibia ash determination. The lowest level of NPP, with or without phytase supplementation, was sufficient for maximum BW gain, feed conversion, and livability. Using nonlinear regression, levels of NPP needed to optimize tibia ash in the absence of phytase were 0.31 +/- 0.004%, 0.23 +/- 0.02%, and 0.22 +/- 0.029% at 49, 56, and 63 d, respectively. When diets were supplemented with 800 U/kg of phytase, the NPP requirement for optimum tibia ash was 0.15 +/- 0.049% at 49 d. At 56 and 63 d, no more than 0.10% NPP (lowest level tested) was sufficient to maximize tibia ash. Compared to current NRC (1994) recommendations, the application of these reduced dietary phosphorus levels could markedly reduce excreta excretion of phosphorus by broilers.

Phosphorus requirements of broiler chicks three to six weeks of age as influenced by phytase supplementation.

Two studies of identical design were conducted in battery brooders utilizing male chicks of a commercial strain. The birds were grown to 3 wk on diets with adequate P and from 3 to 6 wk were fed diets ranging from 0.10 to 0.45% nonphytate P (nPP) in increments of 0.05%, with or without supplementation with 800 units of phytase per kilogram of diet. Measurements included BW gain, feed conversion ratio (FCR), mortality, tibia ash, and fecal P content. Nonlinear regression was used to estimate nPP needs for optimizing BW gain, feed conversion, and tibia ash. In the absence of phytase, nPP levels of 0.33, 0.186, and 0.163% were required to optimize tibia ash, BW gain, and FCR, respectively. The estimated level for optimum tibia ash is in close agreement with current NRC (1994) recommendations. In the presence of 800 units of phytase per kilogram, nPP levels of 0.24, 0.151, and 0.109% were needed to optimize tibia ash, BW gain, and FCR, respectively. Fecal phosphorus levels were markedly reduced at the lower P levels. Further studies are needed to determine whether maximum tibia ash values are needed to sustain optimum production of market broilers.

Evaluation of normal yellow dent corn and high available phosphorus corn in combination with reduced dietary phosphorus and phytase supplementation for broilers grown to market weights in litter pens.

A study was conducted to determine the extent fecal P levels could be reduced while maintaining performance. Various strategies were employed including the use of a high available phosphorus hybrid of corn (HAPC), supplementation with phytase enzyme, and reduced dietary P levels. The use of HAPC resulted in a 50% reduction in phytate-bound dietary P as compared with a normal yellow dent corn (YDC) diet. Dietary nonphytate P was maintained at either NRC (1994) recommendations for appropriate age periods or reduced by 0.075 or 0.15%. Portions of the diets were supplemented with 1,000 units of phytase/kg. Male chicks of a commercial strain were grown to 56 d on the test diets. Broilers fed diets with HAPC had BW, feed conversion, livability, and tibia ash that were equal to or superior to those fed diets with YDC with considerably reduced fecal P content at any dietary level of nonphytate P. Phytase supplementation enabled birds to maintain live performance at lower levels of nonphytate P, further reducing the fecal P output. One of the greatest contributions of phytase was a reduction in mortality at the lower levels of nonphytate P. Dietary P levels could be reduced by 0.075% under NRC (1994) recommendations without adversely affecting live performance; a reduction of 0.15% in conjunction with phytase supplementation maintained BW, feed conversion, and livability but reduced tibia ash. The extent to which dietary P levels can be reduced over the entire feeding program is subject to further research.

Nonphytate phosphorus requirement and phosphorus excretion of broiler chicks fed diets composed of normal or high available phosphate corn with and without microbial phytase.

A study was conducted to evaluate the ability of the young (0 to 3 wk) broiler chicken to utilize the P provided by a high available P corn [HAPC; 0.27% total P and 0.17% nonphytate P] in comparison with yellow dent corn (YDC; 0.23% total P and 0.03% nonphytate P), and to determine the extent to which supplementation with exogenous phytase enzyme could reduce the demands for dietary P and subsequently reduce P excretion. Diets prepared using the two types of corn differed in the amount of phytate-bound P, with the HAPC diets containing approximately 50% less phytate-bound P. Treatment diets were prepared by varying the amount of dicalcium phosphate, and ranged from 0.10 to 0.50% nonphytate P for YDC diets, and from 0.18 to 0.50% nonphytate P for HAPC diets. Sublots of each diet were supplemented with 800 units/kg phytase. Each diet was fed to six pens of five male chicks of a commercial broiler strain from 1 to 21 d of age. Regression analysis was used to estimate nonphytate P requirements for each corn type with and without phytase supplementation. The greatest need for nonphytate P was for maximum tibia ash, with requirements of 0.39, 0.29, 0.37, and 0.32% in diets with YDC, YDC plus phytase, HAPC, and HAPC plus phytase, respectively. Addition of phytase liberated approximately 50% of the phytate-bound P from each diet. These levels were sufficient to support body weight, feed conversion, and livability. Fecal P content of broilers fed diets with YDC at the NRC (1994) recommended level of 0.45% nonphytate P was 1.21%, whereas at the respective requirement points indicated above, the P content was 1.09, 0.87, 0.78, and 0.64% in feces from broilers fed diets with YDC, YDC plus phytase, HAPC, and HAPC plus phytase, respectively. Thus, fecal P output could be reduced while maintaining optimum performance by the use of reduced dietary nonphytate P, introduction of HAPC, and phytase supplementation. One of the greatest benefits of phytase supplementation appeared to be maintaining livability at lower dietary levels of nonphytate P.

A randomized trial comparing prednisone with antithymocyte globulin/prednisone as an initial systemic therapy for moderately severe acute graft-versus-host disease.

Glucocorticoids remain the standard approach to initial systemic management of acute graft-versus-host disease (aGVHD). For patients refractory to steroids, antithymocyte globulin (ATG) is frequently used as salvage therapy. We decided to test whether the combination of corticosteroids and equine ATG would improve the outcome of initial management of aGVHD, especially in high-risk patients such as recipients of unrelated donor (URD) transplants. One hundred patients with grade II to IV aGVHD having undergone a related or URD marrow transplant were enrolled in the study. Of the patients, 46 were randomly assigned to therapy with prednisone (60 mg/m2 per day x 7 days) and 50 received ATG/prednisone (15 mg/kg ATG bid plus 20 mg/m2 prednisone bid x 5 days, each followed by an 8-week prednisone taper). An intent-to-treat analysis of the overall response at day 42 revealed equivalent complete plus partial response rates of 76% in both the prednisone and ATG/prednisone therapy groups (P > .80). In univariate analysis, patient age, donor type, site of involvement, or aGVHD stage did not influence overall response to therapy (all P > .2). When treatment arms were studied separately, no single clinical feature predicted outcome in either group. Complications were more frequent in the ATG/prednisone arm; patients experienced more infections with cytomegalovirus (44% versus 22%; P = .02) and more frequent pneumonitis, both infectious and noninfectious (50% versus 24%; P < .01). Epstein-Barr virus lymphoproliferative disease was uncommon (4 cases) and comparable in both arms (P = .35). There was no significant difference in survival at day 100, 6 months, and 2 years between the 2 treatment arms. The more intensive immunosuppressive combination of ATG/prednisone failed to improve control of aGVHD and may have affected survival by causing more infectious complications. Combination therapy with ATG should thus be reserved as second-line therapy in the management of aGVHD.

Early testicular biopsy in males with acute lymphoblastic leukemia: lack of impact on subsequent event-free survival.

PURPOSE: Children with acute lymphoblastic leukemia (ALL) who had bulky disease (lymphomatous features) at diagnosis had the highest rate of testicular relapse (20%) of any ALL subgroup on previous Children's Cancer Group (CCG) studies in the late 1980s. To limit curative, but sterilizing, testicular irradiation to those with testicular disease, testicular biopsies were performed to detect occult testicular disease within the first 6 months of treatment. Testicular irradiation then was provided to those with occult disease to increase disease-free survival. Identification of those with occult disease was believed to be a factor that would influence ultimate survival in such patients in that era. PATIENTS AND METHODS: One hundred ninety-nine patients had bilateral testicular wedge biopsies performed during the first maintenance therapy phase of the four different chemotherapy regimens. Patients with positive biopsy results were treated with testicular irradiation and continued on therapy. RESULTS: Eleven of 199 biopsy results (5.5%) were judged positive. Patients with positive biopsy results given testicular radiation had a 45% subsequent adverse event rate, compared with 36% for those with a negative biopsy results (P = 0.4). The survival rates for the two groups were similar. The low rate of positive biopsy specimens resulted in discontinuation of the procedure before closure of the study. CONCLUSION: Positive testicular biopsy results early in remission identified patients at a slightly higher risk of subsequent adverse events but did not influence survival. However, because negative biopsy results (94.5%) did not alter the prescribed treatment, the small number of positive biopsy results did not warrant undertaking the procedure in most male patients with ALL, and this procedure was abandoned.

Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia.

To investigate if decreased exposure to common childhood infections is associated with risk of childhood acute lymphoblastic leukaemia (ALL) we conducted a case-control study of 1842 newly diagnosed and immunophenotypically defined cases of ALL under age 15, and 1986 matched controls in the US. Data regarding day care, sibship size and common childhood infections were obtained through parental interviews. Data were analysed stratified by leukaemia lineage and separately for 'common' childhood ALL (age 2-5 years, CD19, CD10-positive). Neither attendance at day care nor time at day care was associated with risk of ALL overall or 'common' ALL. Ear infections during infancy were less common among cases, with odds ratios of 0.86, 0.83, 0.71 and 0.69 for 1, 2-4, 5+ episodes, and continuous infections respectively (trend P = 0.026). No effect of sibship size or birth interval was seen. With one exception (ear infections), these data do not support the hypothesis that a decrease in the occurrence of common childhood infection increases risk of ALL.

Xenotransplantation of human lymphoid malignancies is optimized in mice with multiple immunologic defects.

While it is known that mice with genetic immune defects are useful for establishing durable engraftment of human tumor xenografts, the relative role of components of host innate and adoptive immunity in engraftment has not been determined. We directly compared the ability of four strains of genetically immunodeficient mice (NOD/SCID, SCID, Nude and Rag-1-deficient) to successfully engraft and support the human cell lines Daudi, Raji, Namalwa and Molt-4 as subcutaneous tumors. We additionally examined the effect of further immunosuppression of the mice by whole body irradiation at a dose of 600 cGy for Nude and Rag-1 and 300 cGy for SCID mice and by administration of anti-natural killer (asialo-GM1) antibody on tumor growth. Mice with each of the defects supported xenografts to varying degrees. We found differences in growth characteristics in the cell lines tested, with Namalwa consistently producing the largest tumors. With all cell lines studied, optimal growth was achieved using NOD/SCID mice. Overall, tumor growth was somewhat enhanced by pretreatment with radiation with little additional benefit from the addition of anti-asialo-GM1 antibody. The importance of multiple components of the innate and adoptive immune system in xenotransplantation were best demonstrated when results in untreated NOD/SCID mice were compared to SCID, nude and RAG-1-deficient mice. The NOD/SCID mouse with or without additional immunosuppression provides the optimal model for the study of the biology and treatment of human leukemias and lymphomas.

Pharmacokinetics and biodistribution of radioimmunoconjugates of anti-CD19 antibody and single-chain Fv for treatment of human B-cell malignancy.

The comparative advantages and disadvantages of intact antibodies and single-chain Fv as immunotoxins and radioimmunoconjugates have been widely discussed but not directly compared. In this study, the in vivo properties of anti-CD19 B43 monoclonal antibody and its derived single-chain Fv (FVS191) were studied in athymic nude mice bearing CD19-positive human lymphomas. B43 mab and FVS191 were labeled with iodine-125 using iodine-beads, and immunoreactivities were determined to be 57% and 72%, respectively. Scatchard analysis showed a similar high affinity for both. The results of pharmacokinetic studies revealed that FVS191 had a rapid biphasic clearance from the circulation (T1/2alpha=2.5 min, T1/2beta=3.7 h); The T1/2alpha and T1/2beta phases of B43 mab were determined to be 0.72 h and 57 h respectively. Biodistribution studies compared the uptake of labeled antibodies by CD19-positive and by CD19-negative tumors. The peak percentages of injected dose were 5.7% at 12 h for B43 and 2.45% at 1 h for FVS191. Radiolocalization indices (RI) demonstrated tumor-specific uptake for both, but higher uptake for B43. The optimal RI was seen at 15 min for FVS191 and 6 h for B43. FVS191 was unstable in vivo, approximately 50% of the injected dose being degraded in blood in 100 min. Radioactivity detected in the urine was present mainly as the deiodinized form of FVS191. The results suggest that B43 mab is favored over FVS191 in biodistribution properties and in vivo stability. Because B43 Mab showed early tumor-specific uptake, high RI values, and favorable tissue-to-blood ratios, it is a potential candidate for radioimmunotherapy and immunotoxin therapy of B-cell leukemia and lymphoma.

AF4 encodes a ubiquitous protein that in both native and MLL-AF4 fusion types localizes to subnuclear compartments.

Acute leukemia with t(4;11)(q21,q23) translocation results from the in-frame fusion of the MLL to the AF4/FEL gene. In previous studies, we and others demonstrated that AF4 transcripts are present in a variety of hematopoietic and nonhematopoietic human cells. To further study the wild-type and leukemia fusion AF4, we used glutathione S-transferase (GST)-fusion proteins as immunogens to produce rabbit polyclonal antibodies that were specific for normal and chimeric AF4 proteins. Using Western blotting analysis, we demonstrated that the AF4 gene encodes proteins with apparent molecular weight of 125 and 145 kD. A 45-kD protein coprecipitated with AF4 protein in immunoprecipitation. Also, the anticipated MLL-AF4-encoded 240-kD protein was detected in all cell lines with t(4;11) translocations; fusion proteins were present in lesser quantity than the wild-type AF4. The proteins recognized by the antibodies are of the predicted sizes of the AF4 and MLL-AF4-encoded proteins based on previous DNA sequencing analysis. The MLL-AF4 fusion protein had a similar subcellular distribution as AF4. Both t(4;11) and non-t(4;11) leukemic cells showed a similar pattern of punctate nuclear staining in all cell lines tested using confocal immunofluorescence microscopy. AF4 antibodies should be useful for further elucidation of the function of AF4 in normal cellular physiology, as well as the function of MLL-AF4 in leukemogenesis. The antibodies should also be helpful for the diagnosis of the MLL-AF4 fusion proteins in t(4;11) leukemias.