Characterization of patients with an increased susceptibility to bacterial infections and a genetic deficiency of leukocyte membrane complement receptor type 3 and the related membrane antigen LFA-1

Three children from two unrelated families had a history of recurrent bacterial infections, and their neutrophils were shown to have deficient phagocytic and respiratory responses and possible deficiencies in chemotaxis or adherence. Their neutrophils were strikingly deficient in the ability to ingest or give a respiratory burst in response to unopsonized bakers' yeast or zymosan (Z). Tests for neutrophil and monocyte CR1 (C3b/iC3b receptor) and CR3 (iC3b receptor) demonstrated rosettes with both EC3b and EC3bi. However, EC3bi were bound only to CR1, and not to CR3, because EC3bi rosettes were inhibited completely by anti-CR1. Neutrophils, monocytes, and natural killer (NK) cells also did not fluorescence stain with monoclonal antibodies specific for the alpha-chain of CR3 (anti-Mac-1, anti-Mol, OKM1, and MN-41). Quantitation of C receptors with 125I monoclonal anti-CR1 and anti-CR3 indicated that neutrophils from each patient expressed normal amounts of CR1 per cell but less than 10% of the normal amount of CR3. Examination of neutrophils by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that a normal glycoprotein of approximately 165,000 daltons was missing. Immunoblotting of these gels indicated that the missing band was the alpha-chain of CR3. Subsequent analysis of all three patients' cells also demonstrated a deficiency of LFA-1 alpha-chain and the common beta- chain that is shared by the CR3/LFA-1/p150,95 membrane antigen family. The deficiency of LFA-1 probably explained the absent NK cell function, as normal NK cell activity is inhibited by anti-LFA-1 but not by anti- CR3. The reduced phagocytic and respiratory responses to Z were probably due to CR3 deficiency, because treatment of normal neutrophils with anti-CR3, but not anti-FLA-1, inhibits responses to Z by 80% to 90%. Ingestion of Staphylococcus epidermidis by normal neutrophils was shown to be partially inhibited by monoclonal antibodies to the alpha- chain of either CR3 or LFA-1, and monoclonal antibody to the common beta-chain inhibited ingestion by 75%. Thus, both CR3 and LFA-1 may have previously unrecognized functions as phagocyte receptors for bacteria. The absence of this type of nonimmune recognition of bacteria by these children's neutrophils may be one of the reasons for their increased susceptibility to bacterial infections.     

The acetylcholinesterase defect in paroxysmal nocturnal hemoglobinuria: evidence that the enzyme is absent from the cell membrane

Paroxysmal nocturnal hemoglobinuria (PNH) is a myelodysplastic disease characterized by erythrocytes that show abnormally increased sensitivity to complement-mediated lysis. Complement-sensitive PNH erythrocyte membranes have previously been shown to lack acetylcholinesterase (AchE) activity, but the molecular basis of this deficiency has been unclear. We have used monoclonal antibodies to four different epitopes on the AchE molecule to show that abnormal PNH erythrocytes failed to bind these antibodies. Moreover, abnormal PNH erythrocytes contained no protein immunoprecipitable by these antibodies, while normal complement-insensitive erythrocytes from PNH patients showed normal amounts of immunoprecipitable AchE which had normal electrophoretic mobility. These data suggest that abnormal PNH erythrocytes lack AchE enzyme activity due to the absence of the AchE molecule from the cell membrane.     

Chronic myelogenous leukemia: a multivariate analysis of the associations of patient characteristics and therapy with survival

The prognostic importance of patient pretreatment clinical and laboratory features was investigated in a group of 303 patients with Philadelphia chromosome-positive benign-phase chronic myelogenous leukemia. Intensive chemotherapy was given to 97 patients, and 78 underwent an early elective splenectomy. The overall median survival time, dated from hospital admission, was 39 months. Patient characteristics associated with shortened survival were age 60 years or older, black race, the presence of hepatomegaly, splenomegaly, symptoms, weight loss, and poor performance status. Adverse blood and bone marrow parameters were anemia, thrombocytosis or thrombocytopenia, a high proportion of peripheral blasts plus promyelocytes or of basophils, a high proportion of marrow blasts or basophils, decreased marrow megakaryocytes, and cytogenetic abnormalities in addition to the Philadelphia chromosome. Several of these factors were interrelated. A multivariate regression analysis demonstrated that the combination blood basophilia, race, additional cytogenetic abnormalities, age and marrow basophilia had the strongest predictive relationship to survival time. This resulted in a model segregating patients into low-, intermediate-, and high-risk groups, with median survivals of 53, 39, and 25 months, respectively. Another model was derived that did not include the marrow features and identified splenomegaly and platelet counts as adding to the prognosis prediction by blood basophilia, race, and age. Evaluation of the effect of therapy, after adjusting for differences in prognostic characteristics, showed that intensive chemotherapy was associated with survival prolongation among patients at intermediate and high risk of death. We conclude that a combination of pretreatment factors identifies different risk subcategories in patients with chronic myelogenous leukemia and is helpful in assessing overall prognosis and treatment effect.     

Human interleukin-4 enhances stromal cell-dependent hematopoiesis: costimulation with stem cell factor

Interleukin-4 (IL-4) has distinct hematopoietic activities, primarily as a costimulant with other cytokines to enhance colony formation of hematopoietic progenitors. We investigated the influence of IL-4 on stromal cell-supported long-term cultures (LTCs) of normal human bone marrow. Addition of IL-4 to LTCs of unseparated bone marrow or highly enriched CD34+ cells resulted in a significant increase of myeloid progenitors in the nonadherent, as well as in the stromal cell-adherent cell populations. In contrast, the total cell number was not influenced by IL-4, suggesting a selective effect on primitive progenitor cells. Cord blood cells or CD34+ bone marrow cells were incubated with stem cell factor (SCF) and/or IL-4 in stromal cell-free cultures. In these experiments, a twofold to fivefold increase of myeloid progenitor cells was observed in the presence of SCF and IL-4 as compared with SCF alone. Preincubation of the stromal cell cultures with IL-4 resulted in an enhanced adherence of CD34+ cells to the stromal layer. Secretion of hematopoietic growth factors produced by the stromal cells, such as granulocyte-macrophage colony-stimulating factor (G-CSF), and IL-1, was inhibited by IL-4. Thus, the increase of hematopoietic progenitors in LTCs, as observed in the presence of IL-4, can be at least partially explained by a costimulation of SCF and IL-4 on primitive progenitor cells and by an enhancement of hematopoietic cells to stroma. The downregulation of CSFs by IL-4 might prevent the expansion of the mature hematopoietic cell compartment.     

Central nervous system disease in acquired immunodeficiency syndrome: prospective correlation using CT, MR imaging, and pathologic studies

A prospective study compared the abilities of high-resolution computed tomography (HRCT) and magnetic resonance (MR) imaging in detection and evaluation of central nervous system disease in neurologically symptomatic patients with acquired immunodeficiency syndrome (AIDS). Eighteen CT scans and 19 MR images in 14 patients were compared. HRCT images with contrast material enhancement were superior to unenhanced 0.35-T MR images for differentiating a lesion from surrounding edema, discriminating between lesions in close proximity, locating lesions for biopsy, judging lesion activity, detecting small cortical lesions with minimal edema, and spatial resolution. MR imaging was superior to CT scanning in evaluation of white-matter lesions and detection of small lesions surrounded by edema. MR imaging exhibited higher contrast resolution and greater sensitivity. Complementary uses of MR and CT imaging are suggested.     

Optimal pulse sequence for imaging hepatic metastases

For magnetic resonance (MR) imaging studies in which the diagnosis is dependent on image contrast, it is essential that an optimized imaging technique be used. Using detection of hepatic metastases as an example, the authors describe a rational strategy for optimizing MR imaging technique. First, for a single patient with proved hepatic metastases, a variety of imaging sequences is discussed and evaluated, leading to characterization of the patient's hepatic tissues. Then the characteristics of the tissues of a representative patient population are presented. These are used to determine two optimal pulse sequences that maximize the achievable signal difference-to-noise ratio achievable in a fixed imaging time. The recommended imaging sequence for detection of hepatic metastases at 0.15 T is either a three-dimensional volume spin-echo (SE) sequence with echo time (TE) = 12 msec and repetition time (TR) = 184 msec or a multisection inversion recovery sequence with TE = 22 msec, inversion time = 250 msec, and TR = 1,375 msec. The variation of this optimum pulse sequence with field strength is also presented.     

An artificial intelligence deep learning model for identification of small bowel obstruction on plain abdominal radiographs

Objectives:Small bowel obstruction is a common surgical emergency which can lead to bowel necrosis, perforation and death. Plain abdominal X-rays are frequently used as a first-line test but the availability of immediate expert radiological review is variable. The aim was to investigate the feasibility of using a deep learning model for automated identification of small bowel obstruction.Methods:A total of 990 plain abdominal radiographs were collected, 445 with normal findings and 445 demonstrating small bowel obstruction. The images were labelled using the radiology reports, subsequent CT scans, surgical operation notes and enhanced radiological review. The data were used to develop a predictive model comprising an ensemble of five convolutional neural networks trained using transfer learning.Results:The performance of the model was excellent with an area under the receiver operator curve (AUC) of 0.961, corresponding to sensitivity and specificity of 91 and 93% respectively.Conclusion:Deep learning can be used to identify small bowel obstruction on plain radiographs with a high degree of accuracy. A system such as this could be used to alert clinicians to the presence of urgent findings with the potential for expedited clinical review and improved patient outcomes.Advances in knowledge:This paper describes a novel labelling method using composite clinical follow-up and demonstrates that ensemble models can be used effectively in medical imaging tasks. It also provides evidence that deep learning methods can be used to identify small bowel obstruction with high accuracy.     

Radionuclide bone imaging in spondylolysis of the lumbar spine in children

Bone scintigraphy and radiography were performed in seven children with back pain. Six of the children with radiographic evidence of a pars interarticularis defect also had abnormal scintigrams. Increased uptake of the bone imaging agent occurred at six of the ten sites of radiographic pars interarticularis defects, implying increased bone metabolic activity. However, the location of scintigraphic abnormalities did not correspond to the location of radiographic abnormalities in several cases. Possible explanations for the discordant findings are: (a) normal bone metabolism at the site of an old spondylolysis and (b) radiographically inapparent stress fractures. Measurements of absorbed radiation dose indicate that plain radiography, including oblique views where appropriate, has a lower absorbed radiation dose than scintigraphy or tomography and should be performed prior to these studies.