Monoclonal antibody 7G3 recognizes the N-terminal domain of the human interleukin-3 (IL-3) receptor alpha-chain and functions as a specific IL-3 receptor antagonist

The human interleukin-3 receptor (IL-3R) is expressed on myeloid, lymphoid, and vascular endothelial cells, where it transduces IL-3- dependent signals leading to cell activation. Although IL-3R activation may play a role in hematopoiesis and immunity, its aberrant expression or excessive stimulation may contribute to pathologic conditions such as leukemia, lymphoma, and allergic reactions. We describe here the generation and characterization of a monoclonal antibody (MoAb), 7G3, which specifically binds to the IL-3R alpha-chain and completely abolishes its function. MoAb 7G3 immunoprecipitated and recognized in Western blots the IL-3R alpha-chain expressed by transfected cells and bound to primary cells expressing IL-3R alpha. MoAb 7G3 bound the IL-3R alpha-chain with a kd of 900 pmol/L and inhibited 125I-IL-3 binding to high- and low-affinity receptors in a dose-dependent manner. Conversely, IL-3 but not granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibited 125I-7G3 binding to high- and low-affinity IL- 3Rs, indicating that MoAb 7G3 and IL-3 bind to common or adjacent sites. In keeping with the inhibition of IL-3 binding, MoAb 7G3 antagonized IL-3 biologic activities, namely stimulation of TF-1 cell proliferation, basophil histamine release, and IL-6 and IL-8 secretion from human endothelial cells. Two other anti-IL-3R alpha-chain MoAbs failed to inhibit IL-3 binding or function. Epitope mapping experiments using truncated IL-3R alpha-chain mutants and IL-3R alpha/GM-CSFR alpha chimeras revealed that 31 amino acids in the N-terminus of IL-3R alpha were required for MoAb 7G3 binding. MoAb 7G3 may be of clinical significance for antagonizing IL-3 in pathologic conditions such as some myeloid leukemias, follicular B-cell lymphoma, and allergy. Furthermore, these results implicate the N-terminal domain of IL-3R alpha in IL-3 binding. Since this domain is unique to the IL-3/GM- CSF/IL-5 receptor subfamily, it may represent a novel and common binding feature in these receptors.     

The association between the neutrophil-to-lymphocyte ratio and mortality in critical illness: an observational cohort study

IntroductionThe neutrophil-to-lymphocyte ratio (NLR) is a biological marker that has been shown to be associated with outcomes in patients with a number of different malignancies. The objective of this study was to assess the relationship between NLR and mortality in a population of adult critically ill patients.MethodsWe performed an observational cohort study of unselected intensive care unit (ICU) patients based on records in a large clinical database. We computed individual patient NLR and categorized patients by quartile of this ratio. The association of NLR quartiles and 28-day mortality was assessed using multivariable logistic regression. Secondary outcomes included mortality in the ICU, in-hospital mortality and 1-year mortality. An a priori subgroup analysis of patients with versus without sepsis was performed to assess any differences in the relationship between the NLR and outcomes in these cohorts.ResultsA total of 5,056 patients were included. Their 28-day mortality rate was 19%. The median age of the cohort was 65 years, and 47% were female. The median NLR for the entire cohort was 8.9 (interquartile range, 4.99 to 16.21). Following multivariable adjustments, there was a stepwise increase in mortality with increasing quartiles of NLR (first quartile: reference category; second quartile odds ratio (OR) = 1.32; 95% confidence interval (CI), 1.03 to 1.71; third quartile OR = 1.43; 95% CI, 1.12 to 1.83; 4th quartile OR = 1.71; 95% CI, 1.35 to 2.16). A similar stepwise relationship was identified in the subgroup of patients who presented without sepsis. The NLR was not associated with 28-day mortality in patients with sepsis. Increasing quartile of NLR was statistically significantly associated with secondary outcome.ConclusionThe NLR is associated with outcomes in unselected critically ill patients. In patients with sepsis, there was no statistically significant relationship between NLR and mortality. Further investigation is required to increase understanding of the pathophysiology of this relationship and to validate these findings with data collected prospectively.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0731-6) contains supplementary material, which is available to authorized users.     

A retropharyngeal multinodular goitre

Thyroid goitre usually presents as a mid-line lump in the neck with or without compressive symptoms. More commonly, the goitre can extend inferiorly into the mediastinum resulting in a retrosternal goitre. We present an unusual case of goiterous enlargement of the thyroid gland into the retropharyngeal space presenting as a retropharyngeal mass.     

Childhood sexual abuse (CSA) experiences: an underestimated factor in perinatal care

BACKGROUND: Childhood sexual abuse can have several negative consequences on pregnancy, birth, and the early neonatal period. However, most obstetricians are not aware if their patients have a history of childhood sexual abuse. We therefore investigated childhood sexual abuse experiences in 226 women three to eight months after delivery of a healthy child. METHODS: 415 women were approached to answer a self-administered questionnaire including obstetrical questions and questions focusing on abuse experiences. 320 women agreed to participate, 226 (69.1% of the women fulfilling inclusion criteria) of which returned a completed questionnaire. Sexual abuse was explored using a modified version of a questionnaire developed by Wyatt. The complete questionnaire was designed in cooperation with the German "Frauennotruf", a society providing care for victims of sexual abuse. RESULTS: The prevalence of childhood sexual abuse was a minimum of 11.5% and a maximum of 14.6% if women who were not sure about such experiences during their childhood were included. Another 1.3% of the women had experienced sexual abuse as an adult. Lifetime sexual abuse prevalence was 12.8% and 15.9%, respectively. Of the women with an experience of childhood sexual abuse, 42.3% mentioned an ongoing abuse situation for at least six months. CONCLUSIONS: As approximately every 9th woman presenting for obstetrical care has experienced childhood sexual abuse, and as those experiences may have a negative impact on fetal and maternal well-being, adequate counseling models should be offered to victims of sexual abuse.     

Tibial torsion in non-arthritic Indian adults: A computer tomography study of 100 limbs

Background:

Knowledge of normal tibial torsion is mandatory during total knee replacement (TKR), deformity correction and fracture management of tibia. Different values of tibial torsion have been found in different races due to biological and mechanical factors. Value of normal tibial torsion in Indian limbs is not known, hence this study to determine the norm of tibial torsional value in normal Indian population.

Materials and Methods:

Computer tomography (CT) scans were performed in 100 non-arthritic limbs of 50 Indian adults (42 males, eight females; age 26-40 years). Value of tibial torsion was measured using dorsal tangent to tibial condyles proximally and bimalleolar axis distally.

Results:

Normal tibial torsion was found to be 21.6 ± 7.6 (range 4.8 to 39.5) with none of the values in internal rotation. Right tibia was externally rotated by 2 degrees as compared to the left side (P 0.029). No significant difference was found in male and female subjects. Value of tibial torsion was less than in Caucasian limbs, but was comparable to Japanese limbs when studies using similar measurement technique were compared.

Conclusions:

Indian limbs have less tibial torsion than Caucasian limbs but the value of tibial torsion is comparable to Japanese limbs.     

Occurrence of allergic conditions in asthmatics with analgesic intolerance

BACKGROUND: The study aimed to determine whether allergic conditions accompany analgesic intolerance. METHODS: A total of 132 analgesic-intolerant patients with bronchial asthma admitted to the adult allergy unit from January 1991 to October 1997 and 103 patients with bronchial asthma randomly selected from among the asthmatics referred to our department between January and October 1997 were enrolled in the study. Those having analgesic intolerance and bronchial asthma were accepted as group I; patients having only asthma were accepted as group II. A standard questionnaire was completed for all the patients. Physical examination, routine skin prick tests, determination of total IgE levels and blood type, and oral analgesic provocation tests were also performed. RESULTS: The results showed that some allergic conditions were significantly more common in group I (22.7% and 7.8% for food allergy/intolerance [P<0.05], 16.7% and 7.8% for antibiotic allergy, 16.7% and 2.9% for dermographism, 9.8% and 1.0% for metal allergy, and 9.1% and 1.0% for chronic urticaria for groups I and II, respectively [P<0.001]). In addition, the mean of the total IgE level in the serum was higher in group I than group II (77.6 and 53.7 IU/ml; P<0.05), and the cumulative analgesic consumption was more in group I (14.2+/-17.1 and 9.1+/-12.5 boxes; P<0.05). CONCLUSIONS: Dermographism; chronic urticaria; antibiotic, metal, and food allergy; high levels of total IgE; and a high amount of cumulative analgesic consumption may be the conditions accompanying analgesic intolerance in asthmatics.