AllergoOncology: Opposite outcomes of immune tolerance in allergy and cancer.

While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2-biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines.

AllergoOncology - the impact of allergy in oncology: EAACI position paper.

Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE-mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state-of-the-art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE-mediated tumour antigen cross-presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment.

Enhanced angular current intensity from Schottky emitters.

Even though the Schottky emitter is a high-brightness source of choice for electron beam systems, its angular current intensity is substantially lower than that of thermionic cathodes, rendering the emitter impractical for applications that require high beam current. In this study, two strategies were attempted to enhance its angular intensity, and their experimental results are reported. The first scheme is to employ a higher extraction field for increasing the brightness. However, the tip shape transformation was found to induce undesirably elevated emission from the facet edges at high fields. The second scheme exploits the fact that the angular intensity is proportional to the square of the electron gun focal length [Fujita, S. & Shimoyama, H. (2005) Theory of cathode trajectory characterization by canonical mapping transformation. J. Electron Microsc. 54, 331-343], which can be increased by scaling-up the emitter tip radius. A high angular current intensity (J(Omega) approximately 1.5 mA sr(-1)) was obtained from a scaled-up emitter. Preliminary performance tests were conducted on an electron probe-forming column by substituting the new emitter for the original tungsten filament gun. The beam current up to a few microamperes was achieved with submicron spatial resolution.

Progesterone receptor localization and isoforms in myometrium, decidua, and fetal membranes from rhesus macaques: evidence for functional progesterone withdrawal at parturition.

OBJECTIVE: It is not known whether withdrawal of progesterone (P) action is a prerequisite for parturition in women or in nonhuman primates because concentrations of circulating progesterone or progesterone receptors (PR) in myometrium and decidua do not decrease before delivery. To examine this potentially important regulatory mechanism, we determined PR isoforms, PR localization, and mRNA in myometrium, decidua, and fetal membranes from rhesus monkeys during pregnancy and in spontaneous labor at term. METHODS: Gestational tissues were obtained midpregnancy (day 80-100), late pregnancy (day 130-145), and during spontaneous labor at term (day 161-167). Samples of rhesus monkey myometrium, decidua, chorion-decidua, and amnion were collected and analyzed for total nuclear and cytosolic PR by competitive binding assay. Progesterone receptor isoforms were identified and quantified by Western blot analysis, and PR mRNA was determined by a specific ribonuclease protection assay. Nuclear PR was localized by immunohistochemistry with monoclonal anti-PR (JZB39) after microwave stabilization. RESULTS: Myometrium and decidua showed no change in total PR during pregnancy and labor. Nuclear PR was not detected in fetal membranes by binding assay but was localized in amnion epithelial and mesenchymal cells and in chorion laeve cytotrophoblasts by immunohistochemistry. Staining for PR was substantially less by serial antibody dilution in fetal membranes than in decidua. Message for PR was confirmed in all tissues analyzed. A significant (P <.05) shift in the ratio of PR isoforms (from PR-B dominance at midpregnancy to PR-A dominance in labor) was observed in myometrium but not in decidua. Both PR-A and PR-B isoforms and PR nuclear staining were nearly undetectable in amnion obtained during labor. CONCLUSION: A shift to PR-A dominance in myometrium at term together with a loss of PR in fetal membranes provides evidence for a functional progesterone withdrawal mechanism, which may facilitate the initiation of parturition in primates.

The ratio of progesterone receptor isoforms changes in the monkey corpus luteum during the luteal phase of the menstrual cycle.

Recent evidence suggests that progesterone is required for ovulation, luteinization, and the maintenance of luteal structure and function in primates. Progesterone action is mediated by intracellular progesterone receptors (PRs), and PRs are detectable by immunocytochemistry in the monkey corpus luteum. However, changes in total luteal PR and PR isoform expression have not been quantitated in the corpus luteum during its life span in the menstrual cycle. This study was initiated to identify and quantify PR isoforms in the macaque corpus luteum throughout the luteal phase of the natural cycle by means of Western blotting. Several antibodies generated against the human PR recognized two bands of consistent molecular weights in monkey tissues, and these bands comigrated with PR-A and PR-B from human T47D cells. Taken together, these data suggest that the two proteins identified were macaque PR-A and PR-B. The estimated molecular weights of monkey PR-A and PR-B were approximately 90,000 and 120,000, respectively. PRs were detected in a variety of macaque tissues, including the endometrium, whole ovary, and decidua, but not in spleen, which is PR-negative by other techniques. Whereas PR-A was the predominant isoform observed in endometrium and decidua, PR-B predominated in the ovary without a dominant follicle or corpus luteum as well as in the corpus luteum. In luteal tissue, PR-A levels decreased (p < 0.05) over the course of the luteal phase, while PR-B levels were unchanged. Hence the ratio of PR-B to PR-A (PR-B:PR-A) increased (p < 0.05) from early to very late luteal phase. Since PR-B:PR-A can alter gene expression in response to progestins and antiprogestins in vitro, the temporal changes in PR-B:PR-A in the monkey corpus luteum may contribute to functional differences in luteal responses to progesterone and other steroids in vivo.

Familial renal tubular dysgenesis: a disorder not isolated to proximal convoluted tubules.

The autopsy findings of a newborn with renal tubular dysgenesis, born to first cousins of Moslim Arab descent, are described. Hypocalvaria and hyperflexible joints were noted in addition to the renal lesion. A microdissection study demonstrated marked shortening of all the nephron segments from the glomeruli to the collecting tubules, rather than an isolated abnormality of the proximal convoluted tubules.

Syndromal associations of common origin of the carotid arteries.

The term "common origin of the carotid arteries" (COCA) has been proposed to replace the older terms "origin of the left carotid artery from the innominate stem" and "bicarotid trunk with anomalous right or left subclavian artery." These anatomic patterns are usually reported to occur in about 11% of whites and 20-25% of blacks and have been reported to have increased frequency in patients with esophageal atresia-tracheoesophageal fistula, DiGeorge anomaly, and anomalous origin of the left coronary artery from the pulmonary artery. COCA is a significant, if not invariant, feature of the great arteries in the condition usually called in the more recent literature "anomalous origin of the innominate artery," the most frequent cause of symptomatic tracheal compression by anomalous systemic arteries. Analysis of associations of COCA with various other congenital cardiovascular lesions showed, in addition, significant association with congenital polyvalvular disease, truncus arteriosus, aorticopulmonary window, trisomy 13, 18, and 21 syndromes, acrocephalosyndactyly (especially Apert syndrome), tetralogy of Fallot not associated with DiGeorge anomaly, and clinical Noonan phenotype. Pentalogy of Cantrell was associated with no increase in incidence of COCA.

Branching patterns of right pulmonary artery in cardiovascular anomalies.

The branch of the right pulmonary artery (RPA) to the upper lobe of the right lung (RUL), the truncus anterior of the RPA, and the pars anterior of the left pulmonary artery, which supplies the left upper lung lobe (LUL), were demonstrated by both dissection of postmortem specimens and angiography for 20 infants and children, by angiography only for 57, and by specimen dissection only for 59 (total 136). In posteroanterior angiograms, the RUL artery branches from the RPA near the right lateral border of the vertebral column, while the LUL artery or arteries arise more laterally, near the left midclavicular plane. This pattern is reversed in situs inversus (eight patients studied). Thirty-nine patients in other categories of congenital cardiovascular disease showed an abnormal RUL or LUL arterial pattern, including pulmonary isomerism, right lung type (RUL artery pattern present bilaterally, 12 patients); pulmonary isomerism, left lung type (RUL artery pattern absent bilaterally, 11 patients); scimitar syndrome (RUL artery pattern normal, 1 patient; absent bilaterally, 4 patients); and left pulmonary artery sling (RUL artery normal, one; hypoplastic, one; absent, two patients). Five patients with tetralogy of Fallot (TOF) with right aortic arch (RAA) and 1 of 15 with RAA not TOF or situs inversus showed a relatively large RUL artery arising more laterally than usual. Three of six patients with double outlet right ventricle had the LUL artery larger than usual plus two accessory RUL arteries, and one patient with crossed pulmonary arteries showed a similar pattern. Two patients with single ventricle had an RUL artery of normal pattern although the RUL bronchus was absent, and one patient with single ventricle and situs inversus had a comparable pattern in the left lung. The ease of demonstration of the right and left upper lobe branches of the pulmonary artery by dissection or angiocardiography warrants greater attention to their patterns in patients with congenital cardiovascular disease. Dissociation of upper lobe bronchial and vascular patterns is unusual and may also be of diagnostic value.

Association of Down syndrome and segmental tracheal stenosis with ring tracheal cartilages: a review of nine cases.

Four patients with Down syndrome and midtracheal stenosis, three with proven absence of the midtracheal pars membranacea ("hourglass trachea"), are reported. Five previously reported patients who had Down syndrome and tracheal stenosis of this type are summarized. Respiratory difficulty and stridor were the reported clinical features of all but one of the patients whose clinical story is available. That approximately half the patients with tracheal stenosis with hourglass trachea and midtracheal absence of the tracheal pars membranacea reported had Down syndrome suggests that the association of this pattern of congenital tracheal stenosis with Down syndrome is, although infrequent, significant.

Studies of vertebral coronal cleft in rhizomelic chondrodysplasia punctata.

Dissection and serial section-reconstruction preparations from vertebrae with coronal cleft of a 2 5/12-year-old girl with rhizomelic chondrodysplasia punctata are described. The cartilage plate between the dorsal and ventral vertebral ossification centers, abnormal thickness of which is the explanation of the radiologic coronal cleft, shows differences in thickness, with dorsal and ventral midline extensions and with small foci of communication of the cancellous bone of the dorsal and ventral ossification centers of the vertebral body bilaterally. Although the process in coronal cleft is in some ways similar to that of radiologic "retarded epiphyseal closure," the explanation of the coronal clefts in rhizomelic chondrodysplasia punctata appears to be overproduction of cartilage in the zone between the dorsal and ventral vertebral body ossification centers, plus reduced removal of cartilage cells from this zone. No evidences of persistence of notochord cells were seen microscopically in sections of the coronal clefts.

Tracheal cartilaginous sleeve.

Tracheal cartilaginous sleeve (TCS) is a rare congenital malformation in which discrete cartilaginous rings are replaced by a grossly uninterrupted cartilaginous sleeve. Seven previous patients with TCS have been reported in the world literature; in each instance, TCS was associated with craniosynostosis (CS). We report details of five additional patients with TCS, of whom four had a dominantly inherited CS. Gross examination of the available tracheas and bronchi demonstrates a cartilaginous sleeve with posterior interruption but lacking a normal pars membranacea. The stained and cleared tracheas all demonstrate variable ring formation, usually limited to the posterolateral aspect. The functional significance of TCS, if any, is unknown. No data are available on the prevalence of TCS in CS syndromes. The formation of TCS implies a common mesenchymal defect in which normally discrete structures fuse and is probably analogous to other mesenchymal abnormalities seen in these patients.

Microdissection study of the myenteric plexus in acardia, ataxia-telangiectasia, cystic fibrosis, extrahepatic biliary atresia, pediatric AIDS and Werdnig-Hoffmann disease.

Microdissection-point count morphometric study of the myenteric (Auerbach) plexus or esophagus, small intestine, and colon was done for infants and children with acardia (2), ataxia-telangiectasia (5), cystic fibrosis of the pancreas (CFP) (25), extrahepatic biliary atresia (EBA) (17), pediatric AIDS (10), and Werdnig-Hoffmann disease (WHD) (8). Values for fractional area of neural tissue in the plane of the plexus were compared to those of control patients in same age range as those in each disease category by t-test. Statistically abnormal values included low values for small intestine and colon in Werdnig-Hoffmann disease, high values for small intestine and colon in biliary atresia, and high value for colon but a low value for small intestine in cystic fibrosis. Values for all three loci were within the normal range for ataxia telangiectasia and pediatric AIDS. The mechanisms of the low value for small and large intestines in WHD, which causes chronic constipation as a result of skeletal muscle weakness, and of the high values for colon in CFP and EBA, both causing malabsorption with bulky stools, are unclear. The value for small intestine in acardia was normal for term but lower than expected for fetal bowel of the same size, possibly because of reduced neural crest inflow to the fetal bowel.

The urinary system in Down syndrome: a study of 124 autopsy cases.

We examined 124 autopsy cases of Down syndrome for the presence of renal and urinary tract abnormalities. The cases were divided into three groups: (I) fetuses of 16-22 weeks gestation (n = 18), (II) stillborns or newborns who died on the first day of life (n = 9), and (III) Down patients 1 day to 25 years of age (n = 97). Kidney weight was reduced by a mean of 14.4% compared with expected values. Renal hypoplasia, defined as kidney weight less than two-thirds expected, was found in 18 cases. Glomerular microcysts were found in 23 of 97 cases in group III. Focal dilatation of tubules was found in 10, simple cysts in 7, and immature glomeruli deep in the renal cortex in 18 cases. Obstructive uropathy occurred in 2 of 18 (11.1%) in group I, 2 of 9 (22.2%) in group II, and 4 of 97 (4.1%) in group III. Obstructive uropathy with bilateral cystic dysplastic kidneys resulted in Potter's sequence. We suggest that obstructive uropathy is associated with Down syndrome. When severe, it results in Potter's sequence and an early perinatal death. A chromosomal analysis is recommended in any case of obstructive uropathy in the fetal or neonatal period.

The question of parallax-effect on radiographic assessment of short trachea in infants and children.

Disproportionately short trachea, can be recognized in AP chest radiographs of infants and older children taken during quiet respiration and showing an evaluable air tracheobronchogram, by the thoracic vertebral level of the carina (normally at T4 in neonates and infants, and at T5 in children two years of age or older). To establish the extent to which a parallax-effect of differing angles of X-ray beam relative to the patient can influence the radiologic assessment of carinal level, we measured the tracheal-vertebral distance at the carina in 29 lateral radiographs of neonates, infants and children, prepared diagrams of the loci of carinal beam intercept of the vertebral column for different angles of beam to body, from tracings of lateral radiographs of two 2-week-old infants, one with trachea of normal length and one with short trachea; of a nine-year-old child with short trachea, and of a ten-year-old with normal trachea, and made radiographs of a postmortem tracheobronchogram of a two-day-old infant at different beam angles. We conclude that tube-body angles of the order of 10-15 degrees from vertical at 27 inches (68.6 cm) or at 40 inches (101.6 cm) FFD do not significantly affect the apparent thoracic vertebral level of the carina in AP chest radiographs, and that a beam angle of 20 degrees or more from vertical is necessary to change the apparent level of tracheal bifurcation by one vertebral body, depending on the patient's age and on whether the patient's position relative to the X-ray beam is lordotic or anti-lordotic.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic aspects and syndromal associations of short trachea with bronchial intubation.

Conditions with disproportionately short trachea, with a reduced number of tracheal cartilage rings and a high level of tracheal bifurcation, have been reported. We have seen accidental bronchial intubation in nine patients with short trachea. This risk can be reduced by recognition of conditions associated with short trachea, by awareness that methods for calculating endotracheal tube length from body length can overpredict tube length for patients with short trachea, and when feasible, by use of preintubation chest roentgenograms showing air bronchograms to establish the thoracic level of tracheal bifurcation. Twelve patients with short trachea, four with bronchial intubation, and six conditions not previously associated with short trachea, are reported. Three of the patients also had laryngeal hypoplasia.

Incidence of short trachea in patients with myelomeningocele.

Short trachea, typically due to reduced tracheal cartilage ring number, produces high tracheal bifurcation which can be demonstrated in radiographs with evaluable air bronchograms. Accidental bronchial intubation with sequelae has been reported in short trachea patients who have tracheal intubation. Short trachea is associated with a number of syndromes, including DiGeorge anomaly and several types of congenital heart disease and skeletal dysplasias. Review of chest radiographs of 87 patients with myelomeningocele revealed that 31 (36%) had short tracheas. Two patients had a total of 3 episodes of bronchial intubation. This degree of association of short trachea with myelomeningocele, the frequency of myelomeningocele, and the number of surgical procedures performed on many such patients suggest that special attention to the short trachea is warranted in myelomeningocele patients because of the risk of accidental bronchial intubation and subsequent sequelae. Twelve (14%) of the myelomeningocele patients lacked radiographic evidence of the presence of twelfth ribs and 11 (13%) had hypoplasia of the twelfth ribs.

Serial section-reconstruction of anomalous tracheobronchial branching patterns from CT scan images: bridging bronchus associated with sling left pulmonary artery.

The use of the technique of wax-plate serial section-reconstruction, based on contiguous axial plane CT images of the upper thorax, to prepare a replica of the central air-way (trachea and major bronchi) of an infant with sling left pulmonary artery type 2B, with bridging bronchus, abortive right main bronchus, and tracheal stenosis due to absence of the tracheal pars membranacea with "ring" tracheal cartilages is described. The technique is applicable to demonstration of the anatomic features of other abnormalities of branching pattern or caliber of the trachea and major bronchi.

Acrocephalospondylosyndactyly--a possible new syndrome: analysis of the vertebral and intervertebral components.

Apert-Crouzon syndrome (formerly ACS type 2; 10130) is now considered a subset of autosomal dominant Apert acrocephalosyndactyly type 1 (10120), with features of craniosynostoisis, syndactyly of all extremities, maxillary hypoplasia, "parrot-beaked" nose, hypertelorism, exophthalmos, external strabismus, and short upper lip. We report a 3 1/2-month-old infant with features of Apert syndrome, plus thoracic vertebral anomalies radiographically similar to those seen in spondylothoracic dysplasia, a condition in which block thoracic vertebrae with widely open neural arches and a fan-shaped thoracic cage are found. Our patient also had flared metaphyseal ends of humeri, dislocated radii with immobile elbows, an unusual tail-like protuberance in the coccygeal area, and a solid cartilaginous tracheal wall. To date, in ongoing reviews of radiographs of other patients with acrocephalosyndactyly or acrocephalopolysyndactyly complexes and of relevant literature, we have not identified other patients with these findings. The vertebrae and intervertebral discs of the patient in this report, three patients with Jarcho-Levin syndrome, and one with Apert syndrome were measured from anteroposterior chest radiographs; the findings clearly distinguish the condition in our patient from Jarcho-Levin syndrome or Apert syndrome.

Morphometric studies of cystic and tubulointerstitial kidney diseases with hepatic fibrosis in children.

Portal tract fibrosis with biliary ductular enlargement or proliferation occurs in a number of genetic diseases that have cystic or tubulointerstitial renal lesions. These include some with renal cystic disease such as autosomal recessive diseases (e.g., infantile polycystic disease, juvenile polycystic disease, and Meckel's syndrome), autosomal dominant diseases (e.g., adult polycystic disease) and, rarely, tuberose sclerosis and dominant glomerulocystic disease. Portal tract fibrosis with biliary enlargement and proliferation occurs also with tubulointerstitial kidney diseases. These probably include at least three disorders in the category nephronophthisis-congenital hepatic fibrosis (one autosomal recessive disease and two either autosomal or X-linked recessive diseases) plus Jeune's syndrome (the tubulointerstitial diseases Fanconi's familial nephronophthisis and anti-tubular membrane antibody disease do not regularly cause hepatic fibrosis). Morphometric data on ratios of bile ductules to connective tissue in hepatic portal tracts show high values for infantile polycystic disease (mean, 0.616) compared to lower values for juvenile polycystic disease (mean, 0.286). That the cystic renal lesions of the first two diseases differ in type and time course is known. Similar data on ratios of glomeruli plus tubules to connective tissue in renal cortices and of tubules to connective tissue in outer medullary zones of kidneys, respectively, are as follows: for Fanconi's nephronophthisis, 0.445 and 0.197; for anti-tubular basement membrane antibody disease, 0.585 and 0.164; and for the three types of nephronophthisis-congenital hepatic fibrosis studied, 0.668 and 0.446, 1.39 and 0.921, and 1.18 and 0.12. These data support clinical impressions that the category nephrophthisis-congenital hepatic fibrosis includes more than one disease entity.