MRI analysis of neurodevelopmental anatomy in myelomeningocele: prenatal vs postnatal repair.

OBJECTIVE: Prenatal myelomeningocele (MMC) repair offers improved motor function and decreased rates of cerebrospinal fluid (CSF) diversion compared to than postnatal repair. However, comparative analysis of other associated neuroanatomical findings is lacking. The purpose of this study is to use magnetic resonance imaging (MRI) imaging to compare characteristic Chiari II malformation stigmata in patients who underwent fetal MMC repair vs. postnatal repair. METHODS: A retrospective review was performed of neonates who underwent prenatal or postnatal MMC repair at our institution and had postnatal MRIs. We analyzed anatomical findings characteristically seen with Chiari II malformation on brain MRI in patients who underwent prenatal MMC repair vs. postnatal repair. RESULTS: CSF diversion was required in 24% of prenatal cohort vs. 67% of postnatal cohort (p = 0.002), and syrinx was present in 12% of prenatal cohort compared to 42% in postnatal cohort (p = 0.03). Corpus callosum (CC) morphology was abnormal in 52% of prenatal cohort vs. 53% of postnatal cohort (p = 0.92), while falx morphology was normal in 92% of the prenatal cohort vs. 34% of the postnatal cohort (p = <0.001). Prenatal cohort patients had shorter tentorium to foramen magnum distance than postnatal cohort patients (18.4mm vs. 22.4mm, p = 0.01), overall larger foramen magnum diameter (22.9mm vs. 18.9mm, p < 0.001), and a smaller mean degree of hindbrain herniation (1.5mm vs. 8.7mm, p < 0.001). Finally, the cerebral aqueduct was patent in 79% of prenatal cohort vs. 100% of postnatal cohort (p = 0.007). There was no significant difference in presence of gray matter heterotopia, presence of septum pellucidum, or size of massa intermedia between the two cohorts. CONCLUSIONS: We report baseline variations in developmental neuroanatomy in patients with MMC including rates of CC dysgenesis, gray matter heterotopia and additional cranial and spinal MRI findings. We found that prenatal surgery results in changes to infratentorial anatomy, with minimal effect on supratentorial brain development. This information will be useful in myelomeningocele counseling and in understanding how prenatal repair of myelomeningocele affects brain development. This article is protected by copyright. All rights reserved.

Stopping antibiotic therapy after 72 h in patients with febrile neutropenia following intensive chemotherapy for AML/MDS (safe study): A retrospective comparative cohort study.

BACKGROUND: Induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is almost universally complicated by febrile neutropenia(FN). Empirical broad-spectrum antibiotic therapy (EBAT) strategies advocated by guidelines result in long periods of broad-spectrum antibiotic therapy. We compared the outcome of AML/MDS patients treated with a 3-day versus a prolonged (until neutrophil recovery) regimen. METHODS: This is a retrospective comparative cohort study in AML or MDS patients undergoing remission-induction chemotherapy from 2011 to 2019, comparing 2 tertiary care hospitals with different strategies regarding antibiotic treatment for FN. At Erasmus University medical center(EMC), EBAT was stopped after 3 days of FN, in absence of a clinically or microbiologically documented infection. In the University Hospitals Leuven(UZL), a prolonged strategy was used, where EBAT was given until neutrophil recovery. The primary endpoint was a serious medical complication(SMC) defined as death or ICU admission in the 30 days after the start of chemotherapy. FINDINGS: 305 and 270 AML or MDS patients received chemotherapy at EMC and UZL, respectively. Broad-spectrum antibiotic treatment was given for a median of 19 days (IQR13-25) at UZL versus 9 days at EMC (IQR5-13) (p <0·001). With the 3-day EBAT strategy, an SMC was observed in 12·5% versus 8·9% with the prolonged strategy (p = 0·17). The hazard ratio for an SMC was not significantly higher with the 3-day strategy (HR 1·357,95%CI 0·765-2·409). INTERPRETATION: This study suggests that during remission induction chemotherapy it is safe to stop antibiotics after 3 days of FN in absence of infection. A comparison of both strategies in a prospective trial should be pursued.

Invasive fungal infections in patients treated with Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) inhibitors are increasingly used in untreated and previously treated chronic lymphocytic leukaemia (CLL) patients. Invasive fungal infections (IFI) were rarely observed in patients treated for CLL in the pre-BTK era. In this article, we describe two patients with CLL who developed an IFI during treatment with the BTK inhibitor ibrutinib. The atypical presentation and the serious course of this complication are described.

Central diabetes insipidus: A rare complication of IVH in a very low birth weight preterm infant.

A 710 g male infant was born at a referring hospital at a gestational age of 23 weeks and 2 days via vaginal delivery and was transferred to our facility at 14 days of age. His delivery was complicated by the breech presentation with difficult head extraction. The infant's initial course was significant for respiratory distress syndrome, grade III-IV intraventricular hemorrhage (IVH), acute kidney injury, and large PDA. On the day of life 29, a gradual increase in serum sodium level refractory to increasing total fluid volume was noted. The combination of persistent hypernatremia (150-160 mmol/l), polyuria (8.4 ml/kg/hr), high plasma osmolality (323 mosm/kg), hyposthenuria (75 mosm/kg) and an undetectable serum ADH (<0.8 pg/ml) confirmed the diagnosis of central diabetes insipidus (CDI). Serum sodium and urine output decreased and urine osmolality increased after subcutaneous DDAVP administration.CDI is an uncommon cause of hypernatremia in the neonatal period. The diagnosis can be difficult as excessive urine output and high serum sodium can often be attributed to high insensible water loss in the extremely premature newborn. CDI in our patient was thought to be due to grade III-IV IVH complicated by post-hemorrhagic hydrocephalus.In conclusion, the diagnosis of central DI should be considered as a complication of severe IVH in the extremely premature neonate who demonstrates persistent hypernatremia, polyuria, decreased urine osmolality, and increased plasma osmolality. Serum ADH levels can be helpful in confirming the central origin of DI and subcutaneous desmopressin can be an effective treatment in the preterm infant.

Axenfeld-Rieger syndrome: a case report.

Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant condition manifesting as a heterogeneous group of features. Of particular note are the ocular and craniofacial anomalies and dental features such as hypodontia, microdontia, taurodontism, enamel hypoplasia, conical-shaped teeth, shortened roots and delayed eruption. To treat cases with ARS effectively, a multidisciplinary approach is required, and this report describes the complex and long-term management of a case with input from Paediatric Dentistry, Orthodontics, Restorative Dentistry, Speech and Language Therapy, Oral and Maxillofacial Surgery and Radiology.

The influence of using digital diagnostic information on orthodontic treatment planning - a pilot study.

The purpose of this pilot study was to assess whether orthodontic treatment planning is reproducible when carried out using digital records compared with clinical examinations or using standard records. The study also assessed patients' opinion of face-to-face consultations and potential use of teleorthodontics. The study was designed as a prospective observational cross-sectional pilot study and carried out in a UK dental teaching hospital involving 27 subjects. Four consultant Orthodontists carried out treatment planning, firstly following a clinical examination, then using standard records, and then using digital records. Each subject completed a questionnaire. Cohen's kappa coefficient and Fleiss' kappa coefficient were used to assess intra-observer reproducibility and inter-observer reproducibility of treatment planning decisions, respectively. A change in the diagnostic information format affected treatment planning reproducibility for half of the observers. Inter-observer reproducibility was greater when using hard copy records in comparison to digital records. No subjects were unsatisfied with their face-to-face consultation.

Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies.

Polycomb repressive complex 2 (PRC2) is involved in trimethylation of histone H3 lysine 27 (H3K27), chromatin condensation and transcriptional repression. The silencing function of PRC2 complex is mostly attributed to its intrinsic activity for methylating H3K27. Unlike in B-cell lymphomas, enhancer of zeste homolog 2 (EZH2) mutations in myeloid malignancies are inactivating/hypomorphic. When we assessed the mutational status in myeloid malignancies (N=469 cases examined), we found EZH2 and EED/SUZ12 mutations in 8% and 3.3% of cases, respectively. In addition to mutant cases, reduced EZH2 expression was also found in 78% cases with hemizygous deletion (-7/del7q cases involving EZH2 locus) and 41% of cases with diploid chromosome 7, most interestingly cases with spliceosomal mutations (U2AF1/SRSF2 mutations; 63% of cases). EZH2 mutations were characterized by decreased H3K27 trimethylation and increased chromatin relaxation at specific gene loci accompanied by higher transcriptional activity. One of the major downstream target is HOX gene family, involved in the regulation of stem cell self-renewal. HOXA9 was found to be overexpressed in cases with decreased EZH2 expression either by EZH2/spliceosomal mutations or because of -7/del7q. In summary, our results suggest that loss of gene repression through a variety of mutations resulting in reduced H3K27 trimethylation may contribute to leukemogenesis.

Detection of volatile organic compounds using porphyrin derivatives.

Seven different porphyrin compounds have been investigated as colorimetric gas sensors for a wide range of volatile organic compounds. The porphyrins examined were the free base and Mg, Sn, Zn, Au, Co, and Mn derivatives of 5,10,15,20-tetrakis[3,4-bis(2-ethylhexyloxy)phenyl]-21H,23H-porphine. Chloroform solutions of these materials were prepared and changes in their absorption spectra induced by exposure to various organic compounds measured. The porphyrins that showed strong responses in solution were selected, and Langmuir-Blodgett films were prepared and exposed to the corresponding analytes. This was done to determine whether they are useful materials for solid state thin film colorimetric vapor sensors. Porphyrins that readily coordinate extra ligands are shown to be suitable materials for colorimetric volatile organic compound detectors. However, porphyrins that already have bound axial ligands when synthesized only show a sensor response to those analytes that can substitute these axial ligands. The Co porphyrin displays a considerably larger response than the other porphyrins investigated which is attributed to a switch between Co(II) and Co(III) resulting in a large spectral change.

A solution concentration dependent transition from self-stratification to lateral phase separation in spin-cast PS:d-PMMA thin films.

Thin films with a rich variety of different nano-scale morphologies have been produced by spin casting solutions of various concentrations of PS:d-PMMA blends from toluene solutions. During the spin casting process specular reflectivity and off-specular scattering data were recorded and ex situ optical and atomic force microscopy, neutron reflectivity and ellipsometry have all been used to characterise the film morphologies. We show that it is possible to selectively control the film morphology by altering the solution concentration used. Low polymer concentration solutions favour the formation of flat in-plane phase-separated bi-layers, with a d-PMMA-rich layer underneath a PS-rich layer. At intermediate concentrations the films formed consist of an in-plane phase-separated bi-layer with an undulating interface and also have some secondary phase-separated pockets rich in d-PMMA in the PS-rich layer and vice versa. Using high concentration solutions results in laterally phase-separated regions with sharp interfaces. As with the intermediate concentrations, secondary phase separation was also observed, especially at the top surface.

Alkylamine sensing using langmuir-blodgett films of n-alkyl-N-phenylamide-substituted zinc porphyrins.

Two porphyrin compounds, zinc(II) 5,10,15,20-tetrakis(3,5,5-trimethyl- N-phenylhexanamide)porphyrin and zinc(II) 5,10,15,20-tetrakis(2,2-dimethyl- N-phenylpropanamide)porphyrin, have been investigated as possible candidates for the detection of alkylamines. UV-visible spectroscopy has shown that their solution absorption spectra are significantly modified upon interaction with a range of organic analytes, including acetic acid, butanone, ethylacetate, hexanethiol, octanal, octanol, alkylamines, and trimethylphosphite. Large spectral changes are observed for the family of alkylamines as a result of the specific affinity between zinc and the amine moiety. Langmuir-Blodgett (LB) films of the porphyrins have been fabricated in order to assess their solid-state sensing capability toward amines. The surface pressure-area (Pi- A) isotherms reveal a clear three-phase Langmuir film behavior and show that these monolayer films may be compressed to a relatively high surface pressure ( approximately 40-50 mN m (-1)). The isotherm data alongside molecular modeling suggest a relatively flat orientation of the porphyrin rings of both compounds: that is, a mutually parallel alignment of the plane of the porphyrin ring and that of the water surface. LB films deposited at 15 mN m (-1) have been exposed to alkylamine vapor (carried by N 2). A red shift and increase in intensity of the Soret band absorbance is observed which can be reversed by flowing pure N 2 over the gently heated sample (60 degrees C) after exposure. Primary amines were expected to invoke the greatest sensing response due to (i) their larger association constants with these porphyrins compared to secondary and tertiary amines and (ii) the ease of diffusion of amines which is expected to follow the order primary > secondary > tertiary due to the steric hindrance arising from the bulky secondary and tertiary amines. However, the magnitude of the absorbance change is largest for exposure to the secondary amines, dipropylamine and dibutylamine, for both porphyrins, compared to primary and tertiary amines. This trend follows that observed when the amines were added to solutions of the porphyrins. The rate of response of the porphyrin LB films falls as the molecular weight of the diffusing alkylamine increases. Furthermore, a greater rate of response is observed for the phenylhexanamide porphyrin compared to the phenylpropanamide porphyrin due to its lower molecular density within the LB film and therefore more porous structure.

Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation.

Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vbeta) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vbeta family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.

Experimental and simulational study of the operation conditions for a high transmission mass filter.

The operation conditions of a double pulsed field mass filter were studied using both experiment and simulation. The mass filter consists of two pairs of parallel plates and operates on the time-of-flight principle. The study showed that the ions' beam deflection angle is a critical factor in optimizing the mass filter transmission efficiency. This angle is dependent on the accelerating voltage, ion mass, and horizontal velocity of the ions. The optimum operating conditions for the mass filter were found and used to study the mass distribution of palladium ions produced by a magnetron sputtering source. The study shows that this mass filter is suitable for technological applications because of its high transmission and wide mass range.

Purification and molecular characterization of recombinant rat betacellulin.

A method for the large scale expression and purification of rat betacellulin (BTC) from Escherichia coli has been developed using a cleavable fusion protein strategy. Insoluble fusion protein collected as inclusion bodies was dissolved in urea under reducing conditions, re-folded, and purified by gel filtration chromatography and C(4) RP-HPLC. Authentic rat BTC was obtained after proteolytic cleavage of the fusion protein with Factor Xa. Factor Xa cleaved an additional site within the BTC protein, generating a truncated isoform separable from full-length BTC by heparin-affinity chromatography. Recombinant rat BTC stimulated the proliferation of mouse Balb/c 3T3 fibroblasts and competed for binding to the ErbB1 receptor in a dose-dependent manner analogous to that of BTC purified from natural sources.

The effects of partial and total interosseous membrane transection on load sharing in the cadaver forearm.

This study was performed to examine the effects of partial and total transection of the interosseous membrane (IOM) on load transfer in the forearm. Twenty fresh frozen forearms were instrumented with custom designed load cells placed in the proximal radius and distal ulna. Simultaneous measurements of load cell forces, radial head displacement relative to the capitellum, and local tension within the central band of the IOM were made as the wrist was loaded to 134 N with the forearm at 90 degrees of elbow flexion and in neutral pronation supination. For valgus elbow alignment (radial head contacting the capitellum), mean force carried by the distal ulna was 7.1% of the applied wrist force and mean force transferred from radius to ulna through the IOM was 4.4%. For varus elbow alignment (mean 2.0 mm gap between the radial head and capitellum), mean distal ulna force was 28% and mean IOM force was 51%. Section of the proximal and distal one-thirds of the IOM had no significant effect upon mean distal ulnar force or mean IOM force. Total IOM section significantly increased mean distal ulnar force for varus elbow alignment in all wrist positions tested. The mean level of applied wrist force necessary to close the varus gap (89 N) decreased significantly after both partial IOM section (71 N) and total IOM section (25 N). The IOM became loaded only when the radius displaced proximally relative to the ulna, closing the gap between the radius and capitellum. As the radius displaced proximally, the wrist becomes increasingly ulnar positive, which in turn leads to direct loading of the distal ulna. This shift of force to the distal ulna could present clinically as ulnar sided wrist pain or as ulnar impaction after IOM injury.

Activation of the phosphatidylinositol 3-kinase-Akt/protein kinase B signaling pathway in arachidonic acid-stimulated human myeloid and endothelial cells: involvement of the ErbB receptor family.

Although arachidonic acid has been demonstrated to stimulate a wide variety of cellular functions, the responsible mechanisms remain poorly defined. We now report that arachidonic acid stimulated the activity of class Ia phosphatidylinositol 3-kinase (PI3K) in human umbilical vein endothelial cells, HL60 cells, and human neutrophils. Pretreatment of endothelial cells with AG-1478, an inhibitor of the ErbB receptor family, resulted in the suppression of PI3K activation by arachidonic acid. The fatty acid enhanced the tyrosine phosphorylation of ErbB4 but not of ErbB2 or ErbB3. The ability of arachidonic acid to stimulate PI3K activity in neutrophils was suppressed by indomethacin and nordihydroguaiaretic acid, inhibitors of the cyclooxygenases and lipoxygenases, respectively, but not by 17-octadecynoic acid, an inhibitor of omega-hydroxylation of arachidonic acid by cytochrome P450 monooxygenases. Consistent with this, the activity of PI3K in neutrophils was stimulated by 5-hydroxyeicosatetraenoic acid. Arachidonic acid also transiently stimulated the phosphorylation of Akt on Thr-308 and Ser-473. Although PI3K was not required for the activation of the mitogen-activated protein kinases, ERK1, ERK2, and p38, in arachidonic acid-stimulated neutrophils, the fatty acid acted via PI3K to stimulate the respiratory burst. These results not only define a novel mechanism through which some of the actions of arachidonic acid are mediated but also demonstrate that, in addition to ErbB1 (epidermal growth factor receptor), ErbB4 can also be transactivated by a non-epidermal growth factor-like ligand.

Effects of radial head excision and distal radial shortening on load-sharing in cadaver forearms.

BACKGROUND: The present study was performed to measure changes in radioulnar load-sharing in the cadaveric forearm following two orthopaedic surgical procedures that often have varying results: radial head excision and distal radial shortening. A better understanding of the biomechanical consequences of those procedures could aid surgeons in obtaining a more satisfactory clinical outcome. METHODS: Miniature load-cells were inserted into the proximal part of the radius and the distal part of the ulna in twenty fresh-frozen cadaveric forearms. Load-cell forces, radial head displacement relative to the capitellum, and local tension within the central band of the interosseous membrane were measured simultaneously as the wrist was loaded to 133.5 N in neutral pronation-supination and neutral radioulnar deviation. Testing was repeated after incremental distal radial shortening and after removal of the radial head. RESULTS: With the elbow flexed to 90 degrees and in valgus alignment (the radial head in contact with the capitellum), the mean force in the distal part of the ulna was 7.1% of the applied wrist force and the mean force in the interosseous membrane was 4.0%. With the elbow in varus alignment (a mean initial gap of 1.97 mm between the radial head and the capitellum), the respective mean values were 27.9% and 51.2%. After excision of the radial head, the mean force in the distal part of the ulna increased to 42.4% of the applied wrist force and the mean force in the interosseous membrane increased to 58.8%, in both varus and valgus elbow alignment. The mean distal ulnar force increased with progressive distal radial shortening in both varus and valgus elbow alignment; after 6 mm of radial shortening, the distal ulnar force averaged 92.4% (in varus alignment) and 60.9% (in valgus alignment). Equal distal load-sharing between the radius and ulna occurred after approximately 5 mm of radial shortening with the elbow in valgus alignment and after approximately 2 mm of radial shortening with the elbow in varus alignment. In valgus alignment, the force in the interosseous membrane was negligible after all degrees of radial shortening; in varus alignment, the mean force in the interosseous membrane decreased from 51.2% (0 mm of distal radial shortening) to 0% (6 mm of distal radial shortening) because of progressive slackening of the interosseous membrane. CONCLUSIONS: Radial head excision shifted the applied wrist force that normally would be transmitted to the elbow, through radial head-capitellar contact, to the interosseous membrane. The resulting proximal radial displacement created an ulnar-positive wrist and increased distal ulnar loading. Radial shortening and ulnar lengthening procedures have been designed to shift the applied wrist force from the distal part of the radius to the distal part of the ulna; it is commonly assumed that these procedures have equivalent biomechanical effects. We found that radial shortening resulted in slackening of the interosseous membrane, thereby negating its ability to transmit load through the forearm. Slackening of the interosseous membrane would not be expected with distal ulnar lengthening procedures. CLINICAL RELEVANCE: When the radial head has been fractured or excised, the mechanical status of the interosseous membrane is critical to the load-sharing process. If the interosseous membrane remains intact, distal ulnar loads will be limited to less than half of the applied wrist force; if the interosseous membrane has been damaged, nearly the entire applied wrist force will be shifted to the ulna. The amount of radial shortening or ulnar lengthening performed at the time of surgery during joint-leveling procedures has been largely empirical. We found that distal ulnar load increased by approximately 10% for each millimeter of radial shortening.

Measurement of betacellulin levels in bovine serum, colostrum and milk.

Betacellulin, a member of the epidermal growth factor (EGF) family, was originally isolated and identified from the conditioned medium from a murine pancreatic beta-cell carcinoma cell line. Recently, we isolated bovine betacellulin from a growth factor enriched cheese whey extract, but there is no information on the presence of betacellulin in other biological fluids. We have cloned the cDNA for bovine betacellulin, produced recombinant betacellulin and shown that it has a similar potency to the purified native molecule in stimulating the proliferation of Balb/c3T3 fibroblasts. We have produced a polyclonal antiserum to bovine betacellulin which did not cross-react with EGF or transforming growth factor-alpha (TGF-alpha). The antibody was used in a homologous RIA that was able to detect betacellulin in pooled bovine colostrum sampled during the first 3 days after calving (2.30+/-0.11 ng/ml mean+/-s.e.m.; n=6), in bovine milk soluble fraction (1.93+/-0.64 ng/ml mean+/-s.e.m.; n=5) and in bovine cheese whey (2.59+/-0.16 ng/ml mean+/-s.e.m.; n=3). The betacellulin concentration in foetal bovine serum (FBS) (3.68+/-0.59 ng/ml mean+/-s.e.m.; n=6) greatly exceeded that of betacellulin in serum from male calves 1 and 5 weeks of age (0.53+/-0.15 ng/ml and 0.70+/- 0.09 ng/ml respectively; mean+/-s.e.m.; n=9). Betacellulin measured in the serum of these same animals when aged between 27 and 43 weeks was below the detection limits of the RIA. Sera from 10 out of 36 unmated heifers contained betacellulin levels within the detection limits of the assay (0.433+/-0.06 ng/ml mean+/-s.e.m.; n=10). The presence of betacellulin in bovine colostrum and milk suggests that it plays a role in the growth and development of the neonate and/or mammary gland function. The results also show that betacellulin is undetectable in the castrated adult male circulation. Additionally, although present in very low amounts, serum betacellulin could be under hormonal regulation in the female, since betacellulin was detected in sera from 27% of the unmated heifers examined in this study. The high levels of betacellulin detected in FBS relative to newborn and adult serum suggests a possible endocrine role for this growth factor in the bovine foetus.

Structure-function and biological role of betacellulin.

Betacellulin (BTC) belongs to the epidermal growth factor (EGF) family of peptide ligands that are characterised by a six-cysteine consensus motif that forms three intra-molecular disulfide bonds crucial for binding the ErbB receptor family. BTC was initially described, purified and cloned from a mouse insulinoma cell line. BTC is proteolytically processed from a larger membrane-anchored precursor and is a potent mitogen for a wide variety of cell types. BTC binds and activates ErbB-1 and ErbB-4 homodimers and is further characterised by its unique ability to activate all possible heterodimeric ErbB receptors. BTC is widely expressed in most tissues and various body fluids, including milk. Expression is particularly high in the pancreas where it is thought to play a role in the differentiation of pancreatic beta cells. While much is known about the ErbB receptor binding characteristics of BTC and its effect on a variety of cultured cells under different conditions, the challenge that lies ahead is to determine the role of BTC in vivo. This review will focus on the structure of BTC and the various biological effects ascribed to this member of the EGF family.

Prolonged survival in hereditary surfactant protein B (SP-B) deficiency associated with a novel splicing mutation.

Hereditary surfactant protein B (SP-B) deficiency has been lethal in the first year of life without lung transplantation. We tested the hypothesis that SP-B gene mutations may result in milder phenotypes by investigating the mechanisms for lung disease in two children with less severe symptoms than have been previously observed in SP-B deficiency. Immunostaining patterns for pulmonary surfactant proteins were consistent with SP-B deficiency in both children. DNA sequence analysis indicated that both children were homozygous for a mutation in exon 5 that created an alternative splice site. Reverse transcriptase PCR and sequence analysis confirmed use of this splice site, which resulted in a frameshift and a premature termination codon in exon 7. The predominant reverse transcriptase PCR product, however, lacked exon 7, which restored the reading frame but would not allow translation of the exons that encode mature SP-B. Western blot analysis detected reduced amounts of mature SP-B as well as an aberrant SP-B proprotein that corresponded to the size expected from translation of the abnormal transcript. We conclude that a novel splicing mutation was the cause of lung disease in these children and that hereditary SP-B deficiency can be the cause of lung disease in older children.