Travel-related Zika virus cases in Canada: October 2015-June 2017.

BACKGROUND: Zika virus (ZIKV) is an emerging mosquito-borne disease that can cause severe birth defects if contracted congenitally. Since late 2015, there has been a large increase in the number of travel-related cases of Zika virus infection in Canada. OBJECTIVE: The objective of this study was to describe the epidemiology of travel-related Zika cases in Canada from October 2015 to June 2017 and review them in the context of the international outbreak in the Americas. METHODS: Zika virus infections were confirmed by polymerase chain reaction (PCR) detection of viral RNA and/or the serological identification of ZIKV-specific antibodies in serum. Cases of ZIKV infection were identified by provincial and territorial health authorities, and reported on a regular basis to the Public Health Agency of Canada (PHAC). Case information requested included date of illness onset, age category, sex, pregnancy status, and location(s) and dates of travel. Estimates for the monthly number of Canadians travelling outside of Canada to other countries in the Americas were obtained from Statistics Canada and the International Air Transport Association (IATA). Data to produce the epidemic curves of autochthonous cases for each region of the Americas were extracted from country-specific epidemic curves on the Pan American Health Organization website. RESULTS: As of June 7, 2017, 513 laboratory confirmed cases and two Zika-related birth/fetal anomalies were reported across all 10 provinces. Illness in Canadian travellers generally coincided with outbreak intensity in the country of exposure rather than travel volume. There has been no evidence of autochthonous (local) transmission in Canada. Currently, cases are on the decline both in Canada and internationally. CONCLUSION: The surge in Canadian ZIKV infections in 2016 was directly related to the incursion and spread of ZIKV into the Americas. Although cases are now on the decline worldwide, it remains to be seen whether a resurgence of cases in previously affected or new areas will occur. Both outbreak intensity and seasonality of ZIKV transmission should be monitored over time in order to inform the timing of public health education campaigns, as some may turn out to be more effective in the off-peak travel season when the risk of disease transmission may be higher. Ongoing education and awareness among travellers, particularly for pregnant women and those planning pregnancies, is still indicated.

Development of a low-maintenance measurement approach to continuously estimate methane emissions: A case study.

The chemical breakdown of organic matter in landfills represents a significant source of methane gas (CH4). Current estimates suggest that landfills are responsible for between 3% and 19% of global anthropogenic emissions. The net CH4 emissions resulting from biogeochemical processes and their modulation by microbes in landfills are poorly constrained by imprecise knowledge of environmental constraints. The uncertainty in absolute CH4 emissions from landfills is therefore considerable. This study investigates a new method to estimate the temporal variability of CH4 emissions using meteorological and CH4 concentration measurements downwind of a landfill site in Suffolk, UK from July to September 2014, taking advantage of the statistics that such a measurement approach offers versus shorter-term, but more complex and instantaneously accurate, flux snapshots. Methane emissions were calculated from CH4 concentrations measured 700m from the perimeter of the landfill with observed concentrations ranging from background to 46.4ppm. Using an atmospheric dispersion model, we estimate a mean emission flux of 709µgm-2s-1 over this period, with a maximum value of 6.21mgm-2s-1, reflecting the wide natural variability in biogeochemical and other environmental controls on net site emission. The emissions calculated suggest that meteorological conditions have an influence on the magnitude of CH4 emissions. We also investigate the factors responsible for the large variability observed in the estimated CH4 emissions, and suggest that the largest component arises from uncertainty in the spatial distribution of CH4 emissions within the landfill area. The results determined using the low-maintenance approach discussed in this paper suggest that a network of cheaper, less precise CH4 sensors could be used to measure a continuous CH4 emission time series from a landfill site, something that is not practical using far-field approaches such as tracer release methods. Even though there are limitations to the approach described here, this easy, low-maintenance, low-cost method could be used by landfill operators to estimate time-averaged CH4 emissions and their impact downwind by simultaneously monitoring plume advection and CH4 concentrations.

The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.

To determine the phenotype and natural history of a founder genetic subtype of autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) caused by a p.S358L mutation in TMEM43. The age of onset of cardiac symptoms, clinical events and test abnormalities were studied in 412 subjects (258 affected and 154 unaffected), all of which occurred in affected males significantly earlier and more often than unaffected males. Affected males were hospitalized four times more often than affected females (p ≤ 0.0001) and died younger (p ≤ 0.001). The temporal sequence from symptoms onset to death was prolonged in affected females by 1-2 decades. The most prevalent electrocardiogram (ECG) manifestation was poor R wave progression (PRWP), with affected males twice as likely to develop PRWP as affected females (p ≤ 0.05). Left ventricular enlargement (LVE) occurred in 43% of affected subjects, with 11% fulfilling criteria for dilated cardiomyopathy. Ventricular ectopy on Holter monitor was common and occurred early: the most diagnostically useful clinical test. No symptom or test could rule out diagnosis. This ARVC subtype is a sex-influenced lethal arrhythmogenic cardiomyopathy, with a unique ECG finding, LV dilatation, heart failure and early death, where molecular pre-symptomatic diagnosis has the greatest clinical utility.

C/EBPbeta-mediated transcriptional regulation of bcl-xl gene expression in human breast epithelial cells in response to cigarette smoke condensate.

In earlier studies, we have shown that cigarette smoke condensate (CSC), a surrogate for cigarette smoke, is capable of transforming the spontaneously immortalized human breast epithelial cell line, MCF10A. These transformed cells displayed upregulation of the anti-apoptotic gene, bcl-xl. Upregulation of this gene may impede the apoptotic pathway and allow the accumulation of DNA damage that can lead to cell transformation and carcinogenesis. In the present study, we have determined the mechanism of CSC-mediated transcriptional upregulation of bcl-xl gene expression in MCF10A cells. We cloned the human bcl-xl promoter (pBcl-xLP) and identified putative transcription factor binding sites. Sequential deletion constructs that removed the putative cis-elements were constructed and transfected into MCF10A cells to determine the CSC-responsive cis-element(s) on the pBcl-xLP. Gel-shift, super-shift and chromatin immunoprecipitation analysis confirmed that CCAAT/enhancer-binding protein (C/EBPbeta) specifically bound to a C/EBP-binding site on the pBcl-xLP in vitro and in vivo. Additionally, overexpression of C/EBPbeta-LAP2 stimulated pBcl-xLP activity and Bcl-xL protein levels, which mimicked the conditions of CSC treatment. Our results indicate that C/EBPbeta regulates bcl-xl gene expression in MCF10A cells in response to CSC treatment; therefore, making it a potential target for chemotherapeutic intervention of cigarette smoke-induced breast carcinogenesis.

Neuroinflammation and behavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism.

Autism is a neurodevelopmental disorder presenting before 3 years of age with deficits in communication and social skills and repetitive behaviors. In addition to genetic influences, recent studies suggest that prenatal drug or chemical exposures are risk factors for autism. Terbutaline, a beta2-adrenoceptor agonist used to arrest preterm labor, has been associated with increased concordance for autism in dizygotic twins. We studied the effects of terbutaline on microglial activation in different brain regions and behavioral outcomes in developing rats. Newborn rats were given terbutaline (10 mg/kg) daily on postnatal days (PN) 2 to 5 or PN 11 to 14 and examined 24 h after the last dose and at PN 30. Immunohistochemical studies showed that administration of terbutaline on PN 2 to 5 produced a robust increase in microglial activation on PN 30 in the cerebral cortex, as well as in cerebellar and cerebrocortical white matter. None of these effects occurred in animals given terbutaline on PN 11 to 14. In behavioral tests, animals treated with terbutaline on PN 2 to 5 showed consistent patterns of hyper-reactivity to novelty and aversive stimuli when assessed in a novel open field, as well as in the acoustic startle response test. Our findings indicate that beta2-adrenoceptor overstimulation during an early critical period results in microglial activation associated with innate neuroinflammatory pathways and behavioral abnormalities, similar to those described in autism. This study provides a useful animal model for understanding the neuropathological processes underlying autism spectrum disorders.

beta2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort.

The beta2-adrenergic receptor is part of the catecholamine system, and variants at two polymorphic sites in the gene coding for the receptor (ADRB2) confer increased activity. Overstimulation of this receptor may alter brain development, and has been linked to autism in non-identical twins. The objective of this study was to determine whether alleles in ADRB2 are associated with diagnosis of autism in the Autism Genetic Resource Exchange (AGRE) population. Three hundred and thirty-one independent autism case-parent trios were included in the analysis. Subjects were genotyped at activity-related polymorphisms rs1042713 (codon 16) and rs1042714 (codon 27). Association between autism and genotypes at each polymorphic site was tested using genotype-based transmission disequilibrium tests, and effect modification by family and pregnancy characteristics was evaluated. Sensitivity to designation of the proband in each family was assessed by performing 1000 repeats of the analysis selecting affected children randomly. A statistically significant OR of 1.66 for the Glu27 homozygous genotype was observed. Increased associations with this genotype were observed among a subset of Autism Diagnostic Observation Schedule confirmed cases and a subset reporting experience of pregnancy-related stressors. In conclusion, the Glu27 allele of the ADRB2 gene may confer increased risk of autism and shows increased strength with exposure to pregnancy related stress.

Association of Clinical Cytogeneticists chorion villus sampling database 1987-2000.

OBJECTIVES: To produce a fully searchable Microsoft Access database of mosaic and non-mosaic cytogenetic abnormalities, detected during diagnostic chorionic villi sampling (CVS) to aid laboratories in predicting pregnancy outcome, in particular differentiating between cases of likely genuine fetal cytogenetic abnormalities and those likely to represent confined placental mosaicism (CPM). METHODS: Retrospective collection of referral data, initial karyotype data, follow-up karyotype data and pregnancy outcome data from almost all cytogenetically abnormal diagnostic CVS, processed in UK National Health Service laboratories, between 1987 and 2000. Collection of similar data from a published series of CVS and individual case reports. RESULTS: A fully searchable database of abnormal CVS cases, containing over 5000 entries, has been produced. This is available to download at http://www.ncl.ac.uk/cvs/. CONCLUSIONS: Following detection of a cytogenetic abnormality during prenatal diagnosis using CVS, use of this database allows rapid access to comparable cases from the United Kingdom and the literature. This database will improve the speed of availability and quality of information available to clinicians and patients for pregnancy management and counselling purposes. The database has been designed with future data collection in mind, and can be developed for wider research use, through more detailed registries of individual chromosome abnormalities.

CT-targeted irradiation of the breast and internal mammary lymph nodes using a 5-field technique.

PURPOSE: To develop an effective and resource-efficient radiotherapy technique to treat the breast and regional nodes, including the ipsilateral internal mammary nodes. METHODS AND MATERIALS: Eighty female patients who underwent MRI scans for a variety of indications had coronal, T1-weighted images of the chest performed to determine the position of the internal mammary chain (IMC). Based on these results, a 5-field treatment technique was developed that would include the breast, supraclavicular fossa, and ipsilateral IMC, while maintaining a low dose to the heart, lungs, and contralateral breast. This technique was implemented in a cohort of 13 patients. RESULTS: The lateral position of the right and left IMC were measured in three cephalo-caudad positions: at the clavicular heads, upper manubrium, and midsternum (at the 2nd/3rd rib interspace). The mean lateral separation between the right and left IMC chains at each level (and 95% confidence interval) at each level were 5.8 cm (4.67-7.00), 5.6 cm (4.49-6.73), and 5.9 cm (4.66-7.19), respectively. Treatment was delivered to 13 patients using a 5-field technique, with tangential photon fields for the breast, anterior and posterior supraclavicular/axillary field, and a matching anterior electron field. Three-dimensional treatment planning of a representative case confirmed adequate coverage of the planning target volume (PTV). The median dose to the whole heart was 10 Gy, and 20% of the ipsilateral lung received more than 20 Gy. Seven of the 13 patients treated experienced moist desquamation at the junction of the electron field and breast tangents, and 1 patient had persistent ulceration at 3 months' follow-up. CONCLUSION: The 5-field technique described in this paper provides good coverage to the breast and regional nodes with acceptable toxicity, and without requiring three-dimensional treatment planning or intensity-modulated radiotherapy techniques.

Urinary basic fibroblast growth factor: a noninvasive marker of progressive cystic renal disease in a child.

Autosomal recessive polycystic kidney disease (ARPKD) is a hereditary condition with an estimated incidence of 1 in 20,000 live births. Various growth factors have been implicated in the causation of this disease. We describe a child with ARPKD whose levels of urinary basic fibroblast growth factor (bFGF) were markedly elevated. The concentrations of bFGF increased further following right nephrectomy, in response to the compensatory growth of the remaining kidney. We hypothesize that measurement of urinary bFGF may be useful as a noninvasive marker to assess progression of cystic renal development.

Radiofrequency ablation of atrial tachycardia originating from the triangle of Koch.

Atrial tachycardia (AT) originating in the triangle of Koch is reported rarely and presents a potential risk of atrioventricular (AV) block during radiofrequency (RF) catheter ablation. Eight patients with AT in the triangle of Koch undergoing RF ablation are presented. There were five women and three men, ranging in age from 32 to 74 years. One patient had bicuspid aortic valve disease, and the other seven patients had no structural heart disease. At electrophysiological study, AT was inducible in all eight patients. In one patient, AV nodal re-entrant tachycardia was also inducible. The site of AT was located by recording the earliest atrial activation during AT and successful RF ablation. Fluoroscopy confirmed the corresponding site to the region of the triangle of Koch. The earliest atrial activation was 35+/-9 ms before the surface P wave, and was recorded at the apex of the triangle of Koch near the bundle of His in six patients and midway between the bundle of His and coronary sinus os in two patients. At the successful RF application site, His potential was not recorded in any patient. The mean AV ratio was 5:1 (range 1:1 to 12:1). RF ablation at the successful site resulted in accelerated junctional rhythm in four of the eight patients and successfully terminated AT in all eight patients, with first-degree AV block in one patient. In conclusion, AT from the triangle of Koch is a distinct entity and RF ablation can be successfully performed; however, a potential risk of AV block remains.

Dorsal and intermediate neuronal cell types of the spinal cord are established by a BMP signaling pathway.

We have studied the role of Bmp signaling in patterning neural tissue through the use of mutants in the zebrafish that disrupt three different components of a Bmp signaling pathway: swirl/bmp2b, snailhouse/bmp7 and somitabun/smad5. We demonstrate that Bmp signaling is essential for the establishment of the prospective neural crest and dorsal sensory Rohon-Beard neurons of the spinal cord. Moreover, Bmp signaling is necessary to limit the number of intermediate-positioned lim1+ interneurons of the spinal cord, as observed by the dramatic expansion of these prospective interneurons in many mutant embryos. Our analysis also suggests a positive role for Bmp signaling in the specification of these interneurons, which is independent of Bmp2b/Swirl activity. We found that a presumptive ventral signal, Hh signaling, acts to restrict the amount of dorsal sensory neurons and trunk neural crest. This restriction appears to occur very early in neural tissue development, likely prior to notochord or floor plate formation. A similar early role for Bmp signaling is suggested in the specification of dorsal neural cell types, since the bmp2b/swirl and bmp7/snailhouse genes are only coexpressed during gastrulation and within the tail bud, and are not found in the dorsal neural tube or overlying epidermal ectoderm. Thus, a gastrula Bmp2b/Swirl and Bmp7/Snailhouse-dependent activity gradient may not only act in the specification of the embryonic dorsoventral axis, but may also function in establishing dorsal and intermediate neuronal cell types of the spinal cord.

Equivalent genetic roles for bmp7/snailhouse and bmp2b/swirl in dorsoventral pattern formation.

A bone morphogenetic protein (BMP) signaling pathway acts in the establishment of the dorsoventral axis of the vertebrate embryo. Here we demonstrate the genetic requirement for two different Bmp ligand subclass genes for dorsoventral pattern formation of the zebrafish embryo. From the relative efficiencies observed in Bmp ligand rescue experiments, conserved chromosomal synteny, and isolation of the zebrafish bmp7 gene, we determined that the strongly dorsalized snailhouse mutant phenotype is caused by a mutation in the bmp7 gene. We show that the original snailhouse allele is a hypomorphic mutation and we identify a snailhouse/bmp7 null mutant. We demonstrate that the snailhouse/bmp7 null mutant phenotype is identical to the presumptive null mutant phenotype of the strongest dorsalized zebrafish mutant swirl/bmp2b, revealing equivalent genetic roles for these two Bmp ligands. Double mutant snailhouse/bmp7; swirl/bmp2b embryos do not exhibit additional or stronger dorsalized phenotypes, indicating that these Bmp ligands do not function redundantly in early embryonic development. Furthermore, overexpression experiments reveal that Bmp2b and Bmp7 synergize in the ventralization of wild-type embryos through a cell-autonomous mechanism, suggesting that Bmp2b/Bmp7 heterodimers may act in vivo to specify ventral cell fates in the zebrafish embryo.

Cholesterol efflux-mediated signal transduction in mammalian sperm: cholesterol release signals an increase in protein tyrosine phosphorylation during mouse sperm capacitation.

We previously demonstrated that mouse sperm capacitation is accompanied by a time-dependent increase in protein tyrosine phosphorylation that is dependent on the presence of BSA, Ca2+, and NaHCO(3), all three of which are also required for this maturational event. We also demonstrated that activation of protein kinase A (PK-A) is upstream of this capacitation-associated increase in protein tyrosine phosphorylation. BSA is hypothesized to modulate capacitation through the removal of cholesterol from the sperm plasma membrane. In this report, we demonstrate that incubation of mouse sperm medium containing BSA results in a release of cholesterol from the sperm plasma membrane to the medium; release of this sterol does not occur in medium devoid of BSA. We next determined whether cholesterol release leads to changes in protein tyrosine phosphorylation. Blocking the action of BSA by adding exogenous cholesterol-SO-(4) to the BSA-containing medium inhibits the increase in protein tyrosine phosphorylation as well as capacitation. This inhibitory effect is overcome by (1) the addition of increasing concentrations of BSA at a given concentration of cholesterol-SO-(4) and (2) the addition of dibutyryl cAMP plus IBMX. High-density lipoprotein (HDL), another cholesterol binding protein, also supports the capacitation-associated increase in protein tyrosine phosphorylation through a cAMP-dependent pathway, whereas proteins that do not interact with cholesterol have no effect. HDL also supports sperm capacitation, as assessed by fertilization in vitro. Finally, we previously demonstrated that HCO-(3) is necessary for the capacitation-associated increase in protein tyrosine phosphorylation and demonstrate here, by examining the effectiveness of HCO-(3) or BSA addition to sperm on protein tyrosine phosphorylation, that the HCO-(3) effect is downstream of the site of BSA action. Taken together, these data demonstrate that cholesterol release is associated with the activation of a transmembrane signal transduction pathway involving PK-A and protein tyrosine phosphorylation, leading to functional maturation of the sperm.

The role of tolloid/mini fin in dorsoventral pattern formation of the zebrafish embryo.

A highly conserved TGF-&bgr; signaling pathway is involved in the establishment of the dorsoventral axis of the vertebrate embryo. Specifically, Bone Morphogenetic Proteins (Bmps) pattern ventral tissues of the embryo while inhibitors of Bmps, such as Chordin, Noggin and Follistatin, are implicated in dorsal mesodermal and neural development. We investigated the role of Tolloid, a metalloprotease that can cleave Chordin and increase Bmp activity, in patterning the dorsoventral axis of the zebrafish embryo. Injection of tolloid mRNA into six dorsalized mutants rescued only one of these mutants, mini fin. Through chromosomal mapping, linkage and cDNA sequence analysis of several mini fin alleles, we demonstrate that mini fin encodes the tolloid gene. Characterization of the mini fin mutant phenotype reveals that Mini fin/Tolloid activity is required for patterning ventral tissues of the tail: the ventral fin, and the ventroposterior somites and vasculature. Gene expression studies show that mfn mutants exhibit reduced expression of ventrally restricted markers at the end of gastrulation, suggesting that the loss of ventral tail tissues is caused by a dorsalization occurring at the end of gastrulation. Based on the mini fin mutant phenotype and the expression of tolloid, we propose that Mini fin/Tolloid modifes the Bmp activity gradient at the end of gastrulation, when the ventralmost marginal cells of the embryo are in close proximity to the dorsal Chordin-expressing cells. At this time, unimpeded Chordin may diffuse to the most ventral marginal regions and inhibit high Bmp activity levels. In the presence of Mini fin/Tolloid, however, Chordin activity would be negatively modulated through proteolytic cleavage, thereby increasing Bmp signaling activity. This extracellular mechanism is amplified by an autoregulatory loop for bmp gene expression.

Pigeon fanciers' lung: the mucin antigen is present in pigeon droppings and pigeon bloom.

BACKGROUND: Pigeon intestinal mucin has been implicated as an important antigen pigeon fanciers' lung. This study investigated whether mucin is detectable in pigeon droppings and bloom, the likely antigenic sources in disease. METHODS: Soluble extracts of a number of materials found in a pigeon loft were prepared and specific IgG subclass antibodies to these antigens were measured in 14 antibody-positive pigeon fanciers. Cross-reactivity between these materials and purified pigeon intestinal mucin was investigated by inhibition of anti-mucin ELISA. Mucin was purified from the soluble extracts of these crude antigen mixtures by CsCl density gradient centrifugation. RESULTS: The patterns of IgG subclass responses to purified pigeon intestinal mucin and to the four materials collected from the pigeon loft were similar. Subclass differences between symptomatic and asymptomatic individuals, demonstrable against purified mucin, were similarly seen against pigeon droppings and pigeon bloom. Both pigeon droppings and pigeon bloom were capable of inhibiting IgG binding to purified pigeon mucin, and mucin inhibited substantially the binding of IgG to these materials. Glycoprotein with a density similar to that described for pigeon intestinal mucin was purified from each source. CONCLUSION: Pigeon intestinal mucin is present in a variety of materials found in the environment of the pigeon loft in a form capable of reacting with anti-mucin antibodies in the sera of exposed individuals. Reduction in exposure to these materials may decrease the likelihood of developing pigeon fanciers' lung and minimise reactions in sensitised individuals.

Involvement of the cytoskeleton in the movement of cortical granules during oocyte maturation, and cortical granule anchoring in mouse eggs.

Exocytosis of cortical granules in mouse eggs is required to produce the zona pellucida block to polyspermy. In this study, we examined the role of microfilaments and microtubules in the regulation of cortical granule movement toward the cortex during oocyte maturation and anchoring of cortical granules in the cortex. Fluorescently labeled cortical granules, microfilaments, and microtubules were visualized using laser-scanning confocal microscopy. It was observed that cortical granules migrate to the periphery of the oocyte during oocyte maturation. This movement is blocked by the treatment of oocytes with cytochalasin D, an inhibitor of microfilament polymerization, but not with nocodazole or colchicine, inhibitors of microtubule polymerization. Cortical granules, once anchored at the cortex, remained in the cortex following treatment of metaphase II-arrested eggs with each of these inhibitors; i.e., there was neither inward movement nor precocious exocytosis. Finally, the single cortical granule-free domain that normally becomes localized over the metaphase II spindle was not observed when the chromosomes become scattered following microtubule disruption with nocodazole or colchicine. In these instances a cortical granule-free domain was observed over each individual chromosome, suggesting that the chromosome or chromosome-associated material, and not the spindle, dictates the localization of the cortical granule-free domain.

Ventral and lateral regions of the zebrafish gastrula, including the neural crest progenitors, are established by a bmp2b/swirl pathway of genes.

A bone morphogenetic protein (BMP) signaling pathway is implicated in dorsoventral patterning in Xenopus. Here we show that three genes in the zebrafish, swirl, snailhouse, and somitabun, function as critical components within a BMP pathway to pattern ventral regions of the embryo. The dorsalized mutant phenotypes of these genes can be rescued by overexpression of bmp4, bmp2b, an activated BMP type I receptor, and the downstream functioning Smad1 gene. Consistent with a function as a BMP ligand, swirl functions cell nonautonomously to specify ventral cell fates. Chromosomal mapping of swirl and cDNA sequence analysis demonstrate that swirl is a mutation in the zebrafish bmp2b gene. Interestingly, our analysis suggests that the previously described nonneural/neural ectodermal interaction specifying the neural crest occurs through a patterning function of swirl/bmp2b during gastrulation. We observe a loss in neural crest progenitors in swirl/bmp2b mutant embryos, while somitabun mutants display an opposite, dramatic expansion of the prospective neural crest. Examination of dorsally and ventrally restricted markers during gastrulation reveals a successive reduction and reciprocal expansion in nonneural and neural ectoderm, respectively, in snailhouse, somitabun, and swirl mutant embryos, with swirl/bmp2b mutants exhibiting almost no nonneural ectoderm. Based on the alterations in tissue-specific gene expression, we propose a model whereby swirl/bmp2b acts as a morphogen to specify different cell types along the dorsoventral axis.

Basic fibroblast growth factor: a missing link between collagen VII, increased collagenase, and squamous cell carcinoma in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have deficiencies of collagen type VII and have elevated levels of fibroblast collagenase, and a greatly increased risk of cutaneous squamous cell carcinoma. Patients with other genetic blistering disorders do not have elevated collagenase or an increased risk of squamous cell carcinoma, despite chronic wounding. The connection between collagen type VII deficiency, increased collagenase, and squamous cell carcinoma is not understood. MATERIALS AND METHODS: Urine from 81 patients with RDEB (39 patients), junctional epidermolysis bullosa (JEB; 12 patients), and epidermolysis bullosa simplex (EBS; 30 patients), as well as unaffected family members of RDEB patients (33 patients), was tested for the presence of basic fibroblast growth factor (bFGF) using a sensitive radioimmunoassay. These patients included many who were enrolled in the Epidermolysis Bullosa Registry and others who were referred by their physicians. RESULTS: Fifty-one percent of patients with RDEB had elevated levels (> 5000 pg/g) of urinary bFGF. In contrast, none of the patients with JEB had elevated levels of bFGF. Twenty-one percent of clinically unaffected family members had elevated levels of bFGF, and 13% of patients with EBS had elevated levels of bFGF. The frequency of elevated bFGF values among all groups was statistically significant (p = 0.002), and the levels of bFGF in RDEB patients were significantly elevated compared with those of other groups (p < 0.05). CONCLUSIONS: We have found that patients with RDEB have elevated levels of bFGF, which may contribute to increased fibroblast collagenase and the development of squamous cell carcinoma. These results suggest a novel treatment for RDEB, namely, angiogenesis inhibitors, which may antagonize the effects of bFGF in this disorder. There are currently no other means of treatment for this disorder, which has a high morbidity and mortality rate.