Apolipoprotein A-V deficiency enhances chylomicron production in lymph fistula mice.

Apolipoprotein A-V (apoA-V), a liver-synthesized apolipoprotein discovered in 2001, strongly modulates fasting plasma triglycerides (TG). Little is reported on the effect of apoA-V on postprandial plasma TG, an independent predictor for atherosclerosis. Overexpressing apoA-V in mice suppresses postprandial TG, but mechanisms focus on increased lipolysis or clearance of remnant particles. Unknown is whether apoA-V suppresses the absorption of dietary lipids by the gut. This study examines how apoA-V deficiency affects the steady-state absorption and lymphatic transport of dietary lipids in chow-fed mice. Using apoA-V knockout (KO, n = 8) and wild-type (WT, n = 8) lymph fistula mice, we analyzed the uptake and lymphatic transport of lipids during a continuous infusion of an emulsion containing [(3)H]triolein and [(14)C]cholesterol. ApoA-V KO mice showed a twofold increase in (3)H (P < 0.001) and a threefold increase in (14)C (P < 0.001) transport into the lymph compared with WT. The increased lymphatic transport was accompanied by a twofold reduction (P < 0.05) in mucosal (3)H, suggesting that apoA-V KO mice more rapidly secreted [(3)H]TG out of the mucosa into the lymph. ApoA-V KO mice also produced chylomicrons more rapidly than WT (P < 0.05), as measured by the transit time of [(14)C]oleic acid from the intestinal lumen to lymph. Interestingly, apoA-V KO mice produced a steadily increasing number of chylomicron particles over time, as measured by lymphatic apoB output. The data suggest that apoA-V suppresses the production of chylomicrons, playing a previously unknown role in lipid metabolism that may contribute to the postprandial hypertriglyceridemia associated with apoA-V deficiency.

Congenital nasolacrimal duct fistula in Brown Swiss cattle.

BACKGROUND: An increased incidence of nasolacrimal duct fistula in the offspring of dam J and three of her sons (bulls A, B and C) prompted a study to investigate the prevalence and clinical manifestation of this anomaly. The dam J, bull B, 255 direct offspring of bulls A, B, and C and eight other direct and indirect offspring of cow J were examined. The periocular region of each animal was examined for unilateral or bilateral nasolacrimal duct fistula and the location, appearance and size of the lesions. RESULTS: Of 265 cattle examined, 54 had unilateral (n = 24) or bilateral fistula (n = 30). The prevalence of affected offspring differed significantly among the three bulls. The fistulae were located medial to the medial canthus of the eye and were 1 to 10 mm (median, 1 mm) in height and 1 to 12 mm (median, 2 mm) in length. The shape of the opening was circular in 58, oval in 23 and slit-like in three. One other animal had a large opening with an atypical shape and another had an abnormal medial canthus with several fistulous openings. Seventy openings were pigmented and 52 were hairless. The fistulae were clinically significant in 12 animals. CONCLUSIONS: The findings suggest a hereditary cause of nasolacrimal duct fistula in Brown Swiss cattle.

Bilateral congenital lacrimal fistula in a Brown Swiss bull.

A five-year-old Brown Swiss bull was referred to the Department of Farm Animals, University of Zurich, because of bilateral epiphora that was unresponsive to treatment. Clinical examination revealed a fistulous opening medial to the medial canthus of both eyes and mucopurulent discharge from both openings. Attempts to flush the nasolacrimal duct via the lacrimal points resulted in the fluid exiting via the fistulous opening. Retrograde flushing of the nasolacrimal duct from the nasolacrimal opening resulted in the flush fluid flowing back out the nasolacrimal opening. Bilateral lacrimal fistula medial to the medial canthus of the eye was diagnosed based on the findings. The same anomaly was diagnosed a year later in 4 related female animals referred to our Department for other reasons. Three of the cases were sired by the bull described above and one was sired by his half-brother. Therefore, an autosomal recessive mode of inheritance of this anomaly was assumed. Clinical, epidemiological and molecular studies of the offspring of both bulls are underway to further investigate this anomaly.

Bile acids regulate hepatic gluconeogenic genes and farnesoid X receptor via G(alpha)i-protein-coupled receptors and the AKT pathway.

Bile acids are important regulatory molecules that can activate specific nuclear receptors and cell signaling pathways in the liver and gastrointestinal tract. In the current study, the chronic bile fistula (CBF) rat model and primary rat hepatocytes (PRH) were used to study the regulation of gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase) and the gene encoding short heterodimeric partner (SHP) by taurocholate (TCA). The intestinal infusion of TCA into the CBF rat rapidly (1h) activated the AKT (approximately 9-fold) and ERK1/2 (3- to 5-fold) signaling pathways, downregulated (approximately 50%, 30 min) the mRNA levels of PEPCK and G-6-Pase, and induced (14-fold in 3 h) SHP mRNA. TCA rapidly ( approximately 50%, 1-2 h) downregulated PEPCK and G-6-Pase mRNA levels in PRH. The downregulation of these genes by TCA was blocked by pretreatment of PRH with pertussis toxin (PTX). In PRH, TCA plus insulin showed a significantly stronger inhibition of glucose secretion/synthesis from lactate and pyruvate than either alone. The induction of SHP mRNA in PRH was strongly blocked by inhibition of PI3 kinase or PKCzeta by specific chemical inhibitors or knockdown of PKCzeta by siRNA encoded by a recombinant lentivirus. Activation of the insulin signaling pathway appears to be linked to the upregulation of farnesoid X receptor functional activity and SHP induction.

Hepatic Metabolomic and Transcriptomic Responses Induced by Cecal Infusion of Sodium Propionate in a Fistula Pig Model.

Short-chain fatty acids (SCFAs) are the major products of the microbial fermentation of indigestible carbohydrates. SCFAs are known to improve the host metabolism, but their underlying mechanism of action remains elusive. In this study, 16 growing pigs were infused with saline or sodium propionate solution (25 mL, 2 mol/L) through a cecal fistula twice a day during a 28 day experimental period. The results showed that the cecal infusion of the SCFA propionate decreased serum and liver triglyceride levels and increased serum PYY secretion in growing pigs. Hepatic metabolomics identified 12 metabolites that were significantly altered by propionate. These included decreased levels of lipid metabolism-related stearic acid and glycerol-2-phosphate; increased levels of TCA cycle components including malic acid, fructose-6-phosphate, and succinic acid; and decreased levels of the amino acid metabolism products aspartic acid and serine. Hepatic transcriptomics demonstrated that propionate inhibited fatty acid synthesis and promoted the lipid metabolic process. Pathway enrichment analysis showed that propionate accelerated gluconeogenesis and decreased glycolysis. Taken together, these data support a role of the SCFA propionate on host lipid and glucose metabolism.

Transcatheter Closure of Congenital Coronary Artery Fistulas with a Giant Coronary Artery Aneurysm in Children: Experiences from a Single Center.

BACKGROUND: Transcatheter closure of congenital coronary artery fistulas (CCAFs) is an alternative therapy to surgery; however, data regarding transcatheter closure for CCAF with a giant coronary artery aneurysm (CAA) in pediatric patients are still limited due to the rarity of the disease. We aimed to evaluate the efficacy and safety of transcatheter closure for CCAF with a giant CAA in a pediatric population at a single center. METHODS: Medical records of pediatric patients (<18 years old) who underwent transcatheter closure of CCAF with a giant CAA between April 2007 and September 2016 at Guangdong Cardiovascular Institute (Guangdong, China) were reviewed. RESULTS: Twelve patients (median age, 6.1 years; range, 1.9-11.0 years) underwent successful transcatheter closure procedures. One patient underwent closure at both the entry and exit points of the CAA, three patients underwent closure at the exit point of the CAA, and eight patients underwent closure at the entry point of the CAA. After a mean follow-up of 7.2 years (range, 0.5-9.8 years), one patient (with closure at the exit point of the CAA) underwent transcatheter re-intervention because of a significant residual shunt. She eventually underwent a surgical procedure due to aneurysm dilation after the second intervention. One patient experienced thrombus formation within the CAA after the procedure. Among those with closure at the entry point of the CAA, a mild-to-moderate residual shunt was detected in three patients. CONCLUSIONS: Transcatheter closure appears to be a safe and effective alternative therapy for CCAF with a giant CAA in the pediatric population. Closure at the entry point of the CAA, and closure at both the entry and exit points when feasible, may reduce the risk of postinterventional complications.

Genetic aspects of the BOR syndrome--branchial fistulas, ear pits, hearing loss, and renal anomalies.

A pedigree of branchio-oto-renal dysplasia (the BOR syndrome) is reported, including the documentation by serial audiometric studies of the onset and rapid progression of hearing loss in the twin sister of an affected child. The literature on this syndrome is analyzed to derive some figures for use in genetic counseling of such families. Branchio-oto-renal dysplasia is an autosomal dominant disorder in which affected individuals may have preauricular pits, lachrymal duct stenosis, hearing loss, branchial fistulas or cysts, structural defects of the outer, middle, and inner ear, and renal anomalies, which may range from mild hypoplasia to complete absence. Not all features of the syndrome are expressed in all carriers of the gene, but few carriers lack all the features, and the pits, branchial clefts, and hearing loss, are frequently expressed. Those offspring of affected persons who have pits or fistulas are likely (about 80%) to have hearing loss of varying degrees of severity. A minority of heterozygotes (about 7%) may have hearing loss without pits or fistulas. The risk of severe renal malformation is probably fairly low. Whether families that show dominant inheritance of pits, clefts, and deafness without renal anomalies represent variants of the BOR syndrome or a separate entity (the BO syndrome), is still not clear. At present, any individual with preauricular pits and branchial clefts deserves both otologic and renal investigation.

Portohepatic shunt in a Down syndrome patient with an interchange trisomy 47,XY,-2,+der(2),+der(21)t(2;21)(p13;q22.1)mat.

A rare vascular portohepatic anomaly was identified in a Down syndrome patient with a 47,XY,-2,+der(2),+der(21)t(2;21)(p13;q22.1) mat chromosomal complement. This vascular defect involves a direct communication between the right portal vein and the inferior vena cava (IVC). We discuss the possibility that this vascular defect is a rare manifestation in Down syndrome. Alternatively, the existence of these 2 rare events in the same patient raises the possibility that they are causally related.

Bilateral congenital oval window microfistulae in a mother and son.

This article details case histories of a son and his mother who were studied over a seven-year period before making the diagnosis of bilateral oval window microfistulae in both of them. The boy demonstrated a slowly progressive bilateral and symmetrical sensorineural hearing loss closely resembling that of his mother. The case reports emphasize their respective histories, diagnostic evaluation, surgical observations, and treatment.

Pendred's syndrome with atypical features.

One of seven cases of Pendred's syndrome had mixed hearing loss, bilateral congenital stapes foot-plate fixation, surgically proven unilateral perilymph fistula and delayed fluctuating hearing loss in the unoperated ear. A unifying hypothesis is proposed to link these diversified findings.

Congenital aural and pre-auricular sinuses in the South African Bantu.

The incidence of ear pits was studied in the South African Bantu population. A short account of the anatomy, occurrence, inheritance, developmental origin, complications and treatment of this anomaly was given. Mention has been made of the clinical significance and the possible association between ear pits and other systemic and ear abnormalities, including deafness. There seems to be a higher incidence of other abnormalities in children born with sinuses. The blanket term 'pre-auricular fistula' should possibly be discarded in favour of auricular sinuses or ear pits.

Hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary fistulae: a case report. One genotype, three phenotypes?

The authors present a rare case of hypertrophic cardiomyopathy associated with left ventricular noncompaction cardiomyopathy and coronary artery-left ventricular fistulae in a 42-year-old woman presenting with non-ST-elevation myocardial infarction. Coronary angiography, transthoracic echocardiography and cardiac magnetic resonance revealed the structural abnormalities of the left ventricle and the coronary tree.

The role for dickkopf-homolog-1 in the pathogenesis of Crohn's disease-associated fistulae.

BACKGROUND: One of the most challenging conditions in Crohn's disease (CD) patients is the treatment of perianal fistulae. We have recently shown that epithelial-to-mesenchymal transition (EMT) plays a crucial role during CD-fistulae development. Dickkopf-homolog 1 (DKK-1) is known to play a key role during EMT. Here, we investigated a role for DKK-1 in the pathogenesis of CD-associated fistulae. METHODS: Dkk-1 protein expression in CD-fistula specimens were investigated by immunohistochemistry. Colonic lamina propria fibroblasts (CLPF) were obtained from either non-IBD control patients or patients with fistulizing CD. HT-29 intestinal epithelial cells (IEC) were either grown as monolayers or spheroids. Cells were treated with either TNF-α, TGF-ß or IL-13. Knock-down of DKK-1 or ß-Catenin was induced in HT-29-IEC by siRNA technique. mRNA expression was determined by real-time-PCR. RESULTS: Dkk-1 protein was specifically expressed in transitional cells lining the fistula tracts. TGF-ß induced DKK-1 mRNA expression in HT-29-IEC, but decreased it in fistula CLPF. On a functional level, DKK-1 knock-down prevented TGF-ß-induced IL-13 mRNA expression in HT-29-IEC. Further, loss of ß-Catenin was accompanied by reduced levels of DKK-1 and, again, IL-13 in IEC in response to TGF-ß. In turn, treatment of HT-29-IEC as well as fistula CLPF with IL-13 resulted in decreased levels of DKK-1 mRNA. Treatment with TNF-α or the bacterial wall component, muramyl-dipeptide, decreased DKK-1 mRNA levels in HT-29-IEC, but enhanced it in fistula CLPF. DISCUSSION: We demonstrate that DKK-1 is strongly expressed in cells lining the CD-fistula tracts and regulates factors involved in EMT initiation. These data provide evidence for a role of DKK-1 in the pathogenesis of CD-associated perianal fistulae.