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M Sinaasappel

Publications and source records attributed to M Sinaasappel.

At least 19 recordsLinked to original sources
PubMed2005

Cystic fibrosis: terminology and diagnostic algorithms.

There is great heterogeneity in the clinical manifestations of cystic fibrosis (CF). Some patients may have all the classical manifestations of CF from infancy and have a relatively poor prognosis, while others have much milder or even atypical disease manifestations and still carry mutations on each of the CFTR genes. It is important to distinguish between these categories of patients. The European Diagnostic Working Group proposes the following terminology. Patients are diagnosed with classic or typical CF if they have one or more phenotypic characteristics and a sweat chloride concentration of >60 mmol/l. The vast majority of CF patients fall into this category. Usually one established mutation causing CF can be identified on each CFTR gene. Patients with classic CF can have exocrine pancreatic insufficiency or pancreatic sufficiency. The disease can have a severe course with rapid progression of symptoms or a milder course with very little deterioration over time. Patients with non-classic or atypical CF have a CF phenotype in at least one organ system and a normal (<30 mmol/l) or borderline (30-60 mmol/l) sweat chloride level. In these patients confirmation of the diagnosis of CF requires detection of one disease causing mutation on each CFTR gene or direct quantification of CFTR dysfunction by nasal potential difference measurement. Non-classic CF includes patients with multiorgan or single organ involvement. Most of these patients have exocrine pancreatic sufficiency and milder lung disease. Algorithms for a structured diagnostic process are proposed.

Action Potentials↗
PubMed2002

Nutrition in patients with cystic fibrosis: a European Consensus.

This document is the result of an European Consensus conference which took place in Artimino, Tuscany, Italy, in March 2001 involving 33 experts on nutrition in patients with cystic fibrosis, organised by the European Cystic Fibrosis Society, and sponsored by Axcan-Scandipharm, Baxter, Dr Falk Pharma, Fresenius, Nutricia, SHS International, Solvay Pharmaceuticals (major sponsor). The purpose of the conference was to develop a consensus document on nutrition in patients with cystic fibrosis based on current evidence.

Adolescent↗
PubMed2001

Identification of seven novel mutations including the first two genomic rearrangements in SLC26A3 mutated in congenital chloride diarrhea.

Congenital chloride diarrhea (CLD) is an autosomal recessive disorder characterized by defective intestinal electrolyte absorption, resulting in voluminous osmotic diarrhea with high chloride content. A variety of mutations in the solute carrier family 26, member 3 gene (SLC26A3, previously known as CLD or DRA) are responsible for the disease. Since the identification of the SLC26A3 gene and the determination of its genomic structure, altogether three founder and 17 private mutations have been characterized within miscellaneous ethnic groups. We screened for mutations in seven unrelated families with CLD. The diagnoses were confirmed by fecal chloride measurements. The combined PCR-SSCP and sequencing analyses revealed altogether seven novel mutations including two missense mutations (S206P, D468V), two splicing defects (IVS12-1G>C, IVS13-2delA), one nonsense mutation (Q436X), one insertion/deletion mutation (2104-2105delGGins29-bp), and an intragenic deletion of SLC26A3 exons 7 and 8. Two previously identified mutations were also found. This is the first report of rearrangement mutations in SLC26A3. Molecular features predisposing SLC26A3 for the two rearrangements may include repetitive elements and palindromic-like sequences. The increasingly wide diversity of SLC26A3 mutations suggests that mutations in the SLC26A3 gene may not be rare events.

Antiporters↗
PubMed1999

Microvascular oxygen pressure in the pig intestine during haemorrhagic shock and resuscitation.

1. The aim of this study was to investigate the relation between microvascular and venous oxygen pressures during haemorrhagic shock and resuscitation in the pig intestine. To this end microvascular PO2 (microPO2) was measured by quenching of Pd-porphyrin phosphorescence by oxygen and validated for the intestines. In addition, mesenteric venous blood gasses, blood flow, ilial CO2 production and global haemodynamics were also measured. 2. In one group (n = 11), moderate shock was induced by withdrawal of 40% of the circulating blood volume. Seven of these animals were resuscitated with a crystalloid solution and four with the withdrawn blood. In a second group of three animals, a more severe shock was induced by withdrawal of 50% of the circulating blood volume; these animals were not resuscitated. 3. Baseline mesenteric venous PO2 and microPO2 values were similar (60 +/- 9 and 60 +/- 11 mmHg, respectively). During moderate shock, microPO2 dropped significantly below mesenteric venous PO2 (26 +/- 10 versus 35 +/- 8 mmHg). After resuscitation with crystalloid solution, microPO2 and mesenteric venous PO2 rose to 44 +/- 9 and 44 +/- 6 mmHg, respectively. In the group that received the withdrawn blood, values were 41 +/- 9 and 53 +/- 12 mmHg, respectively. Severe shock resulted in a drop in the mesenteric venous PO2 (n = 3) to a value similar to that seen in the moderate shock group, but the gut microPO2 dropped to a much lower value than that of the moderate shock group (15 +/- 5 versus 26 +/- 10 mmHg). 4. The results indicate that the oxygenation of the microcirculation of the gut can become lower than the venous PO2 under conditions of haemorrhagic shock.

Animals↗
PubMed1999

Directing portal flow is essential for graft survival in auxiliary partial heterotopic liver transplantation in the dog.

BACKGROUND/PURPOSE: Auxiliary liver transplantation is an attractive alternative for orthotopic liver transplantation in patients with certain inborn errors of metabolism of the liver in which complete resection of the liver is unnecessary or even contraindicated. Because in these diseases portal hypertension is mostly absent, finding a balance in portal blood distribution between native liver and graft is complicated. The objective of this study was to investigate requirements for long-term (180 days) graft survival in auxiliary partial heterotopic liver transplantation (APHLT) in a dog model. METHODS: A metabolic defect was corrected in 26 dalmation dogs with a 60% beagle heterotopic auxiliary liver graft. Four groups of different portal inflow were studied. In the ligation group the portal vein to the host liver was ligated. In the split-flow group graft and host liver received separate portal inflow. In the banding group the distribution of the portal flow was regulated with an adjustable strapband and in the free-flow group the portal blood was allowed to flow randomly to host or graft liver. RESULTS: Metabolic correction increased in all groups after transplantation from 0.19 +/- 0.02 to 0.70 +/- 0.05 (P< .0001) but remained significantly better in the ligation and split-flow groups (graft survival, 135 +/- 27 and 144 +/- 31 days). In the banding group metabolic correction decreased significantly after 70 days, and although the grafts kept some function for 155 +/- 14 days, in 4 of 6 dogs portal thrombosis was found. In the free-flow group, competition for the portal blood led to reduced correction within 12 days and total loss of function in 96 +/- 14 days. Graft function also was assessed with technetium (Tc) 99m dimethyl-iminodiacetic acid uptake. A good linear association between HIDA uptake and metabolic correction was observed (r = 0.74; P < .0005). Grafts that contributed more than 15% to the total uptake of HIDA showed biochemical correction. This indicates a critical graft mass of about 15% to 20% of the hepatocyte volume to correct this metabolic defect. CONCLUSION: Auxiliary partial heterotopic liver transplantation can be a valuable alternative treatment for inborn errors of hepatic metabolism if the native liver and the graft receive separate portal blood inflow.

Animals↗
PubMed1999

Microcirculatory oxygenation and shunting in sepsis and shock.

OBJECTIVE: To review optical spectroscopic techniques for assessment of the determinants of tissue oxygenation and to evaluate the notion that the disturbances in oxygen pathways in sepsis can be accounted for by enhanced functional shunting of parts of the microcirculation. DATA RESOURCES: Experimental data from previous research and the literature were analyzed. STUDY SELECTION: The data selected pertained to a) whether cellular distress in sepsis is caused by tissue hypoxia or disturbed metabolic pathways, b) optical spectroscopic techniques used to study microcirculatory oxygenation, and c) possible mechanisms underlying shunting of the microcirculation in hypoxemia and sepsis. STUDY SYNTHESIS: Despite resuscitation of oxygen-derived variables, signs of regional tissue hypoxia persist in sepsis. The mechanisms underlying this condition are expected to be associated with oxygen pathways in the microcirculation. Optical spectroscopic techniques are providing new insights into these mechanisms. These include absorption spectroscopy for hemoglobin saturation of erythrocytes, reduced nicotinamide adenine dinucleotide fluorescence for tissue mitochondrial bioenergetics, and palladium-porphyrin phosphorescence for microvascular PO2. Reduced nicotinamide adenine dinucleotide videofluorescence studies have shown the heterogeneous nature of hypoxia. Measurement of gut microvascular PO2 in pigs has shown the development of a PO2 gap between microvascular PO2 and venous PO2 during hemorrhage and endotoxemia, with a larger gap occurring in sepsis than in hemorrhage. It is hypothesized that this difference is caused by the enhanced shunting of the microcirculation present in sepsis. CONCLUSIONS: Microcirculatory distress may form one of the earliest stages in the progress of sepsis to multiple organ failure, and shunting of the microcirculation may be an important contributing factor to this development. To evaluate the severity of microcirculatory distress and the effectiveness of resuscitation strategies, new clinical technologies aimed at the microcirculation will need to be developed. It is anticipated that optical spectroscopy will play a major role in the development of such tools.

Humans↗
PubMed1999

PO2 measurements in the rat intestinal microcirculation.

Microvascular partial oxygen pressure (PO2) data measured with the quenched phosphorescence of palladium-porphyrin (Pd-porphyrin) with the use of optical fibers have provided new insight into the behavior of the microvascular oxygenation in models of shock. However, the actual microcirculatory compartment measured by this fiber technique has not yet been demonstrated. The purpose of this study was to investigate whether the PO2 of the intestines, as measured using a fiber phosphorometer, reflects the microvascular compartment. To this end, a new intravital phosphorometer with an improved sensitivity to high-PO2 levels (up to 180 mmHg) was developed and validated. With this setup, PO2 values were measured at different inspired oxygen fractions (15, 25, and 50% oxygen) in first-order arterioles, capillaries, and venules of the ileum of rats. Simultaneously, the PO2 was measured with an optical fiber attached to another phosphorometer. PO2 measurements with the fiber phosphorometer show excellent correlation with the PO2 in the capillaries and first-order venule vessels (r2 = 0.94, slope 0.99). We therefore conclude that values measured with the fiber phosphorometer correlate with the capillary and venular PO2.

Animals↗
PubMed1998

Low-volume resuscitation with a hemoglobin-based oxygen carrier after hemorrhage improves gut microvascular oxygenation in swine.

Using palladium-porphyrin quenching of phosphorescence, we investigated the influence of diaspirin cross-linked hemoglobin (DCLHb) on gut microvascular oxygen pressure (microPO2) in anesthetized pigs. Values of gut microPO2 were studied in correlation with regional intestinal as well as global metabolic and circulatory parameters. A controlled hemorrhagic shock (blood withdrawal of 40 mL/kg) was followed by resuscitation with either a combination of lactated Ringer's solution (75 mL/kg) and modified gelatin (15 mL/kg)(lactR/Gel) or 10% DCLHb (5 mL/kg). After resuscitation, gut microPO2 was similarly improved in the lactR/Gel group (from 25 +/- 10 mm Hg to 53 +/- 8 mm Hg) and the DCLHb group (from 23 +/- 9 mm Hg to 46 +/- 6 mm Hg), which was associated with increased gut oxygen delivery. However, the improvement after resuscitation with DCLHb was sustained for longer periods of time (75 vs 30 min). Mesenteric venous PO2 was increased after resuscitation with lactated Ringer's solution and modified gelatin but not with DCLHb, which was associated with an increased gut oxygen consumption in the latter group. We conclude that measurement of microPO2 by the palladium-porphyrin phosphorescence technique revealed DCLHb to be an effective carrier of oxygen to the microcirculation of the gut. Also, this effect can be achieved with a lower volume than is currently used in resuscitation procedures.

Animals↗
PubMed1998

Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1.

Crigler-Najjar syndrome type 1 (CN-1) is a recessively inherited, potentially lethal disorder characterized by severe unconjugated hyperbilirubinemia resulting from deficiency of the hepatic enzyme bilirubin-UDP-glucuronosyltransferase. In all CN-1 patients studied, structural mutations in one of the five exons of the gene (UGT1A1) encoding the uridinediphosphoglucuronate glucuronosyltransferase (UGT) isoform bilirubin-UGT1 were implicated in the absence or inactivation of the enzyme. We report two patients in whom CN-1 is caused, instead, by mutations in the noncoding intronic region of the UGT1A1 gene. One patient (A) was homozygous for a G-->C mutation at the splice-donor site in the intron, between exon 1 and exon 2. The other patient (B) was heterozygous for an A-->G shift at the splice-acceptor site in intron 3, and in the second allele a premature translation-termination codon in exon 1 was identified. Bilirubin-UGT1 mRNA is difficult to obtain, since it is expressed in the liver only. To determine the effects of these splice-junction mutations, we amplified genomic DNA of the relevant splice junctions. The amplicons were expressed in COS-7 cells, and the expressed mRNAs were analyzed. In both cases, splice-site mutations led to the use of cryptic splice sites, with consequent deletions in the processed mRNA. This is the first report of intronic mutations causing CN-1 and of the determination of the consequences of these mutations on mRNA structure, by ex vivo expression.

Adult↗
PubMed1997

Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64.

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. In the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region. Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. Moreover, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 region, or that represents incomplete penetrance of the BRIC genotype.

Cholestasis, Intrahepatic↗
PubMed1997

Complementation of the genetic defect in Gunn rat hepatocytes in vitro by highly efficient gene transfer with cationic liposomes.

In this article, we report complementation of the genetic defect of isolated Gunn rat hepatocytes by a highly efficient method for lipofection. Transfections were performed 24 h after plating by using the cationic liposome DOTAP. On average, transfection efficiencies of 21% lacZ+ cells with Wag/Rij rat cells and 27% lacZ+ cells with Gunn rat cells could be obtained when the parenchymal cells were transfected in a hormone-defined, serum-free medium. LacZ expression vectors with the CMV promoter were more effective than constructs containing the RSV or the TK promoter. A linear relationship between the viability of hepatocytes after isolation and the percentage of lacZ+ cells was observed with both rat strains, with a maximum of 40% lacZ+ cells at a viability of 94%. The transfection efficiencies were significantly lower in the absence of growth factors, in dexamethasone-containing medium, or when serum was present during plating. Our data are consistent with the assumption that a mitotic event is required for efficient lipofection. Bilirubin conjugation activity could be detected in microsomes from Gunn rat hepatocytes after transfection with two different B-UDPGT expression constructs. Highest conjugation activity was achieved with a vector containing a terminal intron. With this construct on average 4% of the bilirubin conjugation activity of normal human liver microsomes could be achieved in total microsomes of transfected Gunn rat hepatocytes. The implications of our data for gene therapy of hepatic disease with nonviral vectors, in particular bilirubin conjugation deficiency (Crigler-Najjar disease) are discussed.

Animals↗
PubMed1997

Oral calcium phosphate: a new therapy for Crigler-Najjar disease?

BACKGROUND & AIMS: Calcium phosphate binds unconjugated bilirubin in vitro, and dietary calcium phosphate supplementation reduces the serum bilirubin level in rats with hereditary unconjugated hyperbilirubinemia (Gunn rats). The aim of this study was to evaluate the effect of oral calcium phosphate supplementation on plasma bilirubin levels in patients with Crigler-Najjar disease. METHODS: A placebo-controlled, double-blind, crossover design was used. Eleven patients, 2-42 years of age, participated. The group included 5 patients with type I disease who were all treated with phototherapy and 6 patients with type II disease who were primarily treated with phenobarbital. In addition to plasma bilirubin levels, dietary intake and urinary and fecal excretion of calcium and phosphate were evaluated. RESULTS: A modest but significant decrease in serum bilirubin was observed in patients with type I disease (18% +/- 6%, P = 0.03) but not in patients with type II disease during treatment with calcium phosphate. Urinary output of calcium and phosphate did not change during the treatment period. CONCLUSIONS: Oral calcium phosphate may be a useful adjuvant to photo-therapy in Crigler-Najjar type I disease.

Administration, Oral↗
PubMed1997

Fecal polyamine concentration in children with and without nutrient malabsorption.

BACKGROUND: Fermentation products of malabsorbed nutrients are thought to be responsible for intestinal adaptation following small bowel resection in rats. It has been suggested that either short-chain fatty acids or polyamines (mainly putrescine and cadaverine) could be the fermentation products involved. There are no data available on fecal polyamine content in humans. The present study compared the fecal polyamine concentrations in children with and without malabsorption. METHODS: Sixteen (8 girls, 8 boys) malabsorption patients (cystic fibrosis: 13, short bowel syndrome: 2, biliary atresia: 1) with a mean age of 8 years were compared to 17 (9 girls, 8 boys) sick children without malabsorption (mean age 5.7 years). Three-day fecal collections were performed and analyzed for fat and polyamine concentrations. High-performance liquid chromatography (HPLC) was used for the measurement of polyamine concentrations. RESULTS: Mean and SEM for fecal fat excretion was 13.4 +/- 2.5 g/day and 1.5 +/- 0.3 g/day in the malabsorption and control group respectively. Median fecal cadaverine and putrescine concentrations were 3723 mumol.kg-1 feces and 4737 mumol.kg-1 feces for the malabsorption group and 114 mumol.kg-1 feces and 306 mumol.kg-1 feces for the control group (p < 0.007 and < 0.00001 respectively). No significant differences were found for fecal spermine and spermidine concentrations between the two groups. CONCLUSIONS: Children with malabsorption show very high fecal putrescine and cadaverine concentrations. Our results support the hypothesis that fecal polyamines could be important.

Adolescent↗
PubMed1997

Clinical use of acid steatocrit.

Malabsorption of fat is an important gastrointestinal cause of malnutrition and growth retardation in childhood. The gold standard for the evaluation of fat malabsorption is the faecal fat balance method. The acid steatocrit method has recently been introduced as a simple method to evaluate faecal fat. The present study was aimed at evaluating the acid steatocrit in clinical practice. Faecal fat excretion and acid steatocrit results were determined in 42 children, half with and half without fat malabsorption. Acid steatocrit results correlated significantly with both faecal fat excretion (p < 0.01) and faecal fat concentration (p < 0.001). Sensitivity and specificity of the acid steatocrit for the diagnosis of malabsorption were 90% and 100%, respectively. We consider the acid steatocrit method useful for the screening and monitoring of patients with steatorrhoea.

Adolescent↗
PubMed1997

Observations on initial cell loss after intraportal hepatocyte transplantation of 5'-bromo-deoxy-uridine-labeled hepatocytes.

In the present study, attempts are made to improve posttransplant survival of intraportally transplanted hepatocytes in a syngeneic hepatocyte transplantation (HTX) model. Engrafted hepatocytes were detected and quantified after pretransplant labeling with 5'-bromo-deoxy-uridine. In order to enhance the survival percentage, three mechanisms that possibly influence cell survival were manipulated: (1) administration of Matrigel (extracellular-matrix components, Matrigel Basement Membrane Complex, Micronic BV, Lelystad, The Netherlands) in order to improve the environmental conditions of the transplanted hepatocytes; (2) immunosuppression of the recipients by 5 Gy total body irradiation and cyclosporin-A administration (25 mg/kg, 3 x weekly), and (3) Kupffer cell depletion by injection of dichloromethylene-diphosphonate-filled liposomes. The results were analyzed in relation to HTX without treatment. Cell survival was approximately 14% (10 days after HTX), and the transplanted hepatocytes were distributed equally throughout the various recipient liver lobes. However, no increase was attained by Matrigel coadministration, immunosuppression, or Kupffer cell depletion.

Animals↗
PubMed1997

Intestinal excretion of unconjugated bilirubin in man and rats with inherited unconjugated hyperbilirubinemia.

Patients with Crigler-Najjar syndrome and Gunn rats cannot form bilirubin glucuronides owing to a lack of bilirubin UDP-glucuronosyltransferase activity. Because increased serum and tissue bilirubin levels remain constant, an alternative excretory route has to substitute for this deficiency. Gunn rats excrete in bile only 2-13% of the bilirubins eliminated in Wistar rats. In contrast, the biliary excretion rate of urobilinogen in Gunn and Wistar rats is comparable. The sum of bilirubins and urobilinogen excreted in the bile of Gunn rats amounts to 10-30% of pigments excreted in Wistar rats. Despite this low biliary excretion, the intestinal content and fecal excretion of bile pigments in Gunn and Wistar rats were similar. These data support an extrabiliary entrance of unconjugated bilirubin into the intestine. Additional proof for this was found in that the intestinal lumen of Gunn rats still contains a high amount of bilirubins and urobilinogen after 3 d of external biliary drainage. A similar procedure in Wistar rats resulted in the complete disappearance of bile pigments from the intestine. The direct transmural transport of bilirubin from blood to all parts of the intestinal lumen was demonstrated by injecting 14C-bilirubin i.v. into Gunn rats with isolated parts of small and large intestine. In Crigler-Najjar and Gilbert's syndrome patients, the biliary excretion of bile pigments has previously been shown to be strongly reduced. Their stools, however, contained approximately the same amount of bile pigments as in normal subjects. Although only traces of unconjugated bilirubin were detected in the stool of normal persons (4 +/- 3% of total bile pigments), higher amounts were found in patients with Crigler-Najjar disease (20 +/- 12&). These results suggest a direct intestinal permeation of unconjugated bilirubin in severe unconjugated hyperbilirubinemia both in man and rats.

Animals↗