Biomedical subjects
Publications and source records attributed to R Shamir.
Of 59 Sephardic Jewish and Arab children in whom functional abdominal pain was diagnosed, we found that 20% were homozygote for the familial Mediterranean fever gene. Inclusion of genetic screening for familial Mediterranean fever may be advisable in the investigation of recurrent abdominal pain among children of Mediterranean extraction.
We present a new methodology for computational analysis of gene and protein networks. The aim is to generate new educated hypotheses on gene functions and on the logic of the biological network circuitry, based on gene expression profiles. The framework supports the incorporation of biologically motivated network constraints and rules to improve specificity. Since current data is insufficient for de-novo reconstruction, the method receives as input a known pathway core and suggests likely expansions to it. Network modeling is combinatorial, yet data can be probabilistic. At the heart of the approach are a fitness function which estimates the quality of suggested network expansions given the core and the data, and a specificity measure of the expansions. The approach has been implemented in an interactive software tool called GENESYS. We report encouraging results in preliminary analysis of yeast ergosterol pathway based on transcription profiles. In particular, the analysis suggests a novel ergosterol transcription factor.
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Clustering large data sets is a central challenge in gene expression analysis. The hybridization of synthetic oligonucleotides to arrayed cDNAs yields a fingerprint for each cDNA clone. Cluster analysis of these fingerprints can identify clones corresponding to the same gene. We have developed a novel algorithm for cluster analysis that is based on graph theoretic techniques. Unlike other methods, it does not assume that the clusters are hierarchically structured and does not require prior knowledge on the number of clusters. In tests with simulated libraries the algorithm outperformed the Greedy method and demonstrated high speed and robustness to high error rate. Good solution quality was also obtained in a blind test on real cDNA fingerprints.
Accumulating evidence clearly shows that atherosclerosis begins in youth. The National Cholesterol Education Program (NCEP) has recommended that children at high risk of developing coronary artery disease as adults be screened so that those with elevated low-density lipoprotein (LDL) cholesterol levels can be treated, primarily by modification of diet. The initial approach to these youthful patients is to use the NCEP step I diet. This diet provides calories and nutrients that support normal growth and development, but limits saturated fat and total fat intake to no more than 10 and 30 percent of total calories, respectively, and cholesterol intake to no more than 100 mg per 1,000 kcal per day, to a maximum of 300 mg. If the goal of reducing the LDL cholesterol level to below 130 mg per dL (3.35 mmol per L) is not achieved, the more restrictive step II diet should be initiated. However, the step II diet may not provide sufficient calories and nutrients to support normal growth and development; therefore, trained nutritionists may be required to effectively manage a child on this diet.
UNLABELLED: It has recently been suggested that in adults with coeliac disease, faecal blood loss may play a role in the development of iron deficiency. A group of 45 children diagnosed with coeliac disease during 1996 and 1997 were therefore prospectively evaluated for the presence of gluten in their diet, iron deficiency anaemia, and faecal occult blood. Sixty children admitted for elective surgery or asthma served as controls. Faecal occult blood was found in four iron deficient children on normal diet, of whom three were newly diagnosed. Occult blood loss disappeared in three of the four children when gluten was removed from their diet. Faecal occult blood was found in 26.7% of children on gluten-containing diet, but not in children on gluten-free diet (P = 0.01), or in control children (P = 0.001). CONCLUSION: Our data suggest that the incidence of occult blood loss in coeliac disease occurs mainly in newly diagnosed cases and responds to a gluten-free diet. Occult blood testing may not be warranted in the absence of iron deficiency anaemia nor in children with iron deficiency anaemia who are on a gluten-free diet.
UNLABELLED: Iron studies are difficult to interpret in patients with chronic inflammatory states such as inflammatory bowel disease (IBD). Serum transferrin receptor (TfR) has been reported to be a reliable tool for the diagnosis of iron deficiency in adults. Our aim was to evaluate the role of serum TfR in diagnosing iron deficiency in children and adolescents with IBD. A total of 63 consecutive patients with IBD, aged 9 to 22 years (median 15 years), were tested for serum haemoglobin level, mean corpuscular volume (MCV), and serum iron, transferrin, ferritin and serum TfR levels. Those found to be anaemic were compared with seven age-matched subjects with iron deficiency anaemia (IDA) and 24 age-matched children without signs of anaemia or inflammation. Of the 63 patients with IBD, 26 had anaemia. Based on ferritin levels and MCV indices, anaemia was classified as IDA in 11 patients and as anaemia of chronic disease (ACD) in 15 patients. Mean serum TfR level in normal controls was 3.5 mg/l (range 1.2-8.2 mg/l). Mean (+/-SD) serum TfR levels were significantly lower in the IBD patients with ACD (5.3 +/- 2.3 mg/l) than in the IBD patients with IDA (8.2 +/- 3.1 mg/l) (P < 0.05). Serum TfR levels above 5 mg/l identified 10/11 IBD patients with IDA. The calculated TfR/ferritin ratio was 84 (range 17-367) for controls and 133 (range 6.4-1840) for IBD patients. A cut-off level of 350 (91% sensitivity, 100% specificity, 100% positive predictive value, 98% negative predictive value) was established for the diagnosis of IDA in IBD. CONCLUSION: The results suggest that serum transferrin receptor is a useful parameter for the diagnosis of iron deficiency in inflammatory bowel disease, in particular, the transferrin receptor/ferritin ratio with a cut-off level > or = 350.
Optical mapping is a novel technique for generating the restriction map of a DNA molecule by observing many single, partially digested copies of it, using fluorescence microscopy. The real-life problem is complicated by numerous factors: false positive and false negative cut observations, inaccurate location measurements, unknown orientations, and faulty molecules. We present an algorithm for solving the real-life problem. The algorithm combines continuous optimization and combinatorial algorithms applied to a nonuniform discretization of the data. We present encouraging results on real experimental data and on simulated data.
A dynamic programming algorithm is developed for maximum-likelihood reconstruction of the set of all ancestral amino acid sequences in a phylogenetic tree. To date, exhaustive algorithms that find the most likely set of ancestral states (joint reconstruction) have running times that scale exponentially with the number of sequences and are thus limited to very few taxa. The time requirement of our new algorithm scales linearly with the number of sequences and is therefore applicable to practically any number of taxa. A detailed description of the new algorithm and an example of its application to cytochrome b sequences are provided.
BACKGROUND: Hyperbilirubinemia and liver enzyme abnormalities are commonly observed in sepsis. However, the frequency in premature neonates and the specific relation to gram-negative bacteria are not known. PATIENTS AND METHODS: Charts of all preterm infants who had positive blood cultures for either gram-negative bacteria or coagulase-negative staphylococci were reviewed. Neonates with gram-negative bacteremia (n = 54) were compared with neonates with coagulase-negative staphylococcal bacteremia (n = 31). In addition infants with gram-negative bacteremia and elevated liver enzymes (n = 25) were compared with infants with gram-negative bacteremia and normal liver enzymes (n = 29). RESULTS: Liver enzyme abnormalities accompanied 46.3% (25 of 54) of gram-negative bacteremia and 12.9% (4 of 31) of episodes of coagulase-negative staphylococcal bacteremia (P = 0.002). Serum concentrations of liver enzymes were significantly higher in infants with gram-negative bacteremia than in those with coagulase-negative staphylococcal bacteremia (P < 0.0001), but no difference in alkaline phosphatase serum values was observed. Infants with gram-negative bacteremia and elevated liver enzymes were not fed for a longer period than infants with gram-negative bacteremia and normal liver enzymes (7.3 +/- 6.3 days vs. 4.0 +/- 4.3 days, P = 0.03), and this was accompanied by significant conjugated hyperbilirubinemia (P < 0.0001). Ventilation, total parenteral nutrition and medications were not responsible for the observed differences. Klebsiella pneumoniae bacteremia was commonly associated with elevated liver enzymes (12 of 18), whereas none of the infants with Pseudomonas aeruginosa bacteremia had elevated liver enzymes. CONCLUSIONS: Gram-negative bacteremia is commonly associated with cholestasis in premature neonates. Liver enzyme abnormalities are more common than elevated conjugated bilirubin, not all gram-negative bacteria have the same effect and the lack of enteral feeding seems to play a more significant role than the administration of parenteral nutrition.
BACKGROUND: Cholestasis is a frequent problem in patients on total parenteral nutrition. Cisapride has a prokinetic effect on the biliary system, but its effect on hepatic excretory function is unknown. OBJECTIVES: To study the effect of cisapride on TPN-induced cholestasis in a rat model. METHODS: Bile flow and bile salt secretion rate were measured in rats given TPN. There were four groups of 8 to 13 animals each. After a one hour baseline period during which all four groups received i.v. saline infusion, two groups received a TPN solution for another 2 hours, while saline was infused in the two control groups. At the beginning of the second hour, 2 mg/kg cisapride was injected i.v. as a bolus into one experimental and one control group. Bile was collected from the common bile duct. RESULTS: At the end of the third hour, TPN caused a significant reduction in bile flow (P < 0.02) and bile salt secretion rate (P < 0.001) (61.24 vs. 50.74 microliters/min/kg, and 1.173 vs. 0.799 mumol/min/kg, respectively). Addition of cisapride abolished the cholestatic effect of TPN. CONCLUSIONS: Cisapride has a protective effect against TPN-associated cholestasis. This may have clinical significance, and further studies are warranted.
Recent high-density microarray technologies allow, in principle, the determination of all k-mers that appear along a DNA sequence, for k = 8 - 10 in a single experiment on a standard chip. The k-mer contents, also called the spectrum of the sequence, is not sufficient to uniquely reconstruct a sequence longer than a few hundred bases. We have devised a polynomial algorithm that reconstructs the sequence, given the spectrum and a homologous sequence. This situation occurs, for example, in the identification of single nucleotide polymorphisms (SNPs), and whenever a homologue of the target sequence is known. The algorithm is robust, can handle errors in the spectrum and assumes no knowledge of the k-mer multiplicities. Our simulations show that with realistic levels of SNPs, the algorithm correctly reconstructs a target sequence of length up to 2,000 nucleotides when a polymorphic sequence is known. The technique is generalized to handle profiles and HMMs as input instead of a single homologous sequence.
Novel DNA microarray technologies enable the monitoring of expression levels of thousands of genes simultaneously. This allows a global view on the transcription levels of many (or all) genes when the cell undergoes specific conditions or processes. Analyzing gene expression data requires the clustering of genes into groups with similar expression patterns. We have developed a novel clustering algorithm, called CLICK, which is applicable to gene expression analysis as well as to other biological applications. No prior assumptions are made on the structure or the number of the clusters. The algorithm utilizes graph-theoretic and statistical techniques to identify tight groups of highly similar elements (kernels), which are likely to belong to the same true cluster. Several heuristic procedures are then used to expand the kernels into the full clustering. CLICK has been implemented and tested on a variety of biological datasets, ranging from gene expression, cDNA oligo-fingerprinting to protein sequence similarity. In all those applications it outperformed extant algorithms according to several common figures of merit. CLICK is also very fast, allowing clustering of thousands of elements in minutes, and over 100,000 elements in a couple of hours on a regular workstation.
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To study the role of carboxyl ester lipase (CEL) in hepatic retinoid (vitamin A) metabolism, we investigated uptake and hydrolysis of chylomicron (CM)-retinyl esters (RE) by rat hepatoma (McArdle-RH7777) cells stably transfected with a rat CEL cDNA. We also studied tissue uptake of CM-RE in CEL-deficient mice generated by targeted disruption of the CEL gene. CEL-transfected cells secreted active enzyme into the medium. However, both control and CEL-transfected cells accumulated exogenously added CM-RE or CM remnant (CMR)-derived RE in equal amounts. Serum clearance of intravenously injected CM-RE and cholesteryl ester were not different between wild-type and CEL-deficient mice. Also, the uptake of the two compounds by the liver and other tissues did not differ. These data indicate that the lack of CEL expression does not affect the uptake of dietary CM-RE by the liver or other tissues. Moreover, the percentage of retinol formed in the liver after CM-RE uptake, the levels of retinol and retinol-binding protein in serum, and retinoid levels in various tissues did not differ, indicating that CEL deficiency does not affect hepatic retinoid metabolism and retinoid distribution throughout the body. Surprisingly, in both pancreas and liver of wild-type, heterozygous, and homozygous CEL-deficient mice, the levels of bile salt-dependent retinyl ester hydrolase (REH) activity were similar. This indicates that in the mouse pancreas and liver an REH enzyme activity, active in the presence of bile salt and distinct from CEL, is present, compatible with the results from our accompanying paper that the intestinal processing and absorption of RE were unimpaired in CEL-deficient mice.