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Biomedical subjects

N Salem

Publications and source records attributed to N Salem.

At least 37 records · Page 2Linked to original sources
PubMed2001

Familial Mediterranean fever in Lebanon: mutation spectrum, evidence for cases in Maronites, Greek orthodoxes, Greek catholics, Syriacs and Chiites and for an association between amyloidosis and M694V and M694I mutations.

Seventy-nine unrelated Lebanese patients were tested for 15 mutations in the MEFV gene: A761H, A744S, V726A, K695R, M694V, M694I, M694del, M6801 (G --> C), M680I (G --> A) in exon 10, F479L in exon 5, P369S in exon 3, T267I, E167D and E148Q in exon 2, using PCR digestion, ARMS, DGGE and/or sequencing. Mutations were detected in patients belonging to all communities, most interestingly the Maronite, Greek orthodox, Greek catholic, Syriac and Chiite communities. The most frequent mutations are M694V and V726A (27% and 20% of the total alleles respectively). M694I, E148Q and M680I mutations account respectively for 9%, 8% and 5%. Each of the K695R, E167D and F479L mutations was observed once and all the remaining mutations were not encountered. Of the alleles 33% do not carry any of the studied mutations. The mutation spectra, clinical features and severity of the disease differed among the Lebanese communities. The genotype-phenotype analysis showed a significant association (P < 0.001) between amyloidosis and the presence of mutations at codon 694 in exon 10 (both M694V and M694I). None of the patients carrying other mutations developed amyloidosis.

Amyloidosis↗
PubMed2001

Familial Mediterranean Fever: association of elevated IgD plasma levels with specific MEFV mutations.

Familial Mediterranean Fever (FMF) is a recessively inherited disorder, characterized by episodic fever, abdominal and arthritic pain, as well as other forms of inflammation. Some FMF patients present higher IgD serum levels, and it is not yet known whether such an elevation is related to specific genotypes or correlated with a specific phenotype. In order to evaluate the association between known FMF-related mutations and IgD levels in confirmed patients, as well as the correlation between those levels and the presence of specific clinical signs, genotypic analysis and IgD plasma measurements were performed for 148 Lebanese and Jordanian FMF patients. Most common mutational patterns were M694V heterozygotes (19%) and homozygotes (17%), and V726A heterozygotes (18%) and homozygotes (5%), with an additional 11% combining both mutations. Twenty-one patients had higher IgD levels (superior to 100 microg/ml). The risk for higher IgD levels was significantly associated with M694V homozygote status (OR = 6.25) but not with heterozygotic one (OR = 1). Similarly, the risk for higher IgD was also found with V726A homozygotes (OR = 2.2) but not with heterozygotes (OR = 1.05). The use of colchicine was not statistically associated with IgD levels. Clinically, hyper IgD was also found significantly associated with arthritis (OR = 18). Thus, homozygotic status for M694V, and to a lesser extent V726A, is associated with increased risk for higher IgD plasma levels, regardless of colchicine use. Elevated IgD plasma levels are also correlated with the severity of FMF manifestations, and especially with arthritis.

Cytoskeletal Proteins↗
PubMed2001

Chronic nutritional deprivation of n-3 alpha-linolenic acid does not affect n-6 arachidonic acid recycling within brain phospholipids of awake rats.

Using an in vivo fatty acid model and operational equations, we reported that esterified and unesterified concentrations of docosahexaenoic acid (DHA, 22 : 6 n-3) were markedly reduced in brains of third-generation (F3) rats nutritionally deprived of alpha-linolenic acid (18 : 3 n-3), and that DHA turnover within phospholipids was reduced as well. The concentration of docosapentaenoic acid (DPA, 22 : 5 n-6), an arachidonic acid (AA, 20 : 4 n-6) elongation/desaturation product, was barely detectable in control rats but was elevated in the deprived rats. In the present study, we used the same in vivo model, involving the intravenous infusion of radiolabeled AA to demonstrate that concentrations of unesterified and esterified AA, and turnover of AA within phospholipids, were not altered in brains of awake F3-generation n-3-deficient rats, compared with control concentrations. Brain DPA-CoA could be measured in the deprived but not control rats, and AA-CoA was elevated in the deprived animals. These results indicated that AA and DHA are recycled within brain phospholipids independently of each other, suggesting that recycling is regulated independently by AA- and DHA-selective enzymes, respectively. Competition among n-3 and n-6 fatty acids within brain probably does not occur at the level of recycling, but at levels of elongation and desaturation (hence greater production of DPA during n-3 deprivation), or conversion to bioactive eicosanoids and other metabolites.

Acyl Coenzyme A↗
PubMed2001

Reversal of docosahexaenoic acid deficiency in the rat brain, retina, liver, and serum.

The loss of docosahexaenoic acid (DHA) from the retina or brain has been associated with a loss in nervous-system function in experimental animals, as well as in human infants fed vegetable oil-based formulas. The reversibility of the loss of DHA and the compensation by an increase in the n-6 docosapentaenoic acid (DPAn-6) was studied in young adult rats. Long-Evans rats were subjected to a very low level of n-3 fatty acids through two generations. The F2 generation, n-3-deficient animals at 7 weeks of age were provided a repletion diet containing both alpha-linolenate and DHA. A separate group of F2 generation rats had been maintained on an n-3-adequate diet of the same composition. Tissues from the brain, retina, liver, and serum were collected on weeks 0, 1, 2, 4, and 8 from both groups of animals. The concentrations of DHA, DPAn-6, and other fatty acids were determined and the rate of recovery and length of time needed to complete DHA recovery were determined for each tissue. The DHA level in the brain at 1 and 2 weeks after diet reversal was only partially recovered, rising to approximately 20% and 35%, respectively, of the n-3-adequate group level. Full recovery was not obtained until 8 weeks after initiation of the repletion diet. Although the initial rate of retinal DHA accretion was greater than that of brain DHA, the half-time for DHA recovery was only marginally greater. On the other hand, the levels of DHA in the serum and liver were approximately 90% and 100% replaced, respectively, within 2 weeks of diet reversal. A consideration of the total amounts and time courses of DHA repleted in the nervous system compared with the liver and circulation suggests that transport-related processes may limit the rate of DHA repletion in the retina and brain.-- Moriguchi, T., J. Loewke, M. Garrison, J. N. Catalan, N. Salem, Jr. Reversal of docosahexaenoic acid deficiency in the rat brain, retina, liver, and serum. J. Lipid Res. 2001. 42: 419--427.

Animals↗
PubMed2001

Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans.

A physiological compartmental model of alpha-linolenic acid metabolism was derived from the plasma concentration-time curves for d5-18:3n-3, d5-20:5n-3, d5-22:5n-3, and d5-22:6n-3 in eight healthy subjects. Subjects received a 1-g oral dose of an isotope tracer of alpha-linolenate (d5-18:3n-3 ethyl ester) while subsisting on a rigorously controlled beef-based diet. By utilizing the Windows Simulation and Analysis Modeling program, kinetic parameters were determined for each subject. Half-lives and mean transit times of the n-3 fatty acids in the plasma were also determined. The model predicted plasma values for the n-3 fatty acids in good accordance with the measured steady state concentrations and also predicted dietary linolenic acid intake for each subject in accordance with values determined by lipid analysis of the diet. Only about 0.2% of the plasma 18:3n-3 was destined for synthesis of 20:5n-3, approximately 63% of the plasma 20:5n-3 was accessible for production of 22:5n-3, and 37% of 22:5n-3 was available for synthesis of 22:6n-3. The inefficiency of the conversion of 18:3n-3 to 20:5n-3 indicates that the biosynthesis of long-chain n-3 PUFA from alpha-linolenic acid is limited in healthy individuals. In contrast, the much greater rate of transfer of mass from the plasma 20:5n-3 compartment to 22:5n-3 suggests that dietary eicosapentaenoic acid may be well utilized in the biosynthesis of 22:6n-3 in humans.

Absorption↗
PubMed2001

Nonprogressive autosomal recessive ataxia maps to chromosome 9q34-9qter in a large consanguineous Lebanese family.

Congenital ataxias are a heterogeneous group of predominantly nonprogressive disorders characterized by hypotonia, developmental delay followed by the appearance of ataxia, and often associated with dysarthria, mental retardation, and atrophy of the cerebellum. We performed a genome-wide screen on a large inbred Lebanese family presenting a nonprogressive autosomal recessive congenital cerebellar ataxia associated with short stature (MIM 213200), already described by Mégarbané and colleagues. The disease locus was assigned to a 12.1 cM interval on chromosome 9q34-9qter between D9S67 and D9S312. Differential diagnosis with other hereditary ataxias linked to the same region is discussed.

Ataxia↗
PubMed2001

Measuring clinical performance: comparison and validity of telephone survey and administrative data.

OBJECTIVE: To compare and validate self-reported telephone survey and administrative data for two Health Plan Employer Data and Information Set (HEDIS) performance measures: mammography and diabetic retinal exams. DATA SOURCES/STUDY SETTING: A telephone survey was administered to approximately 700 women and 600 persons with diabetes randomly chosen from each of two health maintenance organizations (HMOs). STUDY DESIGN: Agreement of survey and administrative data was assessed by using kappa coefficients. Validity measures were assessed by comparing survey and administrative data results to a standard: when the two sources agreed, that was accepted as the standard; when they differed, confirmatory information was sought from medical records to establish the standard. When confirmatory information was not available ranges of estimates consistent with the data were constructed by first assuming that all persons for whom no information was available had received the service and alternately that they had not received the service. PRINCIPAL FINDINGS: The kappas for mammography were .65 at both HMOs; for retinal exam they were .38 and .40. Sensitivity for both data sources was consistently high. However, specificity was lower for survey (range .44 to .66) than administrative data (.99 to 1.00). The positive predictive value was high for mammography using either data source but differed for retinal exam (survey .69 to .78; administrative data .99 to 1.00). CONCLUSIONS: Administrative and survey data performed consistently in both HMOs. Although administrative data appeared to have greater specificity than survey data the validity and utility of different data sources for performance measurement have only begun to be explored.

Adult↗
PubMed2001

Ethanol consumption alters electroretinograms and depletes neural tissues of docosahexaenoic acid in rhesus monkeys: nutritional consequences of a low n-3 fatty acid diet.

BACKGROUND: Alcohol amblyopia is a rare neuropathy characterized by the development of blurred vision and a reduction in visual acuity. Further diagnostic details of this condition have shown abnormalities in the electroretinogram (ERG) that include an increase in implicit times in the a- and b-waves and a depression of b-wave amplitude. METHODS: Periodically, the ERGs and the fatty acyl composition of nervous tissue were analyzed from alcohol-consuming rhesus monkeys (Macaca mulatta) (mean consumption 2.6 g kg/day over a 5-year period) and controls that were maintained on a nutritionally sufficient diet that had low, yet adequate, amounts of linoleic acid but very low alpha-linolenic acid. RESULTS: Animals consuming alcohol had increased a- and b-wave implicit times and decreased b-wave amplitudes in their electroretinograms compared with those of the dietary control group at 2.5 and 5 years. The fatty acyl composition of brain specimens obtained by surgical biopsy at baseline, 2.5 years, and 5 years demonstrated that docosahexaenoic acid (DHA) had decreased in both groups of animals compared with baseline values. In the brains of the alcohol-treated animals, DHA was even further decreased (2.5 years: -20%; 5 years: -33%) compared with the diet controls. In the retinas of the alcohol-consuming animals at 5 years, there was a similar decrease in DHA (-35%) compared with controls. Generally, the n-6 fatty acid, docosapentaenoic acid (DPAn-6) increased in these tissues, apparently compensating for the loss of DHA. CONCLUSIONS: A reciprocal change in the DHA/DPAn-6 ratio is known to be associated with abnormal electroretinograms in a number of species. Thus, a marginal intake of n-3 fatty acids in some alcohol abusers may, in part, be responsible for the biochemical changes that underlie the diminished retinal function associated with the visual abnormalities observed in alcohol-amblyopic patients.

Alcoholism↗
PubMed2000

n-3 fatty acid deficiency decreases phosphatidylserine accumulation selectively in neuronal tissues.

We have previously shown that the docosahexaenoate (22:6n-3) status in membrane phospholipids influences the biosynthesis and accumulation of phosphatidylserine (PS) in brain microsomes and C6 glioma cells. In the present study, we investigated whether the observed effect of membrane docosahexaenoic acid status on PS accumulation is universal or occurs specifically in neuronal tissues. We observed that rat brain cortex, brain mitochondria, and olfactory bulb, where 22:6n-3 is highly concentrated, contain significantly higher levels of PS in comparison to liver and adrenal, where 22:6n-3 is a rather minor component. Phospholipid molecular species analysis revealed that in brain cortex, mitochondria, and olfactory bulb 18:0,22:6n-3 was the most abundant species representing 45-65% of total PS. In nonneuronal tissues such as liver and adrenal, 18:0,20:4n-6 was the major PS species. Dietary depletion of n-3 fatty acids during prenatal and postnatal developmental periods decreased the brain 22:6n-3 content by more than 80%, with a concomitant increase in 22:5n-6 in all tissues. Under these conditions, an approximately 30-35% reduction in total PS in rat brain cortex, brain mitochondria, and olfactory bulb was observed, while PS levels in liver and adrenal were unchanged. The observed reduction of PS content in neuronal membranes appears to be due to a dramatic reduction of 18:0,22:6n-3-PS without complete replacement by 18:0,22:5n-6-PS. These results establish that variations in membrane 22:6n-3 fatty acid composition have a profound influence on PS accumulation in neuronal tissues where 22:6n-3 is abundant. These data have implications in neuronal signaling events where PS is believed to play an important role.

Adrenal Glands↗
PubMed2000

[Maternal and perinatal morbidity and mortality associated with hellp syndrome] .

OBJECTIVES: Our purpose was to describe the effects of serious obstetric complications on maternal and perinatal outcome in pregnancies complicated by Hellp syndrome. STUDY DESIGN: Retrospective study. PATIENTS: Sixteen patients managed from January 1994 through December 1998 in whom pregnancy was complicated by Hellp Syndrome. RESULTS: The incidence of Hellp syndrome among women with severe preeclampsia and/or eclampsia (164 cases) was 9.7%. Fourteen cases occurred before and two after delivery. In nine cases, Hellp occurred before 32 weeks of gestation and later in two other cases. Mean gestational age at delivery was 32.4 weeks. Serious maternal morbidity included acute renal failure (five cases), disseminated intravascular coagulation (two cases), pulmonary oedema (one case), severe ascites (five cases), pleural effusion (three cases), adult respiratory distress syndrome (one case). Abruptio placenta, acute renal failure and disseminated intravascular coagulation were always associated. Ten patients required transfusions with blood products. Caesarean delivery was performed in 15 cases. General anaesthesia was used in all patients. There was one maternal death from multiple organ failure. Perinatal outcome was poor. Six perinatal deaths were related to abruptio placenta, intrauterine asphyxia and extreme prematurity. CONCLUSION: The high maternal and perinatal mortality and morbidity reported with the presence of Hellp syndrome requires maternal-fetal follow-up in a tertiary centre where intensive maternal and neonatal care are available.

Adult↗
PubMed2000

A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C.

Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)1. Six different USH1 loci have been reported. So far, only MYO7A (USH1B), encoding myosin VIIA, has been identified as a gene whose mutation causes the disease. Here, we report a gene underlying USH1C (MIM 276904), a USH1 subtype described in a population of Acadian descendants from Louisiana and in a Lebanese family. We identified this gene (USH1C), encoding a PDZ-domain-containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas. In patients we found a splice-site mutation, a frameshift mutation and the expansion of an intronic variable number of tandem repeat (VNTR). We showed that, in the mouse inner ear, only the sensory hair cells express harmonin. The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region. As several of these transcripts were absent from the eye, we propose that USH1C also underlies the DFNB18 form of isolated deafness.

Adaptor Proteins, Signal Transducing↗
PubMed2000

X-linked transposition of the great arteries and incomplete penetrance among males with a nonsense mutation in ZIC3.

We report on a Lebanese family in which two maternal cousins suffered and died very early in life from cardiac malformations. Both presented with a transposition of the great arteries associated with one or several other cardiac defects. Various minor midline defects were also observed, but there were no situs abnormalities other than a persistent left superior vena cava in one. A maternal uncle of these two babies was born cyanotic and died on the third post-natal day. Analysis of the ZIC3 gene, revealed the presence of a mutation in the second exon leading to a truncation of the protein. Surprisingly, another maternal uncle of the two affected cousins also had the mutation but was not clinically affected. To our knowledge, this is the first instance of incomplete penetrance in a male for a mutation in a chromosome X gene.

Alternative Splicing↗
PubMed2000

Nutritional deprivation of alpha-linolenic acid decreases but does not abolish turnover and availability of unacylated docosahexaenoic acid and docosahexaenoyl-CoA in rat brain.

We applied our in vivo fatty acid method to examine concentrations, incorporation, and turnover rates of docosahexaenoic acid (22:6 n-3) in brains of rats subject to a dietary deficiency of alpha-linolenic acid (18:3 n-3) for three generations. Adult deficient and adequate rats of the F3 generation were infused intravenously with [4, 5-(3)H]docosahexaenoic acid over 5 min, after which brain uptake and distribution of tracer were measured. Before infusion, the plasma 22:6 n-3 level was 0.2 nmol ml(-1) in 18:3 n-3-deficient compared with 10.6 nmol ml(-1) in control rats. Brain unesterified 22:6 n-3 was not detectable, whereas docosahexaenoyl-CoA content was reduced by 95%, and 22:6 n-3 content in different phospholipid classes was reduced by 83-88% in deficient rats. Neither plasma or brain arachidonic acid (20:4 n-6) level was significantly changed with diet. Docosapentaenoic acid (22:5 n-6) reciprocally replaced 22:6 n-3 in brain phospholipids. Calculations using operational equations from our model indicated that 22:6 n-3 incorporation from plasma into brain was reduced 40-fold by 18:3 n-3 deficiency. Recycling of 22:6 n-3 due to deacylation-reacylation within phospholipids was reduced by 30-70% with the deficient diet, but animals nevertheless continued to produce 22:6 n-3 and docosahexaenoyl-CoA for brain function. We propose that functional brain effects of n-3 deficiency reflect altered ratios of n-6 to n-3 fatty acids.

Acyl Coenzyme A↗
PubMed2000

Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration.

Docosahexaenoic acid (DHA), an n-3 fatty acid, is rapidly deposited during the period of rapid brain development. The influence of n-3 fatty acid deficiency on learning performance in adult rats over two generations was investigated. Rats were fed either an n-3 fatty acid-adequate (n-3 Adq) or -deficient (n-3 Def) diet for three generations (F1-F3). Levels of total brain n-3 fatty acids were reduced in the n-3 Def group by 83 and 87% in the F2 and F3 generations, respectively. In the Morris water maze, the n-3 Def group showed a longer escape latency and delayed acquisition of this task compared with the n-3 Adq group in both generations. The acquisition and memory levels of the n-3 Def group in the F3 generation seemed to be lower than that of the F2 generation. The 22:5n-6/22:6n-3 ratio in the frontal cortex and dams' milk was markedly increased in the n-3 Def group, and this ratio was significantly higher in the F3 generation compared with the F2 generation. These results suggest that learning and cognitive behavior are related to brain DHA status, which, in turn, is related to the levels of the milk/dietary n-3 fatty acids.

Animals↗
PubMed2000

Effects of gestational alcohol exposure on the fatty acid composition of umbilical cord serum in humans.

This study examined the effects of maternal periconceptional alcohol intake on polyunsaturated fatty acid (PUFA) concentrations in human neonates. The area percentage of each fatty acid in cord blood serum from 12 infants born to control women (who consumed <2 mL absolute ethanol/d) was compared with that of 9 infants born to women whose periconceptional alcohol intake averaged > or = 30mL absolute ethanol/d. Periconceptional alcohol use was associated with a 30% increase in the proportion of docosahexaenoic acid (22:6n-3) in cord blood (3.0% of total lipid in control infants compared with 3.9% in alcohol-exposed infants; P < 0.01). The rise in the proportion of 22:6n-3 was responsible for increases in the ratio of n-3 to n-6 fatty acids and the ratio of long-chain n-3 to n-6 fatty acids (P < 0.055). Examination of the lipid-class fatty acid profile indicated that serum lipid alterations were localized to the cholesterol esters; 22:6n-3 in the cholesterol esters of alcohol-exposed infants increased 54% (P < 0.011) and arachidonic acid increased 55% (P < 0. 005). The relative fatty acyl composition of maternal serum showed a significant increase in 18:0 fatty acids in the alcohol-exposed group (25%, P < 0.005) but there were no changes in the other fatty acids. The increase in the proportion of 22:6n-3 was unexpected but is consistent with the hypothesis that this essential lipid may be conserved selectively. These results imply that the lifelong neurobehavioral and sensory dysfunction in fetal alcohol syndrome and other alcohol-related neurodevelopmental disorders may be due in part to PUFA dysregulation.

Adolescent↗
PubMed2000

Plasma total cholesterol concentrations do not predict cerebrospinal fluid neurotransmitter metabolites: implications for the biophysical role of highly unsaturated fatty acids.

Low concentrations of a metabolite of serotonin found in cerebrospinal fluid (CSF), 5-hydroxyindolacetic acid (5-HIAA), are strongly associated with suicidal and violent behaviors. Although lowering of plasma total cholesterol has been suggested to increase mortality from suicide and violence by decreasing concentrations of CSF 5-HIAA via changes in membrane biophysical properties, highly unsaturated fatty acids may play a more important role. Violent and nonviolent comparison groups, early- and late-onset alcoholics, and healthy comparison subjects were studied to control for alcohol use and predisposition to violence. Fasting plasma total cholesterol and CSF were assayed under stringently controlled conditions. When all groups were combined (n = 234), plasma cholesterol concentrations had a weak positive correlation with CSF 5-HIAA (r = 0.18, P < 0.01). However, age correlated with both plasma total cholesterol and CSF 5-HIAA concentrations. When age was included in multiple regression models, the correlation between cholesterol and CSF 5-HIAA concentrations was not significant. Cholesterol correlated weakly with CSF 5-HIAA concentrations only in late-onset alcoholics after age was controlled for, but the relation was not significant after correction for multiple testing. CSF homovanillic acid did not correlate with plasma total cholesterol in any group. Plasma total cholesterol had no apparent relation to CSF neurotransmitter metabolites in any group of subjects. Highly unsaturated essential fatty acids, which are also critical determinants of membrane biophysical properties and may be linked to brain serotonin concentrations, should also be considered in studies examining the effect of lowering fat intake on the incidence of suicide and violence.

Adult↗