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N Bissada

Publications and source records attributed to N Bissada.

At least 19 recordsLinked to original sources
PubMed2006

Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities.

ALS2 is an autosomal recessive form of spastic paraparesis (motor neuron disease) with juvenile onset and slow progression caused by loss of function of alsin, an activator of Rac1 and Rab5 small GTPases. To establish an animal model of ALS2 and derive insights into the pathogenesis of this illness, we have generated alsin-null mice. Cytosol from brains of Als2(-/-) mice shows marked diminution of Rab5-dependent endosome fusion activity. Furthermore, primary neurons from Als2(-/-) mice show a disturbance in endosomal transport of insulin-like growth factor 1 (IGF1) and BDNF receptors, whereas neuronal viability and endocytosis of transferrin and dextran seem unaltered. There is a significant decrease in the size of cortical motor neurons, and Als2(-/-) mice are mildly hypoactive. Altered trophic receptor trafficking in neurons of Als2(-/-) mice may underlie the histopathological and behavioral changes observed and the pathogenesis of ALS2.

Animals↗
PubMed2001

Human ABCA1 BAC transgenic mice show increased high density lipoprotein cholesterol and ApoAI-dependent efflux stimulated by an internal promoter containing liver X receptor response elements in intron 1.

By using BAC transgenic mice, we have shown that increased human ABCA1 protein expression results in a significant increase in cholesterol efflux in different tissues and marked elevation in high density lipoprotein (HDL)-cholesterol levels associated with increases in apoAI and apoAII. Three novel ABCA1 transcripts containing three different transcription initiation sites that utilize sequences in intron 1 have been identified. In BAC transgenic mice there is an increased expression of ABCA1 protein, but the distribution of the ABCA1 product in different cells remains similar to wild type mice. An internal promoter in human intron 1 containing liver X response elements is functional in vivo and directly contributes to regulation of the human ABCA1 gene in multiple tissues and to raised HDL cholesterol, apoAI, and apoAII levels. A highly significant relationship between raised protein levels, increased efflux, and level of HDL elevation is evident. These data provide proof of the principle that increased human ABCA1 efflux activity is associated with an increase in HDL levels in vivo.

ATP Binding Cassette Transporter 1↗
PubMed2000

Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis.

Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism, and has been hypothesized to exert either pro- or anti-atherogenic effects, depending on its localization. Decreased plasma LPL activity is associated with the high triglyceride (TG);-low HDL phenotype that is often observed in patients with premature vascular disease. In contrast, in the vessel wall, decreased LPL may be associated with less lipoprotein retention due to many potential mechanisms and, therefore, decreased foam cell formation. To directly assess this hypothesis, we have distinguished between the effects of variations in plasma and/or vessel wall LPL on atherosclerosis susceptibility in apoE-deficient mice. Reduced LPL in both plasma and vessel wall (LPL(+/-)E(-/-)) was associated with increased TG and increased total cholesterol (TC) compared with LPL(+/+)E(-/-) sibs. However despite their dyslipidemia, LPL(+/-)E(-/-) mice had significantly reduced lesion areas compared to the LPL(+/+)E(-/-) mice. Thus, decreased vessel wall LPL was associated with decreased lesion formation even in the presence of reduced plasma LPL activity. In contrast, transgenic mice with increased plasma LPL but with no increase in LPL expression in macrophages, and thus the vessel wall, had decreased TG and TC and significantly decreased lesion areas compared with LPL(+/+)E(-/-) mice. This demonstrates that increased plasma LPL activity alone, in the absence of an increase in vessel wall LPL, is associated with reduced susceptibility to atherosclerosis. Taken together, these results provide in vivo evidence that the contribution of LPL to atherogenesis is significantly influenced by the balance between vessel wall protein (pro-atherogenic) and plasma activity (anti-atherogenic).

Animals↗
PubMed1999

A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration.

We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.

Adaptation, Physiological↗
PubMed1997

Ethnic variation and in vivo effects of the -93t-->g promoter variant in the lipoprotein lipase gene.

Recently, a (t-->g) transition at nucleotide -93 in the lipoprotein lipase (LPL) gene promoter has been observed in Caucasians. Here, we have compared the frequency of the -93g carriers in three distinct populations (Caucasians, South African Blacks, and Chinese). The carrier frequency in the Caucasian population was 1.7% (4/232), which was in contrast to the South African Black population, which had a frequency for this allele of 76.4% (123/161) of the individuals tested. This transition was not observed in the Chinese population under study. Near complete linkage disequilibrium between the -93g and the previously described D9N mutation was observed in the Caucasian population but not in South African Blacks. To further assess the ancestral origins of these DNA changes, DNA haplotyping using a CA repeat 5' to these substitutions was performed. The -93t allele was associated with only a few specific dinucleotide repeat sizes. In contrast, the -93g allele occurred on chromosomes with many different repeat lengths. The broad distribution of repeats on -93g carrying chromosomes, their high frequency in the South African Black population, and the conservation of the -93g allele among different species may suggest that the -93g allele is the ancestral allele on which a transition to t and the D9N mutations arose. The very high frequency of the -93g allele distinct from the N9 allele in a cohort of Black South Africans allowed us to specifically assess the phenotypic effects of the -93g allele on lipids. Individuals homozygous for the g allele at -93 showed mildly decreased triglycerides compared with individuals homozygous for the t allele (1.14 +/- 0.66 mmol/L versus 0.82 +/- 0.3; P = .04). Thus, the -93g allele in this cohort is associated with low plasma triglyceride levels.

Adult↗
PubMed1997

Relationship between lipoprotein lipase and high density lipoprotein cholesterol in mice: modulation by cholesteryl ester transfer protein and dietary status.

Plasma lipoprotein lipase (LPL) activity correlates with high density lipoprotein (HDL) cholesterol levels in humans. However, in several mouse models created either through transgenesis or targeted inactivation of LPL, no significant changes in HDL cholesterol values have been evident. One possible explanation for this species difference could be the absence of plasma cholesteryl ester transfer protein (CETP) activity in mice. To explore this possibility and further investigate interactions between LPL and CETP modulating HDL cholesterol levels in vivo, we examined the relationship between LPL activity and HDL levels in mice expressing the simian CETP transgene, compared with littermates not carrying the CETP gene. On a chow diet, increasing LPL activity was associated with a trend towards increased HDL levels (51 +/- 29 vs. 31 +/- 4 mg/dL highest vs. lowest tertiles of LPL activity, P = 0.07) in mice expressing CETP, while no such effects were seen in the absence of CETP (65 +/- 12 vs. 61 +/- 15 mg/ dL). Furthermore, in the presence of CETP, a significant positive correlation between LPL activity and HDL cholesterol was evident (r = 0.15, P = 0.006), while in the absence of CETP no such correlation was detected (r = 0.15, P = 0.36), highlighting the interactions between LPL and CETP in vivo. When mice were challenged with a high fat, high carbohydrate diet, strong correlations between LPL activity and HDL cholesterol were seen in both the presence (r = 0.45, P = 0.03) and absence (r = 0.73, P < 0.001) of CETP. Therefore, under altered metabolic contexts, such as those induced by dietary challenge, the relation between LPL activity and HDL cholesterol may also become evident. Here we have shown that both genetic and environmental factors may modulate the association between LPL activity and HDL cholesterol, and provide explanations for the absence of any changes in HDL values in mice either transgenic or with targeted disruption of the LPL gene.

Animals↗
PubMed1996

Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype.

Huntington disease (HD) is caused by expansion of a CAG trinucleotide repeat in exon 1 of a novel gene. The HD protein (huntingtin) plays a critical role in early embryonic development since homozygous targeted disruption of the murine HD gene results in embryonic lethality by day 7.5. To rescue this phenotype by transgene based huntingtin expression it is therefore essential to express the protein early enough in development in the appropriate cells. Since YAC based transgenes are known to be regulated in an appropriate temporal and tissue-specific manner, we sought to rescue the embryonic lethality by breeding YAC transgenic mice expressing human huntingtin with mice heterozygous for the targeted disruption. We generated viable offspring homozygous for the disrupted murine HD gene but expressing human huntingtin derived from the YAC. This result clearly shows that YAC transgene based expression of huntingtin occurs prior to 7.5 days gestation. Additionally, we show that human huntingtin expression in YAC transgenic mice follows an identical tissue distribution and subcellular localisation pattern as that of the murine endogenous protein and that expression levels of 2-3 times endogenous can be achieved. This shows that human huntingtin under the influence of its native promoter, despite differences to the murine protein, is functional in a murine background and can compensate for loss of the murine protein. These results show that YAC transgenic approaches are a particularly promising route to producing an animal model for disorders associated with CAG expansion.

Animals↗
PubMed1995

Clinical spectrum of adrenal myelolipoma: analysis of 8 tumors in 7 patients.

Adrenal myelolipoma is a rare, benign, and biochemically nonfunctioning tumor. Most patients with adrenal myelolipoma are asymptomatic and the condition is discovered incidentally at autopsy. Review of the literature reveals 70 patients with surgically documented adrenal myelolipoma. We report 7 additional patients with 8 adrenal myelolipomas, of whom 5 underwent surgical removal because of tumor size, unusual imaging features or symptomatology. Of our patients 4 had symptomatic lesions requiring surgical removal, while 1 had an adrenal myelolipoma that was discovered intraoperatively. Of the remaining 2 patients 1 had a small (3 cm.) lesion discovered incidentally on excretory urography and 1 had bilateral adrenal myelolipoma discovered incidentally on computerized tomography.

Adrenal Gland Neoplasms↗
PubMed1993

Isolated lymphoma of genitourinary tract and adrenals.

With the routine use of computed tomographic imaging, intrinsic involvement of the genitourinary tract in newly diagnosed non-Hodgkin's lymphoma is seen in as many as 10 percent of patients. Incidental discovery of an extranodal, extra-lymphatic lesion in the genitourinary tract without clinical or radiographic evidence of disease elsewhere, however, is an uncommon occurrence. The clinical presentation and imaging findings in 4 patients with initial manifestation of lymphoma isolated to the kidney, ureter, bladder, and adrenals, respectively, are presented. These patients had no evidence of lymphoma elsewhere, and imaging studies mimicked the more common neoplasms affecting these organs.

Adrenal Gland Neoplasms↗
PubMed1993

A diabetic rabbit model for pig islet xenotransplantation.

An alloxan-diabetic rabbit model was established for the testing of the function of discordant xenogeneic pig islets isolated and purified from adult pig pancreata. The functional state of the pig islet transplants and immunological state of the rabbit recipients were assessed. Intraportal transplantation of 0.47 +/- 0.01 ml of pig islets with estimated 57418 +/- 5020 in number containing an estimated insulin content of 33.93 +/- 2.97 units (n = 7; mean +/- SEM) resulted in the normalization of blood glucose with a corresponding rise in insulin levels in the diabetic rabbit recipients for 2 days. An intravenous glucose tolerance test performed in 4 recipients during the normoglycemic period resulted in an improved K rate (2.5 +/- 0.4) over the diabetic controls, but this was significantly lower than the normal control animals (K rate = 4.5 +/- 0.4; n = 8). In vitro studies demonstrated that the preformed antibodies detected in the rabbit recipients were cytotoxic to the pig islet cells and lymphocytes. Heat treatment at 56 degrees C and mercaptoethanol treatment markedly reduced the cytotoxic activities of the sera. These findings implicated involvement of complement and IgM class antibodies in the killing of the pig islet cells. Furthermore, pig islet transplants at the kidney capsule site were coated with IgM class antibodies. This study has demonstrated that pig islets can be successfully isolated and purified in sufficient numbers for xenotransplantation studies in alloxan-diabetic rabbit. The porcine islet-to-alloxan diabetic rabbit combination can serve as a highly stringent and useful discordant model for assessing the effectiveness of various immunomodulation and immunosuppressive regimens. The finding of an optimal approach to immunorejection would potentially be applicable to actual clinical islet xenotransplantation in diabetic patients.

Animals↗
PubMed1991

Extent of bladder and ureteric involvement and urologic management in patients with enterovesical fistulas.

A retrospective review of hospital charts from 1978-1989 identified 21 patients with acquired enterovesical fistulas. Nine patients with fistulas secondary to benign inflammatory processes required extensive bladder resection; 2 of these had ureteric involvement. Of the 9 patients requiring extensive bladder resection, necrotic and severely inflamed bladder was excised and the bladder was closed in a multilayered fashion with absorbable sutures. An omental flap was used when possible. Postoperative bladder drainage was maintained for seven to fourteen days. Ureteral involvement was managed by stenting in 1 case and ureteroureterostomy in another. No postoperative bladder leaks or recurrent fistulas were reported. Extensive inflammatory involvement of the bladder wall may necessitate a large vesical resection. Excision of diseased bladder tissue, multilayered closure, and the use of omental interposition may help reduce postoperative complications and the risk of recurrence. Associated ureteral involvement may be present in these patients and requires urologic management.

Female↗
PubMed1988

Clinical and microbiologic effects of local tetracycline irrigation on periodontitis.

This investigation was conducted on seven individuals referred for treatment of moderate adult periodontitis. Twenty-eight sites with an average probing depth of 5.6 +/- 0.9 mm were evaluated. One tooth per jaw quadrant was randomly assigned to receive one of the following treatments: (I) no treatment, i.e., control; (II) saline irrigation; (III) tetracycline irrigation and (IV) scaling and root planing (SC/RP). A plaque control program was instituted one week prior to the experimental period and reinforced throughout the eight-week study. Irrigation was performed every 48 hours during the first two weeks of the experiment for Groups II and III, and the single treatment of SC/RP was carried out immediately following the baseline examination for Group IV. Clinical and microbiologic changes were monitored every two weeks using plaque and gingival indices, gingival fluid flow, probing depths, bleeding on probing and dark-field microscopic examination of the subgingival microbial flora. The tetracycline and SC/RP treatment modalities resulted in statistically significant clinical and microbiological improvements when compared with the control. Tetracycline irrigation alone and SC/RP alone had a similar effect in changing the subgingival microflora from one associated with disease to one associated with health. Thus, these treatment modalities are effective methods of producing statistically significant alterations in the subgingival microflora. The property of substantivity may contribute to the sustained duration of the effect of locally delivered tetracycline.

Adult↗
PubMed1985

The effect of Keyes' method of oral hygiene on the subgingival microflora compared to the effect of scaling and/or surgery.

The present study was conducted on 18 individuals to determine if Keyes' method of oral hygiene would present an alternative to traditional periodontal therapy in terms of establishing a subgingival microflora compatible with periodontal health. Oral hygiene, gingival conditions and subgingival microbial proportions assessed by dark field microscopy were measured at baseline, then once every 2 weeks for the remainder of this 8-week study. In addition, probing depths and bleeding on probing were evaluated. Group I (9 patients) was treated non-surgically, while Group II (9 patients) had received surgical therapy within the last 4 years. Both groups received routine scaling and root planing (Sc/RP) on one arch at time 0, and both were instructed to use Keyes' method of oral hygiene on one side of the mouth while the other side served as a control. This yielded a split-plot experimental design which permitted examination of the effects of Keyes' method of oral hygiene, Sc/RP and surgery. The results revealed no statistically significant differences between Keyes' method of oral hygiene and conventional oral hygiene in patients treated with a single session of Sc/RP. When scaling was not employed, Keyes' method was more effective than conventional oral hygiene. Surgical status was found to be the most significant factor in reducing clinical indicator values and establishing control of the subgingival microflora. In summary, oral hygiene alone had only minimal effects on subgingival microbial proportions. The primary antimicrobial effect observed, as evidenced by shifts in subgingival morphotype proportions, was produced by the Sc/RP procedure. This effect was enhanced by improved access (surgical status).

Adult↗