Anti-HMGB1 antibody reduces weight gain in mice fed a high-fat diet.

Insulin resistance in obesity is believed to be propagated by adipose tissue and liver inflammation. HMGB1 is a multifunctional protein that is pro-inflammatory when released from cells. It has been previously demonstrated that anti-HMGB1 antibody reduces atherosclerotic lesion pro-inflammatory cells and progression of atherosclerosis in a mouse model. To test the potential beneficial role of blocking HMGB1 in adipose tissue and liver inflammation in mice fed an obesogenic diet, we administered anti-HMGB1 antibody to C57Bl/6 mice fed a high (60%)-fat diet. The mice were treated with weekly injections of an anti-HMGB1 antibody or anti-KLH antibody (isotype control) for 16 weeks. Mice that received the anti-HMGB1 antibody gained less weight than the control-treated animals. Anti-HMGB1 treatment also reduced hepatic expression of TNF-alpha and MCP-1, molecules that promote inflammation. However, adipose tissue inflammation, as measured by gene expression analyses and immunohistochemistry, did not differ between the two groups. There also were no differences in glucose or insulin tolerance between the two groups. When feeding mice a high-fat diet, these data suggest that HMGB1 may have a crucial role in weight gain and liver inflammation.

Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice.

BACKGROUND: Obesity is associated with reduced levels of circulating high-density lipoproteins (HDLs) and its major protein, apolipoprotein (apo) A-I. As a result of the role of HDL and apoA-I in cellular lipid transport, low HDL and apoA-I may contribute directly to establishing or maintaining the obese condition. METHODS: To test this, male C57BL/6 wild-type (WT), apoA-I deficient (apoA-I(-/-)) and apoA-I transgenic (apoA-I(tg/tg)) mice were fed obesogenic diets (ODs) and monitored for several clinical parameters. We also performed cell culture studies. RESULTS: ApoA-I(-/-) mice gained significantly more body weight and body fat than WT mice over 20 weeks despite their reduced food intake. During a caloric restriction regime imposed on OD-fed mice, apoA-I deficiency significantly inhibited the loss of body fat as compared with WT mice. Reduced body fat loss with caloric restriction in apoA-I(-/-) mice was associated with blunted stimulated adipose tissue lipolysis as verified by decreased levels of phosphorylated hormone-sensitive lipase (p-HSL) and lipolytic enzyme mRNA. In contrast to apoA-I(-/-) mice, apoA-I(tg/tg) mice gained relatively less weight than WT mice, consistent with other reports. ApoA-I(tg/tg) mice showed increased adipose tissue lipolysis, verified by increased levels of p-HSL and lipolytic enzyme mRNA. In cell culture studies, HDL and apoA-I specifically increased catecholamine-induced lipolysis possibly through modulating the adipocyte plasma membrane cholesterol content. CONCLUSIONS: Thus, apoA-I and HDL contribute to modulating body fat content by controlling the extent of lipolysis. ApoA-I and HDL are key components of lipid metabolism in adipose tissue and constitute new therapeutic targets in obesity.

Influence of serum proteins on conformation of prostate-specific antigen.

Partition behavior of prostate-specific antigen (PSA) was studied in aqueous Dextran-Ficoll two-phase system. It was found that the partitioning of PSA changed in the presence of other proteins, in particular, bovine serum albumin, human serum albumin, human transferrin, and human gamma-globulin. The partition coefficient of PSA in mixtures with increasing amounts of these proteins decreased along the S-shaped curve and dropped to essentially the same value at the 10(4)-10(5) protein: PSA molar ratio. Partition behavior of the above proteins was examined separately. Partition coefficient of a protein represents the protein solvent exposed residues; i.e., it reflects the 3D-structure of the protein in solution. Partition of binary protein mixtures reflects the interaction of the two proteins and therefore characterizes the PSA-induced conformational changes in a protein agent and the change in the PSA conformation induced by a protein agent. In other words, the protein effect on the partition behavior of free PSA may be explained by the effect of the non-specific PSA-protein interactions on PSA conformation. Formation of such PSA-protein encounter complexes was shown to be dominated by the electrostatic forces, since the efficiency of a given protein-agent to induce changes in the partition behavior of PSA was proportional to its absolute mean net charge. Furthermore, in agreement with the earlier hypothesis that the protein segments with increased dynamic propensities (i.e., 'discrete breathers') can be important for conformational transitions accompanying binding processes, our analysis of intrinsically disordered regions (IDR) in all the proteins examined showed that the propensity for intrinsic disorder is related to the PSA partition-modulating capability of the protein.

Chronic insulin therapy reduces adipose tissue macrophage content in LDL-receptor-deficient mice.

AIMS/HYPOTHESIS: Insulin has anti-inflammatory effects in short-term experiments. However, the effects of chronic insulin administration on inflammation are unknown. We hypothesised that chronic insulin administration would beneficially alter adipose tissue inflammation and several circulating inflammatory markers. METHODS: We administered two forms of long-acting insulin, insulin glargine (A21Gly,B31Arg,B32Arg human insulin) and insulin detemir (B29Lys[ε-tetradecanoyl],desB30 human insulin), to LDL-receptor-deficient mice. After 8 weeks on a diet that causes obesity, hyperglycaemia, adipose tissue macrophage accumulation and atherosclerosis, the mice received subcutaneous glargine, detemir or NaCl (control) for 12 weeks. Serum amyloid A (SAA) and serum amyloid P (SAP), metabolic variables, adipose tissue macrophages and aortic atherosclerosis were evaluated. RESULTS: Weight gain was equivalent in all groups. The glycated haemoglobin level fell equivalently in both insulin-treated groups. Plasma cholesterol and triacylglycerol levels, and hepatic triacylglycerol level significantly improved in the glargine compared with the detemir or control groups. Levels of mRNA expression for monocyte chemotactic protein-1 and F4/80, a macrophage marker, in adipose tissue were decreased only in the glargine group (p < 0.05). Visceral adipose tissue macrophage content decreased in both insulin groups (p < 0.05), whereas atherosclerosis decreased only in the glargine group. Circulating SAA and SAP did not decrease in either insulin-treated group, but IL-6 levels fell in the glargine-treated mice. CONCLUSIONS/INTERPRETATION: While chronic insulin administration did not decrease SAA and SAP, administration of glargine but not detemir insulin improved dyslipidaemia, IL-6 levels and atherosclerosis, and both insulins reduced macrophage accumulation in visceral adipose tissue. Thus, chronic insulin therapy has beneficial tissue effects independent of circulating inflammatory markers in this murine model of diet-induced obesity and diabetes.

Quantitative structure-activity relationship studies of TIBO derivatives using support vector machines.

A quantitative structure-activity relationship (QSAR) study is suggested for the prediction of anti-HIV activity of tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepinone (TIBO) derivatives. The model was produced by using the support vector machine (SVM) technique to develop quantitative relationships between the anti-HIV activity and ten molecular descriptors of 89 TIBO derivatives. The performance and predictive capability of the SVM method were investigated and compared with other techniques such as artificial neural networks and multiple linear regression. The results obtained indicate that the SVM model with the kernel radial basis function can be successfully used to predict the anti-HIV activity of TIBO derivatives with only ten molecular descriptors that can be calculated directly from only molecular structure. The contribution of each descriptor to the structure-activity relationships was evaluated. Hydrophobicity of the molecule was thus found to take the most relevant part in the molecular description.

The effect of essential oils from Thymus broussonetii Boiss on transmission of Toxoplasma gondii cysts in mice.

In this study, we have evaluated the effect of essential oils of Thymus broussonetii Boiss, an endemic plant of Morocco in experimental transmission of Toxoplasma gondii cysts in mice. These oils were obtained by hydrodistillation and were administered to mice at 20 microg/animal orally at the time of infection and for several days thereafter. This resulted in total absence of intracerebral cysts in mice who received the essential oils signifying that these essential oils of thyme have a blocking effect on the appearance of the cysts. In addition, no abnormality was observed in the control mice who received the essential oils of thyme.

SAA and PLTP activity in plasma of periodontal patients before and after full-mouth tooth extraction.

OBJECTIVE: To assess whether treatment of advanced periodontal disease affects plasma levels of serum amyloid A (SAA) and phospholipid transfer protein (PLTP) activity. DESIGN: We measured the levels of SAA and PLTP activity in plasma of 66 patients with advanced periodontal disease before and after treatment by full-mouth tooth extraction (FME). RESULTS: At baseline, median SAA levels in our study population were within the normal range (2.7 microg ml(-1)) but SAA was elevated (>5 microg ml(-1)) in 18% of periodontitis patients. Three months after FME, SAA levels were significantly reduced (P = 0.04). SAA did not correlate with any of the periodontal disease parameters. PLTP activity was elevated in patients with periodontitis, compared to the PLTP activity reference group (age-matched systemically healthy adults, n = 29; 18 micromol ml(-1) h(-1)vs 13 micromol ml(-1) h(-1), respectively, P = 0.002). PLTP activity inversely correlated with average periodontal pocket depth (PPD) per tooth (r(s) = -0.372; P = 0.002). Three months after FME, median PLTP activity did not change significantly. CONCLUSIONS: Full-mouth tooth extraction significantly reduces SAA, a marker of inflammation, while it does not affect plasma PLTP activity. However, the inverse correlation between PLTP activity and average PPD suggests that increased PLTP activity may limit periodontal tissue damage.

Cytotoxic effect of essential oil of thyme (Thymus broussonettii) on the IGR-OV1 tumor cells resistant to chemotherapy

The anti-tumor effect of the Moroccan endemic thyme (Thymus broussonettii) essential oil (EOT) was investigated in vitro using the human ovarian adenocarcinoma IGR-OV1 parental cell line OV1/P and its chemoresistant counterparts OV1/adriamycin (OV1/ADR), OV1/vincristine (OV1/VCR), and OV1/cisplatin (OV1/CDDP). All of these cell lines elicited various degrees of sensitivity to the cytotoxic effect of EOT. The IC50 values (mean ± SEM, v/v) were 0.40 ± 0.02, 0.39 ± 0.02, 0.94 ± 0.05, and 0.65 ± 0.03 percent for OV1/P, OV1/ADR, OV1/VCR, and OV1/CDDP, respectively. Using the DBA-2/P815 (H2d) mouse model, tumors were developed by subcutaneous grafting of tumor fragments of similar size obtained from P815 (murin mastocytoma cell line) injected in donor mouse. Interestingly, intra-tumoral injection of EOT significantly reduced solid tumor development. Indeed, by the 30th day of repeated EOT treatment, the tumor volumes of the animals were 2.00 ± 0.27, 1.35 ± 0.20, and 0.85 ± 0.18 cm³ after injection with 10, 30, or 50 æL per 72 h (six times), respectively, as opposed to 3.88 ± 0.50 cm³ for the control animals. This tumoricidal effect was associated with a marked decrease of mouse mortality. In fact, in these groups of mice, the recorded mortality by the 30th day of treatment was 30 ± 4, 18 ± 4, and 8 ± 3 percent, respectively, while the control animals showed 75 ± 10 percent of mortality. These data indicate that the EOT which contains carvacrol as the major component has an important in vitro cytotoxic activity against tumor cells resistant to chemotherapy as well as a significant antitumor effect in mice. However, our data do not distinguish between carvacrol and the other components of EOT as the active factor.

Cytotoxic effect of essential oil of thyme (Thymus broussonettii) on the IGR-OV1 tumor cells resistant to chemotherapy.

The anti-tumor effect of the Moroccan endemic thyme (Thymus broussonettii) essential oil (EOT) was investigated in vitro using the human ovarian adenocarcinoma IGR-OV1 parental cell line OV1/P and its chemoresistant counterparts OV1/adriamycin (OV1/ADR), OV1/vincristine (OV1/VCR), and OV1/cisplatin (OV1/CDDP). All of these cell lines elicited various degrees of sensitivity to the cytotoxic effect of EOT. The IC50 values (mean +/- SEM, v/v) were 0.40 +/- 0.02, 0.39 +/- 0.02, 0.94 +/- 0.05, and 0.65 +/- 0.03% for OV1/P, OV1/ADR, OV1/VCR, and OV1/CDDP, respectively. Using the DBA-2/P815 (H2d) mouse model, tumors were developed by subcutaneous grafting of tumor fragments of similar size obtained from P815 (murin mastocytoma cell line) injected in donor mouse. Interestingly, intra-tumoral injection of EOT significantly reduced solid tumor development. Indeed, by the 30th day of repeated EOT treatment, the tumor volumes of the animals were 2.00 +/- 0.27, 1.35 +/- 0.20, and 0.85 +/- 0.18 cm(3) after injection with 10, 30, or 50 microL per 72 h (six times), respectively, as opposed to 3.88 +/- 0.50 cm(3) for the control animals. This tumoricidal effect was associated with a marked decrease of mouse mortality. In fact, in these groups of mice, the recorded mortality by the 30th day of treatment was 30 +/- 4, 18 +/- 4, and 8 +/- 3%, respectively, while the control animals showed 75 +/- 10% of mortality. These data indicate that the EOT which contains carvacrol as the major component has an important in vitro cytotoxic activity against tumor cells resistant to chemotherapy as well as a significant antitumor effect in mice. However, our data do not distinguish between carvacrol and the other components of EOT as the active factor.

Anti-tumor properties of blackseed (Nigella sativa L.) extracts.

The objective of the present study was to evaluate the in vitro and in vivo anti-cancer effect of Nigella sativa L. seed extracts. The essential oil (IC50 = 0.6%, v/v) and ethyl acetate (IC50 = 0.75%) extracts were more cytotoxic against the P815 cell line than the butanol extract (IC50 = 2%). Similar results were obtained with the Vero cell line. Although all extracts had a comparable cytotoxic effect against the ICO1 cell line, with IC50 values ranging from 0.2 to 0.26% (v/v), tests on the BSR cell line revealed a high cytotoxic effect of the ethyl acetate extract (IC50 = 0.2%) compared to the essential oil (IC50 = 1.2%). These data show that the cytotoxicity of each extract depends on the tumor cell type. In vivo, using the DBA2/P815 (H2d) mouse model, our results clearly showed that the injection of the essential oil into the tumor site significantly inhibited solid tumor development. Indeed, on the 30th day of treatment, the tumor volume of the control animals was 2.5 +/- 0.6 cm(3), whereas the tumor volumes of the essential oil-treated animals were 0.22 +/- 0.1 and 0.16 +/- 0.1 cm(3) when the animals were injected with 30 microL (28.5 mg)/mouse and 50 microL (47.5 mg)/mouse per 48 h (six times), respectively. Interestingly, the administration of the essential oil into the tumor site inhibited the incidence of liver metastasis development and improved mouse survival.

Anti-tumor properties of blackseed (Nigella sativa L. ) extracts

The objective of the present study was to evaluate the in vitro and in vivo anti-cancer effect of Nigella sativa L. seed extracts. The essential oil (IC50 = 0.6 percent, v/v) and ethyl acetate (IC50 = 0.75 percent) extracts were more cytotoxic against the P815 cell line than the butanol extract (IC50 = 2 percent). Similar results were obtained with the Vero cell line. Although all extracts had a comparable cytotoxic effect against the ICO1 cell line, with IC50 values ranging from 0.2 to 0.26 percent (v/v), tests on the BSR cell line revealed a high cytotoxic effect of the ethyl acetate extract (IC50 = 0.2 percent) compared to the essential oil (IC50 = 1.2 percent). These data show that the cytotoxicity of each extract depends on the tumor cell type. In vivo, using the DBA2/P815 (H2d) mouse model, our results clearly showed that the injection of the essential oil into the tumor site significantly inhibited solid tumor development. Indeed, on the 30th day of treatment, the tumor volume of the control animals was 2.5 ± 0.6 cm³, whereas the tumor volumes of the essential oil-treated animals were 0.22 ± 0.1 and 0.16 ± 0.1 cm³ when the animals were injected with 30 µL (28.5 mg)/mouse and 50 µL (47.5 mg)/mouse per 48 h (six times), respectively. Interestingly, the administration of the essential oil into the tumor site inhibited the incidence of liver metastasis development and improved mouse survival.

Study on the antinociceptive effects of Thymus broussonetii Boiss extracts in mice and rats.

In Morocco, Thymus broussonetii is widely used in folk medicine for the treatment of a variety of diseases including gastroenteric and bronchopulmonary disorders and to relieve dolorous process. The antinociceptive effect of the aqueous, butanolic and ethyl acetate extracts of this species was examined in rats and mice using chemical and thermal models. The results obtained showed that aqueous and butanolic extracts exerted an antinociceptive activity in the two phases of formalin (50-300 mg/kg), tail immersion and writhing tests. Whereas, the ethyl acetate extract reduced the nociceptive response only in the second phase of formalin (100-300 mg/kg) and writhing tests. The aqueous extract, which is the most effective, contains active analgesic principles acting both centrally and peripherally. Furthermore, this antinociceptive effect has been avoided by naloxone at a dose of 1mg/kg in the first phase of formalin and hot plate tests indicating that this extract acts partly through an opioid-mediated mechanism. The present results demonstrated that Thymus broussonetii contains active constituents which possess antinociceptive activity justifying its popular use to relieve some pains.

Seroprevalence of T. gondii in sheep from Marrakech, Morocco.

Toxoplasma gondii is a ubiquitous intracellular protozoan parasite transmitted by food. Concerning this parasite, there are few studies done in Morocco. In this study, 261 sera from sheep intended for consumption in Marrakech were subjected to the Toxoplasma ELISA based serology test for the detection of anti-T. gondii specific IgG confirming a past infection. Of the total tested 72 (27.6%) sera were positive for IgG. This result shows that the seroprevalence approaches the world average and is similar to what is found in other cities of Morocco. This has prompted us to investigate other animal species in the region in order to evaluate the degree of contamination by this parasite as well as the potential risk incurred on consumption of their meat.

Stochastic diffusion interactions and coarsening in a system of droplets growing from a supersaturated gas mixture.

In this work we study diffusion interactions among liquid droplets growing in stochastic population by condensation from supersaturated binary gas mixture. During the postnucleation transient regime collective growth of liquid droplets competing for the available water vapor decreases local supersaturation leading to the increase of critical radius and the onset of coarsening process. In coarsening regime the growth of larger droplets is prevailing noticeably broadening the droplet size-distribution function when the condensation process becomes more intensive than the supersaturation yield. Modifications in the kinetic equation are discussed and formulated for a stochastic population of liquid droplets when diffusional interactions among droplets become noteworthy. The kinetic equation for the droplet size-distribution function is solved together with field equations for the mass fraction of disperse liquid phase, mass fraction of water vapor component of moist air, and temperature during diffusion-dominated regime of droplet coarsening. The droplet size and mass distributions are found as functions of the liquid volume fraction, showing considerable broadening of droplet spectra. It is demonstrated that the effect of latent heat of condensation considerably changes coarsening process. The coarsening rate constant, the droplet density (number of droplets per unit volume), the screening length, the mean droplet size, and mass are determined as functions of the temperature, pressure, and liquid volume fraction.

Phase transition dynamics of liquid phase precipitation from a supersaturated gas mixture.

This work presents a self-consistent description of phase transition dynamics of disperse liquid phase precipitating from a supersaturated gas mixture. The unified approach integrates the macroscale transport phenomena of cloud dynamics with the essential microphysical kinetic processes of droplet condensation, evaporation, and droplet collisions simultaneously taking place in stochastic population of liquid droplets. A complete set of governing equations with well-defined dissipative fluxes and kinetic rates is derived for phase transition dynamics from nucleation to postnucleation to coarsening stages. The local thermodynamics of precipitating system, which is considered as ternary mixture of disperse liquid phase and water vapor with dry air, is redefined to explicitly include on equal basis both the vapor content and liquid content into the fundamental thermodynamic relations and equation of state. The molecular kinetic flux regularization method for growth of submicron droplets is reexamined to include, among others, significant contribution of vapor molecular energy flux into total heat flux, resulting in new expressions for the droplet temperature, growth rate, and effective diffusion coefficients. The local kinetic rates are determined on the basis of microscale kinetic equation for the droplet distribution function. This is in contrast to commonly used semiempirical parametrization schemes for kinetic rates with adjustable parameters, wherein the probabilistic aspects of microphysical processes are not rigorously addressed. Stochastic diffusion interactions among droplets competing for the available water vapor and modifications in the kinetic equation for droplets growing in stochastic population with direct long-range diffusion interactions amongst them are discussed and formulated as well.

Postnucleation droplet growth in supersaturated gas with arbitrary vapor concentration.

This work concerns the reexamination and extension of the current theory of phase transition dynamics for liquid droplets growing on soluble aerosols from a supersaturated gas mixture for the general case of arbitrary value of vapor concentration. We found that the inconsistency in the common treatment of the vapor diffusion, due to an implicit assumption of the constancy of gas density in the vicinity of a droplet by neglecting its dependency on temperature and vapor concentration, leads to the obvious discrepancy in the Maxwell expression for the growth rate regarding droplets of near critical size. Restoring the correct treatment of the vapor diffusion in terms of the mass concentration of water vapor and taking into the consideration variations of gas density in the vicinity of a droplet in compliance with the equation of state of moist air, we have obtained a new expression for the droplet growth rate valid for an arbitrary value of vapor concentration. The limitations imposed by the molecular kinetic fluxes to postnucleation diffusional growth of small droplets with a large Knudsen number are also reevaluated to include previously neglected physical effects. In particular, the essential contribution of the vapor molecular energy flux into the total kinetic molecular heat flux as well as the temperature variations of mean thermal velocities of air and vapor molecules in the vicinity of the droplet interface have been taken into consideration. Surprisingly significant differences have been found in new expressions derived for the droplet growth rate and droplet temperature, even in the limit of small vapor concentration, if comparing with commonly used results. These findings could help with better interpretation of experimental measurements to infer more reliable data for the mass and thermal accommodations coefficients.

Thiazolidinediones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans.

AIMS/HYPOTHESIS: Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding. METHODS: Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined. RESULTS: Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells. CONCLUSIONS/INTERPRETATION: Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.

Impact of nitrate intake in drinking water on the thyroid gland activity in male rat.

The purpose of this study was to determine the effects of nitrate on both the activity of the thyroid gland and other biological parameters. After 5-month treatment, nitrate 150 and 500 mg/l induced a significant decrease in the serum level of thyroid hormone T3. For T4, the 500 mg/l dose only reduced its plasma level. On the other hand, nitrate induced a dose-dependent increase in the weight of the thyroid gland. The histological study of the thyroid gland shows vacuolisation and an increase in the size of the follicles accompanied by a flatness of follicular epithelium with nitrate 150 and 500 mg/l. We concluded that the presence of high concentrations of nitrate in drinking water influence the growth, induce morpho-functional modifications of the thyroid gland and might be considered as a goitrigenic factor.

[Toxoplasma gondii: level of carriage in sheep of Marrakech region (Mnabha)]. / Toxoplasma gondii: taux de portage chez les ovins de la région de Marrakech (Mnabha).

Toxoplasma gondii is an ubiquitous parasite with a prevalence variable from country to country. In Morocco very few studies were devoted to this prevalence. To fill this gap we were interested to study the epidemiology of this parasite and to know the level of carriage by the different vectors which are the sources of contamination in humans. The study was done by directly detecting the cysts in the cerebral tissue of the 50 sheep killed and destined for consumption. The results of this preliminary study show that 30% of the cases carry the cysts of T. gondii. To confirm this result and verify the virulence, cerebral specimens were inoculated into mice. These findings are encouraging to complete this study with serological tests and to look for the parasite in cows and goats of this region.

The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice.

AIMS/HYPOTHESIS: Islet amyloid deposits are present in over 85% of Type 2 diabetic patients and have been suggested to be pathogenic. The mechanism that converts islet amyloid polypeptide (IAPP), the unique component of these deposits, into amyloid fibrils in vivo is not known. The amino acid sequence of IAPP is critical but insufficient for beta-pleated sheet formation. As apolipoprotein E (apoE), another component of islet amyloid deposits, plays a critical role in amyloid formation in Alzheimer's disease, we hypothesised that apoE could play an important role in islet amyloid formation. METHODS: Transgenic mice expressing the human form of IAPP ( hIAPP (+/0)) were crossbred with apoE deficient ( apoE (-/-)) mice and followed for 12 months, at which time the prevalence and severity of islet amyloid, as well as plasma glucose, hIAPP, immunoreactive insulin (IRI) and lipid concentrations were measured. RESULTS: The prevalence and severity of islet amyloid after one year of follow up were comparable among hIAPP (+/0) mice that were apoE (+/+), apoE (+/-) or apoE (-/-). Differences in glucose tolerance, lipid abnormalities or changes in pancreatic content or plasma concentrations of hIAPP and/or IRI did not account for these findings. CONCLUSION/INTERPRETATION: Our data shows that, unlike in the localized amyloidosis in the brain characteristic of Alzheimer's disease, apoE is not critical for islet amyloid formation in a transgenic mouse model of Type 2 diabetes mellitus. These results indicate that the mechanisms of localised amyloid formation probably vary among different amyloid-associated disorders. Therefore, therapeutic strategies targeting apoE might not apply equally to patients with different amyloid associated diseases.