Insulin growth factor inhibitor as a potential new anti-schistosoma drug: An in vivo experimental study.

BACKGROUND AND OBJECTIVE: Tyrphostin "AG1024" is an insulin growth factor-1 receptor (IGF-1R) inhibitor that displayed an effect on the viability of larval and mature schistosomes in vitro. We sought to investigate the possible in vivo role of AG1024 as a potential new anti-Schistosoma drug against immature and adult stages of Schistosoma mansoni and its effect on the degree of hepatic fibrosis and insulin pathway. METHODS: The study included a control non-infected group and 5 groups of S. manosoni-infected CD-1 albino mice (20 mice each) assigned to treatment as follows: vehicle-treated, early AG1024, 30µg/100µl DMSO, IP for 10days started 30days post-infection (dpi), early praziquantel (PZQ), 500mg/kg orally for 2days (30dpi), late AG1024 (60dpi), and late PZQ (60dpi). All mice were sacrificed 12 weeks post-infection. Parasitological, chemical and histopathological parameters were studied. Immunohistochemistry of TGF-ß and GLUT4 in liver sections was done to further evaluate the effect of AG1024 on the degree of hepatic fibrosis and insulin signaling pathway, respectively. RESULTS: Early administration of AG1024 (30dpi) resulted in significant reduction of hepatic and intestinal tissue egg count with a reduction of 79.99% and 89.1% respectively. Late administration of AG1024 (60dpi) led to 77.78% reduction of intestinal eggs count; however, hepatic egg count wasn't reduced significantly. No reduction in worm burden was recorded for both administration regimens. Both regimens lead to significant decrease of both ALT and AST, mean hepatic granuloma diameter but an increase in fibrosis percentage (65.2% and 55% respectively). Both early and late treatment with AG1024 showed a significant increment of TGF-ß expression by 71.4% and 39.3%, respectively (p<0.0001) compared to PZQ-treated and infected non-treated groups. Hepatic GLUT4 expression was significantly decreased compared to infected non-treated group (p<0.001) and the corresponding PZQ-treated group. CONCLUSION: Early AG1024 administration induced more significant results compared to early PZQ with a promising activity against egg production and subsequent reduction of tissue egg load rather than direct schistosomicidal effect; however, it induced granuloma fibrosis, TGF-ß expression, and disrupted the insulin signaling pathway.

Possible antifibrotic effect of GDC-0449 (Vismodegib), a hedgehog-pathway inhibitor, in mice model of Schistosoma-induced liver fibrosis.

Liver fibrosis is a pathological process complicating schistosomiasis. It is an active process of continuous extracellular matrix accumulation. In Egypt, schistosomiasis re-infection is a continuing problem especially in rural areas. In this study we examined the antifibrotic effect of GDC-0449 (Vismodegib), a hedgehog-pathway inhibitor as a new molecular target for Schistosoma-induced liver fibrosis, in addition to exploring its effect as antischistosomal drug. The effect of GDC-0449 alone or combined with Praziquantel was tried experimentally in infected mice with Schistosoma mansoni. Fifty CD-1 Swiss female albino mice were used, forty mice were infected with Schistosoma mansoni cercariae. Animals were grouped into five groups; uninfected control, infected untreated, infected treated with Praziquantel (500mg/kg/day) for two days, infected treated with GDC-0449 (40mg/kg/day) for seven days, and infected treated with combined Praziquantel and GDC-0449. Parasitological and chemical parameters, hydroxyproline level and liver granuloma were assessed. Liver fibrosis was reduced significantly evidenced by reduced hydroxyproline levels [P<0.01 for combined (Praziquantel/GDC-0449) treatment groups, P<0.001 for GDC-0449-treated group]. Also, histopathological examination of liver tissues revealed that the mean diameter of granulomas was statistically reduced (P=0.001) with a reduction rate of 24.4% on treatment with GDC-0449. In GDC-0449/Praziquantel combined treatment group, number and mean diameter of the granulomas were reduced significantly P<0.001, and P=0.001 respectively. No antischistosomal effect was recorded for GDC-0449 in this study.

Anti-Toxoplasma antibodies in Egyptian rheumatoid arthritis patients.

OBJECTIVE: To assess seroprevalence of anti-Toxoplasma gondii antibodies; both IgG and IgM in Egyptian rheumatoid arthritis (RA) patients versus a non-RA group and to compare anti-Toxoplasma antibodies seroprevalence among RA patients receiving traditional treatment and RA patients treated with biologic drug. METHODS: 60 RA patients and 60 healthy controls were enrolled in the study. Patients were categorized into two groups: one group included 30 patients receiving disease modifying anti-rheumatic drugs (DMARDs), while the other group included 30 patients receiving biologic agent, infliximab, a TNF-α antagonist. Serum samples of all investigated persons were examined for anti-Toxoplasma antibodies. RA activity markers including rheumatoid factor, anti-cyclic citrullinated protein antibodies, C reactive protein, ESR in addition to disease activity score 28 (DAS28) of RA patients were also evaluated to explore their association with Toxoplasma seropositivity. RESULTS: Anti-Toxoplasma IgG antibodies were detected among 46/60 RA patients (76.7%) versus 29/60 controls (48.3%), (p = 0.001). Anti-Toxoplasma IgG titre was higher among RA group [median, (range) = 232.940 (8.949-653.242) IU/ml] than among controls [median, (range) = 68.820 (2.450-318.945) IU/ml], (p < 0.001). No difference was detected among RA patients either on traditional or biologic treatment regarding anti-Toxoplasma IgG antibodies. No positive anti-Toxoplasma IgM was detected. A positive correlation was detected between anti-Toxoplasma IgG titre and disease activity markers. CONCLUSION: Higher seroprevalence of anti-Toxoplasma IgG antibodies among RA patients compared to controls reflects an association between latent Toxoplasma infection and RA. Our findings support previous studies and necessitate future large-scale studies to elucidate the exact role of Toxoplasma whether a trigger of autoimmunity in RA or an effect of immunosuppression.

Effect of Ascaris lumbricoides infection on T helper cell type 2 in rural Egyptian children.

Ascaris lumbricoides is a neglected parasite that induces changes in host immune response. This study is conducted to define the serum levels of tumor necrosis factor alpha (TNF-α), interleukin-4 (IL-4), and interleukin-5 (IL-5) in some Egyptian children and their relations to intensity of infection, age, and ascariasis symptoms. Stool samples were examined using formol-ether concentration and Kato-Katz thick smear techniques. Sera of 60 A. lumbricoides-infected children and 20 controls were tested by enzyme-linked immunosorbent assay. The mean sera concentrations of TNF-α, IL-4, and IL-5 were 7.41±2.5 pg/mL, 107.60±18.3 pg/mL, and 389.52±28.0 pg/mL, respectively. The controls had mean serum TNF-α 7.10±2.4 pg/mL, IL-4 25.49±2.6 pg/mL, and IL-5 88.76±22.7 pg/mL. The difference in the concentration of sera cytokines was statistically significant for IL-4 and IL-5 (P<0.01) between A. lumbricoides-infected children and controls. The intensity of infection correlated positively with IL-4 and IL-5 at r=0.959 and r=0.919, respectively. The concentrations of IL-4 and IL-5 correlated positively with the age at r=0.845 and r=0.934, respectively. Asthma and gastrointestinal tract upsets were correlated positively with IL-4 and IL-5. These data indicate that A. lumbricoides infection in our locality is associated with significantly high levels of IL-4 and IL-5.

Study of ambulatory blood pressure in diabetic children: prediction of early renal insult.

BACKGROUND: Hypertension is a highly prevalent risk factor for cardiovascular disease in patients with type 1 diabetes mellitus. Elevated blood pressure (BP) promotes the development and progression of microvascular complications, eg, nephropathy and retinopathy. The purpose of this study was to identify and detect early BP changes in diabetic children and adolescents, aiming for the early prediction of future renal and cardiovascular disease risk during childhood. METHODS AND MATERIALS: Ambulatory BP monitoring was undertaken for 40 normotensive type 1 diabetic children with mean age of 11.56±2.82 years, and 24 healthy children as control group with matched age and sex. Albumin/creatinine ratio and glycated hemoglobin were tested. BP indices and standard deviation scores were calculated using reference standards. The data were analyzed by SPSS software version 20 using mean and standard deviations for descriptive data. Correlation and regression analysis tests were used to study relations between BP indices and diabetic parameters. RESULTS: All parameters of BP z-scores were highly significantly increased in diabetic patients compared with controlled group (P<0.0001). The frequency of non-dipping was greater and highly significant in microalbuminuric diabetic patients (P<0.0001). Regression analysis revealed that BP parameters were significantly related to albumin/creatinine ratio, glycated hemoglobin, insulin dose, and body mass index. CONCLUSION: Our observation revealed a clear link between the nocturnal BP and microalbuminuria which mandates BP follow-up via ambulatory BP monitoring with therapeutic intervention to prevent renal and cardiovascular diabetic complications in adulthood.

Cryptosporidium parvum infection among Egyptian school children.

The present study determined cryptosporidiosis among 120 randomly chosen school children aged 4-16 years. Medical sheets were filled out on each child. The fresh stool samples were examined by using Sheather's sugar flotation stained with modified Ziehl Neelsen stain. Blood samples were examined by ELISA and IFA techniques. The results revealed that, the prevalence rate was 13.51% with a peak among the age group (5-10) and. significant relation between males and females. There was a significant relation between infection and low socio-economic level in rural area. Also, a significant relation was obtained between the infection and the presence of animal contact. Watery and loose diarrhea was more significant among infected children. Positive stool samples were among 37 (30.8 %), while ELISA and IFA detected 30 (25%) and 33 (27.5%) respectively. The validity test of ELISA declared sensitivity and specificity with 93.3% and 90% while IFA declared 90.9% and 91.1% respectively.