Retrospective Analysis of Canadian Adults with Tuberous Sclerosis Complex.

BACKGROUND: Our study goal was to characterize the relative frequencies of molecular and phenotypic traits of tuberous sclerosis complex (TSC) in a Canadian adult population. Previous studies have sought to identify TSC-related genotypic and phenotypic trends in pediatric cohorts, but little is known about clinical manifestations and severity when it presents in adults. METHODS: We conducted a retrospective chart review of adult patients seen at the TSC clinic at the University Health Network genetics clinics (Toronto, Ontario) to compare trends in the relative frequency of TSC manifestations with genotype. RESULTS: Fifty-one patients were eligible for this study. Eight patients had a pathogenic/likely pathogenic variant in the tuberous sclerosis complex 1 (TSC1) gene, 18 had a tuberous sclerosis complex 2 (TSC2) pathogenic/likely pathogenic variant, 6 patients had multiple variants identified in TSC1/TSC2 or TSC2/PKD1, 11 had no mutation identified (NMI) and 8 had no genetic testing done. Patients with a pathogenic/likely pathogenic variant in TSC2 presented with an increased involvement of multiple systems and a higher frequency of TSC-related manifestations relative to the other mutation groups. CONCLUSION: Previous studies comparing the wide phenotypic variability with TSC genotype have mainly comprised pediatric cohorts. With a focus on adults, we found trends to be similar across previous literature. An informed multidisciplinary approach should be taken to ensure proper surveillance and management of adults with TSC until a correlation between genotype and phenotype, especially past infancy, is better understood.

Labour induction with 25 micrograms versus 50 micrograms intravaginal misoprostol in full term pregnancies.

We undertook this study in order to compare the efficacy of 25 microg versus 50 microg of intravaginal misoprostol for cervical ripening and labour induction at term. The study population consisted of 120 women with term singleton pregnancies in vertex presentation booked for caesarean section. They had a Bishop scoring of <6 and a reactive fetal heart rate tracing. They were randomized into two groups, A and B, to receive 25 microg and 50 microg of vaginal misoprostol, respectively, 4 hourly with a maximum of five doses until the patient had three contractions in 10 minutes. There was no significant difference in the induction delivery interval between the two groups (12.52+/- 7.05 h in the 25 microg group versus 11.72+/- 6.74 h in the 50 microg group; P = 0.58). Of the women in the 25 microg group, 83.3% delivered vaginally as did 71.67% of those in the 50 microg group, but the difference was not statistically significant (P = 0.128). There were significantly more women requiring oxytocin augmentation in the 25 microg group than in the 50 microg group (P = 0.03). However, there were no significant differences in the rates of caesarean and operative vaginal delivery, meconium stained liquor, fetal distress or in the incidences of hyperstimulation between the two groups. Neonatal outcomes were similar. The intravaginal administrations of 25 microg, as well as 50 microg of misprostol, are equally efficacious in inducing labour. The 25 microg group more often required oxytocin as an adjunct.

A rare case of cervical tuberculosis simulating carcinoma cervix: a case report.

BACKGROUND: This is an unusual case of a 26-year-old P2L2 lady who presented with chief complaints of pain abdomen and irregular bleeding p/v with history of post-coital bleeding. CASE REPORT: On per speculum examination, cervix was replaced by an irregular friable growth, which was bleeding on touch. A clinical diagnosis of carcinoma cervix was made but the cervical biopsy revealed granulomatous inflammation with presence of acid-fast bacilli on cervical smear consistent with tuberculosis. The patient responded to six months of anti-tubercular therapy. CONCLUSION: To conclude, cervical tuberculosis should be considered in the differential diagnosis of carcinoma cervix in young women with suspicious cervix.

Is Porphyromonas gingivalis cell invasion required for atherogenesis? Pharmacotherapeutic implications.

Various studies have demonstrated an association between chronic bacterial infections and atherosclerotic cardiovascular disease. Porphyromonas gingivalis, which can invade endothelial cells, is one pathogen that may link these disorders. If so, antibiotics that block its invasiveness may ameliorate atherosclerotic plaque progression. To explore the role of invasion of P. gingivalis in inflammation- and infection-associated atherosclerosis, 10-wk-old ApoE(+/-) mice were fed either a high fat diet or a regular chow diet. All mice were inoculated i.v., once per week for 24 consecutive wk, with either 50 microl of live P. gingivalis (strain 381) (10(7) CFU); a fimbria-deficient P. gingivalis; or metronidazole before P. gingivalis. Mice were euthanized and evaluated 24 wk after the first inoculation. ApoE(+/-) mice injected with DPG3 or metronidazole showed significantly fewer atheromatous lesions in the proximal aorta and the aortic tree compared with ApoE(+/-) mice injected with wild-type P. gingivalis for either diet condition. Serum amyloid A levels were significantly lower in ApoE(+/-) mice that received either DPG3 or metronidazole before P. gingivalis than from ApoE(+/-) mice that received P. gingivalis alone. Serum cytokine analysis revealed decreased levels of proinflammatory cytokines in both DPG3-injected and metronidazole/P. gingivalis-treated ApoE(+/-) mice compared with mice receiving only P. gingivalis, irrespective of diet. P. gingivalis invasion is a critical phenomenon in the progression of atherosclerosis. The present data offer new insights into the pathophysiological pathways involved in atherosclerosis and pave the way for new pharmacological interventions aimed at reducing atherosclerosis.

Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings.

BACKGROUND: Accumulating evidence implicates a fundamental link between the immune system and atherosclerosis. Toll-like receptors are principal sensors of the innate immune system. Here we report an assessment of the role of the TLR2 pathway in atherosclerosis associated with a high-fat diet and/or bacteria in ApoE(+/-) mice. METHODS AND RESULTS: To explore the role of TLR2 in inflammation- and infection-associated atherosclerosis, 10 week-old ApoE(+/-)-TLR2(+/+), ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice were fed either a high fat diet or a regular chow diet. All mice were inoculated intravenously, once per week for 24 consecutive weeks, with 50 microl live Porphyromonas gingivalis (P.g) (10(7) CFU) or vehicle (normal saline). Animals were euthanized 24 weeks after the first inoculation. ApoE(+/-)-TLR2(+/+) mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice for all diet conditions. They also displayed profound changes in plaque composition, as evidenced by increased macrophage infiltration and apoptosis, increased lipid content, and decreased smooth muscle cell mass, all reflecting an unstable plaque phenotype. SAA levels from ApoE(+/-)-TLR2(+/+) mice were significantly higher than from ApoE(+/-)-TLR2(+/-) and ApoE(+/-)-TLR2(-/-) mice. Serum cytokine analysis revealed increased levels of pro-inflammatory cytokines in ApoE(+/-)-TLR2(+/+) mice compared to ApoE(+/-)-TLR2(+/-) and TLR2(-/-) mice, irrespective of diet or bacterial challenge. ApoE(+/-)-TLR2(+/+) mice injected weekly for 24 weeks with FSL-1 (a TLR2 agonist) also demonstrated significant increases in atherosclerotic lesions, SAA and serum cytokine levels compared to ApoE(+/-)-TLR2(-/-) mice under same treatment condition. Finally, mass-spectrometry (MALDI-TOF-MS) of aortic samples analyzed by 2-dimensional gel electrophoresis differential display, identified 6 proteins upregulated greater than 2-fold in ApoE(+/-)-TLR2(+/+) mice fed the high fat diet and inoculated with P.g compared to any other group. CONCLUSION: Genetic deficiency of TLR2 reduces diet- and/or pathogen-associated atherosclerosis in ApoE(+/-) mice, along with differences in plaque composition suggesting greater structural stability while TLR-2 ligand-specific activation triggers atherosclerosis. The present data offers new insights into the pathophysiological pathways involved in atherosclerosis and paves the way for new pharmacological interventions aimed at reducing atherosclerosis.

Atheroprotective role of interleukin-6 in diet- and/or pathogen-associated atherosclerosis using an ApoE heterozygote murine model.

BACKGROUND: Pathogens have been implicated in the pathogenesis of inflammatory atherosclerosis. Given the pleiotropic role of interleukin-6 in the regulation of cytokines, lipid homeostasis, vascular remodeling, and apoptosis we hypothesized that IL-6 plays an important role in development and progression to inflammatory atherosclerosis. METHODS AND RESULTS: To explore the role of IL-6 in inflammation- and infection-associated atherosclerosis, 10-week-old ApoE(+/-)-IL-6(+/-) and ApoE(+/-)-IL-6(-/-) mice fed either high fat diet or regular chow diet were inoculated intravenously, once per week for 14 or 24 consecutive weeks with 50 microl live Porphyromonas gingivalis (P.g.) (10(7)CFU) or vehicle (normal saline). Animals were euthanized at 24 weeks of age (14 weeks injection) or 34 weeks of age (24 weeks injection). Histomorphometric analysis of atheromatous lesions, en face analysis over the aortic tree, immunohistochemistry for macrophages and smooth muscle cell, TUNEL staining for apoptotic cells, serum amyloid A (SAA) levels, serum lipids and glucose level, serum cytokines were obtained. ApoE(+/-)-IL-6(-/-) mice showed a significant increase in atheromatous lesions in proximal aorta and aortic tree compared to ApoE(+/-)-IL-6(+/-) mice for all conditions (chow diet and P.g.-inoculated, high fat diet and P.g.-inoculated, high fat diet and vehicle-inoculated) at 14 weeks and greater at 24 weeks. SAA levels from ApoE(+/-)-IL-6(-/-) mice were significantly higher than ApoE(+/-)-IL-6(+/-) mice. IL-6 deficiency led to profound changes in plaque composition evidenced by increased macrophage infiltration, apoptosis, lipid content and decreased smooth muscle cell mass reflecting an unstable plaque phenotype. Array analysis revealed increased levels of proinflammatory cytokines in ApoE(+/-)-IL-6(-/-) mice compared to ApoE(+/-)-IL-6(+/-) mice, irrespective of diet or inoculation. CONCLUSION: The genetic deficiency of IL-6 was found to enhance the formation of diet- and/or pathogen-associated atherosclerotic plaques and suggests that IL-6 may play an atheroprotective role.

Doxycycline affects diet- and bacteria-associated atherosclerosis in an ApoE heterozygote murine model: cytokine profiling implications.

BACKGROUND: It has been postulated that systemic infection with pathogens such as Porphyromonas gingivalis (Pg) elevates the inflammatory response and increases susceptibility to atherosclerosis. We hypothesized that Doxycycline would be beneficial in diet- and/or Pg-induced atherosclerosis given its role in various cell functions and matrix remodeling. METHODS AND RESULTS: ApoE+/- mice were inoculated weekly with Pg and treated with either Doxycycline or saline; animals were fed either a high-fat or chow diet. Animals were euthanized at 14 or 24 weeks and histomorphometric analysis of atheromatous lesions in proximal aorta, levels of SAA and serum cytokine profiling were performed. Histomorphometric analysis demonstrated that in non-infected mice fed a high fat diet, Doxycycline treatment resulted in a reduction of mean lesions from 10.5%+/-.49 to 1.09%+/-0.102 (p<0.05) at 14 weeks and a reduction from 21.5%+/-6.49 to 8.26%+/-0.162 (p=0.106) at 24 weeks. Chow-fed Pg mice treated with Doxyclycline also resulted in a reduction from 0.62%+/-0.128 to 0.0%+/-0.0 (p<0.05) at 14 weeks and a reduction from 0.92%+/-0.23 to 0.0%+/-0.0 (p<0.05) at 24 weeks. Administration of Doxycycline to mice fed a high fat diet and Pg-inoculated resulted in a reduction of mean percentage of atheromatous lesions from 16.46%+/-1.69 to 1.141%+/-0.23 (p<0.05) at 14 weeks and a reduction from 25.27%+/-1.734 to 0.428%+/-0.033 (p<0.05) at 24 weeks. At this timepoint, SAA levels in Pg-infected animals were reduced by five-fold and three-fold in Doxycycline-treated chow and high fat-diet groups, respectively. Cytokine antibody arrays revealed a marked reduction in the levels of pro-inflammatory cytokines in Doxycycline-treated groups whether Pg-infected or fed a high fat diet while anti-inflammatory cytokines were not affected. Consistent with the role of Doxycycline on matrix proteases, at 24 weeks MMP-9 Serum levels were markedly reduced by 60% (p<0.05) and 30% (p<0.05) with Doxycycline treatment in Pg-infected high fat and chow diet groups, respectively. CONCLUSIONS: Doxycycline decreases pro-inflammatory cytokines and results in reduction of atherosclerosis in ApoE+/-Pg-inoculated and/or high fat diet fed mice.