No abstract

Incorporation of both ICO and CTE into a single measure increased biomarker performance in CD. Combinations of fecal calprotectin and serum MMP9 for UC, and combinations of fecal calprotectin, serum MMP9, and serum interleukin-22 in CD, demonstrated the strongest association with imaging/endoscopy-defined inflammation.

Background Gene-environment interplay modulates Inflammatory Bowel Diseases [IBD]. Dioxin-like compounds can activate the Aryl Hydrocarbon Receptor [AhR] and alter macrophage function as well as T cell polarization. We hypothesized that attenuation of the AhR signaling pathway will ameliorate colitis in a murine model of IBD. Design DSS colitis was induced in C57BL/6 AhR null mice [AhR −/−], heterozygous mice [AhR−/+], and their wild type [WT] littermates. Clinical and morphopathological parameters were used to compare the groups. Patients: AhR pathway activation was analyzed in biopsy specimens from 25 IBD patients and 15 healthy controls. Results AhR −/− mice died before the end of the treatment. However, AhR −/+ mice exhibited decreased disease activity compared to WT mice. The AhR −/+ mice expressed less proinflammatory cytokines such as TNFα (6.1 versus 15.7 fold increase) and IL17 (23.7 versus 67.9 fold increase) and increased antiinflammatory IL-10 (2.3 fold increase) compared with the AhR+/+ mice in the colon. Colonic macrophage infiltration was attenuated in the AhR −/+ group. AhR and its downstream targets were significantly upregulated in IBD patients versus control (CYP1A1 – 19.9, and IL8-10 fold increase). Conclusion Attenuation of the AhR receptor expression resulted in a protective effect during DSS-induced colitis, while the absence of AhR exacerbated the disease. Abnormal AhR pathway activation in the intestinal mucosa of IBD patients may promote chronic inflammation. Modulation of AhR signaling pathway via the diet, cessation of smoking or administration of AhR antagonists could be viable strategies for the treatment of IBD.

Two common founder-related gene mutations that affect the low-density lipoprotein receptor (LDLR) are responsible for -80% of familial hypercholesterolemia (FH) in South African Afrikaners. The FH Afrikaner-1 (FHl) mutation (Asp^-»Glu) in exon 4 results in defective receptors with =20% of normal activity, whereas the FH Afrikaner-2 (FH2) mutation (VaUog-^Met) in exon 9 completely abolishes LDLR activity (<2% normal activity). We analyzed the contribution of these mutations and other factors on the variation of hypercholesterolemia and clinical features in Afrikaner FH heterozygotes. The type of FH mutation, plasma triglyceride levels, and age of patients each contributed significantly to the variation in hypercholesterolemia, whereas smoking status, high-density lipoprotein cholesterol levels, and gender had no influence. Although all FH heterozygotes had frank hypercholesterolemia, patients with the FHl mutation had significantly lower cholesterol levels than those with the FH2 mutation. FHl heterozygotes also tended to have milder clinical features. The differences between the two FH groups could not be explained by a difference in the common apolipoprotein E variants. This study demonstrates that mutational heterogeneity in the LDLR gene influences the phenotypic expression of heterozygous FH. autosomal dominant disease caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Characteristic phenotypic features of FH are raised low-density lipoprotein (LDL) cholesterol (C) levels, the presence of tendon xanthomata, and the premature development of coronary heart disease (CHD). These features are more striking and their age of onset earlier in FH homozygotes who inherit two mutant LDLR gene alleles. The mutational heterogeneity of FH explains most of the phenotypic variation found among FH homozygotes, in whom a strong correlation is found between residual receptor activity and the severity of the disease. The founder-related basis for the high prevalence of FH in the Afrikaans-speaking white population of South Africa (Afrikaners) enabled us to study the degree of phenotypic variability caused by different LDLR gene mutations. Two of the three founder mutations identified in the Afrikaner population, which together account for =80% of FH in Afrikaners, 37 have different effects on the cellular expression of the LDLR. The FH Afrikaner-1 (FHl) mutation (Asp^ to Glu; GAC to GAG) in exon 4 of the LDLR gene results in the formation of functionally distinct forms of the mutant receptor; one form exhibits normal receptor activity, whereas another is unable to bind lipoprotein ligands.8 ' 9 As a result, fully upregulated cells homozygous for this mutation express about 20% of normal receptor activity. The FH Afrikaner-2 (FH2) mutation (VaLwe to Met; GTG to ATG) in exon 9 causes the receptor to be rapidly degraded and results in very low receptor activity (<2% of normal receptor activity).

Summary. Serum levels of C‐reactive protein (CRP) and amyloid A protein (SAA) were measured prospectively using immunoradiometric assays in normal pregnant women, newborn infants and women with prelabour rupture of membranes (PROM), focusing on the peripartum period. CRP levels in 50 healthy women at 38 weeks gestation did not differ significantly from previously established normal values. CRP levels in 67 healthy women sampled serially in labour from admission to 96 h postpartum confirm the physiological occurrence of a major acute phase response. The serial CRP levels of 16 women with PROM did not differ significantly from the wide range of CRP levels found in the normal postpartum period. This complicates the use of CRP as an early predictor of clinical chorio‐amnionitis. Serial SAA levels in 17 women at 38 weeks gestation, immediately postpartum and 24 h postpartum showed a parallel rise to CRP in the peripartum period. Significant differences between maternal and neonatal CRP and SAA levels were demonstrated, implying a lack of transplacental transfer during labour.