Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder, thought to be specific for pregnancy and to spontaneously resolve after delivery. Increased rates of gallstone formation and hepatitis C have previously been associated with ICP. However, there are no longitudinal studies to determine its significance as an indicator of subsequent liver or biliary diseases. In this retrospective cohort study with cases and controls we assessed the risk of liver and biliary diseases in 21,008 women, 10,504 with a history of ICP during the years 1972-2000 (cases) and 10,504 with a normal pregnancy (controls). Cases and controls were matched for age, time of delivery, and place of delivery. The diagnoses of liver and biliary disease were traced from the Finnish Hospital Discharge Register with an almost 100% coverage. Several liver and biliary diseases were found to have a significantly higher incidence in patients with ICP than in controls. The rate ratio for hepatitis C was 3.5 (CI 1.6-7.6; P < .001), for nonalcoholic liver cirrhosis 8.2 (CI 1.9-35.5; P < .05), for gallstones and cholecystitis 3.7 (CI 3.2-4.2; P < .001) and for nonalcoholic pancreatitis 3.2 (CI 1.7-5.7; P < .001). In conclusion, there is an association of ICP with several liver and biliary diseases. Some patients with ICP are at risk of the subsequent development of cirrhosis and other severe chronic diseases. Contrary to what has been previously thought, follow-up may need to be considered for these patients.     

Maternal serum-soluble vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation

CONTEXT: Vascular endothelial growth factor (VEGF) promotes placental vascularization, which is inadequate in preeclampsia and intrauterine growth retardation (IUGR). The soluble receptor of VEGF (sVEGFR-1), also known as soluble fms-like tyrosine kinase-1, is produced in the placenta and reduces VEGF activity. Therefore, elevated sVEGFR-1 could contribute to the development of preeclampsia and IUGR. OBJECTIVE: The objective of this study was to study maternal serum sVEGFR-1 concentration in early pregnancy ending in preeclampsia and IUGR. DESIGN: This was a case-control study. SETTING: This study was conducted at Helsinki University Central Hospital (Helsinki, Finland), a tertiary referral center. PATIENTS: Patients included 124 pregnant women, of whom 49 developed preeclampsia, 16 gave birth to IUGR infants without preeclampsia, and 59 remained normotensive and gave birth to normal-sized infants. Serum samples were collected at 12-15 and 16-20 gestational weeks. MAIN OUTCOME MEASURES: Serum sVEGFR-1 concentrations were determined by ELISA. RESULTS: Women with subsequent preeclampsia had higher [median; interquartile range (IQR)] concentrations of sVEGFR-1 at 16-20 wk gestation (436 and 282-699 ng/liter; P = 0.005) than the controls (296 and 184-508 ng/liter). The conclusion was the same if women with mild (340 and 285-750 ng/liter; P = 0.043) or severe (497 and 235-699 ng/liter; P = 0.022) preeclampsia were analyzed separately. An elevated sVEGFR-1 concentration at 16-20 wk gestation is associated with an increased risk of preeclampsia but not of isolated IUGR. Soluble VEGFR-1 concentration decreased by 15% from the first to the second sampling in the controls but not in women with preeclampsia or IUGR. CONCLUSION: Elevated sVEGFR-1 concentrations at 16-20 wk gestation precede the clinical manifestations of preeclampsia. By neutralizing VEGF, sVEGFR-1 may contribute to inadequate placental vascularization.     

Omics and its potential impact on R&D and regulation of complex herbal products

In traditional Chinese medicine (TCM), multicomponent and principally plant-derived drugs are used for disease prevention, symptom amelioration and treatment in a personalized manner. Because of their complex composition and consequent multiple targets and treatment objectives, the application of omics techniques and other integrative approaches seems inherently appropriate and even necessary for the demonstration of their potential preclinical and clinical safety and efficacy. This perspectives article provides proposals for the application of omics methods to the investigation of complex herbal products (CHP),(1) including Chinese herbal medicines (CHM), both in vitro and in vivo, for preclinical and clinical toxicity, pharmacokinetics, pharmacodynamics and efficacy tests. Ultimately, such approaches could aid regulatory scrutiny and potential acceptance, although currently there is no regulatory requirement of omics-based data in any submitted dossier to any regulatory agency, including for conventional drugs and CHP. However, it has been acknowledged that such studies are being increasingly performed, and almost surely will eventually be included into regulatory submission dossiers, possibly initially as supplementary materials. Specifically for CHM and CHP, omics can play a role both in determining product composition and its variability and in monitoring biological effects in carefully selected platforms. Predicting the future is difficult, but it seems possible that regulatory acceptance of omics techniques and a systems biology approach for the study of TCM, CHM and CHP will not be long delayed. It is expected that current studies and plans employing omics techniques and other integrative approaches will prove to be positive and informative.     

Circulating cell-free DNA in health and disease — the relationship to health behaviours,ageing phenotypes and metabolomics

GeroScience - Circulating cell-free DNA (cf-DNA) has emerged as a promising biomarker of ageing, tissue damage and cellular stress. However, less is known about health behaviours, ageing phenotypes...     

A novel mutation in the third extracellular domain of the tumor necrosis factor receptor 1 in a Finnish family with autosomal‐dominant recurrent fever

Objective

To investigate the presence of TRAPS (tumor necrosis factor receptor–associated periodic syndrome), which is a recently defined, dominantly inherited autoinflammatory syndrome caused by mutations in the tumor necrosis factor receptor superfamily 1A gene (TNFRSF1A, CD120a), in a Finnish family with recurrent fever.

Methods

The TNFRSF1A gene was sequenced in both affected and unaffected family members. Flow cytometry and enzyme‐linked immunosorbent assay analyses were used to assess membrane expression and serum levels of the TNFRSF1A protein, respectively.

Results

A missense mutation in exon 4, located in the third extracellular domain of TNFRSF1A and resulting in an amino acid substitution (F112I) close to a conserved cysteine, was found in all 4 affected family members and in 1 asymptomatic individual. The mutation was clearly associated with low levels of soluble TNFRSF1A as well as with the clinical symptoms of recurrent fever and abdominal pain. Impaired shedding of TNFRSF1A after phorbol myristate acetate stimulation was detected in blood granulocytes and monocytes from the 3 adult family members with the mutation, but in the child bearing the mutation and showing clinical symptoms of recent onset, the shedding defect was less marked.

Conclusion

TRAPS should be suspected in any patient who presents with a history of intermittent fever accompanied by unexplained abdominal pain, arthritis, or skin rash, particularly in the presence of a family history of such symptoms. Screening for low serum levels of soluble TNFRSF1A identifies individuals who are likely to have TNFRSF1A mutations.

     

The Anticollagenolytic Potential of Lymecycline in the Long-Term Treatment of Reactive Arthritis

Objective. We sought to determine the antiinflammatory properties of lymecycline in the long-term treatment of reactive arthritis (ReA). Methods. Quantitative assay of collagenase activity by densitometry after sodium dodecyl sulfatepolyacrylamide gel electrophoresis. Results. Therapeutic levels of lymecycline do not directly inhibit the activity of human neutrophil interstitial collagenase, but can prevent the oxidative activation of latent human neutrophil collagenase. Conclusion. This non-antimicrobial, anticollagenolytic property of lymecycline may contribute to its therapeutic efficacy in the treatment of patients with ReA.