Association between genotype and plasma levels of thrombin-activated fibrinolysis inhibitor (TAFI) in the development of preeclampsia

Introduction

The objective was to evaluate if thrombin-activated fibrinolysis inhibitor (TAFI) polymorphisms (G505A, C1040T, and G-438A), and TAFIa plasma levels are associated with preeclampsia.

Materials and Methods

In a case-control study design, we evaluated preeclampsia patients and women with uncomplicated pregnancies. The TAFI polymorphisms were determined by real-time PCR method, and TAFIa plasma levels were established with a chromogenic assay.

Results

We included 87 women in each group. The TAFIa levels in the preeclampsia group were 20.4 μg/mL (CI 95% 17.3-23.5), while in the control group, they were significantly lower: 13.3 μg/mL (12.0-14.5, p 0.003). There were no differences in the genotype distribution or allelic frequency of TAFI polymorphisms between the two groups. In preeclampsia patients and controls heterozygous for the G505A polymorphism, the TAFIa values were 22.8 (16.7-28.9 μg/mL) and 13.2 (11.3-15.0 μg/mL, p 0.019), respectively. In G505A homozygous polymorphism the TAFIa values were 25.7 (18.7-32.6 μg/mL) and 13.5 (1.6-21.9 μg/mL, p 0.041), respectively. In the C1040T and G-438A TAFI wild type polymorphisms, the TAFIa values were 18.3 (12.5-23.9 μg/mL) and 11.5 (9.9-35.0, p 0.033), and 19.4 (10.9-27.9 μg/mL) and 12.5 (10.8-14.2 μg/mL, p 0.006), respectively, without differences in other genotypes.

Conclusions

Preeclampsia by itself may be responsible for the increase in TAFIa values rather than the presence of polymorphisms.     

Rocky Mountain spotted fever in Panama: a cluster description

Rocky Mountain spotted fever (RMSF) is a tick-borne infection caused by Rickettsia rickettsii. We report a cluster of fatal cases of RMSF in 2007 in Panama, involving a pregnant woman and two children from the same family. The woman presented with a fever followed by respiratory distress, maculopapular rash, and an eschar at the site from which a tick had been removed. She died four days after disease onset. This is the second published report of an eschar in a patient confirmed by PCR to be infected with R. rickettsii. One month later, the children presented within days of one another with fever and rash and died three and four days after disease onset. The diagnosis was confirmed by immunohistochemistry, PCR and sequencing of the genes of R. rickettsii in tissues obtained at autopsy.     

Endothelial damage and dysfunction in acute graft-versus-host disease

Clinical studies have suggested a potential involvement of endothelial dysfunction and damage in the development and severity of acute graft-versus-host disease (aGvHD). Accordingly, we found an increased percentage of apoptotic caspase 3 positive blood vessels in duodenal and colonic mucosa biopsies of patients with severe aGvHD. In murine experimental aGvHD, we detected severe microstructural endothelial damage and reduced endothelial pericyte coverage accompanied by reduced expression of endothelial tight junction proteins leading to increased endothelial leakage in aGvHD target organs. During intestinal aGvHD, colonic vasculature structurally changed, reflected by increased vessel branching and vessel diameter. As recent data demonstrated an association of endothelium-related factors and steroid refractory aGvHD (SR-aGvHD), we analyzed human biopsies and murine tissues from SR-aGvHD. We found extensive tissue damage but low levels of alloreactive T-cell infiltration in target organs, providing the rationale for T-cell independent SR-aGvHD treatment strategies. Consequently, we tested the endothelium-protective PDE5 inhibitor sildenafil, which reduced apoptosis and improved metabolic activity of endothelial cells in vitro. Accordingly, sildenafil treatment improved survival and reduced target organ damage during experimental SR-aGvHD. Our results demonstrate extensive damage, structural changes, and dysfunction of the vasculature during aGvHD. Therapeutic intervention by endothelium- protecting agents is an attractive approach for SR-aGvHD complementing current anti-inflammatory treatment options.     

Diacerein decreases TNF-α and IL-1β levels in peritoneal fluid and prevents Baker’s yeast-induced fever in young rats

Objective

To investigate the effect of diacerein, an anti-inflammatory drug, on body temperature and protocols of fever induction in male Wistar rats.

Methods

The effect of diacerein (5.0 mg/kg, s.c.) on rectal temperature (T _R) changes induced by Baker’s yeast (0.135 g/kg, i.p.) and PGE₂ (10 ng/animal, i.t.) was evaluated. T _R changes were recorded over time. The leukocyte count and TNF-α and IL-1β content were evaluated in the peritoneal fluid by means of optical microscopy and enzyme immunoassay (ELISA kits), respectively.

Results

The administration of diacerein to febrile animals attenuated Baker’s yeast-induced fever but did not alter prostaglandin E₂-induced fever. Diacerein prevented the development of Baker’s yeast-induced fever and significantly attenuated the increase in peritoneal leukocytes and decreased IL-1β and TNF-α levels in peritoneal fluid.

Conclusions

These data suggest that diacerein partially protects against Baker’s yeast-induced fever and peritoneal leukocyte migration, and indicate that this effect appears to be due to inhibition of release of cytokines (such as TNF-α and IL-1β).     

Importance and challenges of studying marketed drugs: what is a phase IV study? Common clinical research designs, registries, and self-reporting systems

The new drug application database submitted to the US Food and Drug Administration for drug approval (phases I-III or phases 1-3) is limited both in scope and size. Although randomized controlled trials, the hallmark of phase III trials, are the gold standard for the drug-approval process, they invariably have a number of limitations, including relatively small sample sizes, selective populations, short follow-up, the use of intermediate (surrogate) endpoints (almost always), and limited generalizability. The challenges of monitoring drugs once approved are also numerous. After approval by the Food and Drug Administration, marketed drugs undergo continued scrutiny, and this scrutiny is increasing because of problems that have surfaced with some drugs after their approval. Postmarketing research includes a variety of study designs and the use of registries and self-reporting of drug side effects. Along with this has come great confusion about what postmarketing research is and what a phase IV study is. Among the important strengths of phase IV research are the exposure of a broader range of patients to the drug under study, resulting in more "real-world" information about the drug's safety and efficacy, and consideration of a broader range of clinical endpoints. As a result, phase IV, or postmarketing research, has become an integral part of the drug evaluation process for a wide range of agents. The authors discuss the different types of study designs that are common under the phase IV terminology and provide some examples. They also discuss the use of registries and self-reporting of adverse events using the MedWatch System.     

An inconstant ligament in the popliteal region associated to the superior genicular arteries: surgical importance

Materials and methods In the dissection of 60 knees of 30 cadavers (13 women and 17 men), a ligament was located in the posterior femur face above the lateral or medial condyle.Results This ligamentous structure was found in 12 (20%) out of 60 knees studied (38% of the women and 35% of the men). It had a vertical arrangement and a constant direct relation to the superior (lateral or medial) genicular artery, and in no case it appeared as a posterior reinforcement of the capsule. The superior vessels were fixed by this ligament.Discussion This fixation may provide stability to the vascular tree but it could be a cause of post-surgical hemarthrosis in arthroscopy of the posterior knee area or in posterior or lateral knee approaches or it could be even implicated in vascular injury of the popliteal artery during knee dislocation.Conclusion The objective was to describe this inconstant ligament and to study its clinical relevance for surgical procedures, and particularly for those using the posterior approach to the knee joint.     

Difluoromethylornithine (DFMO) reduces deficits in isolation-induced ultrasonic vocalizations and balance following neonatal ethanol exposure in rats

Neonatal ethanol (EtOH) exposure is associated with central nervous system dysfunction and neurotoxicity in rats. Increases in polyamine levels have been implicated as one underlying mechanism for some of EtOH’s effects on the developing brain. In this study we addressed whether the inhibition of polyamine biosynthesis by α-difluoromethylornithine (DFMO) could reduce behavioral deficits induced by early EtOH exposure. Male and female rat pups received ethanol (6 g/kg/day EtOH i.g.), or isocaloric maltose (control) from postnatal days (PND) 1-8. On PND 8, animals were injected with either saline or DFMO (500 mg/kg, s.c.) immediately following the final neonatal treatment. Subjects were tested for isolation-induced ultrasonic vocalizations (USV) on PND 16; spontaneous activity in an open field apparatus on PND 20 and 21; and balance on PND 31. Animals exposed to EtOH neonatally displayed an increased latency to the first USV and reduced frequencies of USV, hyperactivity and preference for the center of the open field and poorer balance relative to controls. DFMO minimized these deficits in latency to the first USV and balance. These data provide further support that polyamines play a role in some of the functional deficits associated with EtOH exposure during early development and that reducing polyamine activity can improve outcome.