Cardiovascular biomarkers in chronic kidney disease

Cardiovascular disease (CVD) is the major cause of death in patients with advanced chronic kidney disease (CKD). Recent studies have suggested that novel risk factors, uremia- or dialysis-related, are of great importance, as they act synergistically with the highly prevalent traditional risk factors for CVD in CKD patients. Whereas an ideal single biomarker, i.e., one that adds relevant prognostic information in clinical practice over and above that provided by conventional (Framingham) risk factors, has yet to be identified, combinations of several biomarkers or repeated measurements of biomarkers may increase the explanatory power of prognostic information provided by traditional risk factors to predict cardiovascular outcomes. However, because the increase of predictive power is modest, clinical assessment of patient status still remains the cornerstone tool for predicting risk for CVD. On the other hand, the search for better biomarkers may reveal novel pathways linked to CVD that need to be explored in CKD patients. This brief review summarizes some emerging and potentially clinically applicable CVD biomarkers in CKD patients, especially focusing on inflammation and vascular calcification that may provide additional information to conventional risk factors.     

A New Reimbursement System for Innovative Pharmaceuticals Combining Value-Based and Free Market Pricing

Sweden has experienced a national value-based pricing (VBP) system for innovative outpatient drugs operated by the Pharmaceutical Benefits Board - LFN (now called the Dental and Pharmaceutical Benefits agency - TLV) since 2002. VBP has the character of a monopoly system, leading to reimbursement decisions where usage of new medicines is limited to subgroups and not the population for which the drug is approved. VBP relies on a broad societal perspective, encouraging innovations by signaling to firms that value-adding treatments are demanded. However, the VBP system is operated without a drug budget responsibility. The budget responsibility lies at the regional level, not operating VBP, thus an intrinsic conflict is built into the system. The aim of this article is to suggest a modification to the current reimbursement system in Sweden where payment for pharmaceuticals is split between the regional and national levels. The system is expected to make new innovative pharmaceuticals accessible to a larger number of patients and provide more consumer surplus without reducing the producer surplus. In short, the county councils pay the marginal cost of production while the state pays for the innovation.     

Nasal and skin delivery of IC31(®)-adjuvanted recombinant HSV-2 gD protein confers protection against genital herpes

Genital herpes caused by herpes simplex virus type 2 (HSV-2) remains the leading cause of genital ulcers worldwide. Given the disappointing results of the recent genital herpes vaccine trials in humans, development of novel vaccine strategies capable of eliciting protective mucosal and systemic immune responses to HSV-2 is urgently required. Here we tested the ability of the adjuvant IC31^® in combination with HSV-2 glycoprotein D (gD) used through intranasal (i.n.), intradermal (i.d.), or subcutaneous (s.c.) immunization routes for induction of protective immunity against genital herpes infection in C57BL/6 mice. Immunization with gD plus IC31^® through all three routes of immunization developed elevated gD-specific serum antibody responses with HSV-2 neutralizing activity. Whereas the skin routes promoted the induction of a mixed IgG2c/IgG1 isotype profile, the i.n. route only elicited IgG1 antibodies. All immunization routes were able to induce gD-specific IgG antibody responses in the vaginas of mice immunized with IC31^®-adjuvanted gD. Although specific lymphoproliferative responses were observed in splenocytes from mice of most groups vaccinated with IC31^®-adjuvanted gD, only i.d. immunization resulted in a significant splenic IFN-γ response. Further, immunization with gD plus IC31^® conferred 80–100% protection against an otherwise lethal vaginal HSV-2 challenge with amelioration of viral replication and disease severity in the vagina. These results warrant further exploration of IC31^® for induction of protective immunity against genital herpes and other sexually transmitted infections.     

Substance P activates leukocytes and platelets in rabbit microvessels

The effect of substance P on leukocytes and platelets in rabbit skeletal muscle microvasculature was studied by intravital microscopy and electron microscopy. Local application of substance P caused vasodilatation and formation of aggregates of platelets and leukocytes in postcapillary venules with subsequent migration of leukocytes through the vessel wall. Many neutrophils were partially degranulated. Aggregate formation induced by substance P could not be prevented by autacoid antagonists. However, superfusion with calcitonin gene-related peptide prior to challenge with substance P greatly inhibited aggregate formation and leukocyte extravasation.     

Bronchial exudation of bulk plasma at allergen challenge in allergic asthma.

This study examined plasma exudation into the bronchial lumen after allergen challenge. A novel low-trauma technique was developed to challenge and lavage a medium-sized lingular or middle lobe bronchus. Eleven subjects with challenge-assessed pollen-sensitive asthma were allocated to fiberbronchoscopy in the supine position. In the control bronchus 0.5 ml diluent was instilled. The bronchus was occluded proximally 3 min later by inflation of a balloon, and lavage was carried out twice with 25 ml saline. Incremental doses of allergen solution (0.5 ml) were then instilled in the contralateral lung. The challenge continued until a clearly visible bronchial reaction occurred and was immediately followed by the same lavage as on the control side. The lavage liquids were analyzed for the presence of plasma exudation and mast cell activation indices. On the allergen-challenged side, tryptase, reflecting mast cell activation, was increased by 150% (p < 0.01) compared with the control side. Fibrinogen (mol wt 340,000), reflecting large protein exudation, was increased by 840% (p < 0.05), and N-alpha-tosyl-L-arginine-methyl esterase activity, reflecting both large protein exudation and mast cell activation, increased by 480% (p < 0.01). The level of albumin (mol wt 69,000), the major luminal protein under baseline conditions, increased but not significantly. We conclude that activation of mast cells and luminal entry of little sieved plasma exudates occur early after endobronchial allergen provocation in human subjects with allergic asthma.     

Visualization of defective measles virus particles in cerebrospinal fluid in subacute sclerosing panencephalitis

Measles virus particles were visualized in the CSF of two patients with verified subacute sclerosing panencephalitis (SSPE) by using scanning electron microscopy. Immunologic identification of the accumulated particles was performed with monoclonal antibodies, directly conjugated to carboxylated microspheres, specific for different measles virus antigens. The beads were amassed on the filter surface after a 1-hr incubation in the CSF. Spherical particles with a diameter ranging between 150 and 500 nm were detected. Such particles bound specifically to latex beads covered by monoclonal antibodies to measles virus hemagglutinin but not to beads conjugated with monoclonal antibodies specific for nucleoprotein. Adding the two monoclonal antibodies to measles virus hemagglutinin to the CSF agglutinated the virus particles in a dose-dependent way. Further, no particles in the CSF bound to microspheres conjugated with monoclonal antibodies to non-related antigens of Sendai virus, cytomegalovirus, or human immunodeficiency virus. Similarly sized particles were also identified by transmission electron microscopy after concentrating the CSF.