Disease System Analysis: Basic Disease Progression Models in Degenerative Disease

Purpose To describe the disease status of degenerative diseases (i.e., type 2 diabetes mellitus, Parkinson’s disease) as function of disease process and treatment effects, a family of disease progression models is introduced.Methods Disease progression is described using a progression rate (R_dp) acting on the synthesis or elimination parameters of the indirect response model. Symptomatic effects act as disease-dependent or -independent effects on the synthesis or elimination parameters. Protective drug effects act as disease dependent or -independent effects on R_dp.Results Simulations with the ten disease models show distinctly different signature profiles of treatment effects on disease status. Symptomatic effects result in improvement of disease status with a subsequent deterioration. Treatment cessation results in a disease status equal to the situation where treatment had not been applied. Protective effects result in a lasting reduction, or even reversal, of the disease progression rate and the resulting disease status during the treatment period. After cessation of treatment the natural disease course will continue from the disease status at that point.Conclusion Disease system analysis constitutes a scientific basis for the distinction between symptomatic versus protective drug effects in relation to specific disease processes as well as the identification of the exposure-response relationship during the time-course of disease.     

Genetic characterization of environmental isolates of the Cryptococcus neoformans species complex from Brazil.

The genetic affiliation of a large number of isolates of the Cryptococcus neoformans species complex from environmental sources in Brazil has been investigated using amplified fragment length polymorphism (AFLP). The strains of C. neoformans isolated from a single tree, as well as from neighbouring trees, showed high similarity values (> 95%) of their AFLP patterns, thus suggesting considerable genetic homogeneity. The majority of isolates of C. neoformans belonged to AFLP genotype 1, and had serotype A and mating type alpha (= C. neoformans var. grubii). Three isolates belonged to AFLP genotype 2, with serotype D and mating type alpha (= C. neoformans var. neoformans). One isolate, obtained from a building in Rio de Janeiro inhabited by pigeons, belonged to the AD hybrid AFLP genotype 3. All isolates from trees of C. neoformans var. gattii (= C. gattii) belonged to AFLP genotype 6, and their banding patterns showed relatively low genetic homogeneity with a similarity value of about 76%. Isolates of this genotype occupy an environmental niche in the Americas, and they may cause disease in non-AIDS and AIDS patients as well.     

Use of amplified fragment length polymorphism analysis to identify medically important Candida spp., including C. dubliniensis

Non-Candida albicans Candida species are increasingly being isolated. These species show differences in levels of resistance to antimycotic agents and mortality. Therefore, it is important to be able to correctly identify the causative organism to the species level. Identification of C. dubliniensis in particular remains problematic due to the high degree of phenotypic similarity between this species and C. albicans. The use of amplified fragment length polymorphism (AFLP) analysis as an identification method for medically important Candida species was investigated. Our results show very clear differences among medically important Candida species. Furthermore, when screening a large collection of clinical isolates previously identified on CHROMagar as C. albicans, we found a misidentification rate of 6%. AFLP analysis is universally applicable, and the patterns can easily be stored in a general, accessible database. Therefore, AFLP might prove to be a reliable method for the identification of medically important Candida species.     

Sinus Valsalva Aneurysm of the non-coronary cusp initially diagnosed as right ventricular thrombus: A case report

Sinus of Valsalva aneurysms are abnormal bulges of the aortic root caused by a tissue deficiency resulting in an enlargement of the aortic root in the area between the aortic annulus and the sinotubular junction. Frequently, sinus of Valsalva aneurysms are asymptomatic. However, sinus of Valsalva aneurysms can also be potentially fatal due to their risk of rupture. We present a case of a 49-year old asymptomatic male patient with a rare image of a sinus of Valsalva aneurysm of the non-coronary cusp which was initially mistaken for a right ventricular thrombus. Surgical repair of the sinus of Valsalva aneurysm was eventually achieved by a valve sparing root replacement and the patient was discharged 7 days after surgery. This case report shows that sinus of Valsalva aneurysms are vulnerable to misdiagnosis when it is not initially suspected. Because of the potential fatality of this phenomenon we would like to underline the necessary vigilance in the diagnostic process, as sinus of Valsalva aneurysms can be missed when the physician is not aware of this potential rare diagnosis.     

Beta-, not alpha-adrenergic stimulation enhances conduction velocity in cultures of neonatal cardiomyocytes.

BACKGROUND: During both cardiac maturation and myopathy, elevated levels of circulating catecholamines coincide with alterations in impulse propagation. An in vitro model of cultured cardiomyocytes was used to study the effects of adrenergic stimulation on the conduction characteristics of immature heart cells. METHODS AND RESULTS: Neonatal rat cardiomyocytes were cultured on preparations designed to measure conduction velocity (CV). CV was measured on the same preparation twice at t=0 and at t=24 h. Under control conditions (n=7), CV at t=0 (30.9+/-1.9 cm/s) and t=24 (32.4+/-4.4 cm/s) was similar (p=0.70). Immunohistochemistry revealed expression of the gap junction proteins connexin (Cx) 40, Cx43 and Cx45, with Cx43 being highly predominant. Stimulation for 24 h with the beta-adrenergic agonist isoproterenol (ISO) significantly increased CV from 28.0 +/-2.0 cm/s at t=0 to 34.8+/-2.2 cm/s at t=24 (p=0.002, n=5). Microelectrode recordings showed a faster upstroke of the action potential (AP) of ISO-treated cells. Reverse transcribed-polymerase chain reactions (RT-PCR) showed that ISO increased expression of SCN5A and alpha(1c) (alpha-subunit of the cardiac sodium and L-type calcium channel, respectively). Stimulation of cells with ISO did not induce alterations in distribution or expression of Cx40, Cx43 and Cx45 (both mRNA and protein), but slightly increased the phosphorylation of Cx43. Stimulation for 24 h with the alpha-adrenergic agonist phenylephrine did neither affect CV nor the expression of the connexin isoforms, SCN5A and alpha(1c). CONCLUSIONS: Alpha- and beta-adrenergic stimulation differently affect propagation of the electric impulse, which is primarily not caused by a differential effect on intercellular coupling. RT-PCR analysis and an enhanced AP upstroke velocity indicate a higher functional expression level of alpha(1c) and SCN5A in beta-adrenergic stimulated cells, which may explain the observed increase in CV.     

Population Pharmacokinetics of Mycophenolic Acid

Clinical Pharmacokinetics - Objective: The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated...     

Identification and typing of Malassezia species by amplified fragment length polymorphism and sequence analyses of the internal transcribed spacer and large-subunit regions of ribosomal DNA

Malassezia yeasts are associated with several dermatological disorders. The conventional identification of Malassezia species by phenotypic methods is complicated and time-consuming, and the results based on culture methods are difficult to interpret. A comparative molecular approach based on the use of three molecular techniques, namely, amplified fragment length polymorphism (AFLP) analysis, sequencing of the internal transcribed spacer, and sequencing of the D1 and D2 domains of the large-subunit ribosomal DNA region, was applied for the identification of Malassezia species. All species could be correctly identified by means of these methods. The results of AFLP analysis and sequencing were in complete agreement with each other. However, some discrepancies were noted when the molecular methods were compared with the phenotypic method of identification. Specific genotypes were distinguished within a collection of Malassezia furfur isolates from Canadian sources. AFLP analysis revealed significant geographical differences between the North American and European M. furfur strains.     

Survival and infection rates of a polyurethane vascular access graft compared to tunnelled dialysis catheters and brachiobasilic arteriovenous fistulas.

Sir, The polyurethane graft can be used within 24 h and has improvedhaemostasis after cannulation [1,2]. It