Dual activity of triterpenoids: apoptotic versus antidifferentiation effects

Triterpenoids are natural, biologically active compounds extracted from many plants. They possess antiinflammatory, anticancer, and antioxidant properties. In the report presented, antiproliferative effects and leukemia cell growth and apoptosis modulating activities of ursolic acid (UA) and oleanolic acid (OA) were investigated. Both triterpenoids are inhibitors of leukemia cell growth and inductors of apoptosis. However, when applied in combination with anthracycline antitumor antibiotic doxorubicin (Dox), UA and OA diversely modulate therapeutic efficacy of Dox, due to different antioxidant activities. Compare to OA showing synergism/additive effect with Dox, UA (stronger antioxidant) acts antagonistically and reduces leukemia cell growth inhibiting and differentiation effects induced by Dox. In conclusion, these findings suggest that although triterpenoids UA and OA can induce apoptosis, their antioxidant activities can interfere with the therapeutic effect of antitumor antibiotic Dox which mechanism of action is attributed to the production of reactive oxygen species.     

New mathematical methods in pharmacokinetic modeling

In recent years, several new methods for the mathematical modeling have gradually emerged in pharmacokinetics, and the development of pharmacokinetic models based on these methods has become one of the most rapidly growing and exciting application-oriented sub-disciplines of the mathematical modeling. The goals of our MiniReview are twofold: i) to briefly outline fundamental ideas of some new modeling methods that have not been widely utilized in pharmacokinetics as yet, i.e. the methods based on the following concepts: linear time-invariant dynamic system, artificial-neural-network, fuzzy-logic, and fractal; ii) to arouse the interest of pharmacological, toxicological, and pharmaceutical scientists in the given methods, by sketching some application examples which indicate the good performance and perspective of these methods in solving pharmacokinetic problems.     

An anatomic comparison of the original versus a modified inside-out transobturator procedure

Introduction and hypothesis

The objective of this study was to evaluate the modification of a shortened tape and reduced dissection of the inside-out transobturator procedure on the tape??s relationship to the relevant anatomical structures.

Methods

In ten fresh frozen cadavers, relevant distances between the two different tapes and anatomical structures were recorded.

Results

The shorter tape traversed less muscular structures, but consistently traversed the obturator membrane. The median distance from the tape to the obturator canal measured 2.0 versus 1.9?cm, to the anterior obturator nerve 3.0 versus 2.7?cm, and to the posterior obturator nerve 2.2 versus 2.0?cm [modified versus original procedure, respectively (p?>?0.05)]. Significantly, less mesh was inserted in the modified procedure on each side of the body (6.1 versus 9.9?cm, p?Conclusions The shorter, inside-out transobturator tape traverses less muscular structures than its original counterpart, while still consistently anchoring in the obturator membrane at a similarly safe distance from the obturator canal.     

Cervical spondylotic myelopathy: conservative versus surgical treatment after 10 years

It is not known whether the results of decompressive surgery to treat the mild and moderate forms of spondylotic cervical myelopathy (CSM) are any better than those of a conservative approach. A 10-year prospective randomised study was performed. The objective of the study was to compare conservative and operative treatments of mild and moderate, non-progressive, or slowly progressive, forms of CSM. Sixty-four patients were randomised into two groups of 32. Group A was treated conservatively while group B was treated surgically. The clinical outcome was evaluated by modified JOA score, timed 10-m walk, score of daily activities recorded by video and evaluated by two observers blinded to the type of therapy, and by subjective assessment by the patients themselves. Seventeen patents died of natural, unrelated causes, during the follow-up. A total of 25 patients in the conservatively and 22 in the surgically treated group were used for the final evaluation. There was no statistically significant difference between both groups in mJOA score, in subjective evaluation by the patients themselves and in evaluation of video-recordings of daily living activities by two observers blinded to treatment mode. There was neither any difference found in the percentage of patients losing the ability to walk nor in the time taken to cover the 10-m track from a standing start. Comparison of conservative and surgical treatment in mild and moderate forms of CSM in a 10-year follow-up has not shown, on average, a significant difference in results. In both groups, patients get better and worse. According to the power analysis it is necessary admit that these results possess the low ability to answer definitely the question which treatment is better for the patients with a mild and moderate non-progressive CSM because of the low number of patients for the final evaluation and for clinically negligible differences between two compared arms. These findings can serve as a worthy odds-on hypothesis which needs the confirmation.     

Tularemia induces different biochemical responses in BALB/c mice and common voles

Background  

Both BALB/c mice and common voles (Microtus arvalis) are considered highly susceptible to tularemia. However, the common vole is reported to harbour Francisella tularensis in European habitats as well as to survive longer with chronic shedding of the bacterium. The purpose of the present study was to compare the response of these two rodents to a wild Francisella tularensis subsp. holarctica strain infection.     

Early onset of proteinuria and focal segmental glomerulosclerosis in obese,hyperinsulinemic adolescents developing metabolic syndrome

BackgroundThe metabolic syndrome (MTS) is comprised of insulin resistance, glucose intolerance, obesity, hypertension, and dyslipidemia. Secondary renal dysfunction can develop after prolonged duration of each component except for dyslipidemia. Here we present 7 obese individuals in whom MTS and proteinuria developed concomitantly during adolescence.Subject and methodsSeven (f:m = 4:3) individuals (Caucasian or African American, ages 11–17 at disease onset) developed macroproteinuria of whom 6 were directly evaluated and had typical MTS characteristics. Body mass index range was 30.8–73.2 kg/m², being highest in African Americans. All had positive family history of MTS. Six patients underwent complete general, hormonal and metabolic work-up, including fasting and stimulated insulin and C-peptide levels. Genomic DNA of 4 patients and their relatives was studied by linkage analysis for MODY 1–4 genes, and for a locus associated with focal segmental glomerulosclerosis (FSGS) and microalbuminuria.ResultsFasting and stimulated insulin and C-peptide levels were elevated. All patients were normoalbuminemic, and five of six patients had mildly elevated liver enzymes. The 24-h urinary protein excretion range was 2.5–9 g, and decreased markedly in 2 patients who lost weight. Renal biopsy of 3 patients showed FSGS. In 2 pedigrees FSGS was familial. Genomic DNA analysis excluded any linkage with common MODY genes or with familial FSGS.ConclusionsThe early concomitant development of MTS, proteinuria and FSGS appears to be associated with hyperinsulinemia, presenting as early as adolescence, and may be reversed by weight loss. We propose that in genetically predisposed individuals, excessive insulin plays a crucial pathogenic role in development of the metabolic syndrome and FSGS.     

Age-related changes in GAD levels in the central auditory system of the rat

Changes in the levels of gamma-aminobutyric acid (GABA) are known to occur in different parts of the brain during aging. In our study we attempted to define the effect that aging has on glutamate decarboxylase (GAD), the key enzyme in the synthesis of GABA, in the central parts of the auditory system. Age-related changes in GAD65 and GAD67 levels were investigated using immunohistochemistry and Western blotting in the inferior colliculus (IC), the auditory cortex (AC) and the visual cortex in Long-Evans rats. The results show that aging is associated with a decrease in the numbers of GAD65- and 67-immunoreactive neurons and the optical density of their somas in both the IC and AC. Western blot analysis revealed a pronounced age-related decline in the levels of GAD65 and 67 proteins in both the IC and AC. For comparison, in the visual cortex the decrease in both proteins was less pronounced than in the IC and AC. A similar pattern of age-related changes was found in Fischer 344 rats, a strain that manifests a rapid loss of hearing function with aging. The observed age-related decline in the levels of GAD65 and 67 may contribute significantly to the deterioration of hearing function that accompanies aging in mammals, including man.     

Successful treatment of iron overload with phlebotomies in two siblings with congenital dyserythropoietic anemia--type II (CDA-II)

Successful treatment of iron overload by phlebotomies has been reported in two splenectomized siblings with congenital dyserythropoietic anemia--type II (CDA-II). In both patients 400 ml of blood were withdrawn every month. During three years 12 200 ml of blood were removed. The serum ferritin levels decreased from 1450,4 microg/L and 1131,7 microg/L to 447 microg/L and 457 microg/l, respectively. The transferrin saturation dropped from 0,99 at the start of the therapy to 0,64 and 0,86, respectively. The values of Hb, Hct, erythrocyte counts and MCV did not change as well as did not change reticulocyte counts, reticulocyte index, and RDW. Both patients tolerated repeated phlebotomies well. The decrease of bilirubin and normal values of haptoglobin might be the concequence of diminished destruction of erythrocytes and their precursors. Our observation confirms that phlebotomies can be used with success in CDA patients with mild anemia as treatment modality of iron overload.