Paraoxonase/arylesterase in serum of patients with type II diabetes mellitus

The aim of this study was to determine whether the paraoxonase (PON1) status, i.e. PON1 activities and phenotypes (AA, AB and BB), and its relationship with lipid status are different in patients with type II diabetes as compared to healthy population. Diabetic group comprised 175 patients with type II diabetes mellitus (94 men and 81 women) who came to their regular control examination and took the oral glucose tolerance test. Patients with type II diabetes mellitus diagnosis for 12 years on average were on peroral antidiabetics, or insulin or diet, and 3 patients had no therapy prescribed yet. Control group comprised 114 apparently healthy individuals (28 men and 86 women) who were not on any medication. The paraoxonase activity was measured with 2.0 mmol L(-1) paraoxon in the absence and in the presence of 1.0 mol L(-1) NaCl, and with 2.0 mmol L(-1) phenylacetate. Both activities were measured spectrophotometrically at 37 degrees C in 0.1 mol L(-1) Tris-HCl buffer, pH = 8.0, containing 2.0 mmol L(-1) CaCl(2). Sera of diabetic and control subjects were assigned to the paraoxonase phenotypes on the basis of the basal paraoxonase activity distribution. We assigned 45% sera of male and 49% sera of female diabetic patients, and 64% sera of both genders of the control group to the AA low activity phenotype. There were no differences in paraoxonase activities between the gender- and phenotype-matched diabetic and control groups. Enzyme activity against the phenylacetate was higher, and phenotype-dependent, only in diabetic patients. In contrast to AA phenotype individuals, total cholesterol and LDL-cholesterol in the female diabetic group and triglyceride concentration in the male diabetic group assigned to pooled AB and BB phenotypes were higher than in the corresponding controls. It follows from PON1 phenotype distribution that less antiatherogenic paraoxonase B allele is more frequent in type II diabetes mellitus than in the healthy population. Their lipid status is more atherogenic, which could indicate a risk of premature atherosclerosis.     

Multicentric glial brain tumors of a varying degree of differentiation in patient with chronic lymphocytic leukemia

Chronic lymphocytic leukemia is associated with an increased incidence of secondary neoplasms. Primary brain tumors are rarely seen; however, an increased risk relative to the general population has been observed in male patients with chronic lymphocytic leukemia. A case report of a 62-year-old man with progressive chronic lymphocytic leukemia and pronounced neurologic symptoms is presented. Richter's syndrome or brain infiltration with leukemia cells was clinically suspected and suggested by computed tomography findings. Progression of the neurologic symptoms rapidly continued and the patient died. Neuropathologic examination revealed multicentric glial tumors of a varying degree of differentiation located throughout the brain and cerebellum.     

The population history of the Croatian linguistic minority of Molise (southern Italy): a maternal view

This study examines the mitochondrial DNA (mtDNA) diversity of the Croatian-speaking minority of Molise and evaluates its potential genetic relatedness to the neighbouring Italian groups and the Croatian parental population. Intermatch, genetic distance, and admixture analyses highlighted the genetic similarity between the Croatians of Molise and the neighbouring Italian populations and demonstrated that the Croatian-Italian ethnic minority presents features lying between Croatians and Italians. This finding was confirmed by a phylogeographic approach, which revealed both the prevalence of Croatian and the penetrance of Italian maternal lineages in the Croatian community of Molise. These results suggest that there was no reproductive isolation between the two geographically proximate, yet culturally distinct populations living in Italy. The gene flow between the Croatian-Italians and the surrounding Italian populations indicate, therefore, that ethnic consciousness has not created reproductive barriers and that the Croatian-speaking minority of Molise does not represent a reproductively isolated entity.     

Acute interstitial nephritis due to mesalazine

A case of mesalazine-induced acute interstitial nephritis (AIN) in a 41-year-old patient with ulcerative colitis (UC) is reported here. Clinical symptoms such as fever and arthralgia, and laboratory findings such as eosinophilia and renal failure suggested AIN, which was confirmed by biopsy. With withdrawal of mesalazine and intravenous methylprednisolone the patient's renal function was recovered. It is observed that early discontinuation of mesalazine is associated with amelioration of interstitial nephritis in most patients, so the recommendation is that patients receiving mesalazine should undergo routine monitoring of renal function. Delayed diagnosis may lead to permanent renal function impairment.     

Different effect of antiulcer agents on rat cysteamine-induced duodenal ulcer after sialoadenectomy, but not gastrectomy

An attempt has been made to pharmacologically isolate cholinergic, P(2) purinoceptor-mediated and peptidergic (capsaicin-sensitive, tachykinin-mediated) contraction of the guanethidine-treated rat bladder detrusor preparation, in vitro. The effect of experimental diabetes was assessed on these types of contraction. Responses were evoked by electrical field stimulation (single shocks or 1 Hz for 30 s or 10 Hz for 40 s). Single shocks and 1-Hz stimulation were applied in the presence of (a). atropine (1 microM) or (b). P(2) purinoceptor antagonists (50 microM pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid) [PPADS] plus 100 microM suramin. Long-term electrical field stimulation (10 Hz for 40 s) (c). was applied with both atropine and the P(2) purinoceptor antagonists present in the organ bath. The effects of capsaicin (d). and ATP (e). were also studied. Three groups of experimental animals were used: streptozotocin-treated (50 mg.kg(-1) i.p., 8 weeks before the experiment), parallel solvent-treated and untreated rats. (a). Responses to electrical field stimulation in the presence of atropine were reduced by half by PPADS plus suramin, but were resistant to capsaicin tachyphylaxis. They were enhanced in preparations taken from diabetic rats. (b). Contractions to electrical field stimulation in the presence of PPADS plus suramin were reduced by 2/3 by atropine, but were left unchanged by capsaicin or diabetes. (c). Contractions to long-term stimulation had a quick and a sustained phase. Especially the latter was inhibited by capsaicin tachypyhlaxis; it was also strongly reduced in preparations taken from diabetic rats. (d). Contractions to capsaicin (30 nM and 1 microM) were resistant to tetrodotoxin, strongly reduced by a combination of tachykinin NK(1) and NK(2) receptor antagonists, and slightly reduced in preparations from diabetic animals. Capsaicin (1 microM) had no acute inhibitory action on cholinergic or purinergic responses, nor did it cause relaxation in precontracted preparations treated with tachykinin receptor antagonists. (e) ATP-induced contractions were strongly reduced by PPADS plus suramin (50 plus 100 microM) and to a similar degree by 100 plus 200 microM, respectively. It is concluded that experimental diabetes selectively impairs peptidergic, capsaicin-sensitive responses (especially those that involve impulse conduction) in the rat detrusor preparation. The contractile response to electrical field stimulation that remains after atropine plus the P(2) purinoceptor antagonists has a yet unknown transmitter background.     

Photo cross-linkable Biodendrimers as ophthalmic adhesives for central lacerations and penetrating keratoplasties

PURPOSE: Biodendrimer-based hydrogel adhesives were derived from biocompatible building blocks and poly(ethylene glycol) of 3,400, 10,000 and 20,000 g/mole. The leaking pressures were determined for these adhesives when used to seal 4.1-mm central lacerations and penetrating keratoplasties (PKPs) in enucleated porcine eyes. METHODS: Three biodendrimers, ([G1]-PGLSA-MA)(2)-PEG(3,400), ([G1]-PGLSA-MA)(2)-PEG(10,000), and ([G1]-PGLSA-MA)(2)-PEG(20,000), at a range of weight percents were each photo cross-linked in the presence of a photo-initiator to form a hydrated network. These biodendrimer-based adhesives were applied directly to a 4.1-mm linear central laceration. In a PKP, the corneal button was initially secured with 8 or 16 sutures and then sealed with the adhesive. RESULTS: For the 4.1-mm central lacerations, the ([G1]-PGLSA-MA)(2)-PEG(3,400) at 20% and 40% wt/vol, the ([G1]-PGLSA-MA)(2)-PEG(10,000) at 10 and 20% wt/vol, and the ([G1]-PGLSA-MA)(2)-PEG(20,000) at 20% wt/vol held to leaking pressures above 200 mm Hg. In the autograft with 16 sutures, the 20% wt/vol of the ([G1]-PGLSA-MA)(2)-PEG(3,400), ([G1]-PGLSA-MA)(2)-PEG(10,000), and ([G1]-PGLSA-MA)(2)-PEG(20,000) held to a pressure at or above 100 mm Hg. In the autograft with eight sutures, the ([G1]-PGLSA-MA)(2)-PEG(10,000) and ([G1]-PGLSA-MA)(2)-PEG(20,000) formulations at 20% wt/vol held to leaking pressures of 85 +/- 22 and 80 +/- 30 mm Hg, respectively. CONCLUSIONS: The 10% wt/vol ([G1]-PGLSA-MA)(2)-PEG(10,000) formulation withheld leaking pressures above 200 mm Hg when used to secure a 4.1 mm central laceration. The 20% wt/vol ([G1]-PGLSA-MA)(2)-PEG(10,000) and ([G1]-PGLSA-MA)(2)-PEG(20,000) formulations, with 8 or 16 sutures, secured the PKP well above normal IOP. Biodendrimer-based adhesives are of potential use for repairing corneal wounds.     

Interactive effects of insulin-like growth factor-1 and beta-estradiol on endothelial nitric oxide synthase activity in rat aortic endothelial cells

Insulin-like growth factor-1 (IGF-1) and beta-estradiol (E2) have vasodilatory effects, in part, through stimulation of vascular nitric oxide (NO) production. However, their interactive effects on endothelial nitric oxide synthase (eNOS) and NO production have not been previously studied in endothelial cells (EC). Employing rat aortic EC (RAEC), the effects of acute (20 and 30 minutes) and prolonged (4 hours) stimulation with 100 nmol/L IGF-1 and 1 nmol/L E2 (alone or in combination) were assessed with respect to protein levels and enzymatic activities for phosphatidyl inositol 3-kinase (PI3K) and serine/threonine kinase Akt (Akt), enzymes involved in eNOS activation. Exposure to IGF-1 for 30 minutes or E2 for 20 minutes increased insulin receptor substrate-1 (IRS-1) association with the regulatory (p85) subunit of PI3K, enhanced tyrosine phosphorylation of p85, and increased PI3K activity. Combined treatment had a greater effect on p85 phosphorylation and PI3K activity then either agonist alone. Moreover, IGF-1 and E2 enhanced Akt Ser(473) phosphorylation, with the effect of IGF-1 being much greater. Acute expose to both E2 (20 minutes) and IGF-1 (30 minutes) were associated with an increase in eNOS activity. Prolonged exposure (4 hours) to either IGF-1 or E2 increased expression of the p85 subunit as well as eNOS activity. Pretreatment with PI3K antagonist wortmannin (WT) prevented this increase in eNOS activity. The results suggest that IGF-1 and E2 may interact through PI3K/Akt-related pathways to increase eNOS activity.     

Systemically available bone morphogenetic protein two and seven affect bone metabolism

Purpose

Bone morphogenetic protein (BMP)-2 and -7 are used in patients with long-bone fractures, nonunions and spinal fusions. It is unknown whether their potential systemic bioavailability following local bone administration might affect skeletal metabolism. To answer this question, we examined effects of systemically administered BMP-2 and -7 on bone in a newly developed rat model with a low level of calciotropic hormones.

Methods

Removal of thyroid and parathyroid glands (TPTx) in rats resulted in a decreased level of calciotropic hormones and subsequent bone loss assessed by micro computed tomography (micro-CT) and measurement of serum bone formation and resorption markers, including osteocalcin, C-telopeptide, osteoprotegerin and receptor activator of nuclear factor kappa-B ligand. Results were complemented with in vitro studies on osteoblast and osteoclast activity by both BMP-2 and -7. The doses used were calculated from published pharmacodynamic studies and bioavailability results from preclinical BMP-2 and -7 studies.

Results

TPTx resulted in bone loss, which was restored by systemic administration of 10–70 μg/kg of BMP-2 and 10–250 μg/kg of BMP-7. BMP-2 showed a higher capacity for enhancing trabecular microarchitecture, whereas BMP-7 augmented trabecular thickness. In vitro experiments revealed that BMP-2 and -7 when uncoupled increased the number and activity of both osteoblasts and osteoclasts.

Conclusions

Surprisingly, both BMP-2 and -7 showed an increased bone volume in an in vivo environment of low calciotropic hormones. Locally administered BMP-2 and -7 from bone devices might become partially available in circulation but will not mediate systemic bone loss.