Induced pluripotent stem cells as a model for diabetes investigation.

Mouse and human induced pluripotent stem cells (iPSCs) may represent a novel approach for modeling diabetes. Taking this into consideration, the aim of this study was to generate and evaluate differentiation potential of iPSCs from lep(db/db) (db/db) mice, the model of diabetes type 2 as well as from patients with Maturity Onset Diabetes of the Young 3 (HNF1A MODY). Murine iPSC colonies from both wild type and db/db mice were positive for markers of pluripotency: Oct3/4A, Nanog, SSEA1, CDy1 and alkaline phosphatase and differentiated in vitro and in vivo into cells originating from three germ layers. However, our results suggest impaired differentiation of db/db cells into endothelial progenitor-like cells expressing CD34 and Tie2 markers and their reduced angiogenic potential. Human control and HNF1A MODY reprogrammed cells also expressed pluripotency markers: OCT3/4A, SSEA4, TRA-1-60, TRA-1-81, formed embryoid bodies (EBs) and differentiated into cells of three germ layers. Additionally, insulin expressing cells were obtained from those partially reprogrammed cells with direct as well as EB-mediated differentiation method. Our findings indicate that disease-specific iPSCs may help to better understand the mechanisms responsible for defective insulin production or vascular dysfunction upon differentiation toward cell types affected by diabetes.

[Merkel cell carcinoma of the nose]. / Rak nosa z komórek Merkla.

Despite an increasing number of reports Merkel cell carcinoma still is a rare neoplasm. We therefore present the imaging feature of the case of Merkel cell carcinoma involving the nasal region in 65-year woman with lymphoma malignum lymphoplasmocytoides and its rapid progression with fast metastasis to lymph nodes. Surgery and adjuvant radiotherapy, chemotherapy appeared to provide optimal local control.

Compared properties of trandolapril, enalapril, and their diacid metabolites.

The effects of 14-day trandolapril or enalapril treatment of spontaneously hypertensive rats (SHRs) were studied on blood pressure and angiotensin-converting enzyme (ACE) activity measured ex vivo in various organs. Both ACE inhibitors caused dose-dependent decreases in blood pressure and ACE activity, trandolapril being 30- and 400- to 1,000-fold more active than enalapril on blood pressure and ACE activity, respectively. However, comparison of ACE inhibitory activities of the diacid forms of trandolapril and enalapril, i.e., trandolaprilat and enalaprilat, measured in vitro on various tissues, showed that trandolaprilat was only three- to fivefold more active than enalaprilat. To understand the reasons for such discrepancies between ex vivo effects of ACE inhibitors and in vitro actions of their diacid metabolites, we measured the lipophilicities of the compounds and investigated the possibility that trandolapril could display an ACE inhibitory effect by itself. Trandolaprilat was found to be far more lipophilic than enalaprilat, as shown by reverse-phase high-performance liquid chromatography studies performed at pH 7.4 (log kw7.4 = 1.487 vs. 0.108). In addition, trandolapril was practically as active in vitro as its diacid metabolite (IC50 = 2.5 vs. 1.35 nM) in inhibiting ACE activity in the aorta, whereas enalapril was practically devoid of any effect (IC50 = 240 nM). Measurements of relative affinities of inhibitors or metabolites for purified human renal ACE showed that trandolapril displayed about 20% of the affinity of its diacid metabolite (IC50 = 15 vs. 3.2 nM); enalaprilat affinity (34 nM) was within the same range as those of trandolapril and trandolaprilat, whereas enalapril displayed a very low affinity for the purified enzyme (IC50 = 50 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Trandolapril dose-response in spontaneously hypertensive rats: effects on ACE activity, blood pressure, and cardiac hypertrophy.

The dose-related effects of trandolapril on serum angiotensin-converting enzyme (ACE) activity, blood pressure and cardiac hypertrophy were studied after 2-week oral treatment in adult spontaneously hypertensive rats. Trandolapril caused a dose-dependent decrease in mean blood pressure at doses of 0.03-3 mg/kg. Inhibition of serum ACE was demonstrated by even the lowest dose (-9% at 0.003 mg/kg), was about 40% at 0.03 mg/kg, and rose to 84% at 3 mg/kg. Regression of cardiac hypertrophy (heart:body weight) was seen at doses of trandolapril as low as 0.03 mg/kg (-5.1%), which was also the minimal effective antihypertensive dose. Clear dose-response curves were observed for trandolapril from 0.03 mg/kg upwards with respect to hypotensive effect and regression of cardiac hypertrophy, which were not seen with enalapril. Enalapril had no significant effect on plasma ACE activity except at the highest dose (10 mg/kg), despite demonstrating hypotensive effects with smaller doses. These results indicate that trandolapril is a more potent (by a factor of about 30) inhibitor of ACE than enalapril (only 34% inhibition at 10 mg/kg) and causes a greater degree of regression of cardiac hypertrophy.

Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to patients with chronic renal failure and healthy control subjects.

A new, long-acting angiotensin-converting enzyme (ACE) inhibitor, trandolapril, was administered daily for 10 days to 13 patients with chronic renal failure [CRF; creatinine clearance (CLCR) 7-55 ml/min/1.73 m2) and 8 healthy volunteers (CLCR > 80 ml/min/1.73 m2)]. Plasma ACE inhibition parameters were the same, irrespective of the degree of renal insufficiency, although renal failure tended to prolong ACE inhibition. The pharmacokinetics of trandolapril were not affected by CRF; hence, no accumulation of trandolapril was detected. After single or repeated administration the active metabolite, trandolaprilat, showed an inverse correlation between maximal plasma concentrations (Cmax) and CLCR (r = -0.676 day 1 and r = -0.864 day 10) and area under the concentration-time curve (AUC) and CLCR (r = -0.635 day 1 and r = -0.794 day 10). The renal clearance of trandolaprilat showed significant linear correlation (r = > 0.885, p < 0.0001) with CLCR after single (r = 0.879) and repeated administration (r = 0.957). Significantly reduced excretion of trandolaprilat was seen only when the CLCR was < 30 ml/min/1.73 m2. A steady state had been achieved by 7 days in all patients, and extrapolation suggested that this was achieved in most cases after 4 days. The drug was well tolerated. The effect of CRF on the pharmacokinetics and pharmacodynamics of trandolaprilat is of significance only when CLCR is < 30 ml/min/1.73 m2. Hence, in these patients the standard dose should be reduced.

Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to young and elderly patients with mild-to-moderate hypertension.

The new angiotensin-converting enzyme (ACE) inhibitor trandolapril 2 mg was administered daily for 10 consecutive days to young (mean age +/- SEM 44.1 +/- 2.3 years; n = 10) and elderly (mean age +/- SEM 69.3 +/- 0.9 years; n = 14) patients with mild-to-moderate hypertension. All groups had similar baseline blood pressures: mean 164/100 mm Hg. Maximal plasma ACE inhibition on day 10 and residual inhibition 24 h after the last dose was the same, irrespective of age: young, 85.2 and 57.4%; elderly 89.1 and 59.8%, respectively. There was no difference between the results on day 1 for the young and elderly groups. The absorption of trandolapril was rapid (< 1 h in all groups). The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were slightly higher in the older group, but the elimination half-life (t1/2) was the same, with no accumulation after repeat dosing. A steady-state plasma concentration of the active metabolite of trandolapril, trandolaprilat, was reached after 4 days in the two groups, with similar accumulation ratios (young, 1.48; elderly, 1.49). At steady state, the Cmax and AUC 0-24 h for trandolaprilat were similar in the two groups: young, 7.49 +/- 0.98 ng/ml and 82.27 +/- 6.95 ng/ml/h; elderly, 8.35 +/- 0.67 ng/ml/h and 96.75 +/- 5.67 ng/ml/h. Maximal reductions in systolic/diastolic blood pressures (at 6 h postdose) were -14.1%/-16.1% in young patients and -14.6%/-17.5% for the elderly. Significant blood pressure reduction persisted for 48 h after the last dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term culture of rat hepatocytes on porous membranes in hormonally defined serum-free medium.

Rat hepatocytes were cultured on type I collagen-coated porous membranes, in Waxman's modified medium supplemented with very low concentrations of insulin (10(-9)m), glucagon (10(-10)m) and dexamethasone (10(-8)m). Under these experimental conditions, specific differentiated functions were well preserved for at least 15 days, as shown by measures of albumin secretion, EROD and PROD activities, by phase contrast microscopy and PAS and ORO staining for intracellular glycogen and lipid contents. These results suggest that this experimental system may be very useful for long-term in vitro pharmacotoxicological studies.

[Potentiation of deltamethrin toxicity by organophosphorus insecticides]. / Potentialisation de la toxicité de la deltaméthrine par les insecticides organophosphorés.

There is a potential hazard in mixed intoxications by pyrethroids and organophosphate insecticides, due to the fact that low toxicity of pyrethroids on mammals is chiefly due to quick cleavage of molecule by esterases, which can be thwarted by esterase inhibitors. We have developed a method in order to measure the duration and the intensity of potentiation of deltamethrin by a variety of organophosphate compounds. It was demonstrated that some of them (azinphos, dichlorvos, dimethoate, fenitrothion, omethoate) induce an increase of toxicity of deltamethrin. But, the total toxicity of association of Deltamethrin with Dimethoate, Fenitrothion, is weak, and does not prohibit their use. Others (methyl-parathion, acephate, phosphamidon, monocrotophos) have no such effects, even if they have a very high intrinsic toxicity. Cholinesterase inhibitors of the carbamate group are ineffective. It is suggested that the potentiation is mainly in relation with the kinetic of esterase inhibition, which is different, and specific to each organophosphate compound. So, it is essential that a specific toxicological measurement must be performed with any different insecticide, in order to anticipate the danger of a mixed intoxication by pyrethroids and organophosphates.

Free flaps versus conventional surgery.

On the basis of about 60 cases, we discuss the clinical use of groin, latissimus dorsi, dorsalis pedis, scapular, parascapular, and forearm free flaps. These flaps are evaluated in relation to some alternate reconstructive procedures in various regions of the body, with photographic documentation.

The surgical treatment of vascular tumours of the face.

On the basis of 650 vascular tumours of the face treated in the Hospital of Plastic Surgery in Polanica Zdrój, the authors discuss the various methods of surgery evolved during the 30 years of Centre activity. Special attention has been paid to the management of the more difficult lympho- and haemangiomas such as cavernous, hypertrophic and expansive, or progressive forms. Numerous examples of treatment are presented.

The surgical correction of maxillary hypoplasia and midfacial retrusion.

On the basis of 35 maxillary osteotomies of the Le Fort I and III types, the authors discuss the main problems connected with treatment of maxillary hypoplasia and midfacial retrusion. Special attention is paid to cases that demand coordinated treatment including skeletal as well as soft tissue repair and reconstruction. Thanks to combined treatment in all cases, including 7 patients with partial backward displacement of the osteotomized fragments whose occlusion could not be entirely corrected, striking or highly satisfactory improvement of appearance was achieved.