Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration.

A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.

A randomised, phase II study of nintedanib or sunitinib in previously untreated patients with advanced renal cell cancer: 3-year results.

BACKGROUND: This exploratory study evaluated the safety/efficacy of nintedanib or sunitinib as first-line therapy in patients with advanced renal cell carcinoma (RCC). METHODS: Ninety-six patients were randomised (2:1) to either nintedanib (200 mg twice daily) or sunitinib (50 mg kg(-1) once daily (4 weeks on treatment; 2 weeks off)). Primary endpoint was progression-free survival (PFS) at 9 months. P-values reported are descriptive only; the study was not powered for such comparisons. RESULTS: Progression-free survival at 9 months was comparable between nintedanib and sunitinib (43.1% vs 45.2%, respectively; P=0.85). Median PFS was 8.4 months in each group (hazard ratio (HR), 1.12; 95% confidence interval (CI): 0.70-1.80; P=0.64). Median overall survival was 20.4 and 21.2 months for nintedanib and sunitinib, respectively (HR, 0.92; 95% CI: 0.54-1.56; P=0.76). Overall incidence of any grade adverse events (AEs) was comparable (90.6% vs 93.8%); AEs grade ⩾ 3 were lower with nintedanib than sunitinib (48.4% vs 59.4%). Nintedanib was associated with lower incidences of some AEs typical of antiangiogenic tyrosine kinase inhibitors (TKIs): hypertension, hypothyroidism, hand-foot syndrome, cardiac disorders and haematological abnormalities. CONCLUSIONS: In patients with advanced RCC, nintedanib has promising efficacy and similar tolerability to sunitinib, and a manageable safety profile with fewer TKI-associated AEs.

Genetic comparison of Campylobacter jejuni isolated from different cattle farms.

To compare the genotypes of Campylobacter jejuni, isolates of cattle origin were collected from 9 Polish farms and genotyped by ERIC-PCR. We identified 28 genotypes among the 43 C. jejuni isolates, and demonstrated high genomic diversity. The highest level of diversity was observed in strains isolated from stanchion-barn animals in opposition to those from the loose-housing system.

A survey of anti-Ostertagia ostertagii antibody levels in bulk tank milk samples (BTM) in dairy herds in Lower Silesia Region (Poland).

This work presents serological evidence of cattle ostertagiosis in the Lower Silesia Region (Poland), based on the measurement of antibodies in bulk tank milk (BTM) samples. It represents the first evidence of this parasite examined with the use of the ELISA test and milk samples in Poland. The prevalence of Ostertagia ostertagii antibodies was determined in BTM from 32 dairy cattle herds. Antibodies to O. ostertagii were demonstrated in all herds. The optical density ratio (ODR) varied from -0.088 to 1.024. The mean ODR value in the examined region was 0.53.

The effect of undecanones and their derivatives on tumor angiogenesis and VEGF content.

The in vivo effects of some derivatives of aliphatic ketones (2-undecanone, 3-undecanone, 4-undecanone and their derivatives) on L-1 sarcoma tumor angiogenesis and VEGF content were studied in Balb/c mice. Mice that inhaled 10% solution of 3-undecanone(3-on) or 1% solution of 2-undecanone propylene acetal (Acpr2) for 3 days after tumor cells implantation, presented lower neovascular response measured by tumor-induced cutaneous angiogenesis test (TIA) and lower tumor VEGF content in 5-days tumors, than non-inhaled controls. Other substances presented various effects on tumor VEGF concentration and angiogenesis. Histological examination of lesions collected from mice inhaled Acpr2, or non-inhaled controls, revealed small diffused areas of necrosis in the former group. In both groups, slight to moderate inflammatory infiltrations were seen at the tumor's margin. In Acpr2 group, there were less small blood vessels at tumor's margin than in the control group.

The influence of Rhodiola quadrifida 50% hydro-alcoholic extract and salidroside on tumor-induced angiogenesis in mice.

UNLABELLED: The genus Rhodiola (Crassulaceae) consists of more than 100 species. They grow mainly in Tibet, China and Mongolia and are traditionally used as tonic, adaptogen, antidepressant and anti-inflammatory drugs. The best known is Rhodiola rosea (R. rosea) now cultivated also in Europe and North America, and present on the market as dietary supplement. Some authors reported anti-tumor activity of R. rosea extracts. Recently, we have published some data on immunomodulatory and antiangiogenic properties of R. rosea. Rhodiola quadrifida (R. quadrifida) belongs to the same family, but is almost not known in Europe, and there is no information about its possible anti-tumor as well as immunotropic and angiotropic activity. The aim of this study was to determine the influence of 50% hydro-alcoholic extract from rhizomes of R. quadrifida (Mongolian origin) and its main biologically active compound salidroside on tumor-induced angiogenesis. Angiogenesis was induced in the skin of Balb/c mice by grafting of syngeneic L-1 sarcoma cells. Mice were fed R. quadrifida extract or salidroside in daily doses 40, 200 and 400 microg, or 0.5, 1, 2, and 4 microg, respectively. After 72 hours, mice were sacrificed with lethal dose of Morbital. All newly formed blood vessels were identified and counted in dissection microscope. RESULTS: It was found that R. quadrifida extract and salidroside highly significantly decreased neovascular reaction in all doses applied.

The effect of Rhodiola quadrifida extracts on cellular immunity in mice and rats.

Rhodiola quadrifida (Rq) roots and rhizomes are traditionally used in Asia as a tonic, adaptogen, antidepressant and anti-inflammatory drug. The aim of this work was to study the in vivo effect of aqueous and 50% hydro-alcoholic extracts of Rq rhizomes on some parameters of cellular immunity in mice and rats. The metabolic activity of blood phagocyting cells was determined based on the measurement of intracellular respiratory burst after stimulation by PMA in RBA test. Potential bactericidal activity of phagocyting cells was determined in isolated blood leukocytes stimulated with killed microorganisms, according to the PKA test. Proliferative response of lymphocytes stimulated by mitogen concanavaline A (ConA) or lipopolysaccharide (LPS) were determined by MTT assay. Both extracts stimulated granulocytes activity in vitro and increased lymphocyte response to mitogens. The ability of parental strain mice lymphocytes to induce local cutaneous graft-versus-host reaction (GVH) in F1 hybrids was stimulated by 50% hydro-alcoholic extract only.

Intracellular distribution of Photofrin in malignant and normal endothelial cell lines.

Compared to current treatments including surgery, radiation therapy, and chemotherapy, PDT offers the advantage of an effective and selective method of destroying diseased tissues without damaging surrounding healthy tissues. One of the aspects of antitumour effectiveness of PDT is related to the distribution of photosensitizing drugs. The localization of photosensitizers in cytoplasmic organelles during PDT plays a major role in the cell destruction; therefore, intracellular localization of Ph in malignant and normal cells was investigated. The cell lines used throughout the study were: human malignant A549, MCF-7, Me45 and normal endothelial cell line HUV-EC-C. After incubation with Ph cells were examined using fluorescence and confocal microscopy to visualize the photosensitizer accumulation. For cytoplasm and mitochondria identification, cells were stained with CellTracker Green and MitoTracker Green, respectively. Distribution of Ph was different in malignant and normal cells and dependent on the incubation time. The maximal concentration of Ph in two malignant cell lines (A549 and MCF-7) was observed after 4 hours of incubation, and the most intensive signal was observed around the nuclear envelope. Intracellular distribution of Ph in the Me45 cell line showed that the fluorescence emitted by Ph overlaid that from MitoTracker. This indicates preferential accumulation of the sensitizer in mitochondria. Our results based on the mitochondrial localization support the idea that PDT can contribute to elimination of malignant cells by inducing apoptosis, which is of physiological significance.

Changes in blood flow to bones during the hypocalcemic and hypercalcemic phases of the response to parathyroid hormone.

Labeled microspheres were used to measure blood flow to the leg bones of the laying hen at 0, 3, and 30 min after iv injection of parathyroid hormone (PTH) (Wilson) or the synthetic 1 to 34 fragment of bovine parathyroid hormone (PTH 1-34). At 3 min, which corresponds to the hypocalcemic phase of the PTH response, blood flow to the combined femur, tibia, and metatarus was significantly reduced by PTH (Wilson) relative to 0 time and to carrier-injected controls. At 30 min, i.e., the time of maximum hypercalcemia in the hen, blood flow to these bones was significantly increased relative to 0 time. The results obtained with PTH 1-34 were similar, except that the decrease at 3 min was only significant in comparison with the controls injected with inactivated hormone. Femoral blood flow and the venous minus arterial calcium gradients across the femur were positively correlated, irrespective of sampling time (0 or 30 min) or type of injection (PTH [Wilson] or carrier). Taken together, these results suggest that there is a relationship between calcium mobilization from bone and the rate of osseous blood flow. Other organs which showed significant changes in blood flow after PTH (Wilson) were the adrenals, thyroids, and shell gland; the cerebellum, parathyroids, heart, spleen, liver, pancreas, duodenum, magnum, isthmus, and kidneys were not affected.

A multicentre randomized/controlled trial of a conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1 week shortening overall time.

BACKGROUND AND PURPOSE: To compare in a phase III study the loco-regional control, disease-free survival and overall survival induced by an accelerated regimen (AF) as compared with conventional regimen (CF) and to analyze the early and late post-radiation morbidity in both arms. MATERIALS AND METHODS: Patients with age < or = 75, WHO 0-1, suitable for a radical course of radiotherapy T1-T3, N0, M0, stage of glottic and supraglottic laryngeal cancer were randomized to either CF: 66Gy given in 33 fractions over 45 days or AF: 66Gy given in 33 fractions over 38 days (2 fractions every Thursday). A total of 395 patients were included from 05.1995 to 12.1998. RESULTS: Early toxicity: At the end of radiotherapy patients treated with AF complained for more severe reactions than patients treated with CF. In 8 weeks after treatment completion patients treated with AF complained only for more severe pain on swallowing (P=0.027). In 4 months after treatment completion all types of toxicity except for skin teleangiectasia (P=0.001) were similar in the two groups. Loco-regional control: comparison between CF and AF showed no difference in terms of loco-regional control (P=0.37). CONCLUSIONS: The improvement in AF in terms of loco-regional control is estimated to be 3-5% in comparison with conventional regimen and is not significant. The intensity of reactions after 4 months was similar in both arms, what suggests the possibility of further shortening of the overall time by few days or enhancing the total dose within the limits of acceptable morbidity.

Acute effects of gamma-vinyl GABA on the GABAergic system in rats as studied by microdialysis.

The acute effects of the irreversible gamma-aminobutyric acid (GABA) transaminase inhibitor, gamma-vinyl GABA (Vigabatrin), were studied in the central nervous system of the rat. GABA concentrations were monitored in the hippocampus by implantation of microdialysis probes. Two doses of gamma-vinyl GABA (1.6 and 8.0 mM) were administered via the probes and were found to cause a transient increase in the basal GABA outflow (10-fold) during the period of drug administration. In addition, gamma-vinyl GABA pretreatment (1.6 mM) seemed to decrease K(+)-evoked GABA release (P < 0.05). The immediate increase of GABA outflow after gamma-vinyl GABA administration may be the result of direct blockade of GABA uptake sites, a finding which further indicates that the action of GABA transaminase inhibitors may be mediated partly through GABA uptake inhibition.

Increased GABAergic transmission aggravates nucleus basalis magnocellularis lesion-induced behavioral deficits.

Quisqualic acid NBM lesions had no effect on water maze performance, but slightly impaired passive avoidance acquisition. GammavinylGABA treatment alone had no effect on the passive avoidance and water maze performance, but aggravated acquisition deficit in rats subjected to NBM lesioning. However, gammavinylGABA-treated NBM-lesioned rats reached control level of performance.

The effects of selective alpha-2 adrenergic agents on the performance of rats in a 5-choice serial reaction time task.

The present study investigated how the systemic administration of alpha-2 adrenergic agents that modulate the function of the noradrenergic system in brain, affect rousal and sustained attention. Food-deprivated rats were trained to detect and respond to brief flashes of light presented randomly in one of five spatially diverse locations. The effects of single-dose administrations of dexmedetomidine, an alpha-2 agonist, and atipamezole, an alpha-2 antagonists, on the choice accuracy, errors of omissions, speed of responding, and collection of the reward could be assessed in this task. Dexmedetomidine increased the amount of omissions, speed of response, and decreased the number of premature responses, although it did not markedly lengthen response latencies and food collection latency. Atipamezole increased the number of premature responses. Neither dexmedetomidine nor atipamezole had any effect on choice accuracy of rats in this task. The results suggest that dexmedetomidine decreased behavioral activity and arousal of rats, whereas atipamezole had mild stimulant effect on behavior.

Effects of single and repeated administration of vigabatrin on the performance of non-epileptic rats in a delayed non-matching to position task.

The present experiments were performed to investigate the effects of single and repeated administration of vigabatrin (gamma-vinyl-GABA), a novel antiepileptic drug, on a working memory task (delayed non-matching to position task) in non-epileptic rats. At doses of 100, 300 and 500 mg/kg single administrations of vigabatrin and 50, 100 and 200 mg/kg repeated administrations, vigabatrin did not affect the choice accuracy in the delayed non-matching to position task employing delays of 0, 1, 2, 4, 8 and 16 s, whereas repeated administration with 300 mg/kg and a single dose of 1000 mg/kg decreased the behavioral activity as compared to saline treatment. Previous studies have shown that at doses of 50-200 mg/kg (daily administration) and 200-1000 mg/kg (single administration) vigabatrin has anticonvulsant activity. The present results suggest that vigabatrin does not markedly impair working memory in the low range of antiepileptic/anticonvulsive doses.

Effects of single and repeated administration of vigabatrin on the performance of rats in a 5-choice serial reaction time task.

The present study investigated whether pharmacological stimulation of the GABAergic system can affect attention. The effects of vigabatrin, a novel antiepileptic drug, on the performance of rats in a 5-choice serial reaction time task assessing selective attention were studied. The effects of acute (100, 300, 500 and 1000 mg/kg) and subchronic (50, 100, 200 and 300 mg/kg/day) administration of vigabatrin were investigated. Previous studies have shown that with acute administration of 300-500 mg/kg or subchronic administration of 50-200 mg/kg/day vigabatrin has anticonvulsant activity. At acute doses of 100 and 300 mg/kg or subchronic administration of 50-200 mg/kg/day vigabatrin had no effect on selective attention. At acute dosing of 500 mg/kg, vigabatrin slightly decreased behavioral activity of rats through decreasing the number of trials completed and percent of correct responses. The highest doses used caused an overall behavioral impairment with no marked depletion of any particular function. The results showed that administration of vigabatrin at antiepileptic doses produced no or slight impairment in attentional function. The deficits seen with higher doses were possibly due to a decrease in behavioral activity.

Enzyme activity in mice with transplantable leukemia.

Activity of cobalt activated acylase, gamma-glutamyltransferase, leucylaminopeptidase and alanylaminopeptidase in serum and liver of mice with transplantable leukemias (L1210, L1210/ara-C, L1210/CH3-G, AKSL-4, plasmacytoma ADJ-PC-5) were determined. Adenosinotriphosphatase, 5'-nucleotidase and alkaline phosphatase were histochemically localized in lymphatic nodes and spleen. Among the investigated enzymes the rise in serum activity of cobalt activated acylase and gamma-glutamyltransferase was demonstrated. A substantial increase of leucylaminopeptidase and alanylaminopeptidase was shown in the liver. A decrease in the histochemical reactions of all the studied enzymes was observed.

Effects of an inhibitor of GABA-aminotransferase (gamma-vinyl-GABA) on the spatial navigation deficit induced by muscarinic blockade.

The present study investigated whether stimulation of the GABAergic system affects spatial navigation [water-maze (WM)] deficit induced by muscarinic blockade (scopolamine). The effects of various doses of gamma-vinyl-GABA (GVG) (50, 150, and 300 mg/kg) and scopolamine (0.4 and 0.1 mg/kg) were examined alone and in combination. GVG at 50 and 150 mg/kg alone did not impair the performance of rats in the WM yask. At 300 mg/kg, GVG caused slight impairment, increasing latency and total distance swim during training trials. Scopolamine at 0.4 mg/kg clearly impaired the performance of rats in the WM task. When the two drugs were coadministered, no interaction between scopolamine and GVG was observed. Our results do not provide support for any interaction between cholinergic muscarinic and GABAergic mechanisms.

Dose- and parameter-dependent effects of atipamezole, an alpha 2-antagonist, on the performance of rats in a five-choice serial reaction time task.

The present study investigated whether atipamezole (ATI), a potent alpha 2-adrenoceptor antagonist that increases the release of noradrenaline in brain, improves attention in rats. Thus, the effects of ATI on the performance of adult male rats in the five-choice serial reaction time task were studied. Food-deprived rats were trained to detect and respond to brief flashes of light presented randomly in one of five spatially diverse locations. The effects of single-dose administration of ATI (0.03-3.0 mg/kg) on the performance of rats under different parametric manipulations of the task were tested: 1) the visual stimuli were presented at unpredictable intertrial intervals (ITIs) or b) the intensity (brightness) of visual stimuli was reduced, thus placing an additional load on attentional processing for animals. Presenting the stimuli earlier than normally or reducing its intensity markedly impaired the choice accuracy of rats. At doses of 0.03, 0.3, and 1.0 mg/kg, ATI improved the choice accuracy of rats when tested using reduced stimulus intensity. ATI 3.0 mg/kg did not affect accuracy performance when tested using reduced stimulus intensity but impaired it when tested using unpredictable ITIs. The other doses of ATI (0.03, 0.3, and 1.0 mg/kg) did not markedly affect choice accuracy of rats tested using unpredictable ITI. Our results could be explained by the assumption that an acute, systemic administration of ATI affects arousal mechanisms and facilitates the processing of visual stimuli related to reward.

Diptera--ovary structure and oogenesis in midges and flies.

Comparative study of ovary development and oogenesis in the dipterans revealed significant differences between the Nematocera (lower dipterans, midges) and the Brachycera (true flies). The occurrence of these differences emphasizes well the phylogenetic division of the Diptera into these major subgroups. Basic discrepancies were found in the course of ovary development and in the mode of follicular cell differentiation. In contrast to more advanced flies, in midges the initial stages of germ cell differentiation, i.e. divisions of gonial cells, germ cell cluster formation and diversification of cystocytes within clusters take place exclusively in the larval and early pupal stages. Moreover, the formation of cystocyte clusters precedes that of ovarioles. Differences in the behaviour of some follicular cells found between the ovarian follicles of midges and advanced flies suggest that both major dipteran subgroups may differ in the scenario and/or the mechanisms of terminal signalling leading to the determination of the anteriormost part of the body.