Huntington's disease (HD) is a progressive inherited neurological disease characterized by the degeneration of basal ganglia and the accumulation of mutant huntingtin (mHtt) aggregates in specific ...brain areas. Currently, there is no treatment for halting the progression of HD. Cerebral dopamine neurotrophic factor (CDNF) is a novel endoplasmic reticulum located protein with neurotrophic factor properties that protects and restores dopamine neurons in rodent and non-human primate models of Parkinson's disease. Our recent study showed that CDNF improves motor coordination and protects NeuN positive cells in a Quinolinic acid toxin rat model of HD. Here we have investigated the effect of chronic intrastriatal CDNF administration on behavior and mHtt aggregates in the N171-82Q mouse model of HD. Data showed that CDNF did not significantly decrease the number of mHtt aggregates in most brain regions studied. Notably, CDNF significantly delayed the onset of symptoms and improved motor coordination in N171-82Q mice. Furthermore, CDNF increased BDNF mRNA level in hippocampus in vivo in the N171-82Q model and BDNF protein level in cultured striatal neurons. Collectively our results indicate that CDNF might be a potential drug candidate for the treatment of HD.
Huntington's disease (HD) is a neurodegenerative disorder with a progressive loss of medium spiny neurons in the striatum and aggregation of mutant huntingtin in the striatal and cortical neurons. ...Currently, there are no rational therapies for the treatment of the disease. Cerebral dopamine neurotrophic factor (CDNF) is an endoplasmic reticulum (ER) located protein with neurotrophic factor (NTF) properties, protecting and restoring the function of dopaminergic neurons in animal models of PD more effectively than other NTFs. CDNF is currently in phase I-II clinical trials on PD patients. Here we have studied whether CDNF has beneficial effects on striatal neurons in in vitro and in vivo models of HD. CDNF was able to protect striatal neurons from quinolinic acid (QA)-induced cell death in vitro via increasing the IRE1α/XBP1 signalling pathway in the ER. A single intrastriatal CDNF injection protected against the deleterious effects of QA in a rat model of HD. CDNF improved motor coordination and decreased ataxia in QA-toxin treated rats, and stimulated the neurogenesis by increasing doublecortin (DCX)-positive and NeuN-positive cells in the striatum. These results show that CDNF positively affects striatal neuron viability reduced by QA and signifies CDNF as a promising drug candidate for the treatment of HD.
The time domain-random walk method was developed further for simulating mass transfer in fracture flows together with matrix diffusion in surrounding porous media. Specifically, a time domain-random ...walk scheme was developed for numerically approximating solutions of the advection-diffusion equation when the diffusion coefficient exhibits significant spatial variation or even discontinuities. The proposed scheme relies on second-order accurate, central-difference approximations of the advective and diffusive fluxes. The scheme was verified by comparing simulated results against analytical solutions in flow configurations involving a rectangular channel connected on one side with a porous matrix. Simulations with several flow rates, diffusion coefficients, and matrix porosities indicate good agreement between the numerical approximations and analytical solutions.
Within the framework of geological repositories for radioactive waste, structural concretes must be adapted to the underground chemical conditions. CEM I cement-based materials are characterised by ...high pH that may produce an alkaline plume in the near-field of the repository. In order to avoid this problem, low-pH cements have been designed. This study compares the physico-chemical behaviour of a low-pH material with a CEM I cement paste, both being subjected to leaching by an aqueous solution. An original experimental setup was designed to reproduce the underground conditions using a specific CO2 regulation device. Under these conditions, the low-pH material was strongly degraded, which results in coarser porosity, whereas thickness degradation of the CEM I cement paste is limited by the precipitation of a magnesium-calcite crust over the surface, which reduces the exchange of soluble species. This paper also presents a new approach for microstructure characterisation based on high-resolution X-ray microtomography.
Summary
We set out to study connected porosity of crystalline rock using X‐ray microtomography and scanning electron microscopy with energy dispersive X‐ray spectroscopy (SEM‐EDS) with caesium ...chloride as a contrast agent. Caesium is an important radionuclide regarding the final deposition of nuclear waste and also forms dense phases that can be readily distinguished by X‐ray microtomography and SEM‐EDS. Six samples from two sites, Olkiluoto (Finland) and Grimsel (Switzerland), where transport properties of crystalline rock are being studied in situ, were investigated using X‐ray microtomography and SEM‐EDS. The samples were imaged with X‐ray microtomography, immersed in a saturated caesium chloride (CsCl) solution for 141, 249 and 365 days and imaged again with X‐ray microtomography. CsCl inside the samples was successfully detected with X‐ray microtomography and it had completely penetrated all six samples. SEM‐EDS elemental mapping was used to study the location of caesium in the samples in detail with quantitative mineral information. Precipitated CsCl was found in the connected pore space in Olkiluoto veined gneiss and in lesser amounts in Grimsel granodiorite. Only a very small amount of precipitated CsCl was observed in the Grimsel granodiorite samples. In Olkiluoto veined gneiss caesium was found in pinitised areas of cordierite grains. In the pinitised areas caesium was found in notable excess compared to chloride, possibly due to the combination of small pore size and negatively charged surfaces. In addition, elevated concentrations of caesium were found in kaolinite and sphalerite phases. The findings concerning the location of CsCl were congruent with X‐ray microtomography.
Lay description
Crystalline rocks have small amount of empty space, porosity, in them. This porosity has large influence on the properties of the rock and therefore its applications. Different techniques exist to visualise this pore space. In this work we have used X‐ray tomography and scanning electron microscopy with energy dispersive X‐ray spectroscopy (SEM‐EDS). As the pores in crystalline rock usually have diameters of few micrometres or less, it is difficult to see them without something to enhance the contrast and highlight the pore space. Therefore we tested a method to highlight the pore space with a contrast agent introduced via saturated water solution, which forms dense phases that are clearly visible in both X‐ray tomography and SEM‐EDS. We used CsCl as a contrast agent in two different types of crystalline rock samples. Different immersion times were used to test the speed in which the contrast agent intrudes into the pores of the rock. The samples were dried after the immersion. Thereafter methyl methacrylate was intruded into the sample and polymerised therein to fix the CsCl in place. The results showed that CsCl phases highlighted the connected pore space of the rock in both X‐ray tomography and SEM‐EDS. Open fissures showed improved contrast and especially noteworthy contrast improvement was noted in cordierite that had undergone alteration to pinite, a mixture of clay minerals. In pinite it was also noted that caesium was found often in considerably higher abundance than its counter ion chloride. This was possibly due to chloride's negative charge, it was excluded from the smallest pores with negatively charged surfaces.
The incisura angularis is considered to be a typical site for Helicobacter pylori colonization, glandular atrophy, intestinal metaplasia, gastric ulcer, and gastric carcinoma. Our aim was to clarify ...whether it is necessary to biopsy the incisura angularis routinely during gastroscopy, in addition to obtaining biopsies of the corpus and antrum.
A total of 272 consecutive patients, with a mean age +/- SD of 53.8 +/- 15.5 years, had two biopsies taken from the angulus, two from the antrum, and two from the corpus of the stomach during routine upper gastrointestinal endoscopy. Histological specimens were examined according to the updated Sydney System for the classification and grading of gastritis.
Of the 272 patients, 11 (4.0 %) showed chronic inflammation in the angulus biopsy only. Similarly, the angulus was the only biopsy site which showed neutrophil polymorph infiltration (or "activity") in two patients (0.7 %), intestinal metaplasia in 13 patients (4.7 %), atrophy in three patients (1.1 %), and H. pylori colonization in one patient (0.4 %). Dysplasia (intraepithelial neoplasia) was not found in any of the biopsied sites in any of the 272 patients. H. pylori was found in 39 of the 272 patients (14 %). Of the 272 patients, 120 patients showed abnormalities at the incisura angularis, 101 having gastropathy or erosions, and only 19 showing more specific macroscopic changes, the main ones being ulcer, ulcer scarring, and atrophy. Of the 152 patients with a normal-looking mucosa at the angulus, only six (3.9 %) showed the histological changes of chronic inflammation in the angulus alone. Similarly, the angulus was the only biopsy site which showed neutrophil polymorph infiltration in one patient (1/152, 0.7 %), and intestinal metaplasia in five patients (5/152, 3.3 %). Atrophy and H. pylori colonization were not seen exclusively at the angulus in any of the patients with a macroscopically normal-looking angulus.
Based on our data, routine biopsy of the incisura angularis would provide little additional clinical information to that obtainable from antrum and corpus biopsies.
Summary
Aim : To systematically determine Helicobacter pylori primary antimicrobial resistance in Finland and the associated demographic and clinical features.
Methods : A total of 342 adult patients ...referred for gastroscopy at 23 centres in different parts of Finland and positive for the rapid biopsy urease test were recruited. Clinical and demographic data were collected via a structured questionnaire. Patients with positive H. pylori culture and successful antibiotic sensitivity determination by the E‐test method (n = 292) were included in the present analysis.
Results : The study population consisted of 134 men and 158 women, mean age 56 years (95% CI, 55–58 years). Resistance to metronidazole was 38% (110 of 292) and to clarithromycin 2% (seven of 292). Resistance to metronidazole was higher in women than in men (48% vs. 25%, P < 0.001).
Previous use of antibiotics for gynaecological infections predicted metronidazole resistance (P = 0.01), and previous use of antibiotics for respiratory (P = 0.02) and dental infections (P = 0.02) the clarithromycin resistance. We observed no major geographical variations in metronidazole resistance.
Conclusions : The primary metronidazole resistance of H. pylori was 38% and was common in women previously treated for gynaecological infections. Primary clarithromycin resistance was uncommon (2%) and may associate with previous dental and respiratory infections.
Summary
Aim: To determine the efficacy of three Helicobacter pylori eradication regimens and factors affecting the eradication results in Finland.
Methods: A total of 342 H. pylori‐positive adult ...patients from primary health care referred for gastroscopy at 23 centres in different parts of Finland were randomized to receive either (i) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and metronidazole 400 mg t.d.s. (LAM), (ii) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and clarithromycin 500 mg b.d. (LAC), or (iii) ranitidine bismuth citrate 400 mg b.d., metronidazole 400 mg t.d.s. and tetracycline 500 mg q.d.s. (RMT). A 13C‐urea breath test was performed 4 weeks after therapy.
Results: The eradication result could be assessed in 329 cases. Intention‐to‐treat cure rates of LAM, LAC, and RMT were 78, 91 and 81%. The difference was significant between LAM and LAC (P = 0.01) and between LAC and RMT (P = 0.04). The eradication rates in cases with metronidazole‐susceptible vs. ‐resistant isolates were for LAM 93% vs. 53% (P = 0.00001), for LAC 95% vs. 84%, and for RMT 91% vs. 67% (P = 0.002). Previous antibiotic use, smoking, and coffee drinking reduced the efficacy of therapy.
Conclusions: In unselected patients in primary health care, LAC was the most effective first‐line eradication.
The contribution of serotype‐specific IgG concentration, subclasses, and avidity to opsonophagocytic activity (OPA) against Streptococcus pneumoniae (Pnc) was evaluated in sera of adults and infants ...immunized with different pneumococcal vaccines. Antibody concentrations and avidities were measured by enzymeimmunoassay (EIA) and OPAs by killing assay of Pnc. The most important factor contributing positively to OPA was the specific IgG level. In infants, a tendency to negative correlation was found between the concentration needed for killing of bacteria and avidity, suggesting that less antibodies of high rather than low avidity were required for killing. No such correlation was seen in adults. However, in adults the avidity was high already before vaccination and the variation was narrow. Thus, avidity was probably not a limiting factor influencing OPA. The effect of IgG2/IgG1 ratio on OPA was mostly negative but insignificant.
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