Gastric Pit Cell Hyperplasia and Glandular Atrophy in Carbonic Anhydrase IX Knockout Mice: Studies on Two Strains C57/BL6 and BALB/C

Carbonic anhydrase (CA) isoenzyme IX is a hypoxia-inducible enzyme, which is expressed in the human and rodent gastrointestinal tract and overexpressed in several different tumors. Functionally, it has probably an effect on proliferation and differentiation of gastrointestinal epithelial cells. It may also participate in gastric morphogenesis, since a recent study has shown gastric pit cell hyperplasia and glandular atrophy in CA IX-knockout mice. However, it is not known whether CA IX produces morphological changes in the gastric mucosa, which can turn into a dysplasia or malignancy in the presence of some carcinogenic factors. High-salt diet is considered such a factor which has been shown to modulate Helicobacter pylori-associated carcinogenesis. We produced two strains of CA IX-knockout mice, C57/BL6 and BALB/c, and the mice ate either standard or high-salt feed for 20 weeks. Stomach samples were collected from 40 Car9^−/− knockout mice and 37 wildtype littermates, and the tissue sections were examined for histology. CA IX-deficiency caused gastric pit cell hyperplasia and glandular atrophy in both BALB/c and C57/BL6 strains. Excess dietary salt had no significant effect on the severity of pit cell hyperplasia. No dysplasia was found in any of the groups. In C57/BL6 mice, CA IX-deficiency was associated with gastric submucosal inflammation. The results indicate that CA IX-deficiency provides a useful model to study the mechanisms of gastric morphogenesis and epithelial integrity. Further studies are needed to see whether CA IX has a role in the regulation of immune response. The findings suggest that although CA IX-deficiency is not a tumor-promoting factor per se, it induces glandular atrophy in the body mucosa, a lesion which is considered to be a preneoplastic alteration in the stomach.     

Genetic structure of an endangered raptor at individual and population levels

The Finnish population of White-tailed Eagle (Haliaeetus albicilla) has gone through two major demographic bottlenecks during the last two centuries. Strong conservation measures have allowed the population to recover, but despite the rapid population growth during recent years the species is still classified as endangered. We studied the genetic population structure at both individual and population levels in an attempt to recognize the processes shaping it. We used 9 microsatellite loci and 473 base pair fragment of the mitochondrial DNA control region on samples collected between the years 2003 and 2007 (N = 489). We found a clear isolation by distance pattern at fine scale (i.e. individual level) which is most likely a result of species’ philopatric behaviour. Although we did not find signs of the recent bottlenecks, we did find evidence of an ancient bottleneck that has occurred most likely over 21,000 years ago, long before the genetic divergence of the two present Finnish subpopulations (one along the Baltic Sea coast line and another in Lapland and easternmost Finland). We conclude that the present population structure is mainly a consequence of the species philopatric behaviour over a long time period instead of recent population bottlenecks. Based on our results, the Finnish population seems to have ongoing immigration from neighbouring populations. Hence, even though the population has recovered mainly through local growth, our results suggest that gene flow from genetically differentiated populations have had an impact as well.     

Antrodia hyalina, a new polypore from Russia, and A. leucaena, new to Europe

A new polypore species, Antrodia hyalina, is described from Russia. It is morphologically similar to Antrodia pulvinascens, but differs in having annual, thinner and softer basidiocarps, solid skeletal hyphae, and cylindrical spores. Antrodia leucaena, originally described from China, is reported as new from Finland and Russia on Populus tremula. Antrodia wangii is regarded as a synonym of A. bondartsevae.     

Biogenic nanoporous silicon carrier improves the efficacy of buparvaquone against resistant visceral leishmaniasis

Visceral leishmaniasis is a vector-borne protozoan infection that is fatal if untreated. There is no vaccination against the disease, and the current chemotherapeutic agents are ineffective due to increased resistance and severe side effects. Buparvaquone is a potential drug against the leishmaniases, but it is highly hydrophobic resulting in poor bioavailability and low therapeutic efficacy. Herein, we loaded the drug into silicon nanoparticles produced from barley husk, which is an agricultural residue and widely available. The buparvaquone-loaded nanoparticles were several times more selective to kill the intracellular parasites being non-toxic to macrophages compared to the pure buparvaquone and other conventionally used anti-leishmanial agents. Furthermore, the in vivo results revealed that the intraperitoneally injected buparvaquone-loaded nanoparticles suppressed the parasite burden close to 100%. By contrast, pure buparvaquone suppressed the burden only by 50% with corresponding doses. As the conclusion, the biogenic silicon nanoparticles are promising carriers to significantly improve the therapeutic efficacy and selectivity of buparvaquone against resistant visceral leishmaniasis opening a new avenue for low-cost treatment against this neglected tropical disease threatening especially the poor people in developing nations.     

Decreased free water clearance is associated with worse respiratory outcomes in premature infants

Objective

The goal was to elucidate predictors of decreased free water clearance (DFWC) in very low birth weight (VLBW) infants. We hypothesized that DFWC and fluid retention are linked to the severity of pulmonary problems and prolonged respiratory support, especially to nCPAP treatment.

Methods

The investigation was carried out at Tampere University Hospital between 2001 and 2006. The study population comprised 74 VLBW infants born at 29.21 (24.57–34.14) weeks of gestation. Median birth weight was 1175 (575–1490) grams. We measured plasma and urine osmolality and 24-hour urine volume to calculate free water clearance (FWC) for each infant. If FWC was less than 30 ml/kg/day the infant was classified as having DFWC.

Results

There were 38 (51.4%) infants with DFWC in the study population. The median duration of the observed DFT period was 14 (4–44) days. The gestational age at birth was lower for DFWC infants compared to infants with normal FWC (NFWC), 28.29 (24.57–32.86) vs. 30.00 (25.57–34.14) weeks (p = 0.001). DFWC infants also needed longer ventilator treatment, 2 (0–23) vs. 0.50 (0–23) days (p = 0.046), nCPAP treatment 30 (0–100) vs. 3 (0–41) days (p<0.0001) and longer oxygen supplementation 47 (0–163) vs. 22 (0–74) days (p = 0.011) than NFWC infants. All values presented here are medians with ranges.

Conclusions

DFWC appears to be frequently connected with exacerbation and prolongation of pulmonary problems in VLBW infants. Cautious fluid administration seems to be indicated in VLBW infants with prolonged respiratory problems and DFWC.     

Peroxisomal multifunctional enzyme type 2 from the fruitfly: dehydrogenase and hydratase act as separate entities, as revealed by structure and kinetics

All of the peroxisomal β-oxidation pathways characterized thus far house at least one MFE (multifunctional enzyme) catalysing two out of four reactions of the spiral. MFE type?2 proteins from various species display great variation in domain composition and predicted substrate preference. The gene CG3415 encodes for Drosophila melanogaster MFE-2 (DmMFE-2), complements the Saccharomyces cerevisiae MFE-2 deletion strain, and the recombinant protein displays both MFE-2 enzymatic activities in vitro. The resolved crystal structure is the first one for a full-length MFE-2 revealing the assembly of domains, and the data can also be transferred to structure-function studies for other MFE-2 proteins. The structure explains the necessity of dimerization. The lack of substrate channelling is proposed based on both the structural features, as well as by the fact that hydration and dehydrogenation activities of MFE-2, if produced as separate enzymes, are equally efficient in catalysis as the full-length MFE-2.     

Changes in Uric Acid Levels following Bariatric Surgery Are Not Associated with SLC2A9 Variants in the Swedish Obese Subjects Study

Context and Objective

Obesity and SLC2A9 genotype are strong determinants of uric acid levels. However, data on SLC2A9 variants and weight loss induced changes in uric acid levels are missing. We examined whether the changes in uric acid levels two- and ten-years after weight loss induced by bariatric surgery were associated with SLC2A9 single nucleotide polymorphisms (SNPs) in the Swedish Obese Subjects study.

Methods

SNPs (N = 14) identified by genome-wide association studies and exonic SNPs in the SLC2A9 gene locus were genotyped. Cross-sectional associations were tested before (N = 1806), two (N = 1664) and ten years (N = 1201) after bariatric surgery. Changes in uric acid were compared between baseline and Year 2 (N = 1660) and years 2 and 10 (N = 1172). A multiple testing corrected threshold of P = 0.007 was used for statistical significance.

Results

Overall, 11 of the 14 tested SLC2A9 SNPs were significantly associated with cross-sectional uric acid levels at all three time points, with rs13113918 showing the strongest association at each time point (R² = 3.7−5.2%, 3.9×10⁻²²≤p≤7.7×10⁻¹¹). One SNP (rs737267) showed a significant association (R² = 0.60%, P = 0.002) with change in uric acid levels from baseline to Year 2, as common allele homozygotes (C/C, N = 957) showed a larger decrease in uric acid (−61.4 µmol/L) compared to minor allele carriers (A/X: −51.7 µmol/L, N = 702). No SNPs were associated with changes in uric acid from years 2 to 10.

Conclusions

SNPs in the SLC2A9 locus contribute significantly to uric acid levels in obese individuals, and the associations persist even after considerable weight loss due to bariatric surgery. However, we found little evidence for an interaction between genotype and weight change on the response of uric acid to bariatric surgery over ten years. Thus, the fluctuations in uric acid levels among the surgery group appear to be driven by the weight losses and gains, independent of SLC2A9 genotypes.