TGF-β in progression of liver disease

Transforming growth factor-β (TGF-β) is a central regulator in chronic liver disease contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver-damage-induced levels of active TGF-β enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Being recognised as a major profibrogenic cytokine, the targeting of the TGF-β signalling pathway has been explored with respect to the inhibition of liver disease progression. Whereas interference with TGF-β signalling in various short-term animal models has provided promising results, liver disease progression in humans is a process of decades with different phases in which TGF-β or its targeting might have both beneficial and adverse outcomes. Based on recent literature, we summarise the cell-type-directed double-edged role of TGF-β in various liver disease stages. We emphasise that, in order to achieve therapeutic effects, we need to target TGF-β signalling in the right cell type at the right time.     

Effect of mitochondrial DNA (mtDNA) type on pregnancy rate after embryo transfer in rats

Because the mtDNA is maternally inherited, embryos resulting from matings or artificial inseminations have the same type of mtDNA as that of the mother. However, when embryos are transferred the mtDNA of the embryos may be different to that of the recipient and this may interfere with maternal recognition and the establishment of pregnancy. This study was done to determine whether differences in the mtDNA between embryos and recipients would influence the survival to term of transferred embryos.A total of 1,220 rat embryos were recovered from non-superovulated donors of known mtDNA type. The number and distribution of developmental stages of embryos collected from 51 rats of mtDNA type A (n = 595) were not different (P>0.05) from those collected from 50 rats of mtDNA type B (n = 625). The overall pregnancy rate after transfer of embryos to pseudopregnant rats was 54% (26 48 ). The pregnancy rate was not affected (P>0.05) by the type of mtDNA of the recipient or of the embryo, and the interaction between mtDNA type of embryos and recipients was also not significant (P>0.05). Embryonic survival to birth was low (78 622 , 12.5%) but was not affected (P>0.05) by the type of mtDNA of the recipient (A = 28 250 ; B = 50 372 ) or of the embryo (A = 41 306 ; B = 37 316 ). Survival of pups to weaning was affected by the type of mtDNA of the embryo (P < 0.01) but not by the type of mtDNA of the recipient (P>0.05) and the interaction between mtDNA type of embryos and recipients was also not significant (P>0.05). More pups (P < 0.005) derived from donor rats of mtDNA type A (34 41 ) survived to weaning age than pups from donor rats of mtDNA type B (18 37 ). These results indicate that differences in the type of mtDNA between embryos and recipients do not interfere with establishment of pregnancy in pseudopregnant recipients.     

Riboflavin/UVA collagen cross-linking-induced changes in normal and keratoconus corneal stroma

Purpose

To determine the effect of Ultraviolet-A collagen cross-linking with hypo-osmolar and iso-osmolar riboflavin solutions on stromal collagen ultrastructure in normal and keratoconus ex vivo human corneas.

Methods

Using small-angle X-ray scattering, measurements of collagen D-periodicity, fibril diameter and interfibrillar spacing were made at 1 mm intervals across six normal post-mortem corneas (two above physiological hydration (swollen) and four below (unswollen)) and two post-transplant keratoconus corneal buttons (one swollen; one unswollen), before and after hypo-osmolar cross-linking. The same parameters were measured in three other unswollen normal corneas before and after iso-osmolar cross-linking and in three pairs of swollen normal corneas, in which only the left was cross-linked (with iso-osmolar riboflavin).

Results

Hypo-osmolar cross-linking resulted in an increase in corneal hydration in all corneas. In the keratoconus corneas and unswollen normal corneas, this was accompanied by an increase in collagen interfibrillar spacing (p<0.001); an increase in fibril diameter was also seen in two out of four unswollen normal corneas and one unswollen keratoconus cornea (p<0.001). Iso-osmolar cross-linking resulted in a decrease in tissue hydration in the swollen normal corneas only. Although there was no consistent treatment-induced change in hydration in the unswollen normal samples, iso-osmolar cross-linking of these corneas did result in a compaction of collagen fibrils and a reduced fibril diameter (p<0.001); these changes were not seen in the swollen normal corneas. Collagen D-periodicity was not affected by either treatment.

Conclusion

The observed structural changes following Ultraviolet-A cross-linking with hypo-osmolar or iso-osmolar riboflavin solutions are more likely a consequence of treatment-induced changes in tissue hydration rather than cross-linking.     

Routine screening of blood and urine for severe reactions to anticonvulsant drugs in asymptomatic patients is of doubtful value.

Severe or fatal reactions to anticonvulsant agents are fortunately rare. We examined the value of routine screening of blood and urine to detect early signs of such reactions in asymptomatic patients. The basic assumptions of this type of screening program have been faulty or unproven, and the results of studies, although not definitive, have not supported the value of such programs. Our recommendations, approved by the Canadian Association for Child Neurology, suggest that asymptomatic patients not undergo routine screening of blood and urine but, rather, be informed of the early symptoms of severe toxic reactions and be asked to report them immediately to a physician.     

A model of the copper centres of nitrous oxide reductase (Pseudomonas stutzeri). Evidence from optical, EPR and MCD spectroscopy.

Nitrous oxide reductase (N2OR), Pseudomonas stutzeri, catalyses the 2 electron reduction of nitrous oxide to di-nitrogen. The enzyme has 2 identical subunits (Mr approximately 70,000) of known amino acid sequence and contains approximately 4 Cu ions per subunit. By measurement of the optical absorption, electron paramagnetic resonance (EPR) and low-temperature magnetic circular dichroism (MCD) spectra of the oxidised state, a semi-reduced form and the fully reduced state of the enzyme it is shown that the enzyme contains 2 distinct copper centres of which one is assigned to an electron-transfer function, centre A, and the other to a catalytic site, centre Z. The latter is a binuclear copper centre with at least 1 cysteine ligand and cycles between oxidation levels Cu(II)/Cu(II) and Cu(II)/Cu(I) in the absence of substrate or inhibitors. The state Cu(II)/Cu(I) is enzymatically inactive. The MCD spectra provide evidence for a second form of centre Z, which may be enzymatically active, in the oxidised state of the enzyme. Centre A is structurally similar to that of CuA in bovine and bacterial cytochrome c oxidase and also contains copper ligated by cysteine. This centre may also be a binuclear copper complex.     

Cryptosporidium

This review discusses characteristics of the genus Cryptosporidium and addresses the pathogenesis, reservoirs, public health significance and current applications for the detection and typing of this important pathogen. By increasing knowledge in key areas of Cryptosporidium research such as aetiology, epidemiology, transmission and host interactions, the numbers of cases of human cryptosporidiosis should be reduced.     

3-(Arylamino)-3-phenylpropan-2-olamines as a new series of dual norepinephrine and serotonin reuptake inhibitors

A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.