Guanylyl cyclase stimulation by homologous and heterologous natriuretic peptides in salmonids

A range of homologous (trout ANP, trout CNP, trout VNP) and heterologous (eel ANP, eel ANP-NH₂, rat ANP, porcine CNP) NPs were tested for their effect on guanylyl cyclase in gill and kidney membrane preparations from freshwater and seawater-acclimated rainbow trout and Atlantic salmon. All NPs stimulated guanylyl cyclase at 1 µmol l^-1in all preparations. ANP was the most potent stimulator of kidney guanylyl cyclase and CNP the most potent stimulator of guanylyl cyclase in gills. Some differences were apparent between the potencies of homologous and heterologous peptides at 1 µmol l^-1: tANP was more potent than rANP in the SW trout kidney and tCNP was more potent than pCNP in FW salmon tissues. While eANP was more potent than tANP in trout gills, it was less potent than tANP in FW salmon gills. However, there was no significant difference between the potencies of eANP and eANP-NH₂ in trout or salmon gills. Salinity did not affect guanylyl cyclase activity with the exception that trout ANP at 1 µmol l^-1was more potent in SW trout kidneys than in FW trout kidneys. These results suggest a predomination of NPR-A in the kidney and NPR-B in the gill. It appears that salmonid NPR-A and NPR-B are relatively promiscuous in their ligand affinity, with few differences in the potencies of trout and mammalian NPs and only small differences in cGMP production where these differences do occur.

Liver cell transplantation leads to repopulation and functional correction in a mouse model of Wilson's disease

Background and Aim: The toxic milk (tx) mouse is a non-fatal animal model for the metabolic liver disorder, Wilson's disease. The tx mouse has a mutated gene for a copper-transporting protein, causing early copper accumulation in the liver and late accumulation in other tissues. The present study investigated the efficacy of liver cell transplantation (LCT) to correct the tx mouse phenotype.

Methods: Congenic hepatocytes were isolated and intrasplenically transplanted into 3–4-month-old tx mice, which were then placed on various copper-loaded diets to examine its influence on repopulation by transplanted cells. The control animals were age-matched untransplanted tx mice. Liver repopulation was determined by comparisons of restriction fragment length polymorphism ratios (DNA and mRNA), and copper levels were measured by atomic absorption spectroscopy.

Results: Repopulation in recipient tx mice was detected in 11 of 25 animals (44%) at 4 months after LCT. Dietary copper loading (whether given before or after LCT, or both) provided no growth advantage for donor cells, with similar repopulation incidences in all copper treatment groups. Overall, liver copper levels were significantly lower in repopulated animals (538 ± 68 µg/g, n = 11) compared to non-repopulated animals (866 ± 62 µg/g, n = 14) and untreated controls (910 ± 103 µg/g, n = 6; P < 0.05). This effect was also seen in the kidney and spleen. Brain copper levels remained unchanged.

Conclusion: Transplanted liver cells can proliferate and correct a non-fatal metabolic liver disease, with some restoration of hepatic copper homeostasis after 4 months leading to reduced copper levels in the liver and extrahepatic tissues, but not in the brain.

Renal transplantation in patients with primary immunoglobulin A nephropathy

Background. Opinions on the clinical course and outcome of renal transplantation in patients with primary immunoglobulin A nephropathy (IgAN) have been controversial.
Methods. We conducted a retrospective single-centre study on 542 kidney transplant recipients over the period 1984–2001. Long-term outcome and factors affecting recurrence in recipients with primary IgAN were analysed.
Results. Seventy-five patients (13.8%) had biopsy-proven IgAN as the cause of renal failure, and their mean duration of follow-up after transplantation was 100 ± 5.8 months. Fourteen (18.7%) of the 75 patients had biopsy-proven recurrent IgAN, diagnosed at 67.7 ± 11 months after transplantation. The risk of recurrence was not associated with HLA DR4 or B35. Graft failure occurred in five (35.7%) of the 14 patients: three due to IgAN and two due to chronic rejection. Three (4.9%) of the 61 patients without recurrent IgAN had graft failure, all due to chronic rejection. Graft survival was similar between living-related and cadaveric/living-unrelated patients (12-year graft survival, 88 and 72%, respectively, P = 0.616). Renal allograft survival within the first 12 years was better in patients with primary IgAN compared with those with other primary diseases (80 vs 51%, P = 0.001). Thereafter, IgAN patients showed an inferior graft survival (74 vs 97% in non-IgAN patients, P = 0.001).
Conclusions. Our data suggested that around one-fifth of patients with primary IgAN developed recurrence by 5 years after transplantation. Recurrent IgA nephropathy in allografts runs an indolent course with favourable outcome in the first 12 years. However, the contribution of recurrent disease to graft loss becomes more significant on long-term follow up.

Impaired muscle Ca2+ and K+ regulation contribute to poor exercise performance post-lung transplantation

Lung transplant recipients (LTx) exhibit marked peripheral limitations to exercise. We investigated whether skeletal muscle Ca2+ and K+ regulation might be abnormal in eight LTx and eight healthy controls. Peak oxygen consumption and arterialized venous plasma [K+] (where brackets denote concentration) were measured during incremental exercise. Vastus lateralis muscle was biopsied at rest and analyzed for sarcoplasmic reticulum Ca2+ release, Ca2+ uptake, and Ca2+-ATPase activity rates; fiber composition; Na+-K+-ATPase (K+-stimulated 3-O-methylfluorescein phosphatase) activity and content ([3H]ouabain binding sites); as well as for [H+] and H+-buffering capacity. Peak oxygen consumption was 47% less in LTx (P < 0.05). LTx had lower Ca2+ release (34%), Ca2+ uptake (31%), and Ca2+-ATPase activity (25%) than controls (P < 0.05), despite their higher type II fiber proportion (LTx, 75.0 ± 5.8%; controls, 43.5 ± 2.1%). Muscle [H+] was elevated in LTx (P < 0.01), but buffering capacity was similar to controls. Muscle 3-O-methylfluorescein phosphatase activity was 31% higher in LTx (P < 0.05), but [3H]ouabain binding content did not differ significantly. However, during exercise, the rise in plasma [K+]-to-work ratio was 2.6-fold greater in LTx (P < 0.05), indicating impaired K+ regulation. Thus grossly subnormal muscle calcium regulation, with impaired potassium regulation, may contribute to poor muscular performance in LTx.

Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in type 1 diabetes: a systematic review

Aims For selected individuals with complex Type 1 diabetes, pancreatic islet transplantation (IT) offers the potential of excellent glycaemic controlwithout significant hypoglycaemia, balanced by the need for ongoing systemic immunosuppression. Increasingly, patient-reported outcomes (PROs) are considered alongside biomedical outcomes as a measure of transplant success. PROs in IT have not previously been compared directlywith the closest alternate treatment option, pancreas transplant alone (PTA) or pancreas after kidney (PAK).

Methods We used a Population, Intervention, Comparisons, Outcomes (PICO) strategy to search Scopus and screened 314 references for inclusion.

Results Twelve studies [including PRO assessment of PAK, PTA, islet-after kidney (IAK) and islet transplant alone (ITA); n = 7–205] used a total of nine specified and two unspecified PRO measures. Results were mixed but identified some benefits which remained apparent up to 36 months post-transplant, including improvements in fear of hypoglycaemia, as well as some aspects of diabetes-specific quality of life (QoL) and general health status. Negative outcomes included short-term pain associated with the procedure, immunosuppressant side effects and depressed mood associated with loss of graft function.

Conclusions The mixed resultsmay be attributable to limited sample sizes. Also, some PROmeasures may lack sensitivity to detect actual changes, as they exclude issues and domains of life likely to be important forQoL post-transplantation and when patients may no longer perceive themselves to have diabetes. Thus, the full impact of islet ⁄ pancreas transplantation (alone or after kidney) on QoL is unknown. Furthermore, no studies have assessed patient satisfaction, which may highlight further advantages and disadvantages of transplantation.

Strength training of one limb increases corticomotor excitability projecting to the contralateral homologous limb

The contralateral transfer of strength following unilateral strength training (ULS) is thought to be due to changes within the nervous system. Using transcranial magnetic stimulation (TMS) we compared corticospinal responses following ULS of the right biceps brachii (BB) projecting to the untrained left BB. Motor evoked potentials (MEPs) were recorded from both BB of 23 individuals pre and post 4 weeks heavy load (80% of 1RM) ULS of right BB. TMS was delivered at intensities below active motor threshold (AMT) to saturation of the MEP (MEP_max). ULS resulted in a 28% increase in 1RM right BB strength, resulting in a 19.2% increase in contralateral strength of the left BB (p = .0001). There was a significant increase in MEP amplitude of 30.3% (p = .03), 33% (p = .05), and 26.5% (p = .01) at AMT, 20% above AMT and MEP_max respectively. No significant differences in silent period were seen at AMT, 20% above AMT or MEP_max. This study has demonstrated increased corticospinal excitability projecting to the untrained arm following heavy load ULS.