Nitrite reduces acute lung injury and improves survival in a rat lung transplantation model.

Ischemia/reperfusion injury (IRI) is the most common cause of early mortality following lung transplantation (LTx). We hypothesized that nitrite, an endogenous source of nitric oxide (NO), may protect lung grafts from IRI. Rat lung grafts were stored in preservation solution at 4°C for 6 hours. Both grafts and recipients were treated with nitrite. Nitrite treatment was associated with significantly higher levels of tissue oxygenation, lower levels of cytokines and neutrophil/macrophage infiltration, lower myeloperoxidase activity, reduced oxidative injury and increased cGMP levels in grafts than in the controls. Treatment with either a nitric oxide scavenger or a soluble guanylyl cyclase (sGC) inhibitor diminished the beneficial effects of nitrite and decreased cGMP concentrations. These results suggest that nitric oxide, generated from nitrite, is the molecule responsible for the effects of nitrite via the nitric oxide/sGC/cGMP pathway. Allopurinol, a xanthine oxidoreductase (XOR) inhibitor, abrogated the protective effects of nitrite, suggesting that XOR is a key enzyme in the conversion of nitrite to nitric oxide. In vitro experiments demonstrated that nitrite prevented apoptosis in pulmonary endothelial cells. Nitrite also exhibits longer survival rate in recipients than control. In conclusion, nitrite inhibits lung IRI following cold preservation and had higher survival rate in LTx model.

Epidemiology of motor neuron disease in the Kii Peninsula of Japan, 1989-1993: active or disappearing focus?

During the period 1989-1993, the incidence and migration patterns of patients with motor neuron diseases (MND) in Wakayama Prefecture, including one of the high-incidence Kii Peninsula foci ('Kozagawa focus'), were surveyed to determine whether the focus had truly disappeared or not. Overall, the crude average annual incidence was 1.43 per 100000 population; when age-adjusted to the 1990 Japanese population, it was 1.25 (1.85 for males and 0.61 for females). The average annual age- and sex-specific incidence steadily increased to a peak between 60 and 69 years and dropped after 70. Geographically, the rates varied in the five regions of Wakayama Prefecture from 0.38 to 2.48. The areas with high incidence were distributed in the central and southernmost regions; the highest was in the Kozagawa focus with 9.54 (two ALS cases within five years; 4193 base population, 1990). During the study period, four emigrants from Kozagawa had developed MND one to four decades after leaving the focus. Although the remarkable clustering of MND was thought to have disappeared, the southern Kii Peninsula remains a high-risk area for MND, especially if one interprets the data so as to include the emigrants. In general, the age at onset has increased in the past 20 years from 56.5 to 61.7; male predominance is observed.

[A case of idiopathic hypoparathyroidism with slurred speech and mild dementia].

A case of idiopathic hypoparathyroidism (IHP) is discussed with reference to a study of rats maintained on various low-calcium diets. A 45-year-old man complained of difficulty speaking, especially an inability to speak loudly and of fine finger tremors over the past 2 or 3 years. His brain MRI showed marked calcification in the bilateral basal ganglia and cerebellum and his in sera findings showed low calcium, extremely low levels in all kinds of examined parathyroid hormones and 1,25 (OH)2D, thus we diagnosed idiopathic hypoparathyroidism. His finger tremors stopped soon after administration of 1 alpha D3 2 microgram/day as verified by calcium, phosphorus and creatinine levels in sera, however, a brain CT one year later showed no changes in calcification. As reported earlier in studies of deposition in the soft tissues, especially central nervous system tissues of rats maintained on low-calcium diets, it is difficult to reduce calcium deposition if symptoms appear in adults. Therefore, it is necessary to start therapy as soon as possible in order to prevent additional calcium deposition in the early stage of IHP.

[A case of neurologic type of Wilson's disease with increased aluminum in liver: comparative study with histological findings to metal contents in the liver].

Histological findings and metal contents in the liver were studied in a patient with neurologic type of Wilson's disease. Copper and aluminum contents in the biopsied liver of the patient with Wilson's disease were measured simultaneously by neutron activation analysis at Research Reactor Institute, Kyoto University. Four cases of adult cirrhosis were selected as the control for cirrhosis and five cases of adult liver as the control for neurologically normal. The biopsied liver showed markedly increase in the copper content (814.4 micrograms/g: dry weight) and extremely high content of aluminum (479.4 micrograms/g: dry weight), compared to those of the controls. On the other hand, macroscopically no cirrhosis was observed and the characteristic appearances of macronodular cirrhosis failed to detect histologically. Interestingly the fibrosis or inflammation of the liver was seen faintly. It is likely that toxic metals in the liver such as aluminum, copper and manganese might be implicated in the pathogenesis of neurologic type of Wilson's disease.

Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway.

Carbon monoxide (CO) provides protection against oxidative stress via anti-inflammatory and cytoprotective actions. In this study, we tested the hypothesis that a low concentration of exogenous (inhaled) CO would protect transplanted lung grafts from cold ischemia-reperfusion injury via a mechanism involving the mitogen-activated protein kinase (MAPK) signaling pathway. Lewis rats underwent orthotopic syngeneic or allogeneic left lung transplantation with 6 h of cold static preservation. Exposure of donors and recipients (1 h before and then continuously post-transplant) to 250 ppm CO resulted in significant improvement in gas exchange, reduced leukocyte sequestration, preservation of parenchymal and endothelial cell ultrastructure and reduced inflammation compared to animals exposed to air. The beneficial effects of CO were associated with p38 MAPK phosphorylation and were significantly prevented by treatment with a p38 MAPK inhibitor, suggesting that CO's efficacy is at least partially mediated by activation of p38 MAPK. Furthermore, CO markedly suppressed inflammatory events in the contralateral naïve lung. This study demonstrates that perioperative exposure of donors and recipients to CO at a low concentration can impart potent anti-inflammatory and cytoprotective effects in a clinically relevant model of lung transplantation and support further evaluation for potential clinical use.

Ex vivo application of carbon monoxide in University of Wisconsin solution to prevent intestinal cold ischemia/reperfusion injury.

Carbon monoxide (CO), a byproduct of heme catalysis, was shown to have potent cytoprotective and anti-inflammatory effects. In vivo recipient CO inhalation at low concentrations prevented ischemia/reperfusion (I/R) injury associated with small intestinal transplantation (SITx). This study examined whether ex vivo delivery of CO in University of Wisconsin (UW) solution could ameliorate intestinal I/R injury. Orthotopic syngenic SITx was performed in Lewis rats after 6 h cold preservation in control UW or UW that was bubbled with CO gas (0.1-5%) (CO-UW). Recipient survival with intestinal grafts preserved in 5%, but not 0.1%, CO-UW improved to 86.7% (13/15) from 53% (9/17) with control UW. At 3 h after SITx, grafts stored in 5% CO-UW showed improved intestinal barrier function, less mucosal denudation and reduced inflammatory mediator upregulation compared to those in control UW. Preservation in CO-UW associated with reduced vascular resistance (end preservation), increased graft cyclic guanosine monophosphate levels (1 h), and improved graft blood flow (1 h). Protective effects of CO-UW were reversed by ODQ, an inhibitor of soluble guanylyl cyclase. In vitro culture experiment also showed better preservation of vascular endothelial cells with CO-UW. The study suggests that ex vivo CO delivery into UW solution would be a simple and innovative therapeutic strategy to prevent transplant-induced I/R injury.