FV-1 restriction of age-dependent paralytic lactic dehydrogenase virus infection

A genetic analysis was made of the susceptibility of inbred mice to a paralytic disease elicited by the ip injection of a neuroparalytic strain of lactic dehydrogenase virus. The frequency of disease in susceptible inbred mice was X-ray dose and age dependent. Analysis of the susceptibility of appropriate F1 hybrids and their backcross progeny showed that susceptibility was not linked to the major histocompatibility complex but segregated with the Fv-1 linkage group. Linkage group analysis showed that resistance to paralytic infection was linked to a single gene outside the major histocompatibility complex. By determining the segregation of Gpd-1 isozyme variants among backcross progeny it was shown that inheritance of the Fv-1b allele resulted in virtually absolute restriction of susceptibility. Genetic evidence was obtained indicating that mice that mice that had multiple copies of N-tropic C-type retroviruses in their genomes, and that were permissive for retrovirus expression (Fv-1n/n), were susceptible to paralytic LDV infection. Strains that carried few copies of N-tropic C-type retroviruses in their genomes, or that inherited the Fv-1b allele, were resistant. A significant maternal resistance effect was demonstrable in some backcross generations that appeared to be mediated by H-2b in the major histocompatibility complex.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24060/1/0000312.pd

Growth, reproduction, mortality, and pathologic changes in rats fed gamma-irradiated potatoes

For two years a colony of albino rats was fed diets one-third of which consisted of potatoes which received, for sprout-inhibition purposes, a dose of up to 40 kilorads of irradiation from reactor fuel elements. There were no effects of the irradiation treatment on growth, reproductive performances through four generations, hematology, nor on pathologic changes of these rats. The higher mortality of first-generation males and second-generation females fed the diets containing irradiated potatoes is not believed to be attributable to the irradiation treatment per se. Irradiation was not a factor in the unusually high incidence of a necrotizing arteritis resembling "peri-arteritis nodosa" in the first- and second-generation animals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32435/1/0000517.pd

Hypoxia-induced bacterial translocation in the puppy

Because hypoxia is one of the most common major stresses to which a neonate is exposed, we postulated that it alone might be the cause of intestinal bacterial translocation, which could be the underlying etiology of neonatal sepsis. An animal model, in which hypoxia is the sole stress, was developed in our laboratory and tested in 18 puppies to determine the effect of hypoxia and reoxygenation on intestinal bacterial translocation. In group I (n = 8), following laparotomy and cannulation of the superior mesenteric vein (SMV), the FIO2 was decreased from 21% to 9% for 90 minutes followed by reoxygenation at 21% for 120 minutes. The abdomen was closed and the animals were allowed to recover. After 24 hours the mesenteric lymph nodes (MLNs), spleen, and liver were harvested for bacterial determination and the ileum and jejunum for histological evaluation. Group II (n = 7) was treated the same as group I with the FIO2 maintained at 21%. Group III (n = 3) animals were killed, without intervention, for bacterial analysis. In group I, the systemic PO2 decreased by 75%, SMV PO2 decreased by 64%, and oxygen delivery to the small bowel decreased by 80% in comparison with group II. The mean arterial pressure and cardiac output were not significantly different between group I and group II; however, the mucosal blood flow was decreased by 60% (P P P < .001). This study demonstrates that severe systemic hypoxia and subsequent reoxygenation does not initiate oxidant-mediated, lipid peroxidation injury to the small bowel mucosa, but does allow bacterial translocation to the MLNs. Thus, hypoxia-induced bacterial translocation could serve as a model for neonatal sepsis without apparent bowel injury.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30364/1/0000766.pd

Ibuprofen-mediated infarct size reduction: Effects on regional myocardial function in canine myocardial infarction

Normal, marginal, and central ischemic regional myocardial function were evaluated in a canine model of myocardial infarction during 90 minute left circumflex coronary artery occlusion in 25 anesthetized dogs randomly assigned to intravenous ibuprofen infusion (n = 13, 5.36 mg/kg/h beginning 1 hour before occlusion) or vehicle solution as control (n = 12) and in 15 conscious, unsedated dogs 48 and 72 hours after 90 minute circumflex artery occlusion followed by reperfusion (ibuprofen, 5.36 mg/kg/h by intravenous infusion over 7 hours beginning 1 hour before occlusion, n = 7; or vehicle solution infusion as control, n = 8).Miniature subendocardial sonomicrometer crystal pairs were used to calculate left ventricular regional end-diastolic segment length, end-systolic segment length, and regional percent systolic shortening. Infarct size was estimated in 72 hour animals by a postmortem dual perfusion technique using triphenyltetrazolium histochemical dye and Evan's blue dye for determination of infarct area, risk area, and area not at risk. Ibuprofen treatment significantly reduced infarct size expressed as percent of risk area (mean +/- standard deviation of 44.6 +/- 18 versus 64.4 +/- 16% for control dogs, p Thus, ibuprofen does not improve normal, marginal, or ischemic zone regional myocardial function during acute ischemia or 48 or 72 hours after myocardial reperfusion despite a significant reduction of infarct size.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23860/1/0000099.pd

Platelet depletion in experimental myocardial infarction

Accumulation of platelets in the microvasculature after acute myocardial ischemia may exacerbate tissue injury through the formation of microthrombi and by the release of vasoactive substances. To assess the role of platelets in myocardial ischemic injury and infarction, circulating platelets were reduced by 94±2% (mean±S.E.M.) with sheep antiserum to canine platelets. Regional myocardial ischemia was produced by occlusion of the left circumflex coronary artery (LCCA) for 90 min followed by reperfusion for 5 hours. Infarct size did not differ significantly between antiplatelet serum and nonimmune serum groups: 36±8 vs. 43±4% of the area at risk, determined by a post-mortem dual staining technique (p>0.05). A second occlusion-reperfusion control group, sacrificed at 24 hours, did not differ from 5 hr reperfused groups with regard to infarct size. Coronary sinus thromboxane B 2 (TXB 2 ) concentrations were not altered significantly by platelet depletion. Histopathologic examination confirmed the presence of necrosis in the infarcted myocardium and revealed substantial leukocytic infiltration in both groups. The results suggest that circulating platelets are not required for the full expression of myocardial ischemic injury resulting from temporary coronary artery occlusion followed by reperfusion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41747/1/395_2005_Article_BF01907903.pd

Reduction of myocardial infarct size by neutrophil depletion: Effect of duration of occlusion

Experiments were performed in the dog to examine the effects of neutropenia on ultimate infarct size resulting from short (90 minutes) or prolonged (4 hours) circumflex coronary artery occlusion. Sheep antiserum to canine neutrophils was used to produce neutropenia. Control animals received nonimmune serum. Neutrophil infiltration into myocardial infarcts was examined using histopathologic techniques and a semiquantitative scoring system. In 90-minute occlusions with 24-hour reperfusion, neutropenia was associated with the development of significantly smaller infarcts: normopenic group, 43.2% +/- 3.3% (n = 7) vs. neutropenic group, 26.6% +/- 3.7% (n = 10) of the area at risk, +/- SEM. However, in 4-hour occlusion with 6-hour reperfusion experiments, the tendency of neutrophil depletion to reduce infarct size did not reach statistical significance (46.4% +/- 7.2% vs. 31.5% +/- 6.0% of the area at risk, normopenic vs. neutropenic) despite differences in neutrophil infiltration into the reperfused region. The observed differences in ultimate infarct size could not be attributed to differences in myocardial oxygen consumption. The results suggest that a significant amount of myocardial infarction induced by a limited duration of coronary artery occlusion followed by reperfusion is neutrophil dependent and appears to be less important in determining the fate of myocardium subjected to more prolonged periods of ischemia followed by reperfusion.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26030/1/0000103.pd

Shock-wave thrombus ablation, a new method for noninvasive mechanical thrombolysis

Successful experimental and clinical experience with thrombus ablation has been attained with high-power acoustic energy delivered in a catheter. The goal of this study was to investigate the feasibility of noninvasive thrombus ablation by focused high-power acoustic energy. The source for high-power acoustic energy was a shock-wave generator in a water tank equipped with an acoustic lens with a fixed focal point at 22.5 cm. Thrombus was prepared in vitro, weighed (0.24 +/- 0.08 g), and inserted in excised human femoral artery segments. The arterial segments were ligated, positioned at the focal point and then randomized into either test (n = 8) or control (n = 7). An x-ray system verified the 3-dimensional positioning of the arterial segment at the focal point. A 5 MHz ultrasound imaging system continuously visualized the arterial segment at the focal point before, during and after each experiment. The test segments were exposed to shock waves (1,000 shocks/24 kv). The arterial segment content was then flushed and the residual thrombus weighed. The arterial segment and thrombus were fixed and submitted to histologic examination. The test group achieved a significant ablation of thrombus mass (0.25 +/- 0.15 vs 0.07 +/- 0.003 g; P = 0.0001) after application of shock waves. Arterial segments showed no gross or microscopic damage. Ultrasound imaging revealed a localized (1.9 +/- 0.5 cm2), transient (744 +/- 733 ms), cavitation field at the focal point at the time of application of focused shock waves. Thus, focused high-power acoustic energy can effect noninvasive thrombus ablation without apparent damage to the arterial wall. The mechanism underlying shock-wave thrombus ablation may be associated with the cavitation effect.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29728/1/0000064.pd

Prostacyclin protects ischemic reperfused myocardium in the dog by inhibition of neutrophil activation

Prostacyclin (PGI2) and the stable PGI2 analogue SC39902 (6,9[alpha]-epoxy, 5S-fluoro-11[alpha], 15S-dehydroxyprosta-6, 13E-dien-1-oic acid, sodium salt) were studied in anesthetized open-chest dogs subjected to 90 minutes of left circumflex coronary artery (LCCA) occlusion and 6 hours of reperfusion. PGI2 (50 ng/kg/min, infused into the left atrium) reduced infarct mass by 59% compared to control, but SC39902 (1.5 [mu]g/kg/min) failed to produce a significant reduction in infarct size. Both PGI2 and SC39902 reduced mean arterial blood pressure, heart rate, and rate-pressure product to the same extent. Regional myocardial blood flow measured with radiolabelled tracer microspheres did not demonstrate an increase in regional blood flow to the ischemic myocardium during the 90 minutes of LCCA occlusion in the PGI2 and control treatment groups. Canine neutrophils were isolated from whole blood and activated with opsonized zymosan. PGI2 produced a concentration-dependent inhibition of neutrophil activation as measured by superoxide production in vitro, whereas SC39902 failed to effectively inhibit neutrophil activation. Neutrophil migration into inflammatory skin lesions was effectively attenuated when dogs were pretreated with PGI2 (50 ng/kg/min, intravenously). Therefore, it is suggested that the cytoprotective effect of PGI2 during myocardial ischemia and reperfusion is related to an inhibition of neutrophil migration and the production of cytotoxic activated oxygen species.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26892/1/0000458.pd

Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low- and middle-income countries.

Vitamin D is an essential nutrient for bone health and may influence the risks of respiratory illness, adverse pregnancy outcomes, and chronic diseases of adulthood. Because many countries have a relatively low supply of foods rich in vitamin D and inadequate exposure to natural ultraviolet B (UVB) radiation from sunlight, an important proportion of the global population is at risk of vitamin D deficiency. There is general agreement that the minimum serum/plasma 25-hydroxyvitamin D concentration (25(OH)D) that protects against vitamin D deficiency-related bone disease is approximately 30 nmol/L; therefore, this threshold is suitable to define vitamin D deficiency in population surveys. However, efforts to assess the vitamin D status of populations in low- and middle-income countries have been hampered by limited availability of population-representative 25(OH)D data, particularly among population subgroups most vulnerable to the skeletal and potential extraskeletal consequences of low vitamin D status, namely exclusively breastfed infants, children, adolescents, pregnant and lactating women, and the elderly. In the absence of 25(OH)D data, identification of communities that would benefit from public health interventions to improve vitamin D status may require proxy indicators of the population risk of vitamin D deficiency, such as the prevalence of rickets or metrics of usual UVB exposure. If a high prevalence of vitamin D deficiency is identified (>20% prevalence of 25(OH)D 1%), food fortification and/or targeted vitamin D supplementation policies can be implemented to reduce the burden of vitamin D deficiency-related conditions in vulnerable populations

Comparison of the adrenalytic activity of mitotane and a methylated homolog on normal adrenal cortex and adrenal cortical carcinoma

Mitotane is an important adrenalytic drug for the treatment of adrenal cancer whose use is limited by toxicity. Reports from another laboratory indicated that a methylated homolog of Mitotane (Mitometh) tested in guinea pigs possessed comparable adrenalytic activity but was less toxic than Mitotane. This observation prompted us to undertake a comparative study of these two drugs on the basis that Mitometh may be a superior agent for the treatment of adrenal cancer. Preliminary studies in guinea pigs failed to show a significant adrenalytic effect for either Mitotane or Mitometh. Thus, we extended the study to 13 mongrel dogs weighing 12–15 kg that were treated daily with Mitometh or Mitotane (50–100 mg/kg) for 6 or 12 days. Cortisol decreased to undetectable levels and adrenocorticotropic hormone (ACTH) rose to 10 times the baseline levels within 72 h in Mitotane-treated animals. Despite the achievement of similar drug levels, Mitometh treatment in dogs failed to suppress cortisol or increase ACTH. To determine whether these differences were due to differences in bioavailability, we measured the relative concentration of Mitotane and Mitometh in homogenates of adrenal cortex obtained from Mitotane- and Mitometh-treated dogs. The adrenal concentration of Mitometh determined in Mitometh-treated dogs was 5 times higher than the concentration of Mitotane measured in Mitotane-treated animals. Whereas the adrenal glands of Mitotane-treated dogs showed hemorrhage and necrosis, the Mitometh-treated animals showed no adrenal damage. Despite the lack of adrenalytic activity, Mitometh maintained its toxicity as demonstrated by microscopic evidence of hepatic necrosis and an increase in hepatic enzymes. The adrenalytic effects of both agents was also studied in vitro using a human functioning adrenal cortical carcinoma cell line. NCI-H295. Whereas Mitotane strongly suppressed cell growth, Mitometh had a weaker effect. We conclude that Mitometh is not likely to be effective in the therapy of adrenal cancer. Moreover, the results of this study are supportive of the view that metabolic transformation of Mitotane is in some way linked to its adrenalytic action.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46925/1/280_2004_Article_BF00685036.pd