Multiple sites of oxygen sensing and their contributions to hypoxic pulmonary vasoconstriction

Oxygen sensing by the pulmonary vasculature is important for the regulation of vessel tone and the matching of lung perfusion to ventilation. Airways hypoxia is a major stimulus for vasoconstriction, which diverts blood from hypoxic alveoli to better ventilated areas of the lung. Several hypotheses have emerged to explain how pulmonary arteries sense a decrease in oxygen and mediate hypoxic pulmonary vasoconstriction (HPV). They differ mainly in where they place the main site of HPV: in the endothelial or smooth muscle cells of the artery wall. HPV probably results from synergistic actions on both cell types, but it can proceed in the absence of endothelium, suggesting that the primary oxygen sensor is the smooth muscle cell and endothelium-derived agents modulate the muscle response. Several oxygen-sensing targets have been identified in smooth muscle, including potassium channels, Ca(2+) stores in the sarcoplasmic reticulum (SR) and the Ca(2+) sensitivity of the contractile proteins. The evidence for different oxygen-sensing mechanisms in pulmonary vessels is discussed.     

Inhibition of terminal axonal sprouting by serum from patients with amyotrophic lateral sclerosis

To investigate the pathogenesis of amyotrophic lateral sclerosis, we compared the effect of serum from patients with this disease on the regenerative sprouting of terminal axons in botulinum-treated mouse gluteus muscle with the effects of serum from controls and from patients with diabetic peripheral neuropathy. Serum from 9 of 19 patients with the sporadic form of amyotrophic lateral sclerosis and from 2 of 6 patients with the familial form caused a reduction in the proportion of sprouting terminal axons, as compared with that found in muscles treated with serum from controls or diabetic patients. Immunoglobulin from patients with amyotrophic lateral sclerosis, when tested on immunoblots, recognized a 56-kilodalton protein secreted by denervated rat diaphragm muscle; rabbit antiserum raised against this protein also suppressed terminal axonal sprouting. Thus, we have detected an antibody in the serum of patients with amyotrophic lateral sclerosis that inhibits sprouting of neurons and subsequent reinnervation of skeletal muscle. Whether this antibody is of primary pathogenic importance or represents a secondary response to neuromuscular destruction is not known. In either case, serum from patients with amyotrophic lateral sclerosis may provide reagents for studies of the trophic communications between muscle and motor neurons.     

Reactive astrocytes express p53 in the spinal cord of transgenic mice expressing a human Cu/Zn SOD mutation

In a previous study, we reported increased NOS expression in the astrocytes in the spinal cord of SOD mutant transgenic mice that are used as ALS animal model. Recently, Messmer and Brune suggested that nitric oxide-induced apoptosis is intimately related with p53-dependent signaling pathway, and de la Monte et al. reported increased p53-immunoreactivity in the spinal cord of ALS patients. In the present study, we performed immunocytochemical studies to investigate the changes of p53-immunoreactivity in the brains of the mutant transgenic mice expressing a human Cu/Zn SOD mutation. Immunocytochemistry showed intensely stained p53-IR glial cells with the appearance of astrocytes in all levels of the spinal cord of the mutant transgenic mice, but no p53-IR glial cells were observed in the spinal cord of the control mice. P53-IR astrocytes were also detected in the brain stem of the mutant transgenic mice. In the medulla, they were observed in the medullary reticular formation, hypoglossal nucleus, vestibular nucleus, dorsal motor nucleus of the vagus and nucleus ambiguus. In the pons, their presences were noted in the pontine reticular formation, and trigeminal and facial nuclei. In the midbrain, astrocytes were detected in the mesencephalic reticular formation, red nucleus and periaqueductal gray matter. In the cerebellum, intensely stained p53-IR astrocytes were detected in the intracerebellar nuclei. In contrast to the mutant transgenic mice, no p53-IR astrocytes were detected in the brain stem and spinal cord of the control mice. Further multidisciplinary investigations involving p53-mediated cellular damage and pathogenesis of ALS are needed to clarify the importance of these results.     

Dissection of c-Mpl and thrombopoietin function: studies of knockout mice and receptor signal transduction

The physiological roles and mechanisms of action of thrombopoietin (TPO) and its receptor c-Mpl have been studied through the analysis of mice genetically deficient in these molecules, as well as through the dissection of signaling events utilizing chimeric receptors. The evidence clearly demonstrates that the TPO/c-Mpl system provides dominant control in the regulation of megakaryocytopoiesis. The signaling mechanisms that underlie this process appear to be similar to those noted with other members of the hematopoietic cytokine and cytokine receptor families.     

Long-term neurologic and neurosensory sequelae in adult survivors of a childhood brain tumor: childhood cancer survivor study.

PURPOSE: To describe the neurologic and neurosensory deficits in children with brain tumors (BTs), compare incidence of these deficits with that of a sibling control group, and evaluate the factors associated with the development of these deficits. PATIENTS AND METHODS: Detailed questionnaires were completed on 1,607 patients diagnosed between 1970 and 1986 with a primary CNS tumor. Neurosensory and neurologic dysfunctions were assessed and results compared with those of a sibling control group. Medical records on all patients were abstracted, including radiotherapy dose and volume. RESULTS: Seventeen percent of patients developed neurosensory impairment. Relative to the sibling comparison group, patients surviving BTs were at elevated risk for hearing impairments (relative risk [RR], 17.3; P = <.0001), legal blindness in one or both eyes (RR, 14.8; P = <.0001), cataracts (RR, 11.9; P = <.0001), and double vision (RR, 8.8; P = <.0001). Radiation exposure greater than 50 Gy to the posterior fossa was associated with a higher likelihood of developing any hearing impairment. Coordination and motor control problems were reported in 49% and 26%, respectively, of survivors. Children receiving at least 50 Gy to the frontal brain regions had a moderately elevated risk for motor problems (RR, 2.0; P <.05). Seizure disorders were reported in 25% of patients, including 6.5% who had a late first occurrence. Radiation dose of 30 Gy or more to any cortical segment of the brain was associated with a two-fold elevated risk for a late seizure disorder. CONCLUSION: Children surviving BTs are at significant risk for both early and late neurologic or neurosensory sequelae. These sequelae need to be prospectively monitored.     

CT versus sonography for monitoring radiofrequency ablation in a porcine liver

OBJECTIVE: The objective of this study was to compare CT and sonography for monitoring radiofrequency (RF) lesions in porcine livers. SUBJECTS AND METHODS: RF lesions (n = 12) were created in three pig livers by applying 13 min of current to a multielectrode RF probe with a target temperature of 95 degrees C. Helical unenhanced CT and corresponding axial sonography were performed before ablation, at 2 min, 8 min, and immediately after ablation. Contrast-enhanced CT was performed after ablation. CT scans and sonograms were evaluated by blinded observers for conspicuity of the RF lesion, edge detection (visibility of liver-lesion interface), and artifacts. Hounsfield units were recorded at every time interval, and radiologic-pathologic correlation for lesion size and configuration was performed. RESULTS: Mean size of RF lesions was 3. 03 +/- 0.9 cm. On CT, RF lesions had consistently lower attenuation values than surrounding liver (22.2 H lower than liver at 8 min, p < 0.0001). Echogenicity was variable with sonography (hypoechoic = 59%, hyperechoic = 25%, isoechoic = 16%). Unenhanced CT significantly improved conspicuity, edge detection of RF lesions, and decreased artifacts compared with sonography (p < 0.05). Contrast-enhanced CT improved RF lesion detection, border discrimination, and artifacts compared with sonography (p < 0.05). Unenhanced CT had the best correlation to pathologic size (r = 0.74), followed by contrast-enhanced CT (r = 0.72) and sonography (r = 0.56). Contrast-enhanced CT best correlated with lesion shape, but slightly overestimated size because of areas of ischemia peripheral to the RF lesion. CONCLUSION: In this animal model, unenhanced CT was an effective way to monitor RF ablation compared with sonography because of increased lesion discrimination, reproducible decreased attenuation during ablation, and improved correlation to pathologic size.