Keratinocyte growth factors radioprotect bowel and bone marrow but not KHT sarcoma

Various members of the fibroblast growth factor (FGF) family of proteins have been shown to protect against acute and late radiation damage of normal tissues. Protection of the small bowel, for example, occurs via both increased proliferation and reduced apoptosis. Other beneficial effects of FGFs include promotion of bone growth, pneumonitis prevention, and apoptosis suppression of endothelium in vivo and in vitro after irradiation. This protection against radiation requires only low and infrequent doses of FGFs. Two newly identified members of the FGF family, FGF7 and FGF10, have effects similar to many of the other FGF family proteins, but with more specificity for normal epithelial structures. For this reason, they have also been named keratinocyte growth factors one and two (KGF1 and KGF2, respectively). We therefore examined the potential utility of KGFs for radioprotection of the bone marrow and small bowel and examined safety issues concerning their adverse effects on KHT sarcoma. The results suggest that KGFs could be safely used to prevent radiation toxicity of the abdomen or pelvis and may in fact improve tumor response to radiation.     

Influence of hydralazine administration on oxygenation in spontaneous and transplanted tumor models

PURPOSE: To examine the effects of hydralazine on vascular perfusion and hypoxia in spontaneous vs. first generation and long-term transplanted murine tumor models. METHODS AND MATERIALS: Total anatomic blood vessels were quantified using image analysis of CD31 stained frozen sections, perfused vessels by i.v. injection of fluorescent DiOC(7), and tumor hypoxia was measured using the EF5 hypoxia marker. KHT sarcomas, spontaneous mammary carcinomas, and first generation transplants of the spontaneous tumors were evaluated before and after i.p. administration of 5 mg/kg hydralazine. RESULTS: Although anatomic and perfused vessel spacings were similar among untreated tumors, response to hydralazine varied widely among the three tumor models. In KHT tumors, perfused vessel numbers decreased significantly at 30 min post-hydralazine, then recovered somewhat by 60 min. First-generation transplants showed a less substantial decrease in perfused vessels following hydralazine, which tapered off slightly by 60 min. Finally, spontaneous tumors had only a modest decrease in perfused vessel numbers, with complete recovery at 60 min. Although response of individual tumors varied widely, overall hypoxic marker uptake was significantly increased in both KHT and first generation tumors, and slightly reduced in the spontaneous tumors. CONCLUSION: Response to hydralazine varies substantially between transplanted and spontaneous tumor models. Results suggest that increased tumor pressure may be a critical factor in tumor response to hydralazine, possibly explaining tumor volume dependent variations.     

Nasal nitric oxide and the nasal cycle

OBJECTIVES: To establish the relationship between nasal patency and the nitric oxide (NO) concentration in the nasal airways. METHODS: Unilateral nasal NO concentration (n = 11) and inhaled nasal NO concentration at oropharynx (n = 9) were measured in healthy adult volunteers. Subjects breathed normally through the nose with a known resistance (ranged from none to total occlusion) placed in one nostril. In a subgroup (n = 7), the unilateral nasal NO concentrations were determined with nasal cavity congestion induced by lateral decubitus. RESULTS: When the added nasal resistance was less than 6 cm H(2)0 per liter per second, the peak NO concentrations in the nose remained below 80 parts per billion (ppb). Thereafter, the higher the resistance, the greater the NO concentration. It was up to 1109.7 ppb when the front nostril was totally occluded. There was no correlation between oropharyngeal NO concentrations and resistance in the front of the nose (r = 0.4). There was a significantly negative correlation between nasal cavity volumes and nasal NO concentrations (r = -0.8, P <.001). CONCLUSIONS: Increases in nasal resistance to levels encountered in the nasal cycle and in recumbency augments the NO concentration within the obstructed side of the nose. Although that within the nose changes with patency, the NO concentration is constant down to the lower airways. The modulation role of the upper airways to the inhaled NO concentration remains unclear.     

Retinoblastoma gene abnormalities in early laryngeal cancer

The retinoblastoma gene (Rb) is postulated to be important in carcinoma of the larynx. Its cellular protein (pRb) is involved in regulation of the cell cycle and may be influential in the cells response to irradiation injury. From the University of Liverpool Head and Neck Database we identified 35 patients with a T2 N0 laryngeal squamous carcinoma whom received primary irradiation and had a minimum of 5 years follow up. Laser capture microdissection was performed on paired normal and tumour biopsy material to analyse for loss of heterozygosity (LOH) and microsatelite instability (MI) of the Rb gene and immunohistochemistry (IHC) was carried out to detect pRb expression. Of 35 tumours, 13 were normal, 12 had MI and 5 had LOH of the Rb gene. Abnormalities at the Rb locus did not correlate with loss of pRb expression. There was also no significant difference between the distribution of normal and abnormal gene sequences and whether or not the primary laryngeal tumour recurred after radiotherapy. Rb gene abnormalities occurred in one third of T2 N0 laryngeal carcinomas. These were not in isolation predictive of cure by radiotherapy.     

Isolated hypoglossal nerve palsy: a harbinger of malignancy

The hypoglossal nerve is an underrated nerve usually consigned to a few words in anatomical text books, under the last four cranial nerves. However, paralysis of this nerve may be the first indication of a serious underlying disorder. Excluding previous surgery, radiotherapy and trauma, 50 per cent of cases of isolated hypoglossal nerve palsy are idiopathic. A further 20 per cent are malignant, 20 per cent are vascular and 10 per cent are due to miscellaneous causes. Presentation of an isolated hypoglossal nerve palsy is therefore an ominous sign. There is confusion over both cause and investigation, and management protocols for isolated hypoglossal nerve palsy are ill-defined. We present a case of isolated hypoglossal palsy which was due to a metastatic skull base deposit. This case illustrates the fact that magnetic resonance imaging is the investigation of choice in assessing the entire course of the hypoglossal nerve.     

Understanding chronic heart failure

The key principles of chronic heart failure and the development of clinical management strategies are described. The physiological changes in chronic heart failure and the clinical management of children with heart failure are considered, but the treatment of heart failure related to congenital heart disease or the intensive care management of heart failure are not mentioned as both topics require consideration in their own right. A greater understanding of the maladaptive responses to chronic heart failure has enabled targeted therapy to be introduced with consequent improvement in symptoms, reduction in hospitalisation and lower mortality.