Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity.

Granulocyte macrophage-colony-stimulating factor (GM-CSF) signaling regulates hematopoiesis and immune responses. CSF2RA, the gene encoding the α-subunit for GM-CSF, is significantly downregulated in t(8;21) (RUNX1-ETO or RE) leukemia patients, suggesting that it may serve as a tumor suppressor. We previously reported that GM-CSF signaling is inhibitory to RE leukemogenesis. Here we conducted gene expression profiling of primary RE hematopoietic stem/progenitor cells (HSPCs) treated with GM-CSF to elucidate the mechanisms mediating the negative effects of GM on RE leukemogenicity. We observed that GM treatment of RE HSPCs resulted in a unique gene expression profile that resembles primary human cells undergoing myelopoiesis, which was not observed in control HSPCs. Additionally, we discovered that GM-CSF signaling attenuates MYC-associated gene signatures in RE HSPCs. In agreement with this, a functional screen of a subset of GM-CSF-responsive genes demonstrated that a MYC inhibitor, MXI1 (Max interactor 1), reduced the leukemic potential of RE HSPCs and t(8;21) acute myeloid leukemia (AML) cells. Furthermore, MYC knockdown and treatment with the BET (bromodomain and extra terminal domain) inhibitor JQ1 reduced the leukemic potential of t(8;21) cell lines. Altogether, we discovered a novel molecular mechanism mediating the GM-CSF-induced reduction in leukemic potential of RE cells, and our findings support MYC inhibition as an effective strategy for reducing the leukemogenicity of t(8;21) AML.

Dietary habits and esophageal cancer.

Cancer of the esophagus is an underestimated, poorly understood, and changing disease. Its overall 5-year survival is less than 20%, even in the United States, which is largely a function of a delay in diagnosis until its more advanced stages. Additionally, the epidemiologic complexities of esophageal cancer are vast, rendering screening and prevention limited at best. First, the prevalence of esophageal cancer is unevenly distributed throughout the world. Second, the two histological forms (squamous cell and adenocarcinoma) vary in terms of their geographic prevalence and associated risk factors. Third, some populations appear at particular risk for esophageal cancer. And fourth, the incidence of esophageal cancer is in continuous flux among groups. Despite the varied prevalence and risks among populations, some factors have emerged as consistent associations while others are only now becoming more fully recognized. The most prominent, scientifically supported, and long-regarded risk factors for esophageal cancer are tobacco, alcohol, and reflux esophagitis. Inasmuch as the above are regarded as important risk factors for esophageal cancer, they are not the sole contributors. Dietary habits, nutrition, local customs, and the environment may be contributory. Along these lines, vitamins, minerals, fruits, vegetables, meats, fats, salted foods, nitrogen compounds, carcinogens, mycotoxins, and even the temperature of what we consume are increasingly regarded as potential etiologies for this deadly although potentially preventable disease. The goal of this review is to shed light on the less known role of nutrition and dietary habits in esophageal cancer.

Challenges in the diagnosis of 2009 H1N1 in a lung transplant patient and the long-term implications for prevention and treatment: a case report.

Although respiratory viral infections have been associated with acute rejection and bronchiolitis obliterans syndrome, the long-term impact of the novel pandemic influenza A (2009 H1N1) virus on lung transplant patients has not been defined. We describe the diagnostic challenges and long-term consequences of 2009 H1N1 infection in a lung transplant patient, discuss the potential implications for prevention and treatment, and conclude that even timely antiviral therapy may be insufficient to prevent long-term morbidity.

Hepatocyte growth factor promotes tumor growth in a novel in vivo model of human lung cancer.

Significant progress has been made toward identifying growth factors that display autocrine or paracrine effects on the growth of lung cancer cells. Determining the in vivo relevance of specific growth factors on lung tumor formation, however, has not often been demonstrated in laboratory models. Although hepatocyte growth factor (HGF) has been shown to have mitogenic and motogenic effects on human lung cancer cells in vitro, and to have prognostic importance in patients with lung cancer, the effects of HGF on tumor behavior in vivo remain unknown. We therefore developed an airway tumor xenograft model that allowed us to test the hypothesis that HGF promotes human non-small cell lung cancer (NSCLC) growth in vivo. Human airway tumor xenografts were created in Severe Combined Immunodeficient mice by injecting human lung adenocarcinoma cells into human bronchial segments. After determining the optimal times for tumor-cell injection and the time course of tumor growth, we evaluated the effects of HGF on tumor growth by injecting recombinant HGF, or saline as a control, into the lumen of tumor xenografts for 10 consecutive days. Histologic evaluation 2 to 3 wk later revealed that the HGF-injected xenografts had a significantly greater tumor volume and more tumor cells were located in the submucosal space than were found in the saline-injected xenografts. These data demonstrate the usefulness of this novel in vivo model to study NSCLC, and show that HGF promotes both the growth and invasion of human lung cancer in vivo.

Direct percutaneous jejunostomy: techniques and applications--ten years experience.

PURPOSE: To present 10 years experience with direct fluoroscopically guided percutaneous jejunostomy. MATERIALS AND METHODS: Percutaneous jejunostomy was performed in 62 patients, most of whom had undergone major abdominal surgery. A new or replacement jejunostomy was created for alimentation in 20 and 21 patients, respectively. Jejunostomy was performed for interventional procedures of the bile ducts or intestine in 13 patients and for retrograde gastroesophageal drainage in eight. The distended jejunum was accessed with a 21-gauge needle, immobilized with a gastric anchor, and catheterized with a 10-14-F locking loop drain. RESULTS: The technical success rate was 19 of 20 (95%) for new feeding jejunostomy and 17 of 21 (81%) for replacement feeding jejunostomy. Jejunostomy facilitated drainage, dilation, stone extraction, and recanalization in the bile ducts or intestine in all 13 patients. Retrograde jejunoesophagogastrostomy suction effectively replaced painful nasogastric suction in all eight patients. Two patients who underwent replacement jejunostomy required laparotomy for possible leakage; there was no important procedure-related morbidity and no procedure-related mortality. CONCLUSION: The technical success and complication rates of feeding percutaneous jejunostomy compare favorably with those of surgery or endoscopy. Percutaneous jejunostomy is a useful and underused approach to managing bowel and biliary obstruction.

Expression of mRNA for gastrin-releasing peptide receptor by human bronchial epithelial cells. Association with prolonged tobacco exposure and responsiveness to bombesin-like peptides.

Bombesin-like peptides (BLPs) are important regulators of lung development and may also act as autocrine growth factors in lung tumors. We have previously demonstrated expression of mRNA for the three BLP receptor subtypes (neuromedin B [NMB]) receptor, gastrin-releasing peptide [GRP] receptor, and bombesin receptor subtype 3 [BRS-3]) in human non-small cell lung carcinoma (NSCLC) cell lines and bronchial biopsies using the reverse transcription-polymerase chain reaction (RT-PCR; DeMichele, et al. Am. J. Respir. Cell Mol. Biol. 1994; 11:66-74). We have also previously found that growth responses to BLPs could be elicited in some, but not all, cultures of human bronchial epithelial (HBE) cells (Siegfried, et al. Anat. Rec. 1993; 236:241-247). In this report, we utilized RT-PCR to demonstrate mRNA expression of BLP receptor subtypes in cultured HBE cells and also assessed the response of these cultures to BLPs in proliferation assays. The pattern of mRNA expression was correlated with proliferative response, and the results were also analyzed in relation to smoking history and pulmonary function of the subjects studied. Our results suggest that expression of mRNA for the GRP receptor is associated with a long smoking history (> 25 pack-years [PY], p = 0.02). This association was related to past tobacco exposure, regardless of whether the subjects were still active smokers at the time of tissue procurement. Responsiveness to GRP and NMB in proliferation assays was also found only in those HBE cultures with expression of mRNA for at least one of the known receptors for BLPs, and there was a significant association between expression of mRNA for the GRP receptor and proliferative response to both GRP and NMB (p = 0.048). HBE cultures from subjects with a greater than 25 PY smoking history were also more likely to respond to BLPs in the proliferation assays than cells from subjects with less than a 25 PY history (10 of 16 versus 1 of 7, p = 0.06). Cultures of HBE cells from four of the five subjects with severe obstructive lung disease gave a positive response to GRP and NMB in proliferation assays, compared to five of fifteen without severe obstructive lung disease, but this difference was not significant (p = 0.13). These results suggest there is an increased likelihood of expression of the GRP receptor mRNA in the respiratory epithelium of some individuals with a history of prolonged tobacco exposure, and that expression of the GRP receptor mRNA is accompanied by responsiveness to the mitogenic effects of BLPs. These effects appear to persist after smoking cessation.

Colouterine fistula: computed tomography and vaginography findings.

Colouterine fistulas are difficult to demonstrate radiologically. The authors present a case in which such a fistula was observed with computed tomography and confirmed by vaginography.

Epidural diamorphine and bupivacaine in labour.

A double-blind randomised study was performed to assess the analgesic effect of epidural diamorphine, administered with bupivacaine, on primigravid women in labour. Fifty patients received 0.25% bupivacaine 10 ml via the epidural catheter as their initial dose; patients in Group 1 received diamorphine 5 mg with the bupivacaine. A 0.1% bupivacaine infusion was started at 10 minutes and bolus doses of bupivacaine were given if required. There was a significant reduction in rate of bupivacaine administration, pain scores at 20 and 30 minutes, number of supplements required, and degree of motor blockade in the diamorphine group.

Lignocaine 2% with adrenaline for epidural caesarean section. A comparison with 0.5% bupivacaine.

A randomised double blind controlled trial of freshly prepared 2% lignocaine with 1/200,000 adrenaline and 0.5% plain bupivacaine was conducted on 60 women undergoing elective Caesarean section. The use of the former enabled epidural blockade to above the T6 dermatome to be established in a significantly shorter time than with bupivacaine (p less than 0.005). The quality of sensory blockade and incidence of complications was similar in the two groups. The solutions were of similar potency as measured by the volume required per segment blocked. Motor blockade was more intense with 2% lignocaine with adrenaline (p less than 0.03). More neonates had moderately depressed Apgar scores (5-7) at one minute in the lignocaine group but this difference was not statistically significant, and there was no difference in the distribution of Apgar scores at 3 minutes. Lignocaine with 1/200,000 adrenaline is a useful alternative to 0.5% plain bupivacaine when it is desired to establish rapidly epidural blockade for Caesarean section.

Spina bifida occulta and epidural anaesthesia.

Spina bifida occulta occurs in 5-10% of the population, not all of whom display superficial signs. Attempted epidural puncture at the level of the lesion will almost certainly result in a dural tap. We report a patient who developed a postural headache after Caesarean section under epidural anaesthesia, in whom radiography of the spine later demonstrated spina bifida occulta. This problem has not been described previously, although it is unlikely to be an isolated case.

Documenting the activity and effectiveness of a regional drug information center.

The methods of data collection, storage, and retrieval used by the Rocky Mountain Drug Consultation Center (RMDCC) are described. To substantiate that drug information services provided by RMDCC are clinically useful and have a beneficial effect on therapy, data on medication-related problems and case outcomes, as well as demographic data, are stored in an IBM PC-XT using a system that allows searching and linkage of any number of recorded categories. Data were compiled on 28,081 inquiries from health-care professionals and consumers during 1985 and 1986. Analysis revealed that (1) medication-related problems are common (involving 34% of consumer inquiries), especially among the elderly; (2) a positive effect on therapy was made in the majority (76%) of problem cases; and (3) consumers were given drug information by their physician or pharmacist in fewer than half of the cases in which medications were prescribed and dispensed. A computer-based system to assist in analyzing information can be an important asset in documenting the activity and effectiveness of a regional drug information center.

Thromboxane A2 does not contribute to arrhythmogenesis during evolving canine myocardial infarction.

During the healing phase of evolving myocardial infarction, inflammatory cells invade the affected region and produce metabolites that may influence electrophysiological parameters and the genesis of malignant arrhythmias. We have recently shown an increased synthetic capacity within an evolving infarct for thromboxane A2 (TXA2), a metabolite that has been implicated in arrhythmias associated with early ischemia. The present study used both in vivo and in vitro procedures to define the electrophysiological and arrhythmogenic effects, if any, of thromboxane during evolving myocardial infarction. Thirty-three dogs divided into three groups were studied 3-7 days after transient left anterior descending coronary artery ligation. One group (n = 24) was examined by programmed electrical stimulation in the conscious state and, of the five dogs in this group with sustained ventricular tachycardia (VT), none demonstrated consistent limitation of inducibility by selective inhibition of thromboxane synthetase using three different agents. In the second group, (n = 5) regional conduction velocity was assessed using detailed three-dimensional activation analysis from 232 simultaneous intramyocardial sites, and no change was induced by the thromboxane synthetase inhibitor OKY-1581 in either normal or infarcted myocardial zones during sinus rhythm or with pacing. In the third group (n = 4), isolated ventricular muscle was studied in vitro using both intracellular transmembrane action potential recordings and surface extracellular maps from 48 simultaneous points. Neither intracellular action potential parameters nor extracellularly recorded activation patterns were altered by superfusion with the stable thromboxane analog STA2, the activity of which was verified by bioassay. Thus, despite increased synthetic capacity for thromboxane generation, the presence of TXA2 does not directly influence either electrophysiological indices or arrhythmogenesis.

Anaesthesia for Caesarean section. The potential for regional block.

This study of the obstetric and anaesthetic circumstances relating to 100 consecutive Caesarean sections under general anaesthesia suggests that the general anaesthesia rate for Caesarean section could be reduced from the present 37 to 27% by making maximum use of epidural block and to 16% by using subarachnoid block in addition. The need for general anaesthesia on account of urgency to deliver can be greatly reduced by the administration of epidural analgesia during labour in patients identified as being more likely than average to require Caesarean section, and by the use of subarachnoid block when the need for section arises unexpectantly. Patients' objections to undergoing Caesarean section while conscious were analysed, and suggestions are made for minimising the number of patients who decline. Technical problems with blocks may sometimes be overcome without resort to general anaesthesia, while patients at risk from haemorrhage or coagulopathy will continue to require general anaesthesia.