Gastrostomy-site tumor recurrence is not always fatal.

Percutaneous gastrostomy (PEG) site tumor seeding is a rare occurrence with fewer than 30 reported cases. Reported treatment ranges from observation to wide excision with unanimously poor outcome. We report the first published case of a long-term survivor after resection of a PEG site recurrence and review our treatment approach.

A population-based case-control study of lung cancer and green tea consumption among women living in Shanghai, China.

Epidemiologic evidence regarding the association between the consumption of green tea and lung cancer is limited and inconclusive, although experimental studies have shown consistently that tea preparations and tea polyphenols may inhibit the induction of a variety of cancers, including lung cancer. In this population-based case-control study, we examined the association between past consumption of green tea and the risk of lung cancer. We identified 649 incident cases of primary lung cancer among women diagnosed from February 1992 through January 1994 using the population-based Shanghai Cancer Registry. We randomly selected a control group of 675 women from the Shanghai Residential Registry, frequency-matched to the expected age distribution of the cases. Green tea consumption was ascertained through face-to-face interviews. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. Among nonsmoking women, consumption of green tea was associated with a reduced risk of lung cancer (OR = 0.65; 95% CI = 0.45-0.93), and the risks decreased with increasing consumption. We found little association, however, among women who smoked (OR = 0.94; 95% CI = 0.40-2.22). The inconsistency in the association between drinking tea and the risk of lung cancer reported in previous studies may in part be due to inadequate control of confounding of active smoking.

Kinetic characterization of the pH-dependent oligomerization of R67 dihydrofolate reductase.

Protein-protein recognition results from the assembly of complementary surfaces on two molecules that form a stable, noncovalent, specific complex. Our interest was to describe kinetic aspects of the recognition in order to understand the subtle molecular mechanism of association. R67 dihydrofolate reductase (DHFR) provides an ideal model to investigate kinetic parameters of protein-protein association since it is a homotetramer resulting from the pH-dependent dimerization of homodimers. We took advantage of the presence of a tryptophan residue at the dimer-dimer interface to monitor pH-dependent oligomerization of R67 DHFR using stopped-flow fluorescence techniques. Except for pH near neutrality where dissociation exhibited biphasic kinetics, association and dissociation followed monophasic kinetics fitted on a two-state model. Apparent rate constants of association k(on) and dissociation k(off) were determined at various pHs and pointed to the key role of a histidine located at the dimer-dimer interface in the pH control of tetramerization. The values of the tetramer-dimer equilibrium dissociation constant were calculated from the ratio k(off) /k(on) and correlated well with those previously measured at equilibrium. The thermodynamic parameters and the activation energies of both the association and dissociation were determined and indicated that the association is enthalpy driven and suggested that the formation of four hydrogen bonds (one per monomer) is responsible for the thermodynamic stability of the tetramer. Detailed analysis of the biphasic kinetics led to an original model, in which protonation of the tetramer is the triggering event for the dissociation process while the association involves primarily the unprotonated dimers.

1alpha-hydroxyvitamin D2 is less toxic but not bone selective relative to 1alpha-hydroxyvitamin D3 in ovariectomized rats.

Identification of bone selective vitamin D analogues would provide an interesting substance class for the treatment of osteoporosis. The synthetic prodrug 1alpha-hydroxyvitamin D2 [1alpha(OH)D2] has been shown to combine equal bone-preserving activity with distinctly reduced calcemic effects relative to 1alpha-hydroxyvitamin D3 [1alpha(OH)D3] in 3-month-old ovariectomized (OVX) rats. Therefore, 1alpha(OH)D2 may be a bone-selective compound. The aim of this study was to compare the bone protective and the calcemic activities of chronically administered 1alpha(OH)D2 and 1alpha(OH)D3 in 6-month-old OVX rats over a broad dose range from ineffective to toxic doses. Ninety-six female 6-month-old Fischer-344 rats were used for this experiment. Eighty rats were bilaterally OVX, 8 rats were sham-operated (SHAM), and 8 rats were killed at the time of surgery as a baseline control. Groups of OVX rats received vehicle alone (n = 16) or daily doses in the diet of 0.025, 0.05, 0.1, and 0.2 microg of 1alpha(OH)D2 or 1alpha(OH)D3 per kg body weight (BW) per day (n = 8 each). After calcein double-labeling, all animals were killed 3 months post-OVX. Orally administered 1alpha(OH)D2 was significantly less toxic compared with 1alpha(OH)D3 in terms of BW gain and kidney calcium content. The effects of 1alpha(OH)D2 and 1alpha(OH)D3 on serum calcium and urinary calcium excretion were generally similar at all doses in this study. Both 1alpha(OH)D2 and 1alpha(OH)D3 prevented the estrogen deficiency-induced bone loss in OVX rats, and induced profound bone anabolic effects at high dosages. 1alpha(OH)D3 and 1alpha(OH)D2 also dose-dependently increased total bone mineral density (BMD), cortical area, and cortical thickness in the tibial diaphysis of OVX rats. Bone resorption as assessed by osteoclast numbers (Oc.Ns) in vertebral cancellous bone and urinary excretion of deoxypyridinoline (DPD) was dose-dependently suppressed by 1alpha(OH)D2 and 1alpha(OH)D3. These data show that although 1alpha(OH)D2 was slightly but significantly less toxic compared with 1alpha(OH)D3, it did not have increased skeletal effects at any dose. Taken together, our findings argue against selective metabolic activation of 1alpha(OH)D2 in bone.

Factors affecting plasma bilirubin in preterm infants ventilated for respiratory distress syndrome.

OBJECTIVE: To evaluate the contribution of various factors to plasma bilirubin level in preterm infants with a birth weight of < 1500 gm in need of mechanical ventilation for respiratory distress syndrome (RDS) during their first week of life. METHODOLOGY: A total of 50 very low birth weight (< 1500 gm) preterm infants consecutively admitted to the neonatal intensive care unit were studied. Plasma bilirubin levels were determined every 8 hours for the first week of life. Data relating to daily body weight, daily fluid intake, age at onset of gavage feeds, daily caloric intake, and grade of intraventricular hemorrhage (IVH) were collected. Data relating to mechanical ventilation were collected every 4 hours as follows: fractional inspired O2, arterial PO2, arterial PCO2, and mean airway pressure. An arterial/alveolar PO2 ratio and a corrected oxygenation index were computed for the first 2 days of life. A bilirubin index (BI), defined as the ratio of peak plasma bilirubin level to birth weight1/3, was used to study the association between bilirubin and the above variables. A BI was also used as a criterion for starting and discontinuing phototherapy. Multiple linear regression analysis was used to model BI. RESULTS: IVH (p < 0.0001), age at onset of gavage feeds (p < 0.003), oxygenation index (p < 0.007), and gestational age (p < 0.05) made a significant contribution to variations in BI (37.16%, 43.71%, 48.99%, and 53.33%, respectively). CONCLUSION: Hyperbilirubinemia in ventilated preterm infants with RDS is most likely multifactorial; entities quite distinct from RDS (such as nutrition and IVH) may significantly contribute to its variation.

Risk of developing lung cancer in relation to exposure to fumes from Chinese-style cooking.

In an evaluation of the association between exposure to indoor air pollution from Chinese-style cooking and the risk of lung cancer, epidemiologic and experimental studies were reviewed. The 9 case-referent studies that were identified showed consistent positive associations between the risk of lung cancer and a variety of indices of exposure to indoor air pollution arising from Chinese-style cooking. Three experimental studies showed that volatile emissions from oils heated in woks are mutagenic in several in vitro short-term test systems. Several toxic agents, including some accepted or suspected carcinogens, have been detected in the emissions of the heated cooking oils. While experimental data support the epidemiologic data, it may be premature to conclude that the association is causal. However, simple precautions can be taken to reduce the risk in the event that exposure to indoor air pollution arising from Chinese-style cooking is indeed a cause of lung cancer.

Lung cancer and indoor air pollution arising from Chinese-style cooking among nonsmoking women living in Shanghai, China.

Associations between indoor air pollution from Chinese-style cooking and lung cancer have been found in several investigations. To provide more detailed estimates of the associations while accounting for key confounding factors, we conducted a population-based, case-control study of lung cancer among nonsmoking women living in Shanghai, the People's Republic of China. Five hundred four incident, primary lung cancer cases diagnosed from February 1992 through January 1994 were identified through the population-based Shanghai Cancer Registry. A control group of 601 nonsmoking women was selected randomly from the Shanghai-Residential Registry, and they were frequency-matched to the expected age distribution of the cases. Exposure to indoor air pollutants from Chinese-style cooking was ascertained through in-person interviews. We estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) by unconditional logistic regression. There were similar patterns of excess risk for exposure to indoor air pollutants from Chinese-style cooking across different histological types of lung cancer. Women who did not have a separate kitchen experienced a 28% increased risk of lung cancer (OR = 1.28; 95% CI = 0.98-1.68). We found little association with area of the windows of the apartment where subjects had lived for the longest period of time. Heating cooking oils to high temperatures was associated with a 1.64-fold increased risk of lung cancer (95% CI = 1.24-2.17). An 84% excess risk was found among women who most often cooked with rapeseed oil (OR = 1.84; 95% CI = 1.12-3.02). Lung cancer risks were also related to "considerable" smokiness of the kitchen during cooking (OR = 2.38; 95% CI = 1.58-3.57), frequent eye irritation during cooking (OR = 1.68; 95% CI = 1.02-2.78), to a more than weekly use of frying (OR = 2.09; 95% CI = 1.14-3.84) and deep-frying (OR = 1.88; 95% CI = 1.06-3.32). This population-based case-control study confirmed that exposure to indoor air pollution from Chinese-style cooking, especially cooking unrefined rapeseed oil at high temperatures in woks, may increase the risk of lung cancer.

Patency of infrainguinal polytetrafluoroethylene bypass grafts with distal interposition vein cuffs.

Polytetrafluoroethylene (PTFE) prosthetic bypasses in the lower extremity have poor patency rates, particularly in limb salvage cases. Patency and limb salvage rates of PTFE bypasses supplemented by distal interposition vein cuffs were assessed in patients requiring revascularization for critical limb ischemia, in the absence of a suitable autologous saphenous vein. Between October 1993 and April 1996, 163 patients underwent 185 infrainguinal bypasses. Forty-three limbs in 42 patients (12 women, 30 men; mean age 67 years) did not have a suitable autologous saphenous vein (24%) and had femoropopliteal (20) and infrapopliteal (23) bypasses performed. Patients were examined prospectively at 3-month intervals during the first year and at 6-month intervals thereafter to determine graft patency and limb salvage. Postoperative anticoagulation with warfarin was used in 26 patients. Indications for operation included limb salvage in 41 extremities (21 rest pain/ulceration or gangrene, 20 rest pain alone), and disabling claudication in two. Patients were followed clinically for 2-30 months (mean 10 months). Cumulative 2-year life-table patencies for all grafts, femoropopliteal and infrapopliteal bypasses were 64%, 75% and 62%, respectively. Previous primary patencies at the authors' institution for PTFE bypasses without vein cuffs were 35%, 46% and 12% for the same categories. Cumulative life-table limb salvage for all PTFE/vein cuff bypasses in the present series was 76% compared with 37% in previous PTFE bypasses without vein cuffs. Adjunctive use of distal interposition vein cuffs improves prosthetic graft patency, while producing satisfactory limb salvage. Postoperative anticoagulation did not influence graft patency. PTFE/vein cuff for lower-extremity revascularization shows good 2-year patency and is an acceptable alternate conduit in patients with critical limb ischemia when autologous saphenous vein is absent.

Distinct roles for sodium, chloride, and calcium in excitotoxic dendritic injury and recovery.

The postsynaptic neuronal dendrite is selectively vulnerable to hypoxic-ischemic brain injury and glutamate receptor overactivation. We explored the glutamate receptor pharmacology and ionic basis of rapid, reversible alterations in dendritic shape which occur in cultured neurons exposed to glutamate. Dendrite morphology was assessed with the fluorescent membrane tracer, DiI, or immunofluorescence labeling of the somatodendritic protein, MAP2. Cortical cultures derived from 15-day-old mouse embryos underwent segmental dendritic beading when exposed to NMDA, AMPA, or kainate, but not to metabotropic glutamate receptor agonists. Varicosity formation in response to NMDA or kainate application was substantially attenuated in reduced sodium buffer (substituted with N-methyl-D-glucamine). Furthermore, veratridine-induced sodium entry mimicked excitotoxic alterations in dendrites and additionally caused varicosity formation in axons. Solutions deficient in chloride (substituted with Na methylsulfate) and antagonists of chloride-permeable GABA/glycine receptors reduced NMDA- or kainate-induced varicosity formation. An increase in dendrite volume was observed as varicosities formed, and varicosity formation was attenuated in sucrose-supplemented hypertonic media. Despite marked structural changes affecting virtually all neurons, dendrite shape returned to normal within 2 h of terminating glutamate receptor agonist application. Neurons exposed to kainate recovered more rapidly than those exposed to NMDA, and neurons exposed to NMDA in calcium-free buffer recovered more rapidly than cells treated with NMDA in normal buffer. While sodium, chloride, and water entry contribute to excitotoxic dendritic injury acutely, calcium entry through NMDA receptors results in lasting structural changes in damaged dendrites.

Combined-modality therapy for esophageal cancer: phase I trial of escalating doses of paclitaxel in combination with cisplatin, 5-fluorouracil, and high-dose radiation before esophagectomy.

Several recent reports support administering preoperative chemotherapy and radiotherapy to improve the outcome of patients with resectable esophageal malignancies. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), 5-fluorouracil (5-FU), and cisplatin are known radiosensitizers, and paclitaxel has demonstrated single-agent activity in patients with metastatic esophageal cancer. This study sought to define the maximum tolerated dose of paclitaxel given with 5-FU, cisplatin, and 60 Gy radiotherapy before esophagectomy to patients with potentially resectable lesions. Seventeen patients so treated underwent esophagectomy. Three patients with metastatic disease, treated to obtain more information about the toxicity of the combined-modality regimen, did not undergo surgery. Over 6 weeks, 60 Gy radiation was administered in 2-Gy fractions. During radiation treatment, continuous intravenous infusions of 5-FU 225 mg/m2/d were administered, with paclitaxel given weekly as a 1-hour intravenous infusion immediately preceding a 1-hour cisplatin infusion. Surgery was performed 4 to 6 weeks after the completion of radiotherapy. The 27 patients, one of whom was a woman, had a median age of 58 years and an Eastern Cooperative Oncology Group performance status of 0 (10 patients) or 1. Three patients had a squamous cell histology, while 22 had adenocarcinoma; two had other histologies. The paclitaxel dose levels were 25 mg/m2 in four patients, 40 mg/m2 in five patients, 60 mg/m2 in nine patients, and paclitaxel 50 mg/m2 with 5-FU reduced to 200 mg/m2 in nine patients. The latter proved to be the maximum tolerated dose combination, with cisplatin held constant at 25 mg/m2. This level represents weekly dose intensities of 9.6 Gy radiation, 48 mg/m2 paclitaxel, 24 mg/m2 cisplatin, and 192 mg/m2 5-FU. Diarrhea in four patients, mucositis and dehydration in seven, electrolyte wasting in two, gram-positive catheter-related infection in three, and neuropathy in one proved dose limiting. Hematologic toxicity was relatively mild, with three episodes of nonneutropenic bacteremia, one of which was fatal. Postoperative chemotherapy consisting of four cycles of paclitaxel 175 mg/m2 over 3 hours and cisplatin 75 mg/m2 over 1 hour every 3 weeks was planned but rarely feasible due to postoperative morbidity and poor tolerability of postoperative chemotherapy. Therefore, the use of two induction cycles of this regimen given before the combined-modality study regimen is currently being investigated. Of 17 patients whose surgical specimens were assessed pathologically, three had complete remissions and 14 had partial remissions, five of which were characterized as very good, showing only microscopic foci and marked radiation effects. The median follow-up of the 17 patients who underwent surgery is 50 weeks (range, 5 to 111 weeks). Three relapses occurred at 26, 33, and 43 weeks. We conclude that this is an intense combined-modality preoperative regimen for patients with esophageal cancer. Determining the efficacy of this regimen will require further follow-up and the performance of phase II trials.

Evaluation of recombinant protein r140, a polypeptide segment of tegumental glycoprotein Sm25, as a defined antigen vaccine against Schistosoma mansoni.

To investigate the role of tegumental glycoprotein Sm25 in protective immunity against schistosomiasis, codons 43-182 of its gene (GP22) were amplified by PCR and cloned in the pET 15b bacterial expression system. Recombinant protein r140 was inducibly expressed in the presence of rifampicin and purified by Ni-affinity chromatography. In different vaccination trials, Balb/c mice and Fischer rats repeatedly immunized with r140 in combination with one of several adjuvants (alum, cholera toxin or complexed into proteosomes) produced high titre anti-r140 responses. These antibodies detected an N-glycanase sensitive. 25 kDa antigen in a detergent solubilized worm fraction using Western immunoblotting. The choice of adjuvant affected the isotype distribution of the specific anti-r140 antibodies. Despite the presence of high antibody titres and isotypes which have been shown to correlate with protective immunity, protection against subsequent cercarial challenge was not observed. In addition, no appreciable effects on worm sex ratios or liver egg yields were detected in mice. Studies involving biotin labelling of membrane proteins in live worms showed that the majority of anti-r140 reactive molecules present in adult schistosomes are biotinylated after permeabilization of the parasite surface. Several possibilities to account for the lack of protective immunity are analysed.

Blood boron concentrations in pregnant rats fed boric acid throughout gestation.

Timed-mated Sprague-Dawley rats (28 to 32/group) were exposed to boric acid (BA) in the diet from Gestational Day (GD) 0 to 20. Dietary concentrations of added BA (0%, 0.025%, 0.050%, 0.075%, 0.100%, or 0.200%) yielded average daily intakes equivalent to 0, 3, 6, 10, 13, or 25 mg boron/kg body weight/d. Dams and their fetuses were evaluated for evidence of maternal or developmental toxicity, as reported previously. At termination on GD 20, maternal whole blood was collected in heparinized Vacutainer tubes, stored frozen (-20 degrees C), and subsequently prepared by a high-temperature alkaline ashing procedure for analysis of boron by inductively coupled plasma optical emission spectrometry. Increasing dietary concentrations of BA were positively associated with whole blood boron concentrations in confirmed pregnant rats, specifically 0.229 +/- 0.143, 0.564 +/- 0.211, 0.975 +/- 0.261, 1.27 +/- 0.298, 1.53 +/- 0.546, or 2.82 +/- 0.987 micrograms boron/g whole blood (mean +/- SD) for the control through high-dose groups. Maternal blood boron concentrations were positively correlated with indices of maternal dietary intake of boron and with embryo/fetal toxicity observed at 0.100% and 0.200% BA in the diet reported previously. Thus, blood boron concentrations of 1.27 +/- 0.298 and 1.53 +/- 0.546 micrograms boron/g were associated with the no-observed-adverse-effect level (10 mg boron/kg/d) and lowest-observed-adverse-effect level (13 mg boron/kg/d) for developmental toxicity reported previously.

Postpartum cerebral vasospasm treated with hypervolemic therapy.

In a 23-year-old woman, gravida 1, para 1-0-0-1, headaches and seizures developed 1 week after an uncomplicated delivery. Cerebral angiography revealed severe, diffuse cerebral vasospasm. Her symptoms resolved with hyperosmolar, hypervolemic therapy and nimodipine. Magnetic resonance angiography on postpartum day 23 confirmed persistent, severe vasospasm, and repeat magnetic resonance angiography on postpartum day 33 demonstrated interval improvement. This report documents the time course of a case of postpartum vasospasm and its response to hypervolemic, hyperosmolar therapy and nimodipine.

"Mother-baby" biliary endoscopy: the University of Chicago experience.

OBJECTIVE: The "mother-baby" technique of peroral cholangioscopy is a relatively recent development in biliary endoscopy and permits direct visualization of the biliary tree. This paper presents the experience of one institution with this new technique. METHODS: We used the Olympus mother-baby endoscopy system at the University of Chicago and at one of its affiliated hospitals to examine and treat selected lesions in the biliary tree that had eluded successful diagnosis or treatment by standard means. In addition, we used the baby endoscope alone through surgically created percutaneous tracts to treat selected patients with retained stones. RESULTS: From July 1990 to June 1993, peroral cholangioscopy was performed 18 times in 12 patients at the University of Chicago and affiliated hospitals. The baby endoscope was successfully passed into the bile duct in 15 of 18 cases (83.3%). Additionally, the baby endoscope alone was used through a T-tube or cholecystostomy tract 10 times in six patients. Complications occurred in two patients and were minor; there were no fatalities. With refinement of technique, successful passage of the baby endoscope was accomplished in 100% of patients undergoing peroral cholangioscopy. CONCLUSIONS: Direct visualization of the biliary tree with the ability to sample (brush, biopsy) or treat (basket removal, electrohydraulic or laser lithotripsy) lesions significantly aided in the care of all patients in whom the baby endoscope was successfully passed by providing the correct diagnosis and, when appropriate, by allowing definitive treatment of lesions. The eventual role of this technique in the current cost-conscious climate is unclear, but at present it should be limited to selected referral centers.

Hypnosis in the treatment of patients with severe burns.

Burn injuries are a frequent form of trauma, the care for which typically involves repeated, intrusive procedures and acute, excruciating levels of pain. Although research in the use of hypnosis with burn patients is largely anecdotal there is emerging evidence that the burn unit may be one of the most useful arenas for the clinical application of this technique. The acute, identifiable nature of burn care procedures and the emotional state of patients in trauma care both provide an often receptive setting for the use of this intervention.

Erythropoiesis, erythropoietin, and iron metabolism in elective surgery: preoperative strategies for avoiding allogeneic blood exposure.

Preoperative autologous donation (PAD) of blood and administration of recombinant human erythropoietin (Epoetin alfa) are two strategies for increasing red blood cell (RBC) mass preoperatively. The success of PAD depends primarily on the patient's ability to manufacture new RBCs before surgery to replace those removed during PAD. Red blood cell manufacture depends in turn on adequate supplies of iron and the increased renal production of endogenous erythropoietin following PAD. Successful PAD also requires adequate time for regeneration of predonated RBCs. Parenteral administration of Epoetin alfa causes a dose-dependent stimulation of RBC production. Its use has been studied as an adjunct to PAD and as a method to enhance endogenous erythropoiesis without PAD. Several studies suggest that administration of Epoetin alfa, begun several days before surgery, may stimulate erythropoiesis and help decrease the number of RBC transfusions required postoperatively. The precise role of Epoetin alfa in the surgical setting is not yet established, and optimal dosage regimens have not been determined.

Effects of essential fatty acid deficiency on rat molar pulp cells.

In rats fed an essential fatty acid deficient (EFAD) diet, either during pregnancy (DN) or for 4 wk postnatally (ND), the cell density in the central part of the pulp increased about two- and threefold, respectively, of that in rats who had received a conventional diet containing sunflower oil. Cells were especially numerous around capillaries. The cell density was also increased twofold in the subodontoblastic layer in the outer part of the pulp, cells being smaller in ND compared with DN. In contrast, the odontoblasts were reduced in height, and the Höhl cells formed a thin layer in EFAD rats. This emphasizes some aspects of pulp specificity which reacted differently from odontoblasts. We suggest that the function of killer cells which normally destroy cells at the periphery of the pulp may be impaired by the diet, leading to cell accumulation.

Regulation of vascular endothelial growth factor in cardiac myocytes.

Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)