Intermittency in nuclear multifragmentation at relativistic energy.
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Biomedical subjects
Publications and source records attributed to G Singh.
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A new model for the study of spontaneous bone metastasis has been developed which allows for the quantification of metastatic tumor burden and cancer cell growth rate, and which describes the progressive changes in bone morphology. Walker 256 (W256) cells or vehicle were injected into the left upper thigh muscle of male Fischer rats, which were killed 7, 10 or 14 days later. By day 7, metastases had appeared in the distal femur, in the glomeruli of the kidney, and diffusely throughout the liver and lungs. The extent of tumor burden in these organs increased over time. In the femur, 14 days of tumor burden was associated with a 53 +/- 10% decrease in trabecular bone content, a 61 +/- 15% increase in osteoclast surface, and a 95 +/- 10% decrease in osteoblast surface, as compared with non-tumor-bearing controls. By autoradiography, metastatic tumor cells in all organs were determined to have greater growth rates than did cells in the primary tumor. However, within the femur, W256 cells located adjacent to trabecular bone surfaces had a 33 +/- 7% greater growth rate than did W256 cells located > 50 microns from bone surfaces (P < 0.05), suggesting a mitogenic effect of bone.
To test the hypothesis that bone metastasis is related to the rate of bone remodeling, we have examined the effect of enhanced bone resorption on the growth of spontaneously metastatic Walker 256 (W256) cancer cells. Bone resorption was stimulated in male Fischer rats by injecting Rice H-500 Leydig tumor cells subcutaneously. The resorptive response of the skeleton was confirmed in a pilot study by evaluating parameters of bone morphometry after 4, 7 and 10 days of tumor burden. The distal femoral epiphyses had 35 +/- 10% more osteoclast surface, 83 +/- 11% less osteoblast surface, and 46 +/- 5% less trabecular bone after 10 days of tumor burden, compared to non-tumor-bearing controls. To evaluate the effect of Leydig tumor-induced bone resorption on the growth response of W256 cells, 20 rats were injected intramuscularly with 2 x 10(7) W256 cells, and 20 rats were vehicle-injected. Two days later, 10 rats from each group were injected subcutaneously with Leydig tumor cells. Twelve days after W256/vehicle injection, rats were injected with [3H]thymidine, killed 2 h later, and their femurs, liver, lungs and kidneys were processed for histology. In rats injected with Leydig tumor cells only, enhanced bone resorption was confirmed by a 40 +/- 4% increase in serum calcium concentration, a 48 +/- 8% decrease in trabecular bone content, and a 72 +/- 15% decrease in osteoblast surface, compared with non-tumor-bearing rats. Metastatic W256 cells adjacent to trabecular bone in Leydig tumor-bearing rats had a 56 +/- 18% greater relative [3H]thymidine labeling index (TdR) than did W256 cells in the bones of non-Leydig tumor-bearing rats. The TdRs of W256 cells in the liver, lungs, and kidneys were not affected by Leydig tumor burden. In this model, enhanced bone resorption was associated with the selective growth promotion of metastatic W256 cells in bone, suggesting the existence of a bone-derived factor which is mitogenic to W256 cells.
Colonic mucosa and adenocarcinoma are known to possess gastrin receptors. Recent studies have suggested that some patients with large intestinal cancers and polyps have elevated serum gastrin levels and that gastrin may stimulate growth of colonic neoplasms. The aim of the present investigation was to determine whether endogenous hypergastrinemia--induced by the proton pump inhibitor omeprazole--would influence growth in a subcutaneously implanted murine colonic cancer. The results show that despite a fivefold increase in serum gastrin levels (193 pg/ml median value, range 186-252, in the omeprazole-treated group vs 36 pg/ml median value, range 28-37 in controls), there were no differences in tumor size or survival of tumor-bearing animals. Additionally, there were no differences in serum gastrin values between tumor- (29 pg/ml, range 25-38) and non-tumor- (34 pg/ml, range 25-30) bearing, untreated animals. Endogenous elevation of the serum gastrin hormone to five times the normal level does not demonstrate trophic effects on the murine colon tumor MC-26.
Tissue in situ hybridization has been used on sections of developing rat lung to follow the cellular sites of mRNA expression for a protein identified only in bronchiolar Clara cells. The mRNA for this Clara cell protein (CCP) was first detected on gestational day 16 in only one of the two types of tubules existing in the lung at this developmental stage. During the next 2 days CCP mRNA expression increased uniformly only in the epithelium lining the respiratory tubules. By gestational day 19, CCP mRNA expression became limited to secretory epithelial cells lining the bronchi, and terminal bronchioles. By neonatal day 1, an intense hybridization signal was observed along all of the conducting airways, but it was irregular due to the fact that expression of the CCP gene was limited to the secretory epithelial cells. In adult rats, CCP mRNA was expressed not only in secretory cells of the intrapulmonary airways at all anatomical levels, but also in secretory epithelial cells lining the trachea and its glands, as well as in specific alveolar cells thought to be type II pneumocytes. These findings demonstrate that the regulation of the CCP gene during lung development is a complicated process and that the expression of CCP mRNA does not parallel exactly the sequential development of the airways.
Freeze-dried bovine type I collagen was implanted into periodontally diseased sites of 11 patients in an effort to repair the affected site. Peripheral blood samples taken at 0, 6 and 12 wk were assayed for antibody to human and bovine collagen using an enzyme-linked immunosorbent assay and compared with samples from 9 control subjects. Antibody levels to both human and bovine collagen, which were present at significantly higher levels in the patients at 0 wk than in the control subjects (P less than 0.01 for human and bovine), were significantly lower at 6 wk than at zero time (P less than 0.05 and P less than 0.01 for human and bovine collagens, respectively). At 12 wk post-implantation, the antibody level to human collagen still remained significantly lower (P less than 0.05) than zero time levels but not in respect of the antibody to bovine collagen.
Mitochondrial DNA (mtDNA) is susceptible to damage by a number of anticancer agents either directly or indirectly. This damage is of little consequence if only a few of the mtDNA molecules are damaged. However, multiple drug treatments could result in a significant effect on a cell's ability to survive. The differential effect of anticancer agents on either organ specific toxicities or selective tumor kill can be partially accounted for by differential mtDNA content of cells and on the basis of differential protective mechanisms within mitochondria of various organs or tumor tissue. The concept of damage to mitochondria, especially its genome, is a subject of active investigation in various laboratories. This area of research may provide mechanism(s) by which organ specific toxicities or tumor specific toxicities may be elaborated. Also, the concept of targeting tumor specific mitochondria and/or mtDNA by anticancer agents is very attractive but has not come to fruition due to a lack of understanding of the regulation of the genome in tumor cells. Future investigations in this arena will enhance our knowledge on the interaction between anticancer agents and extranuclear DNA.
The efficacy of phenytoin (PHT), buprenorphine (Bu), and Bu+PHT for the relief of cancer pain of various etiologies was evaluated in a randomized, double-blind study of 3 groups, each comprised of 25 patients. Treatment duration was 1 month. PHT (100 mg by mouth twice daily) provided greater than 50% pain relief to 18 patients (72%) and greater than 75% relief to 4 (16%). Bu (0.2 mg sublingually twice daily) gave 21 patients (84%) greater than 50% relief and 15 patients (60%) greater than 75% relief. Of the Bu-treated patients, 8 had major side effects, while none of the PHT-treated patients experienced significant untoward reactions. Combined therapy (PHT, 50 mg PO+Bu 0.1 mg SL twice daily) provided greater than 50% pain relief to 22 patients (88%) and greater than 75% to 18 (72%); only 3 patients experienced a significant side effect. This study suggests that phenytoin has mild-to-moderate pain-relieving properties of its own and can significantly enhance buprenorphine analgesia. By permitting a lower opioid dose, it may reduce the occurrence of opioid-related side effects. PHT's lack of serious side effects, as well as its documented anxiolytic and antidepressant actions, may add to its comparative usefulness. Further clinical trials of PHT as a coanalgesic and/or adjuvant agent in cancer pain are warranted.
This study was undertaken to determine the relative prevalence of the factors causing chronic ulceration of the leg in the general population. Two hundred and fifty-nine patients with chronic ulceration of the leg were found on screening a Western Australian population of 238,000. (The prevalence of chronic ulceration of the leg was 1.1 per 1000 population.) Two hundred and forty-two of these patients (93%) with 286 chronically ulcerated limbs were fully assessed to determine the factors contributing to ulceration. In 239 limbs (84%) ulceration involved the leg; in these limbs venous disease was the most prevalent cause of ulceration (160 limbs). Arterial disease was found in 66 limbs, with both venous and arterial disease present in 35 limbs. Rheumatoid arthritis was a causative factor in 27 limbs and diabetes was found with 29 limbs with ulceration involving the leg. In 47 limbs (16%) ulceration was confined to the foot; arterial disease (35 limbs) and diabetes (23 limbs) were the most prevalent causes of ulceration in these limbs. Venous disease was infrequent (three limbs). No disorder of the circulation was found in 48 limbs (20%) with ulceration involving the leg, and in 58 (20%) of all ulcerated limbs. More than one aetiological factor was present in 93 limbs (33%). A cause for ulceration was not found in 10 limbs (3.5%).
Field trials were conducted to measure translocation of pesticides by summer and winter forage/pasture species from soil containing aged residues of heptachlor and, to a lesser extent, dieldrin. Substantial amounts of heptachlor epoxide, and lesser amounts of gamma-chlordane were translocated to plants from contaminated soil. Residue levels varied with crop species and stage of plant development. In summer crops residues were higher in soybean > cowpeas > lab-lab > Sorghum > millet > sweet saccaline at the grazing and mature stages. Compared to glasshouse studies undertaken previously, residues in crops grown under field conditions were much lower. This apparently reflects the lower soil moisture levels and the reduced rates of translocation. Heptachlor residues in winter crops were highest in Saia oats > Berseem clover > Haifa clover > Cassia oats > Tetila ryegrass > Schooner barley > Shaftal clover > Hunter river lucerne at the grazing stage. There were no detectable levels in barley and oats at the mature stage. No dieldrin residues were translocated into the various crop species.
Three cases of an unusual neoplasm of the lung appeared as solitary, peripheral pulmonary nodules in asymptomatic patients. These well-circumscribed neoplasms were composed of distinctive papillae covered by uniform cuboidal to columnar cells; more solid areas often were present. Ciliated cells, epithelial mucin, and necrosis were not observed, and mitotic activity was absent. Terminal tight junctions and microvilli were present in the two cases studied ultrastructurally. One specimen contained lamellar bodies and apical cytoplasmic dense bodies. Another case stained positively for a Clara cell-specific antigen, although surfactant apoprotein was not detected by immunostaining in the three cases. All patients have been free of disease (at 11 to 108 months). Papillary adenoma is an uncommon, apparently benign, and morphologically distinctive neoplasm. The immunohistochemical and ultrastructural findings hint at an origin from type II pneumocytes or Clara cells.
Recently there has been increasing concern over transfusion-related diseases, especially acquired immune deficiency syndrome (AIDS). The authors therefore investigated the efficacy of lactated Ringer's solution (LRS) alone as compared with blood plus LRS resuscitation on body weight change and mortality rate after severe trauma-hemorrhagic shock. Rats, 250 to 310 g (n = 85), had a midline laparotomy performed (i.e., trauma induced), the incision was closed, and a carotid artery, jugular vein, and femoral artery were cannulated. The unrestrained, nonheparinized rats were allowed to recover from anesthesia and were bled within 10 minutes to a mean arterial pressure (MAP) of 40 mmHg. This MAP was maintained by removing more blood until the animal was unable to compensate (maximal bleedout; MB). The MAP was further maintained at 40 mmHg by returning fluid (LRS) until 50% of the MB volume (MBV) was returned. The rats were then resuscitated: group 1 with LRS 4 times the MBV; group 2 with 5 x LRS; group 3 with the shed blood returned + 2 x LRS. There was no difference between the groups in the initial weights, MAP, or hematocrit (Hct), percentage of blood volume removed, time to MB, or time to end of hemorrhage. The final Hct and MAP were higher in group 3 (p less than 10(-6)) than in either of the other groups. Body weight gain was greater in group 2 compared with either of the other groups (p less than 0.05) on day 1 after hemorrhage because of edema, but no differences were seen on subsequent days. There were no differences in the survival of animals in the different groups. These results suggest that there should perhaps be a higher threshold for blood transfusion in the management of severe trauma-hemorrhagic shock than is currently practiced.
Despite the fact that trauma patients are not heparinized at the time of injury, most models of hemorrhagic shock involve heparinization before the initiation of hemorrhage. To determine whether preheparinization has any effects on the microvasculature of organs during or after hemorrhage, rats (with and without preheparinization) were bled to a mean arterial blood pressure (BP) of 40 mm Hg. In two groups, this pressure was maintained by withdrawing additional blood until BP could no longer be maintained at 40 mm Hg (maximal bleedout, MB). In another two groups, the BP was maintained at 40 mm Hg until 40% of the MB volume was returned in the form of lactated Ringer's solution. The rats were then resuscitated with four times the volume of MB with lactated Ringer's. At MB or immediately after resuscitation, colloidal carbon black was rapidly infused and the liver, kidney, and spleen were excised, fixed, and sectioned. In additional animals, blood samples for platelet counts and total body fibrinogen estimates were taken before hemorrhage and at MB or at the end of resuscitation. The results indicate that at MB, microvascular patency in the kidney and liver was significantly depressed in the nonheparinized rats but not depressed in the preheparinized rats. This protective effect of heparin is not directly attributable to its anticoagulant properties, since there were no differences in the consumption of platelets or fibrinogen between the nonheparinized and preheparinized groups. Although the microvascular patency improved with resuscitation in the nonheparinized group, the glomeruli counts and perfusion of the spleen remained significantly lower than in the preheparinized group.(ABSTRACT TRUNCATED AT 250 WORDS)
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The immunoglobulin class distribution of antibody to human collagen type I has been examined in sera and gingival extracts from patients with adult chronic periodontitis. Tissue extracts were made either by simple washing or ultrasonication. With either method, IgG and IgA antibodies to collagen were present in higher concentration in tissue extracts than in autologous serum when adjustment was made for dilution differences. No significant differences were found for IgM antibodies. Antibodies to human collagen type I are usually "natural antibodies" of the IgM class and, therefore, our findings suggest a class switch to IgG in inflamed gingivae, presumably due to prolonged antigenic stimulation.
Although ATP-MgCl2 enhances the recovery of renal function after ischemia and reperfusion, it is not known whether this agent has any beneficial effects on renal microcirculation and function in a nonheparinized model of trauma and severe hemorrhage. To study this, a midline laparotomy was performed (i.e., trauma induced) and the rats were bled to and maintained at a mean arterial pressure of 40 mmHg (1 mmHg = 133.32 Pa) until 40% of the maximum shed blood volume was returned in the form of Ringer's lactate (RL) solution. Animals were then resuscitated with 4 times the volume of the shed blood in the form of RL. ATP-MgCl2, 50 mumol/kg body weight, or an equivalent volume of saline, was infused intravenously during and following resuscitation. Renal microcirculation was examined by using colloidal carbon infusion and laser Doppler flow-metry. Glomerular filtration rate (GFR) was assessed with [3H]inulin clearance and cardiac output (CO) was determined by dye dilution technique. The results indicate that the depressed renal microcirculation following hemorrhage and resuscitation was restored by ATP-MgCl2 treatment. GFR was significantly higher in ATP-MgCl2-treated than saline-treated rats. ATP-MgCl2 also increased urine output, restored the decreased CO, and prevented the occurrence of renal edema after hemorrhage and resuscitation. Thus, ATP-MgCl2 appears to be a useful adjunct to crystalloid resuscitation following trauma and severe hemorrhagic shock even in the absence of blood resuscitation.
Peptide YY (PYY) and neuropeptide Y (NPY) inhibit agonist-induced adenosine 3',5'-cyclic monophosphate (cAMP) production and pepsinogen secretion from chief cells. We used radiolabeled PYY and NPY to characterize receptors on chief cells from guinea pig stomach. Binding of 125I-labeled PYY was rapid (70% maximal within 10 min) and specific (not inhibited by secretin, vasoactive intestinal peptide, cholecystokinin, carbachol, prostaglandin E2, forskolin, or cholera toxin). Measurement of the ability of PYY to inhibit binding of 125I-PYY indicated the presence of 1.8 x 10(3) high-affinity [dissociation constant (Kd) = 1.7 nM] and 5.1 x 10(4) low-affinity (Kd = 83.3 nM) sites/cell. Internalization of bound 125I-PYY was suggested by slow and incomplete dissociation in the presence of unlabeled PYY (50% after 2 h) and was examined further by measuring residual binding after washing with acetic acid (pH 2.5), glycine (pH 10.5), or trypsin. After 30 min at 37 degrees C, internalization of radioligand was evidenced by the failure of washing with these solutions to remove 50-65% of bound radioactivity. At 4 degrees C, internalization of 125I-PYY was nearly abolished. Binding of 125I-PYY and 125I-NPY was inhibited by NPY-(13-36) but not by [Leu31,Pro34]NPY indicating that these are Y2 receptors. In guinea pig chief cells, PYY and NPY modulate cAMP-mediated pepsinogen secretion by interacting with specific high-affinity Y2 receptors.