tbuckley/cabot-search huggingface dataset:
Cytosine Deaminase/5-Fluorocytosine-Based Vaccination Against Liver Tumors: Evidence of Distant Bystander Effect
Authors: V Pierrefite-Carle, P Baqué, A Gavelli, M Mala, M Chazal, J Gugenheim, A Bourgeon, G Milano, P Staccini, B Rossi
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: The cytosine deaminase gene of Escherichia coli converts the nontoxic compound 5-fluorocytosine into 5-fluorouracil (5-FU), thereby acting as a suicide gene when introduced into cancer cells, killing the cells when they are exposed to 5-fluorocytosine. We analyzed the efficacy of using cytosine deaminase-bearing cancer cells as an autologous tumor vaccine in a rat model that mimics liver metastasis from colon carcinoma. METHODS: We introduced a plasmid vector containing the E. coli cytosine deaminase gene into a BDIX rat colon carcinoma cell line. Intrahepatic injection of the modified cells in syngeneic animals generates a single experimental liver "suicide tumor." We then analyzed the effect of 5-fluorocytosine treatment in terms of regression of cytosine deaminase-expressing cells in vivo as well as protection against wild-type cancer cells. RESULTS: Treatment with 5-fluorocytosine induced regression of cytosine deaminase-expressing (CD+) tumors, with seven of 11 treated animals being tumor free at the end of 30 days and a statistically significant difference in tumor volumes between treated and control animals (two-sided P <.0001). Intrahepatic injection of CD+ cells followed by 5-fluorocytosine treatment rendered the treated animals resistant to challenge with wild-type tumor cells, with no (zero of seven) treated animals developing wild-type tumors in contrast to all (four of four) control animals. Moreover, in animals with established wild-type liver tumors, injection of CD+ tumor cells followed by 5-fluorocytosine treatment produced a statistically significant increase in survival time (two-sided P <.0001). In vivo immunodepletion and immunohistologic analysis of experimental tumors indicate that natural killer cells are the major immune component involved in this antitumor effect. CONCLUSIONS and IMPLICATIONS: Taken together, these results suggest the potential use of suicide gene-modified tumor cells as therapeutic vaccines against liver metastasis from colon carcinoma.
Mild pressure loading alters right ventricular function in fetal sheep.
Authors: C W Pinson, M J Morton, K L Thornburg
Journal: Circulation Research (1991)

Right ventricular function before and during 10 days of mild pressure loading (10 mm Hg increase in mean pulmonary arterial pressure) was compared with right ventricular function in unloaded near-term fetal sheep. Pressure loading did not alter fetal arterial blood gases or vascular pressures. The right ventricular function curve (stroke volume versus mean right atrial pressure) was not significantly altered by loading. However, the relation between right ventricular stroke volume and increased arterial pressure was dramatically shifted upward, indicating improved ventricular function after the 10-day loading period. Normalized free wall of the loaded right ventricles became thicker (1.2 +/- 0.2 versus 0.9 +/- 0.2 mm/kg, p less than 0.01) and heavier (2.7 +/- 0.4 g/kg versus 2.2 +/- 0.4 g/kg, p less than 0.05) than control, and the ratio of the equatorial radius of curvature to wall thickness decreased (3.2 +/- 0.5 versus 4.5 +/- 0.9, p less than 0.005). Left ventricular free wall and septal weights and thicknesses were not significantly changed. The in vitro diastolic pressure-volume curves of both ventricular chambers of loaded hearts shifted to the left, indicating smaller ventricles than controls at physiological filling pressures. These data suggest the transduction of right ventricular loading effects to the left ventricle. Improved right ventricular function after loading is predicted by the law of Laplace based on the decreased radius of curvature-to-wall thickness ratio.
Contributions of Frequency Distribution Analysis to the Understanding of Coronary Restenosis
Authors: Kenneth G. Lehmann, Rein Melkert, Patrick W. Serruys
Journal: Circulation (1996)

Background Clinical restenosis after balloon angioplasty can be categorized by use of dichotomous terms based on the presence or absence of recurrent myocardial ischemia. In contrast, recent investigations have concluded that late luminal renarrowing, documented through angiographic imaging, occurs to a variable extent in nearly all stenoses. This process has been characterized by a gaussian or normal frequency distribution, with restenosis simply representing an extreme form of this delayed remodeling. In the current study, frequency distribution analysis was used to examine the process of coronary restenosis in a large cohort of patients at risk. Methods and Results Quantitative coronary angiographic analysis was applied to 9279 cineangiograms obtained in 3093 patients before and immediately after angioplasty and after 6-month follow-up. Late loss, defined as the change in minimum lumen diameter of the target stenosis from postdilation to follow-up, did not statistically conform to a normal distribution ( P &lt;.0001 by both χ 2 statistic and Kolmogorov-Smirnov test), even after the exclusion of the 236 stenoses that displayed total occlusions at follow-up angiography. Examination of deviations from a normal curve revealed an excessively high frequency of stenoses that experienced either little change (0.0±0.3 mm) or marked change (1.0 to 2.0 mm) in late loss, with a low frequency of stenoses with intermediate values (0.3 to 1.0 mm). Similarly, although the distribution of percent diameter stenosis of the target lesion was statistically normal immediately after dilation, this gaussian distribution disappeared during the follow-up period. Other angiographic indexes of restenosis also failed to approximate a normal curve. In an attempt to improve the goodness of fit, a probabilistic model of late loss was created on the basis of deconvolution of the observed data distribution. Two theoretical, discrete populations of stenoses were identified, one with and one without overall late luminal narrowing. Unlike the gaussian distribution, this model provided a good representation of the observed data ( P =NS for lack of fit). Conclusions The frequency distributions of angiographic indexes of restenosis often superficially resemble a gaussian curve, an appearance that is artifactually enhanced by the measurement imprecision of current quantitative techniques. Nevertheless, standard indexes of coronary restenosis fail to conform statistically to a normal distribution. The pattern of deviations observed supports the possible existence of discrete subpopulations of lesions, each with a different propensity toward the development of restenosis after coronary intervention.
Regulation of 1,25-dihydroxyvitamin D3 receptor gene expression by 1,25-dihydroxyvitamin D3 in the parathyroid in vivo.
Authors: T Naveh-Many, R Marx, E Keshet, J W Pike, J Silver
Journal: Journal of Clinical Investigation (1990)

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3 dramatically decreases parathyroid hormone (PTH) gene transcription. We have now studied the effect of 1,25(OH)2D3 on the 1,25(OH)2D receptor (VDR) in the parathyroid in vivo. Rats were injected with 1,25(OH)2D3 and the parathyroid-thyroid tissue analyzed for PTHmRNA and VDRmRNA. 1,25(OH)2D3 (50 and 100 pmol ip) decreased PTHmRNA at 6 h with a maximum at 48 h (less than 4% of basal), whereas VDRmRNA was increased only after 6 h with a 1.7-fold increase at 24 h. VDRmRNA levels peaked at 25 pmol 1,25(OH)2D3 with a twofold increase. Serum calcium did not affect VDRmRNA. Parathyroid VDRmRNA ran at 2.2 and 4.4 kb, whereas duodenum VDRmRNA had a single band, all of which increased after 1,25(OH)2D3. Weanling rats on a vitamin D-deficient diet for 3 wk had a more intense 2.2-kb transcript, whereas vitamin D-replete rats had a more intense 4.4-kb band. Dispersed parathyroid-thyroid cells were separated by a flow cytometry (FACS) into a parathyroid cell peak containing PTHmRNA and a second peak with cells positive for thyro-globulin mRNA and calcitonin mRNA. VDRmRNA was concentrated in the parathyroid cell peak. In situ hybridization of parathyroid-thyroid and duodenum for VDRmRNA showed its localization to the parathyroid cells and the duodenal mucosa. Therefore, the VDRmRNA in the parathyroid-thyroid tissue represents predominantly parathyroid cell and not C-cell VDRmRNA which is also a 1,25(OH)2D3 target organ. The increased VDR gene expression in the parathyroid cell would amplify the effect of 1,25(OH)2D3 to decrease PTH gene transcription.
Is the new WHO classification of neuroendocrine tumours useful for selecting an appropriate treatment?
Authors: E. Bajetta, L. Catena, G. Procopio, E. Bichisao, L. Ferrari, S. Della Torre, S. De Dosso, S. Iacobelli, R. Buzzoni, L. Mariani, J. Rosai
Journal: Annals of Oncology (2005)
Industry is deeply involved in funding US research
Authors: J. Hopkins Tanne
Journal: BMJ (2003)

Industry supported 62% of biomedical research in the United States in 2000, almost double the proportion in 1980, while government support declined. About a quarter of academic investigators have affiliations to industry that could influence research and publication, says a review article in JAMA (2003;289:454-65).

The authors, from Yale University School of Medicine, reviewed 37 studies with original data on financial relationships among industry, investigators, and academic institutions. Partnerships between industry and academia have …
Exhaled nitric oxide in COPD: glancing through a smoke screen
Authors: P J STERK, H W F M DE GOUW, F L M RICCIARDOLO, K F RABE
Journal: Thorax (1999)

<h3></h3> Calcium and hormonal replacement therapy (Cal-HRRx) increased adrenergic neurovascular tone (ANVT), systemic vascular resistance (SVR) and NV symptom levels (SL) in 50% of our pilot study (PS). In prospective studies (ProS) serial measurements (SM) were made of: systolic time intervals (STI), SBP, rise in pulse pressure to handgrip (RPPHg, 5 PSI, 3 min), systemic vascular resistance (SVR), and cardiac output (CO) by echo. NVT SL (i.e.: migraine, paresthesias, chest wall SL, etc.) were assessed by the quality of life (QL, 0-100%). STI monitored ANVT (STI=PEP/LVET X 100%). The parameters were studied by: SVR = (mean BP-6) X 80/CO, using standard units. In ProS women with type A/AX/B behavior were randomized from the general population (GenP) into 100/ group (G) with normal CO (4 -7 L/min). A subgroup of type A (SA) with low BP (≤100 mmHg) and CO (≤4) were studied as a G. All women were: postmenopausal, age 55±5, with STI levels at low stress PS G means ± 2, and SBP 110±10 mmHg. Type B women were age-matched controls on the Rx protocol. Daily Cal-HRRx was: 1500 mg Cal, 0.625 estrogen and 2.5 mg progesterone in each G on a double blind placebo cross-over protocol (3mo. each). Data was collected at time 1 (T1=low stress on dietary Cal at 500 mg/day and placebo) and T2 on Cal-HRRx, both at 2 week intervals for 12 weeks. Standard ultrasonic measurements (UM) were made at T1 and T2 (end). Data was placed into a blind matrix for analysis later. ProS G analysis: G means shown. (Table) Where: * = Significant (Sig) difference from GB at P≤0.01 and ** = Sig change from T1 at P≤0.02, both by T test. % = % of total # cases. %NC = %Non-compliance (left study due to high SL). Sig** coronary risk occurred in GA (38% of GenP) due to SBP and ANVT (proven in parallel long-term studies by serial UM, R=0.97, P≤0.001) with Sig** increase in SL during Rx. A RPPHg ≥15 before Rx predicted type A women at risk (R=0.98, P≤0.001). The SA G had decreased SBP but increased coronary risk due to Sig** ANVT increase (STI change) on Rx (proven in long-term parallel studies, R=0.97, P≤0.001). Thus, Cal-HRRx is found to cause Sig vascular risk in 50% of the GenP due to increases in ANVT in type A women.
Relative Risk of Neurological Signs in Siblings of Patients With Schizophrenia
Authors: M F Egan, T M Hyde, J B Bonomo, V S Mattay, L B Bigelow, T E Goldberg, D R Weinberger
Journal: American Journal of Psychiatry (2001)

First-degree relatives of patients with schizophrenia appear to have subtle neurological signs, suggesting that these measures could serve as intermediate phenotypes in genetic studies of schizophrenia. The strength of a possible genetic component is unknown, however, leaving it uncertain whether such traits could increase the power to find schizophrenia susceptibility loci. The authors' goal was to investigate the strength of this possible genetic component.They estimated the relative risk of neurological impairments in a large group of siblings of patients with schizophrenia. Two standard neurological scales (the Neurological Evaluation Scale and the Woods Scale) were used to examine 115 patients, 185 of their siblings, and 88 normal comparison subjects.There were significant differences between the siblings of patients with schizophrenia and the normal comparison subjects only on the Woods Scale. Relative risk of neurological impairment was significantly increased in the sibling group, but the significance was weak to moderate. Neurological impairment was not redundant with several other intermediate phenotypic measures based on cognitive impairment.These data suggest that neurological signs cluster in patients with schizophrenia and their families and could possibly identify a unique component of genetic variance for risk of schizophrenia. However, the fairly low relative risk and the uncertain pathophysiology of such signs may limit their usefulness.
HUNGER AND SATIETY
Authors: ALBERT STUNKARD
Journal: American Journal of Psychiatry (1961)

New physiological discoveries are providing the behavioral sciences with a unique opportunity for the reconstruction of traditional theories of motivation. We are no longer constrained, for example, to view overeating solely as a result of an increased hunger drive. This apparent contradiction results from the demonstration that the hypothalamic centers mediating hunger and satiety have separate anatomical localizations and separable behavioral consequences. Overeating can thus theoretically result either from an increase in hunger drive or from an decrease in satiability. The first possibility has generally been accepted with little question. The second has now been demonstrated by experimental damage to the satiety centers of animals who thereupon present the paradox of an animal which eats itself into obesity through a hunger drive which is actually reduced in intensity. Recent clinical studies suggest that either decreased satiability or increased drive may occur in human obesity. Persons manifesting the "night-eating syndrome" report an inability to stop eating rather than any increased desire to eat. Obese persons who overeat in binges, on the other hand, report compelling urges to overeat at such times.
Resistance to Fas-mediated Apoptosis of Peripheral T Cells in Human T Lymphocyte Virus Type I (HTLV-I) Transgenic Mice with Autoimmune Arthropathy
Authors: Shuji Kishi, Shinobu Saijyo, Masaaki Arai, Shigeru Karasawa, Susumu Ueda, Mari Kannagi, Yoichiro Iwakura, Masahiro Fujii, Shin Yonehara
Journal: The Journal of Experimental Medicine (1997)

Transgenic mice carrying the env-pX region of human T lymphocyte virus type I (HTLV-I) develop autoimmune arthropathy in high incidence. Adopting the approach that Fas-mediated apoptosis has a critical function in the elimination of self-reactive T cells, we examined the involvement of this apoptosis in the induction of autoimmunity in HTLV-I transgenic mice. Splenic T cells derived from the transgenic mice were more resistant to apoptosis induced by anti-Fas mAb than those of the nontransgenic mice, whereas no appreciable difference in apoptosis was detected for thymocytes from either mouse's type. The resistance of transgenic T cells may be due to Tax coded in the pX region, since Tax mediates the inhibition of anti-Fas- induced apoptosis in mature T cell line, Jurkat. Among the transgenic mice, the extent of the resistance to Fas-mediated apoptosis was further enhanced in transgenic T cells with disease. These results suggest that the escape of self-reactive T cells from Fas-mediated apoptosis in the periphery, is critical for the development of autoimmune arthropathy in HTLV-I transgenic mice.
cyclosporine and liver transplantation: Will the midazolam test make blood level monitoring obsolete?
Authors: Paul B. Watkins
Journal: Hepatology (1995)

Immunosuppression therapy with cyclosporine is often hampered by significant interindividual variability in the metabolic clearance of the drug. It has been suggested that much of the variability in cyclosporine clearance is due to differences in the cytochrome P450 3A4 (CYP3A4) content in the liver and intestinal mucosa. A study was conducted in liver transplant recipients to characterize hepatic CYP3A4 variability during the first 10 days after surgery. The formation of 1′-hydroxymidazolam (1′-OH MDZ) was followed in the plasma after i.v. midazolam (MDZ) administration to 21 multiple-organ donors and to recipients of 10 of the 21 donor livers. Liver biopsy tissue was obtained from donors and recipients after the in vivo pharmacokinetic test. For liver donors, the plasma 1′-OH MDZ/MDZ concentration ratio 30 min after the i.v. MDZ dose was well correlated with the hepatic CYP3A4 content (r = 0.87, P &lt; .001). Much of the variability in the two parameters was attributed to the administration of enzyme-inducing drugs before organ procurement. The mean hepatic CYP3A4 content and plasma 1′-OH MDZ/MDZ concentration ratio in six inducer-treated donors was 4.7-fold and 2.3-fold higher than the respective mean value for all other donors. The hepatic CYP3A4 content and plasma 1′-OH MDZ/MDZ ratio for liver recipients, studied on postoperative day 10, was negatively correlated with the respective parameter measured in donors on day 0 (r = −0.60 for CYP3A4 and r = −0.79 for 1′-OH MDZ/MDZ; P &lt; .05 and P &lt; .01). The dynamic changes in hepatic CYP3A4 expression during the perioperative period, some of which appear to be due to the effect of enzyme-inducing drugs, help explain the difficulties often encountered in the achievement and maintenance of therapeutic cyclosporine blood levels after liver transplantation.
Overexpression of the Cardiac Na <sup>+</sup> /Ca <sup>2+</sup> Exchanger Increases Susceptibility to Ischemia/Reperfusion Injury in Male, but Not Female, Transgenic Mice
Authors: Heather R. Cross, Liyan Lu, Charles Steenbergen, Kenneth D. Philipson, Elizabeth Murphy
Journal: Circulation Research (1998)

Abstract —Influx of Ca 2+ into myocytes via Na + /Ca 2+ exchange may be stimulated by the high levels of intracellular Na + and the changes in membrane potential known to occur during ischemia/reperfusion. This increased influx could, in turn, lead to Ca 2+ overload and injury. Overexpression of the cardiac Na + /Ca 2+ exchanger therefore may increase susceptibility to ischemia/reperfusion injury. To test this hypothesis, the hearts of male and female transgenic mice, overexpressing the Na + /Ca 2+ exchange protein, and hearts of their wild-type littermates, were perfused with Krebs-Henseleit buffer and subjected to 20 minutes of ischemia and 40 minutes of reperfusion. Preischemic left ventricular developed pressures and +dP/dt max , as well as −dP/dt min , were higher in the male transgenic hearts compared with wild-type, implying a role for Na + /Ca 2+ exchange in the contraction, as well as the relaxation, phases of the cardiac beat. Postischemic function was lower in male transgenic than in male wild-type hearts (7±2% versus 32±6% of preischemic function), but there was no difference between female transgenic and female wild-type hearts, both at ≈30% of preischemic function. To assess whether this male/female difference was due to female-specific hormones such as estrogen, the hearts of bilaterally ovariectomized and sham-operated transgenic females were subjected to the same protocol. The functional recoveries of ovariectomized female transgenic hearts were lower (17±3% of preischemic function) than those of wild-type and sham-operated transgenic females. The lower postischemic functional recovery in the male transgenic and female ovariectomized transgenic hearts correlated with lower recoveries of the energy metabolites, ATP and phosphocreatine, as measured by 31 P nuclear magnetic resonance spectroscopy. Alternans were observed during reperfusion in male transgenic and female ovariectomized transgenic hearts only, consistent with intracellular Ca 2+ overload. Western analyses showed that alterations in the expression of the Na + /Ca 2+ exchange or L-type Ca 2+ channel proteins were not responsible for the protection observed in the female transgenic hearts. In conclusion, in males, overexpression of the Na + /Ca 2+ exchanger reduced postischemic recovery of both contractile function and energy metabolites, indicating that the Na + /Ca 2+ exchanger may play a role in ischemia/reperfusion injury. From the studies of females, however, it appears that this exacerbation of ischemia/reperfusion injury by overexpression of the Na + /Ca 2+ exchanger can be overcome partially by female-specific hormones such as estrogen.
Cutaneous infection with <i>Alternaria alternata</i> complicating immunosuppression: successful treatment with itraconazole
Authors: None Acland, None Hay, None Groves
Journal: British Journal of Dermatology (1998)

We report an immunosuppressed patient who presented with unusual leg ulceration caused by Alternaria alternata infection. Alternaria is a common saprophyte that is not usually pathogenic in humans. However, infections have previously been documented. Most cases occur in immunocompromised patients and the skin manifestations may vary considerably. The diagnosis is often missed initially as it is not frequently suspected. The treatment is controversial both in choice of agent used and in duration of therapy.