Leucocyte Migration Test and Hypersensitivity to Glafenin

The leucocyte migration test (LMT) was performed on 20 patients with an intolerance to glafenin--a non-narcotic analgesic drug. LMT was found to be positive in 50% of the subjects with intolerance, a highly significant percentage as compared with the control groups. HSA-glafenin was found to be the most appropriate method for presenting the antigen, but glafenin and its hydroxylated metabolites were only found to induce a migration inhibition in the subjects intolerant to glafenin.     

New quinoxaline 1,4-di-N-oxides for treatment of tuberculosis

Some quinoxaline 1,4-di-N-oxides derivatives with very different substituents in 2, 3, 6 and 7 positions have been synthesized in order to obtain new hypoxia selective agents. Some of these products have been tested as antituberculosis agents and very interesting results have been obtained from the first screening.     

Significant safety advantages gained with an improved pressure-regulated blood pump

A prototype of a non-occlusive pressure-regulated blood pump (M-pump) was evaluated in-vitro for safety in a comparative study with the roller and centrifugal pumps. The M-pump consists of collapsible tubing of unique design wrapped under tension around a rotor without a stator. The prototype M-pumps were tested in vitro to evaluate performance with respect to flow/ pressure characteristics, hemolysis, bubble generation (cavitation) and durability. The M-pump and centrifugal pump did not overpressurize at any RPM when the pump outlet was occluded, but the roller pump reached pressures in excess of 1000 mmHg. The M-pump did not generate negative pressures upon occlusion of the inlet, whereas the roller and centrifugal pumps produced near-vacuum pressures. Furthermore, the M-pump was unable to empty a blood reservoir when the height of the pump inlet was placed slightly above the reservoir outlet. The levels of microbubbles in the M-pump were significantly lower than the roller and centrifugal pumps upon sudden restriction of the pump inlet as determined with an ultrasonic bubble detector. The results of our in-vitro evaluation of the M-pump have shown it to have lower hemolysis than the centrifugal pump and lower or comparable hemolysis to roller pumps at flowrates of 0.1, 0.5, 4.0 and 6 L/min. We determined that the M-pump design possesses important safety advantages over roller and centrifugal pumps for cardiopulmonary bypass applications.     

Scorpion alpha and alpha-like toxins differentially interact with sodium channels in mammalian CNS and periphery

Scorpion alpha-toxins from Leiurus quinquestriatus hebraeus, LqhII and LqhIII, are similarly toxic to mice when administered by a subcutaneous route, but in mouse brain LqhII is 25-fold more toxic. Examination of the two toxins effects in central nervous system (CNS), peripheral preparations and expressed sodium channels revealed the basis for their differential toxicity. In rat brain synaptosomes, LqhII binds with high affinity, whereas LqhIII competes only at high concentration for LqhII-binding sites in a voltage-dependent manner. LqhII strongly inhibits sodium current inactivation of brain rBII subtype expressed in HEK293 cells, whereas LqhIII is weakly active at 2 microM, suggesting that LqhIII affects sodium channel subtypes other than rBII in the brain. In the periphery, both toxins inhibit tetrodotoxin-sensitive sodium current inactivation in dorsal root ganglion neurons, and are strongly active directly on the muscle and on expressed muI channels. Only LqhII, however, induced repetitive end-plate potentials in mouse phrenic nerve-hemidiaphragm muscle preparation by direct effect on the motor nerve. Thus, rBII and sodium channel subtypes expressed in peripheral nervous system (PNS) serve as the main targets for LqhII but are mostly not sensitive to LqhIII. Toxicity of both toxins in periphery may be attributed to the direct effect on muscle. Our data elucidate, for the first time, how different toxins affect mammalian central and peripheral excitable cells, and reveal unexpected subtype specificity of toxins that interact with receptor site 3.     

Lung transplantation for advanced bronchioloalveolar carcinoma confined to the lungs

BACKGROUND: Bronchioloalveolar carcinoma (BAC) is a well-differentiated lung adenocarcinoma that has a tendency to spread chiefly within the confines of the lung by aerogenous and lymphatic routes and may therefore be amenable to local therapy. However, a high rate of local recurrence after lung transplantation was recently reported. We describe two patients with unresectable and recurrent extensive BAC limited to the lung parenchyma who underwent lung transplantation with curative intent. METHODS: Patients were chosen to receive lung transplants for BAC if they met the following criteria: (1) recurrent or unresectable BAC limited to the lung parenchyma without nodal involvement and (2) suitable candidate for lung transplantation. RESULTS: The first patient relapsed in the lungs at 9 months after transplantation. The pattern of disease suggested contamination of the new lungs at the time of implantation. Repeat lung transplantation was performed, with cardiopulmonary bypass and irrigation of the remaining upper airway. This patient has had no evidence of local or systemic tumor recurrence at more than 4 years since the second transplantation. The second patient underwent transplantation using the modified technique and expired 16 months after transplantation of other causes. An autopsy showed no evidence of recurrent BAC in the lungs or of metastatic lesions at any site. CONCLUSIONS: Lung transplantation may be an option for unresectable or recurrent BAC confined to the lungs. Isolation of the diseased lungs and the use of cardiopulmonary bypass during surgery may be important in this disease and should be studied further.     

Phenotypic diversity in siblings with partial androgen insensitivity syndrome

The androgen insensitivity syndrome is a heterogeneous disorder with a wide spectrum of phenotypic abnormalities, ranging from complete female to ambiguous forms that more closely resemble males. The primary abnormality is a defective androgen receptor protein due to a mutation of the androgen receptor gene. This prevents normal androgen action and thus leads to impaired virilisation. A point mutation of the androgen receptor gene affecting two siblings with partial androgen insensitivity syndrome is described. One had cliteromegaly and labial fusion and was raised as a girl, whereas the other sibling had micropenis and penoscrotal hypospadias and was raised as a boy. Both were shown to have the arginine 840 to cysteine mutation. The phenotypic variation in this family is thus dependent on factors other than abnormalities of the androgen receptor gene alone.     

Actuarial survival in the premature infant less than 30 weeks' gestation

OBJECTIVE: Because survival from admission to discharge does not provide parents and physicians information about future life expectancy in the premature neonate, we characterized the actuarial survival, defined as the future life expectancy from a given postnatal age, in a large inborn population of premature infants < 30 weeks' gestation. STUDY DESIGN: We determined daily actuarial survival of 1925 inborn infants (23 to 29 weeks' gestation) admitted to the Baylor Affiliated Nurseries from July 1986 through December 1994, stratified by 100-g birth weight and by 1-week gestational-age intervals. RESULTS: In the 501- to 600-g birth weight stratum, actuarial survival improved from 31% at birth, to 61% on day of life 7, and then to 75% on day of life 28; in the 901- to 1000-g birth weight stratum, actuarial survival improved from 88%, to 94%, and then to 98% throughout the same times, respectively. Similar trends were obtained when data were stratified by gestational age. CONCLUSIONS: Survival in the smallest infants improves dramatically during the first few days of life, but there is a significant risk for late death in the smallest of these infants.     

Antisense RNA-mediated reduction of p53 induces malignant phenotype in nontumorigenic rat urothelial cells

p53 mutation is commonly associated with high-grade, high-stage human urothelial carcinomas. Recent studies suggest that p53 mutation in low- grade, low-stage bladder carcinomas may be correlated with the progression of the disease. In the present study, we used antisense RNA methodology in vitro to evaluate the significance of the loss of p53 function at an early stage of urinary bladder carcinogenesis. An immortalized nontumorigenic rat urothelial cell line (MYP3) that strongly expresses wild-type (WT) p53 was transfected with a plasmid (pcDL-SR alpha-296) containing a rat WT p53 cDNA in antisense orientation. The transfection resulted in a significant reduction in p53 mRNA expression and protein synthesis, in stimulation of anchorage- dependent growth, and in acquisition of anchorage-independent growth potential. Three such clones, when tested in athymic nude mice, all formed muscle-invasive, high-grade transitional cell carcinomas at s.c. injection sites. When cells were inoculated into an orthotopic site (urinary bladder), one of two antisense transfectants tested formed bulky tumors in the bladder in all seven nude mice and metastases to lungs in three of the seven mice. Analysis of these cells revealed a decrease in the expression of p21 (WAF1, sdi1, or CIP1) and retinoblastoma (Rb) gene product. Phosphorylation of Rb protein was not inhibited when the cells were starved. No significant difference was observed in the expression of p16 protein. In cell cycle analysis, all antisense transfectants tested escaped from G1 arrest by starvation. Furthermore, secretion of interleukin (IL)-6 into culture medium was increased significantly. Treatment with anti-IL-6 antibody suppressed anchorage-dependent growth. This study directly demonstrates that the loss of p53 function at an early stage of urothelial carcinogenesis may result in acquisition of a malignant phenotype by regulating IL-6 production as well as cell cycle related genes.      

Hemodynamic effect of a low-resistance artificial lung in series with the native lungs of sheep

BACKGROUND: An artificial lung with 1 to 6 month work life could act as a bridge to transplantation. A pumpless artificial lung has been developed. METHODS: The artificial lung was placed in series with the native lungs of adult sheep. Hemodynamics were observed, as the right ventricle generated flow through the device. Through a left thoracotomy, two 20-mm grafts were anastomosed in an end-to-side fashion to the pulmonary artery. The grafts were externalized, and directed flow through the chest wall, to the extracorporeal lung. The animals were recovered, weaned from the ventilator, and when standing, flow was diverted through the device. RESULTS: Five of 7 animals survived 24 hours with 75% to 100% of the cardiac output diverted through the device. All animals were active, with interest in food and water, and able to stand. CONCLUSIONS: The right ventricle perfused the artificial lung with 75% to 100% of the cardiac output for 24 hours. This device demonstrates the feasibility of a pumpless pulmonary assist device relying on the right ventricle for perfusion.