The self-administration of WIN 35,428 and cocaine: comparisons of satiety threshold and elimination half-life in rats

Rats that self-administered cocaine at unit doses between 0.75 and 12 micromol/kg with mean inter-injection intervals between approximately 2 and 18 min also reliably self-administered the cocaine analogue WIN 35,428 (beta-CFT; (-)-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester) at unit doses between 0.1 and 1.6 micromol/kg with mean intervals between 10 and 116 min. The long inter-injection intervals of WIN 35,428 necessitated sessions of more than 12 h. The inter-injection intervals were regular and proportional to the unit dose, consistent with the satiety threshold model. Analysis of the mean intervals as a function of unit doses generated values for the mean satiety threshold of cocaine and WIN 35,428 of 6.10 and 0.87 micromol/kg, respectively. The mean t(1/2) for cocaine and WIN 35,428 were 11.1 and 69.4 min, respectively. The approximately 43-fold lower rate of consumption of WIN 35,428 relative to cocaine was a product of the seven-fold greater pharmacodynamic potency and the six-fold greater pharmacokinetic potency.     

Early prophylactic inhaled beclomethasone in infants less than 1250 g for the prevention of chronic lung disease

OBJECTIVE:

Inflammation plays an important role in the development of chronic lung disease (CLD), which has become a major cause of morbidity in surviving infants less than 1250 g at birth. The authors hypothesized that the progression of this inflammation and, therefore, the establishment of CLD would be decreased with the use of early prophylactic inhaled corticosteroids. Short, and long term respiratory and neurodevelopmental outcomes were also examined.

DESIGN:

A double-blind, randomized placebo controlled trial.

SETTING:

Level-III neonatal intensive care unit.

POPULATION STUDIED:

Sixty infants less than 1250 g at birth, diagnosed with respiratory distress syndrome and requiring ventilatory support at 72 h of age were enrolled in the study.

INTERVENTION:

Infants enrolled received either placebo or beclomethasone diproprionate by a metered dose inhaler, which was used in-line with the ventilator circuit while the infant was ventilated and then via a spacer until 28 days of age.

RESULTS:

Thirty infants were given beclomethasone and 30 were given placebo. There were two deaths in each group. Among the surviving infants, the frequency of moderate-to-severe CLD was 17% in each study group. Mean time to extubation was not different for beclomethasone compared with placebo at 16.4 and 12.5 days (P=0.12), respectively. The requirement for intravenous corticosteroids was lower in the beclomethasone-treated group (RR 0.67, 95% CI 0.43 to 1.04), although this difference was not statistically significant. The incidence of growth failure, infection and intraventricular hemmorhage did not differ between the two groups. Long term outcomes were not different with respect to the incidence of respiratory re-admissions, cerebral palsy, developmental delay, blindness or deafness.

CONCLUSIONS:

Early treatment with inhaled beclomethasone diproprionate did not reduce the incidence of CLD or decrease the duration of mechanical ventilation. The decrease in intravenous corticosteroid use was not statistically significant. Long term outcome was not affected.     

Umbilical cord plasma interleukin-6 and fetal growth restriction in preeclampsia: a prospective study in Norway

OBJECTIVE: To study the association between umbilical plasma levels of interleukin-6 (IL-6) in relation to fetal growth in subgroups of preeclampsia, and in control pregnancies. METHODS: Umbilical cord plasma was collected from 12,804 consecutive births. A total of 271 singleton cases of preeclampsia were identified, and classified as mild or severe, and as disease with early or late onset. As controls, 611 singleton pregnancies without preeclampsia were selected, and the ratio between observed and expected birth weight was used as a measure of fetal growth. In the analysis, we also included maternal smoking during pregnancy. Umbilical cord plasma IL-6 concentration was measured with an IL-6 bioassay. Comparing controls with subgroups of preeclampsia (severe and early onset), this study had a statistical power of 90% to detect a difference in cord IL-6 of 10 pg/mL. RESULTS: In severe preeclampsia, cord plasma IL-6 concentration was lower than among controls (P <.001), and there was a sharp decrease in cord plasma IL-6 with decreasing birth weight ratio (P trend <.001). By further dividing the preeclampsia group into early or late onset, the strong association between low IL-6 levels and low birth weight ratio appeared to be present mainly in early-onset disease. These results were not confounded by maternal smoking. CONCLUSION: Restricted fetal growth related to preeclampsia is associated with reduced umbilical cord plasma IL-6 concentration in cases with early-onset disease. In these cases, fetal growth restriction could be mediated by impaired trophoblast function.     

TUBULAR PROTEINURIA AFTER PERINATAL HYPOXIA

ABSTRACT. Milt7eacute;nyi, M., Pohlandt, F., Bóka, G. and Kun, E. (2nd Department of Paediatrics, Semmelweis University, Medical School, Budapest, Hungary, and the Section of Neonatology, Centre of Paediatrics, University of Ulm, Federal Republic of Germany). Tubular proteinuria after perinatal hypoxia. Acta Paediatr Scand, 70:399, 1981.–Urinary total protein (UTP) and urinary protein pattern have been studied in 23 newborn infants with Apgar scores ±S3 at one minute or acidosis (pH ±7.15) on the first day. On the first and second day UTP excretion was increased in 13 out of 18 patients. At this time the excretion of low molecular weight microproteins (T-4 and T-5) was elevated in 12 patients without increased plasma urea concentration in any case. The increased excretion of the smallest microproteins T-4/T-5 is an early sign of an impaired tubular function.     

Subtle gastric abnormalities in a canine model: detection with low-dose imaging with storage phosphors and its equivalence to conventional radiography

The authors compared low-dose (32% of standard exposure) storage phosphor digital imaging (system resolution: 0.2-mm pixels, 10 bits) with isovoltage 75-kVp conventional radiography (standard exposure) in the detection of subtle simulated gastric abnormalities by using air contrast barium studies. Subtle simulated abnormalities (3-7-mm polyps, 4-15-mm ulcer craters, 4-11-mm-diameter edema, and 11-12-mm linear ulcers) were produced in resected canine stomachs. Receiver operating characteristic analysis of 1,800 observations by six readers indicated that the digital images with and without high-frequency edge enhancement were equivalent to conventional radiographs (mean receiver operating characteristic areas [+/- standard deviation]: 0.76 +/- 0.06, 0.78 +/- 0.04, and 0.77 +/- 0.04, respectively). The accuracy of the diagnosis was equivalent for all three modalities. The following mean accuracies of negative and positive responses, respectively, for unenhanced digital, edge-enhanced digital, and conventional images were determined: 0.71 +/- 0.05 and 0.41 +/- 0.07, 0.71 +/- 0.04 and 0.51 +/- 0.09, and 0.68 +/- 0.04 and 0.43 +/- 0.05. It was concluded that low-dose storage phosphor air-contrast barium studies were equivalent to conventional radiography in the detection of subtle gastric abnormalities.     

In vivo and in vitro binding of C4 molecules on red cells: a correlation of numbers of molecules and agglutination

The fourth component of human complement (C4) is one that is essential to the antibody-mediated classical activation pathway. C4d, present on all normal and most patient red cells (RBCs), may be detected by the human antisera anti-Rodgers (Rg) and -Chido (Ch). A study has been made of the Rg/Ch antigens on normal and patient RBCs in an attempt to understand the mechanism by which C4 is bound to normal RBCs in the absence of RBC antibodies (Abs). Because RBCs from C1q-deficient patients express Rg/Ch, it seems that C1q is not essential for C4 binding. Treatment of normal RBCs with proteolytic enzymes, including trypsin, eliminated positive reactions with anti-Rg/Ch even though the C4d fragment is considered to be resistant to cleavage by trypsin. By correlating agglutination reactions with numbers of bound C4d and C3d molecules, it is evident that both C4d and C3d were affected by trypsin treatment and that anti-Rg/Ch were not capable of agglutinating RBCs with less than 50 molecules of bound C4d. It is concluded that trypsin-sensitive and -insensitive RBC membrane structures may both act as acceptors for C4. RBCs with null phenotypes of the major blood group systems all expressed Rg/Ch antigens, so none of the structures that carry these antigens act preferentially as acceptors for C4.     

Studies on the mechanism of bacterial resistance to complement-mediated killing. II. C8 and C9 release C5b67 from the surface of salmonella minnesota S218 because the terminal complex does not insert into the bacterial outer membrane

The mechanism for consumption of terminal complement components and release of bound components from the surface of serum-resistant salmonella minnesota S218 was studied. Consumption of C8 and C9 by S218 occurred through interaction with C5b67 on the bacterial surface because C8 and C9 were consumed when added to S218 organisms previously incubated in C8-deficient serum and washed to remove all C5b67 on the bacterial surface because C8 and C9 were consumed when added to S218 organisms previously incubated in C8- deficient serum and washed to remove al but cell bound C5b67. Rapid release of (125)I C5 and (125)I C7 from the membrane of S218 was dependent on binding of C8 because (125)I C5 and (125)I C7 deposition in C8D serum was stable and was twofold higher in C8D than in PNHA, and addition of purified C8 or C8 and C9 to S218 previously incubated in C8D serum caused rapid release of (125)I C5 and (125)I C7 from the organism. Analysis by sucrose density gradient ultracentrifugation of the fluid phase from the reaction of S218 and 10 percent PNHS revealed a peak consistent with SC5b-9, in which the C9:C7 ratio was 3.3:1, but the NaDOC extracted bound C5b-9 complex sedimented as a broad peak with C9:C7 of less than 1.2:1. Progressive elution of C5b67 and C5b-9 from S218 but not serum-sensitive S. minnesota Re595 was observed with incubation in buffers of increasing ionic strength. Greater than 90 percent of the bound counts of (125)I C5 or (125)I C9 were released from S218 by incubation in 0.1 percent trypsin, but only 57 percent of (125)I C9 were released by treatment of Re595 with trypsin. These results are consistent with the concept that C5b-9 forms on the surface of the serum-sensitive S. minnesota S218 in normal human serum, but the formed complex is released and is not bactericidal for S218 because it fails to insert into hydrophobic outer membrane domains.