Serum concentrations of brain-derived neurotrophic factor (BDNF) are decreased in colorectal cancer patients.

OBJECTIVE: To determine the usefulness of brain-derived neurotrophic factor (BDNF) as a diagnostic biomarker for colorectal cancer (CRC). MATERIALS AND METHODS: ELISA immunoassay was used to examine BDNF concentrations in the sera of two different retrospective cohorts consisting of CRC patients and age/gender matched controls. Cohort 1 consisted of 99 controls and 97 CRC patients, whereas cohort 2 consisted of 47 controls and 91 CRC patients. RESULTS: In cohort 1, the median concentration of BDNF was significantly (p< 0.0001) lower in CRC patient samples (18.8 ng/mL, range 4.0-56.5 ng/mL) than control samples (23.4 ng/mL, range 3.0-43.1 ng/mL). This finding was validated in an independent patient cohort (CRC patients: 23.0 ng/mL, range 6.0-45.9 ng/mL; control patients: 32.3 ng/mL, range 14.2-62.4 ng/mL). BDNF concentrations did not differ significantly between Dukes' staging in the patient cohort, however patients with Stages A, B, C and D (p< 0.01 for each stage) tumours had significantly reduced BDNF levels compared to healthy controls. Receiver operating characteristic analysis was performed to determine the ability of BDNF to discriminate between healthy controls and those with CRC. At 95% specificity, BDNF concentrations distinguished CRC patients with 25% and 18% sensitivity, respectively, in cohorts 1 and 2 (cohort 1: AUC=0.79, 95% CI 0.70-0.87; cohort 2: AUC =0.69, 95% CI 0.61-0.76). CONCLUSION: The serum levels of BDNF were significantly lower in colorectal cancer patients when compared to a control population, and this did not differ between different Dukes' stages.

Coronary artery calcification, common carotid artery intima-media thickness and aortic pulse wave velocity in patients on peritoneal dialysis.

An increasing body of evidence suggests that atherosclerosis in patients with uremia differs from that found in general population in terms of advancement and localization of vascular lesions. It has also been suggested that different non-invasive techniques of vascular system evaluation are designed to show different types of lesions (i.e. vascular calcification, stiffness or 'classical' atherosclerosis). The aim of the study was to search for possible associations between results obtained with three different non-invasive methods of vascular system assessment in three different vascular sites in patients treated with peritoneal dialysis (PD). 61 patients (28 F, 33 M), mean age of 50.4+/-13.6 years, on maintenance PD for a median period of 10 months (range 1-96 months) were included. Coronary artery disease (CAD) was present in 21 subjects. In all subjects coronary artery calcification score (CaSc) using multi-row spiral computed tomography (MSCT), aortic pulse wave velocity (AoPWV) and ultrasound-based common carotid artery intima-media thickness (CCA-IMT) were performed as methods for assessing coronary calcium burden, arterial stiffness and atherosclerosis, respectively. Median value of CaSc equaled 11.5 Agatston units (range 0-5502.8 units). Median AoPWV was 10.4 m/s (range 7.56-18.1 m/s), and median CCA-IMT-0.6 mm (range 0.3-1.0 mm). In 16 patients (26.2%) at least one plaque in at least one common carotid artery was found on ultrasound. CaSc correlated with AoPWV (R=0.32, p<0.01) and with CCA-IMT (R=0.35, p<0.005), whereas no association was found between AoPWV and CCA-IMT. AoPWV, but not CaSc nor IMT correlated with blood pressure. The values of CCA-IMT and AoPWV increased together with consecutive Agatston categories (with p<0.001 for differences in AoPWV and p<0.05 for CCA-IMT). Patients with at least one plaque found in at least one CCA and patients with CAD were characterized with significantly higher values of CaSc, IMT and PWV, when compared to plaque-free and CAD- negative subjects, respectively. Association between CaSc and both IMT and PWV may suggest that the mechanism of three assessed vascular pathologies may be based, to some extent, on the process of pathologic calcium-phosphate deposition. Lack of correlation found between PWV and IMT may suggest that aortic stiffness and carotid atherosclerosis may partially differ in their pathologic background and/or are dissociated in time.

An association between aortic pulse wave velocity, blood pressure and chronic inflammation in ESRD patients on peritoneal dialysis.

Increased aortic pulse wave velocity (AoPWV) has been identified as a risk factor for cardiovascular morbidity in the general population and in patients on dialysis. Most of the studies in ESRD patients refer to subjects on hemodialysis. Influence of the inflammatory process on aortic stiffening remains largely unknown. The aim of the present study was to evaluate potential relationships between AoPWV and blood pressure, basic anthropometric parameters, selected growth factors and markers of the inflammatory process in ESRD patients treated with peritoneal dialysis. The study population consisted of 43 patients (19 F, 24 M) with a mean age of 50.6 +/- 13.4 years on PD for a mean period of 21.9 +/- 20.7 months. AoPWV was measured using two pressure transducers placed on the carotid and femoral arteries and connected to an automatic processor (Complion Colson AS, Paris, France). Serum levels of Tumor Necrosis Factor alpha (TNFalpha), interleukin 6 (IL-6) and plasma basic Fibroblast Growth Factor (bFGF) were measured with ELISA; C-reactive protein and fibrinogen with nephelometry. Serum lipid profile was also assessed. Blood pressure was measured in an outpatient department under standardized conditions. Mean aortic pulse wave velocity in the study population was 10.7 +/- 2.1 m/s. No difference in AoPWV was found between men and women. AoPWV correlated significantly with age (R = 0.41; p < 0.01) but not with time on dialysis. Positive relationship between AoPWV and body weight and BMI was shown (R = 0.31; p < 0.05 and R = 0.35; p < 0.05, respectively). AoPWV correlated significantly with systolic blood pressure (SBP), mean arterial pressure (MAP) and pulse pressure (PP) (R = 0.46, p < 0.005, R = 0.46, p < 0.005 and R = 0.43, p < 0.01, respectively). AoPWV correlated with serum IL-6 and plasma bFGF (R = 0.32, p < 0.05 and R = 0.4, p < 0.01; respectively). The correlation with serum CRP was borderline significant (p < 0.53). In multiple regression analysis age (beta 0.38; p < 0.005), plasma bFGF level (beta 0.3; p < 0.05), and systolic blood pressure (beta 0.29; p < 0.05) were independently associated with pulse wave velocity. Our results suggest that AoPWV values in patients on PD are associated with factors similar to those encountered in the general population. We suggest that increased aortic stiffening may also be related to the chronic inflammatory process in PD patients.

Chronic electrical stimulation of the auditory nerve using high surface area (HiQ) platinum electrodes.

High surface area cochlear implant electrodes with much smaller geometric surface areas than current designs might be used in the future to increase the number of stimulating electrodes along the carrier. Potential problems with an increase in charge density for a common stimulus resulting from decreasing the geometric surface area would be reduced by the enlarged real surface area of such electrodes. Electrochemically modified (HiQ) platinum (Pt) electrodes, with a real surface area approximately 75 times greater than the current standard Pt electrodes of the same geometric size, had shown in vitro a low polarization (Z(pol)) and electrode impedance (Z(e)), as well as a low residual direct current (DC). In this study we examined the chronic performance of HiQ electrodes in cats, which were bilaterally implanted with a two-channel HiQ or standard Pt scala tympani electrode array and unilaterally stimulated for periods of up to 2390 h. Stimuli consisted of 50 micros/phase charge-balanced biphasic current pulses presented at 2000 pulses/s/channel with a 50% duty cycle. Electrode impedance (Z(e)), access resistance (R(a)) and polarization impedance (Z(pol)) were calculated from current and voltage measurements obtained periodically throughout the implantation period. Immediately following implantation HiQ electrodes showed a significantly smaller Z(pol), resulting in a reduced Z(e) (P<0.0001) compared to standard electrodes, while there was no significant difference between R(a) of both electrode designs (P=0.91). Subsequently, Z(e) generally increased mainly due to a rise in R(a), which dominated Z(e) and obliterated the effect of a lower Z(pol) on Z(e) in HiQ electrodes. Peak R(a) levels correlated closely (r=0.85) with the amount of intracochlear fibrous tissue found adjacent to the array. Following explantation of the array, voltage waveforms for both electrode designs recorded in saline were again very similar to those recorded immediately after implantation. Mean DC levels were consistently lower for HiQ electrodes compared with standard electrodes (22.45 nA vs 134.7 nA). Histopathological examination of corresponding cochlear sections comparing the stimulated test side with the unstimulated control side showed no significant difference (P>0.05) for either animals implanted with HiQ electrodes (n=6) or standard electrodes (n=2). Nor were there any significant differences between the spiral ganglion cell density of the basal turn implanted with HiQ or standard electrodes for both the stimulated test (P=0.31) and the unstimulated control side (P=0.84). Although these findings are based on a small group of animals implanted with standard electrodes (n=2), and those negative statistical results could potentially be due to the small sample size, similar spiral ganglion cell survival was found in a previous study of a larger group of animals using standard electrodes stimulated with the same stimulus paradigm as in the present study [Xu et al. (1997) Hear. Res. 105, 1-29]. Our data indicate that while some initial advantages of HiQ electrodes are lost during chronic implantation due to intracochlear fibrous tissue growth, low DC levels and the high surface area appear to be maintained, suggesting that HiQ electrodes may have important clinical applications.

Mass changes and dissolution of platinum during electrical stimulation in artificial perilymph solution.

The electrochemistry of platinum electrodes in artificial perilymph solution subjected to cyclic and steady-state potentials was studied by a quartz crystal electrochemical microbalance and by analysis of electrolyte for dissolved platinum. The effect of amino acid adsorption appears to be one of blocking sites for platinum oxidation and oxide reduction, a process in which the amino acid competes with chloride from phosphate-buffered saline. For amino acids such as cysteine, which are known to interact strongly with platinum, the voltammograms became nearly featureless and only a small change in mass was observed during cycling of the potential. There were no mass changes of an electrode in solution containing human serum albumen, but its presence did inhibit dissolution of platinum. The overall magnitudes of dissolved platinum found in the buffered solutions were low, remaining below 5 ppb in most cases. Dissolution was greatest in solutions containing high concentrations of cysteine. Extrapolation of the results to implanted auditory prosthesis electrodes indicated that platinum dissolution would not lead to toxic concentrations in the body.

An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue.

OBJECTIVES: This study was designed to evaluate the efficacy and safety of the oxytocin receptor antagonist atosiban in the treatment of preterm labor. STUDY DESIGN: A multicenter, double-blind, placebo-controlled trial with tocolytic rescue was designed. Five hundred thirty-one patients were randomized to receive, and 501 received, either intravenous atosiban (n = 246) or placebo (n = 255), followed by subcutaneous maintenance with the assigned agent. Standard tocolytics as rescue tocolysis were permitted after 1 hour of either placebo or atosiban if preterm labor continued. The primary end point was the time from the start of study drug to delivery or therapeutic failure. Secondary end points were the proportion of patients who remained undelivered and did not receive an alternate tocolytic at 24 hours, 48 hours, and 7 days. RESULTS: No significant difference was found in the time from start of treatment to delivery or therapeutic failure between atosiban and placebo (median, 25.6 days vs 21.0 days, respectively; P =.6). The percentages of patients remaining undelivered and not requiring an alternate tocolytic at 24 hours, 48 hours, and 7 days were significantly higher in the atosiban group than in the control group (all P < or =.008). A significant treatment-by-gestational age interaction existed for the 48-hour and 7-day end points. Atosiban was consistently superior to placebo at a gestational age of > or =28 weeks. Fourteen atosiban-treated patients and 5 placebo-treated patients were randomized at <24 weeks; the incidence of fetal-infant deaths was higher for the atosiban group at <24 weeks. Maternal-fetal adverse events were similar except for injection-site reactions, which occurred more often with atosiban. CONCLUSIONS: In this trial the treatment of patients in preterm labor with atosiban resulted in prolongation of pregnancy for up to 7 days for those at a gestational age > or =28 weeks, and this occurred with a low rate of maternal-fetal adverse effects. In addition, at a gestational age > or =28 weeks, the infant morbidity and mortality of atosiban-initiated standard care were similar to those with placebo-initiated standard care. Given that all patients in this study were eligible for tocolysis and that, in practice, nearly all patients who are eligible for a tocolytic receive one, the benefit of using atosiban is the placebo-like maternal-fetal side effect profile. These observations support the use of this oxytocin receptor antagonist in the treatment of patients in preterm labor with intact membranes. Efficacy and infant outcome data at <28 weeks are inconclusive.

[Nonsteroidal anti-inflammatory drugs--nephrotoxic mechanism of action]. / Niesteroidowe leki przeciwzapalne--mechanizm dzialania nefrotoksycznego.

Non-steroid anti-inflammatory drugs are easily available and commonly used. Mechanism of their action is based on inhibiting prostaglandin synthesis. Prostaglandins are arachidonic acid derivatives that are responsible, among others, for regulation of renal blood flow. In some kidney disorders as well as in hemodynamic disturbances, their increased release aims at balancing substances causing kidney ischemia. Blocking prostaglandin synthesis in such conditions may result in development of nephrotoxic effect, manifesting in water-electrolyte imbalance, acute tubulo-interstitial nephropathy, nephrotic syndrome, acute and chronic renal papillary necrosis as well as acute or chronic renal failure. Analgesic nephropathy with papillary necrosis is a particular form of the nephrotoxic effect of non-steroid anti-inflammatory drugs. Development of this complication has been described in patients abusing phenacetin or other analgesic drugs and especially their combination.

Electrical stimulation of the auditory nerve: direct current measurement in vivo.

Neural prostheses use charge recovery mechanisms to ensure the electrical stimulus is charge balanced. Nucleus cochlear implants short all stimulating electrodes between pulses in order to achieve charge balance, resulting in a small residual direct current (DC). In the present study we sought to characterize the variation of this residual DC with different charge recovery mechanisms, stimulation modes, and stimulation parameters, and by modeling, to gain insight into the underlying mechanisms. In an acute study with anaesthetised guinea pigs, DC was measured in four platinum intracochlear electrodes stimulated using a Nucleus C124M cochlear implant at moderate to high pulse rates (1200-14,500 pulses/s) and stimulus intensities (0.2-1.75 mA at 26-200 microseconds/phase). Both monopolar and bipolar stimulation modes were used, and the effects of shorting or combining a capacitor with shorting for charge recovery were investigated. Residual DC increased as a function of stimulus rate, stimulus intensity, and pulse width. DC was lower for monopolar than bipolar stimulation, and lower still with capacitively coupled monopolar stimulation. Our model suggests that residual DC is a consequence of Faradaic reactions which allow charge to leak through the electrode tissue interface. Such reactions and charge leakage are still present when capacitors are used to achieve charge recovery, but anodic and cathodic reactions are balanced in such a way that the net charge leakage is zero.

Dialysis neutropenia: the role of the cytoskeleton.

Dialysis neutropenia is the result of pulmonary sequestration of neutrophils after complement activation by the dialyzer membrane. Increased expression of neutrophil adhesion receptors, such as CD11b/CD18, suggests that neutrophil adhesion to the capillary endothelium is a possible mechanism. An alternative hypothesis is that the complement fragment C5a modulates neutrophil mechanical properties via the cytoskeleton-largely filamentous actin (F-actin)-stiffening them and thereby slowing their passage through the pulmonary capillaries. To investigate this hypothesis, we developed an assay to measure the F-actin content of neutrophils in whole blood using flow cytometry and the stain NBD-phallacidin. We measured neutrophil F-actin content during hemodialysis of patients with polysulfone (N = 6), Hemophan (N = 6), and Cuprophan membranes sterilized with either ethylene oxide (N = 5) or steam (N = 6). Cell counts, neutrophil and monocyte CD11b expression and plasma C5a concentrations were also measured. The results confirm the strong relationship between the degree of neutropenia, increases in CD11b expression and plasma C5a levels reported by previous researchers. Modulation of the F-actin content of neutrophils was also strongly related to C5a levels, indicating that the neutrophil cytoskeleton is active during dialysis. Modeling of cell counts suggests that with Cuprophan a substantial fraction of neutrophils and monocytes are sequestered before they even pass through the dialyzer, suggesting some form of systemic activation of these cells. Evidence for systemic activation was also seen in measurements of F-actin content, but not CD11b expression, a finding that strengthens the case for the involvement of the cytoskeleton in dialysis neutropenia.

Inhibition of intrarenal NO stimulates renin secretion through a macula densa-mediated mechanism.

Because endothelium-derived factors are known to have multiple actions throughout the body, the role of nitric oxide (NO) produced within the kidney in the regulation of renin release is still unclear. Therefore, the objectives of this study were to determine the effect of local NO synthesis inhibition within the kidney on renin secretion rate (RSR) and to determine whether the macula densa mechanism mediates the effect of NO on renin secretion rate in dogs. The NO synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) was administered via the renal artery at 5 microg x kg(-1) x min(-1) to dogs with normal kidney function and to dogs with the macula densa mechanism blocked, established by using the nonfiltering kidney model. In dogs with normal kidney function, renal arterial pressure (RAP) and glomerular filtration rate (GFR) remained constant throughout the experiment (131 +/- 5 mmHg and 22.6 +/- 3.0 ml/min, respectively). However, intrarenal NO synthesis inhibition decreased renal blood flow (RBF) by 16% (240 +/- 22 to 201 +/- 23 ml/min) and increased renal vascular resistance (RVR) by 24% (0.59 +/- 0.08 to 0.73 +/- 0.09 mmHg x ml(-1) x min). In addition, L-NAME decreased the fractional excretion of lithium by 27% (30.0 +/- 3.7 to 21.6 +/- 4.3%) and decreased the fractional excretion of sodium by 35% (0.86 +/- 0.29 to 0.56 +/- 0.21%). Associated with these changes in renal function, renin secretion rate increased by 194 and 235%. In marked contrast, renin secretion rate remained constant in dogs with the macula densa mechanism blocked. Intrarenal NO synthase blockade decreased RSR by 4 and 10% in dogs with the macula densa mechanism blocked. The RAP, RBF, and RVR responses to intrarenal NO synthesis inhibition in dogs with the macula densa mechanism blocked were similar to the renal hemodynamic response in dogs with normal kidney function. In summary, we have demonstrated that intrarenal NO synthesis blockade enhances renin secretion in dogs. The macula densa mechanism appears to play an important role in mediating the effect of intrarenal NO synthesis inhibition on renin release.

The use of congo red as a lyotropic liquid crystal to carry stains in a model immunotargeting system--microscopic studies.

The lyotropic liquid crystal dye-Congo Red was used as a carrier in a model immunotargeting system constructed from sheep red blood cells (SRBC) representing the antigen target and rabbit IgG anti-SRBC as the specific driving immunoglobulin. Rhodamine B and Hemin stains were chosen as example chemicals carried to the target. The carried stains were introduced to the micellar organization of Congo Red by intercalation. Preserving its supramolecular organization, Congo Red binds spontaneously and selectively to antibodies that have altered structure extorted by interaction with the antigen in the immune complex. The functionality of the studied immunotargeting model was verified by fluorescence and electron microscopy. The results indicate that the supramolecular nature of protein ligands offers new ligation capabilities possibly useful for carrying stains or drugs in immune-oriented systems.

Corticosteroids and fetal intervention interact to alter lung maturation in preterm lambs.

The relationship between cortisol infusion and time of fetal catheterization on postnatal lung function of prematurely delivered lambs was investigated with the hypothesis that the intervention of catheterization would alter fetal responsiveness to the maturational effects of corticosteroids. Fetal catheterization was performed on d 117 or on d 122 of gestation. Cortisol or saline control infusions were begun on d 126, with delivery 60 h later on d 128. The animals were ventilated for 1.25 h after delivery, and compliance, the ventilation efficiency index, labeled albumin leak into and out of the lungs, alveolar and lung saturated phosphatidylcholine and surfactant protein A were measured to evaluate lung performance and biochemical indicators of maturation. Cortisol improved compliance and ventilation efficiency and decreased labeled albumin recovery without changing alveolar saturated phosphatidylcholine or surfactant protein A in the animals catheterized at 122 d relative to 122-d saline-infused animals. However, the animals catheterized at 117 d and infused with saline were as mature as assessed by compliance and ventilation efficiency as the 122-d cortisol-treated animals. The 117-d cortisol-infused animals had significantly augmented lung function relative to either 117-d saline-infused or 122-d cortisol-treated lambs and were the only group that had increased alveolar surfactant protein A and lung saturated phosphatidylcholine pool sizes. This study demonstrates that the response of the fetal lung to a maturational agent such as cortisol is dependent on the history of previous fetal interventions.

Lung function and surfactant distribution in saline-lavaged sheep given instilled vs. nebulized surfactant.

Adult sheep (35 +/- 3 kg) underwent saline lung lavage and 1.5 h of mechanical ventilation to induce acute lung injury. Animals received 100 mg lipid/kg body wt of tracheally instilled surfactant (Inst Surf) or either nebulized surfactant (Neb Surf) or nebulized saline (Neb Saline) and were killed 3 h later. Inst Surf and Neb Surf groups had significant improvements in oxygenation (P < 0.01) and peak inspiratory pressures (PIP) (P < 0.05) compared with pretreatment values. Improvements in oxygenation and PIP for Inst Surf animals were significantly greater than for Neb Surf animals (P < 0.05). Volumes of maximal pressure of quasi-static pressure-volume curves measured at the time the animals were killed were significantly greater for Inst Surf and Neb Surf animals than for animals given Neb Saline (P < 0.05). Alveolar recovery of exogenous surfactant was 100 times greater for Inst Surf animals (1,732 +/- 70 mg) than for Neb Surf animals (15.3 +/- 2.9 mg) at the time they were killed. Although there were no differences in exogenous surfactant distribution patterns at the lobar level between the two surfactant-treated groups, distribution histograms calculated for 10-g lung pieces revealed the Neb Surf animals had significantly more pieces within 25% of the mean value of 1.0 (42.7 +/- 6.9%) than did Inst Surf animals (20.8 +/- 5.5%) (P < 0.01). Exogenous surfactant therapy improved lung function with significantly different quantities of surfactant deposited in lung tissue for the two delivery methods evaluated.

Platelet-activating factor antagonists decrease lung protein leak in preterm ventilated rabbits.

OBJECTIVE: The preterm ventilated lung is characterized by an increased protein leak from the pulmonary vascular spaces into the air spaces, which interferes with lung function and plays a role in neonatal respiratory distress syndrome. To investigate the role of platelet-activating factor in this process, platelet-activating factor antagonists were given to preterm ventilated rabbits. STUDY DESIGN: New Zealand White rabbits were delivered on day 28 of 31 days' gestation. Each rabbit pup received saline solution or one of two platelet-activating factor antagonists and were ventilated for 30 minutes with measurement of compliance, surfactant pool size, and protein leak into and out of the lung. Statistical analysis was performed with analysis of variance followed by Student-Newman-Keuls correction for multiple comparisons. RESULTS: There were no differences in lung compliance, surfactant pool size, or protein leak out of the air spaces among any of the groups. Treatment with the platelet-activating factor antagonists decreased the protein leak into the air spaces by greater than 50% and into the lung as a whole by 40% (p less than 0.01). CONCLUSION: Platelet-activating factor plays a role in the protein leak seen in the preterm lung, which contributes to neonatal respiratory distress syndrome.

The modified Pereyra procedure: a clinical and urodynamic review.

OBJECTIVE: To review the clinical and urodynamic outcome of treatment by the modified Pereyra procedure in 93 women with genuine stress incontinence. DESIGN: Retrospective review. SETTING: Harbor/UCLA Medical Center and Los Angeles County Women's Hospital, Los Angeles, California, USA. MAIN OUTCOME MEASURES: Clinical and urodynamic assessment one year after modified Pereyra procedure. RESULTS: Overall 82% of patients were subjectively cured while only 63% were objectively cured. Women with failed surgery had significantly lower pre-operative maximum urethral closure pressures. The procedure had a low operative and postoperative morbidity with no significant disturbance of voiding function noted at one year follow-up. CONCLUSIONS: Our results with the modified Pereyra procedure for stress incontinence showed a significantly lower success rate than has been reported from many previous studies.

Surfactant protein A metabolism in preterm ventilated lambs.

Surfactant protein A (SP-A) metabolism was studied in vivo in 33 preterm ventilated lambs at 138 +/- 1 days gestational age by measuring recoveries of exogenously administered surfactant containing both radiolabeled SP-A and labeled saturated phosphatidylcholine (Sat PC) given via the trachea at birth. Endogenously secreted SP-A was also labeled with [35S]methionine and followed over 24 h. The exogenously labeled SP-A left the alveolar pool more rapidly than did Sat PC over the first 5 h of life (P less than 0.05), and both exogenously labeled SP-A and Sat PC were detected within lamellar bodies by 2 h, indicating uptake from the airspaces. The quantity of SP-A in alveolar washes increased about twofold from birth to 5 h of age, whereas alveolar Sat PC pools were constant over 24 h. The SP-A endogenously labeled with [35S]methionine was recovered at highest specific activities in the alveolar washes at 10 and 45 min after birth with no labeled SP-A detectable in lamellar body fractions until 2 h. The curve for endogenous SP-A labeling of lamellar bodies was similar to that for exogenous labeling, indicating that SP-A was initially secreted by a pathway independent of lamellar bodies with subsequent SP-A labeling of lamellar bodies. The kinetics of SP-A metabolism were very different than for Sat PC in preterm lambs.

Lung albumin recovery in surfactant-treated preterm ventilated lambs.

Preterm ventilated animals and infants with respiratory distress syndrome (RDS) develop proteinaceous alveolar edema. To study the effect of postnatal age on intravascular radiolabeled albumin accumulation into lungs, preterm lambs at 132 days gestational age were ventilated after treatment with sheep surfactant or cow surfactant extract for periods as long as 24 h. Lambs not treated with surfactant were studied for only 5 h because of severe respiratory failure. All lambs were given radiolabeled albumin by intravascular injection 1 h before they were killed, and the net recovery of the labeled albumin was measured in the lung tissue and air space as quantified by alveolar lavage. Net 1-h radiolabeled albumin recoveries in the lungs decreased from 5 to 6% soon after birth to 0.9% at 24 h in the surfactant-treated groups (p less than 0.01). At 3 h there was less labeled albumin recovery by alveolar lavages in lambs treated with sheep surfactant than in control lambs and lambs treated with cow surfactant extract (p less than 0.05). Protein in alveolar washes from lambs treated with cow surfactant extract exceeded that in lambs treated with sheep surfactant at 3 h (p less than 0.05), but protein recoveries had decreased to similar values by 24 h, indicating a net clearance of air-space protein. These studies demonstrate a sixfold decrease in net albumin accumulation from birth to 24 h of age despite continued ventilation and oxygen exposure of the premature lamb lungs.

The effect of maternal cocaine use on the fetus: changes in antepartum fetal heart rate tracings.

Fetal heart rate tracings of pregnancies complicated by cocaine use were analyzed to evaluate the effects of subacute maternal cocaine use on the fetus. Nonstress tests were performed twice weekly on patients from the perinatal substance abuse clinic with screening of maternal urine samples for cocaine, amphetamines, phencyclidine, and opiates at the time of each examination. Nonstress tests performed when the urine toxicology screen was positive for cocaine alone (positive cocaine nonstress tests) were paired with those from the same patient but performed when the screen was negative (negative cocaine nonstress tests). The nonstress tests were analyzed with the Lyons scoring system, which evaluates the baseline heart rate, the oscillatory amplitude of the baseline, the oscillatory frequency, decelerations, and accelerations. Twenty pairs of nonstress tests from 20 patients were analyzed. The total score was higher on the negative cocaine nonstress test in 70% of the pairs and equal in the remaining 30% (p less than 0.001). Significant differences occurred in the oscillatory amplitude (p less than 0.001), frequency (p = 0.002), and acceleration scores (p = 0.03) but not the fetal heart rate baseline or the deceleration scores. The observed changes may reflect alterations in fetal central nervous system neurotransmitters and fetal state regulation, which may affect the developing central nervous system of cocaine-exposed fetuses and in turn play a role in the developmental and behavioral abnormalities observed in cocaine-exposed infants.

Corticosteroid and thyrotropin-releasing hormone effects on preterm sheep lung function.

Four groups of twin sheep fetuses were catheterized at 121 days of gestational age and intravenously infused with saline, 0.75 mg.kg-1.h-1 cortisol for 60 h, five intermittent bolus injections of 5 micrograms/kg thyrotropin-releasing hormone (TRH) at 12-h intervals, or both hormones before delivery at 128 days. At birth, the lambs were randomized to receive surfactant or no treatment. Surfactant treatment improved lung function of all the groups. Corticosteroids alone and in combination with TRH improved compliance and gas exchange as well as pressure-volume curves. Corticosteroids alone dramatically decreased the recovery of intravenously administered radiolabeled albumin in the lung tissue and air space and improved the pulmonary response to surfactant treatment. There were no additional effects of TRH when given with corticosteroids on lung function or albumin leak. There were no changes in alveolar surfactant-saturated phosphatidylcholine pool sizes after any hormone treatment. The single significant effect of combined corticosteroid and TRH treatment was a fivefold increase in surfactant protein A in alveolar lavage fluid relative to all other groups.