A Canadian perspective on the use of immunoglobulin therapy to reduce infectious complications in chronic lymphocytic leukemia.

Infections are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (cll), who typically have increased susceptibility because of hypogammaglobulinemia (hgg) related to their disease and its treatment. Immunoglobulin replacement therapy (igrt) has been shown to reduce the frequency of bacterial infections and associated hospitalizations in patients with hgg or a history of infection, or both. However, use of igrt in cll is contentious. Studies examining such treatment were conducted largely before the use of newer chemoimmunotherapies, which can extend lifespan, but do not correct the hgg inherent to the disease. Thus, the utility of igrt has to be re-evaluated in the current setting. Here, we discuss the evidence for the use of igrt in cll and provide a practical approach to its use in the prevention and management of infections.

Endothelium-dependent relaxations in sheep pulmonary arteries and veins: resistance to block by NG-nitro-L-arginine in pulmonary hypertension.

1. The effect of the nitric oxide synthase inhibitor, NG-nitro-L-arginine (L-NOARG), on endothelium-dependent relaxation to a receptor-independent agent, ionomycin, was examined in isolated pulmonary arteries and veins from control, short-term and chronic pulmonary hypertensive sheep. All vessel segments were contracted to optimal levels of active force with endothelin-1 to record endothelium-dependent relaxation. 2. Pulmonary hypertension was induced by continuous pulmonary artery air embolization for 1 day (short-term) and 14 days (chronic) and was associated with a 2 and 3 fold increase in pulmonary vascular resistance respectively. 3. L-NOARG (0.1 mM) reduced the maximum relaxation (Rmax) to ionomycin in large and medium-sized pulmonary arteries from control sheep by approximately 70%. By contrast, L-NOARG (0.1 mM) did not inhibit the Rmax to ionomycin in matched vessels from short-term and chronic pulmonary hypertensive sheep. 4. Resistance of ionomycin-induced relaxations to inhibition by L-NOARG, was confined to the arterial vasculature in chronic pulmonary hypertensive animals, as relaxations to ionomycin in large and medium-sized chronic pulmonary hypertensive veins were, like those in control veins, abolished by L-NOARG. Both large and medium-sized pulmonary veins from short-term pulmonary hypertensive sheep, however, were resistant to block by L-NOARG. 5. Neither sensitivity (pEC50) nor Rmax to ionomycin in large, short-term pulmonary hypertensive arteries was affected when the extracellular concentration of K+ was increased isotonically to 30 mM. Nifedipine (0.3 microM) was present throughout to prevent high K(+)-induced smooth muscle contraction. In the presence of this high extracellular K+, however, L-NOARG (0.1 mM) caused complete inhibition of the relaxation to ionomycin, whereas in normal extracellular K+ (4.7 mM), L-NOARG only weakly inhibited ionomycin relaxations. 6. In conclusion, the onset of pulmonary hypertension in sheep following air embolization, is associated with the development of resistance of endothelium-dependent relaxations to block by L-NOARG. The mechanism of L-NOARG resistance appears to be due to the up-regulation of a K+ channel-mediated backup vasodilator mechanism which can compensate for the loss of nitric oxide (NO)-mediated relaxation. Although this mechanism remains functionally 'silent' in the presence of NO it is able to maintain adequate endothelium-dependent vasodilatation during pulmonary hypertension if NO synthesis is compromised.

Effect of changing lung liquid volume on the pulmonary circulation of fetal lambs.

During fetal life the lung develops as a liquid-filled structure with low blood flow compared with postnatal life. We studied the effects of liquid expansion of the fetal lung by measuring vascular conductance in perfused lungs in situ and arterial diameters in excised lungs of fetal lambs. Pulmonary vascular conductance invariably rose as the lung was deflated from its initial volume; maximal deflation to residual volume increased conductance 122%. With reexpansion, conductance fell progressively, culminating in cessation of flow at lung volumes of twice the initial volume. These changes persisted after vagotomy and thoracic sympathectomy and therefore were mechanical in character. Lung expansion from residual volume initially expanded 300- to 500-micron arteries but compressed arteries greater than 1,500 micron. Further expansion reduced the caliber of all arteries. Thus increasing lung liquid volume progressively constricts the pulmonary circulation in the fetus. Because the fetal pulmonary vascular resistance-lung volume relationship differs from that of the U-shaped form found in adult lungs, concepts based on the adult pulmonary circulation are not appropriate for liquid-filled fetal lungs.

Antibody to a cDNA-derived calreticulin protein from Amblyomma americanum as a biomarker of tick exposure in humans.

The antibody responses of human and animal hosts were studied to determine the utility of antibody against recombinant tick calreticulin (rTC), a cDNA-derived protein isolated from salivary glands of Amblyomma americanum L., as a biologic marker of tick exposure. Rabbits fed upon by either A. americanum or Dermacentor variabilis Say developed significant anti-rTC antibody responses, as measured by both ELISA and immunoblot assay. In contrast, gerbils exposed to Aedes aegypti did not develop anti-rTC antibodies, as measured by ELISA or immunoblot assay. The utility of the assay was next evaluated in humans at high risk for tick exposure. During April through September 1990, 192 military personnel who originated from either Fort Chaffee, Arkansas or Fort Wainwright, Alaska were studied during maneuvers in tick infested areas at Fort Chaffee. Study subjects completed a questionnaire and had pre- and post-maneuvers serum specimens analyzed for antibodies to rTC. In adjusted analysis (controlling for age, fort of origin, attached tick during maneuvers, and bed netting use), the use of bed netting and home station were associated with post-maneuvers anti-rTC antibody seropositivity by ELISA. Subjects from Fort Wainwright were more likely to be seropositive for anti-rTC antibody (adjusted odds ratio = 5.3, 95% confidence interval [CI] = 1.1-25.6). Personnel who did not report the use of bed netting were more likely to be anti-rTC seropositive (adjusted odds ratio = 6.8, 95% CI = 1.4-32.4). Immunoblot assays showed that humans had specific anti-rTC antibody responses. The animal experiments demonstrate that hosts exposed to naturally feeding ticks develop anti-rTC antibodies. The data also indicate that hosts exposed to Ae. aegypti saliva may not develop antibodies against rTC. Observations in tick-exposed humans support the hypothesis that anti-rTC antibody seropositivity is a biologic marker of tick exposure.

High-frequency oscillatory ventilation compared with conventional mechanical ventilation in newborn lambs: effects of increasing airway pressure on intracranial pressures.

We tested the hypothesis that intracranial pressures and cerebral perfusion pressure in the newborn are more seriously affected by increasing airway pressure during high-frequency oscillatory ventilation (HFOV) than during conventional mechanical ventilation (CMV). Mean airway pressure was acutely elevated in stepwise fashion to 25 cm H2O in six anesthetized, paralyzed newborn lambs. Pressure (mean +/- SE) increased similarly during HFOV and CMV in the jugular vein (7 +/- 1 and 8 +/- 1 cm H2O, respectively), the sagittal sinus (6 +/- 1 and 7 +/- 1 cm H2O), and the cerebrospinal fluid of the lateral ventricle (4 +/- 1 and 6 +/- 1 cm H2O). Decreases in arterial blood pressure (-13 +/- 2 and -10 +/- 2 cm H2O) and cerebral perfusion pressure (-17 +/- 2 and -16 +/- 2 cm H2O) were also similar during HFOV and CMV. Intracranial pressure-volume curves were generated by incrementing cerebrospinal fluid volume in eight lambs. Curves generated during HFOV and CMV were similar, reflecting a similar intracranial compliance during the two ventilatory modes. These data indicate that intracranial compliance and the effects of increasing airway pressure upon intracranial pressures are not significantly different between HFOV and CMV.

The effect of high frequency oscillatory ventilation on extravascular lung water in the rabbit.

High frequency ventilation (HFV) systems have the theoretical advantage of producing less barotrauma and lung damage because of the associated smaller oscillations in alveolar pressure compared to conventional ventilators. An index of lung damage is an increase in extravascular lung water but previous studies using HFV have produced conflicting results. Lung wet-to-dry ratio, extravascular lung water and blood mass were measured in 30 rabbits divided into three groups (n = 10); spontaneously breathing (SV), conventional positive pressure ventilation (CV) and high frequency oscillatory ventilation (HFV). HFV maintained normal blood gases and produced a significant reduction in the wet-to-dry weight ratio compared to SV and CV (P less than 0.05). Extravascular lung water and blood mass were significantly reduced in HFV compared to SV (P less than 0.05). It is concluded that the system of HFV used in this study has clinical potential in the treatment of lung injury.

The effects of oxytocin on the pulmonary and systemic circulation in pregnant ewes.

The haemodynamic effects of oxytocin on the pulmonary and systemic circulation were studied in six awake, pregnant (greater than 140 days gestation) ewes. Bolus doses of oxytocin 0.2 units/kg and then 0.8 units/kg were administered. A dose of 0.2 units/kg resulted in small but significant increases in mean pulmonary artery pressure (14%, P less than 0.05) and pulmonary vascular resistance (24%, P less than 0.05. A bolus of 0.8 units/kg resulted in a significant increase in mean arterial pressure (20%, P less than 0.05) and systemic vascular resistance (33%, P less than 0.05). Acute pulmonary hypertension was then induced with glass bead microemboli (150-200 microns), with an increase in pulmonary artery pressure of 26 mmHg and pulmonary vascular resistance of 448 dyn. s. cm-5. Boluses of oxytocin 0.2 and 0.8 units/kg were then administered. There were no significant changes, except for a 30% increase in systemic vascular resistance at one minute after oxytocin, 0.8 units/kg (P less than 0.05).

Hypotension in fetal and newborn lambs; different patterns of reflex heart rate control revealed by autonomic blockade.

Reflex heart rate (HR) responses to hypotension were studied in chronically instrumented fetal and newborn lambs. Studies spanned 106-141 days of gestation and 1-22 days after birth. Brief hypotensive stimuli (10 s) were produced by inflation of a cuff implanted around the inferior vena cava; HR and mean arterial pressure (MAP) were recorded from a carotid arterial catheter. Autonomic nervous control of HR was examined using selective sympathetic beta-adrenergic blockade (propranolol 1 mg/kg), cholinergic blockade (atropine 0.2-0.3 mg/kg), and total autonomic blockade (propranolol plus atropine). In newborn lambs (n = 4) HR increased progressively as MAP was reduced in the range 5-50%. Tachycardia during mild hypotension (less than 15% MAP fall) was due to sympathetic activation as it was abolished by propranolol. During severe hypotension (greater than 30% MAP fall) tachycardia was reduced by selective beta-adrenergic blockade and by cholinergic blockade, and totally abolished by total autonomic blockade; thus withdrawal of vagal tone plus augmentation of sympathetic activity contribute to the increase of HR in response to large MAP falls in the newborn. Fetal lambs (n = 4) responded with tachycardia in mild hypotension (less than 15% MAP fall) but this was reversed when hypotension was severe (greater than 30% MAP fall). The primary tachycardia was due to sympathetic activation and was indistinguishable from the newborn response.(ABSTRACT TRUNCATED AT 250 WORDS)

Epithelial surfaces of the trachea and principal bronchi in the rat.

The epithelial surfaces in the trachea and principal bronchi of healthy rats were examined by scanning electron microscopy. A system of four cell types, ciliated, microvillous, brush, and goblet cells, in this order of frequency, were found and intermediate type cells were not seen. An extensive area of the surface examined was covered by densely ciliated epithelium. The presence of other cell types beneath the cilia was confirmed by transmission electron microscopy. Areas up to 1 mm in diameter and randomly distributed were observed where microvillous cells predominated and only occasional ciliated cells were found. Most ciliated cells in these areas were adjacent to glandular openings or goblet cells. The larger microvilli of the brush cells were arranged in a coronal configuration elucidated by the scanning electron microscope. Preparatory techniques recently introduced for the examination of soft tissue in the scanning electron microscope facilitated the confirmation of cell types present and the microarchitecture of the epithelial surface.

Modification of respiratory center output in the unanesthetized fetal sheep "in utero".

Diaphragmatic electromyographic activity, tracheal and amniotic fluid pressures, lung liquid flow, and carotid and jugular venous pressures were measured on eight fetal lambs who survived for periods of 9-43 days postoperatively. The fetal gestational age ranged from 98 to 113 days at operation. Respiratory center output of the fetus as indicated by electromyographic activity was modified by the following stimuli. It was suppressed by anesthesia and fetal hypoxia (Pao2 = 12 mmHg), tonically reduced by lung inflation, and stimulated by cyanide injections (150-600 mug) into the fetal jugular vein. Neuromuscular transmission to the diaphragm was blocked with d-tubocurarine (0.2-0.6 mg). These experiments indicate that central and motor pathways to the diaphragm are sufficiently mature by 101 days in the fetal sheep to permit their output to be modified by chemical and mechanical stimuli.

New features in the development of the submucosal gland of the respiratory tract.

The development of submucosal glands in the respiratory tract was studied by light and scanning electron microscopy in the rat, fetal dog and fetal sheep. From the results obtained the present concepts about the formation of these glands in man were questioned and an alternative hypothesis proposed. With scanning electron microscopy the development of the submucosal gland was seen to begin with an aggregation of low electron-responsive cells. Within such an aggregate, a pit, several microns in diameter, was formed. This pit was usually surrounded by medium electron-responsive cells possessing primary cilia in the rat, and by low electron-responsive cells in the fetal dog. In the rat medium electron-responsive cells appeared in other areas of the aggregate, preceded by apical elevations on the low electron-responsive cells. Further development in the rat led to a disappearance of the low electron-responsive cells, differentiation of ciliated and brush cells, and enlargement of the gland orifice. With light microscopy it was observed that the initial gland buds in both the rat and fetal sheep contained lumina several microns in size. These have not been reported by previous investigators. The bud extended into the underlying tissue and developed many simple tubules. The lumina of these tubules were consistently larger than the channel close to the epithelial surface. The cells of these tubules were also the first to differentiate into mucous and serous cells. The development of glands in the rat, in contrast to the sheep, began after birth. In the sheep, unlike the rat, the lumina of the developing glands were often filled with acidic mucosubstances, even though the cells of these glands did not stain for such material. Hence it is suggested that this material is derived from the mucin-containing cells of the surface epithelium and is carried into the interior of the developing gland by the fluid present in the respiratory tract during intrauterine life.

Morphological effects of chronic tracheal ligation and drainage in the fetal lamb lung.

The relationship between lung liquid flow and fetal lung development has been studied at the cellular level using ultrastructural techniques. Continuous in utero tracheal ligation and drainage (over a period of 21-28 days) both result in malformations of the developing fetal lamb lung. Ligated lungs are larger, and drained lungs are smaller, than normal lungs at a similar gestational age. These changes are not merely due to altered lung liquid volume, but actual tissue growth thas been affected. Future alveolar wall thinning is enhanced in ligated lungs and inhibited in drained lungs, whilst the presence of differentiated alveolar type II cells (probably related to surfactant production) is decreased in ligated lungs and markedly enhanced in drained lungs. These results indicate the importance of fetal lung liquid in the regulation of pulmonary development in the fetus.

Age-dependent pattern of autonomic heart rate control during hypoxia in fetal and newborn lambs.

Autonomic nervous control of heart rate (HR) during hypoxia was studied longitudinally using 9 chronically catheterized fetal lambs (109 day to term) and 10 newborn lambs (2--28 days old). Changes in heart rate (deltaHR) during hypoxia were age-dependent. Before 120 days of gestation deltaHR was insignificant, but between 120 days to term bradycardia occurred. The newborn response was marked tachycardia. Autonomic influences on HR were quantified using atropine and propranolol blockade. In fetal lambs, antagonistic increases in parasympathetic and sympathetic outflows were evident during hypoxia. In hypoxic lambs 120 days to term, net bradycardia reflected predominant parasympathetic cardio-deceleration; before 120 days of gestation both the parasympathetic and sympathetic outflows increased, but no net deltaHR occurred. In hypoxic newborn lambs, sympathetic and parasympathetic changes contributed synergistically to the net tachycardia. Thus the pattern of autonomic control of HR during hypoxia differs in fetal and newborn lambs. Changes in sympathetic and parasympathetic influences are antagonistic in the fetus, but synergistic in the newborn.

Effect of ventilation on pulmonary blood volume of the fetal lamb.

Blood volume changes in the fetal lung following the onset of ventilation were studied by isotopic measurement of red blood cell and plasma volume in rapidly frozen lungs of ten near term fetal lambs. Total pulmonary blood volumes of fetal lambs ventilated with 3% O2 and 7% CO2 in nitrogen (so that blood gas levels were little changed from fetal values), or with air, were compared with measurements in unventilated lambs. Regional correlations of blood volume and blood flow (measured with isotope-labeled microemboli) within the lungs were also examined. Total pulmonary blood volume averaged 5.6 ml/kg body weight in unventilated fetal lambs and was approximately 43% greated in fetal lambs after 5-20 min of air ventilation, but not significantly different in lambs ventilated with 3% O2 and 7% CO2 in nitrogen. Thus it is ventilation with air, rather than the introduction of gas into the alveoli, which enlarges the fetal pulmonary vascular bed. Regional pulmonary blood volume and blood flow were correlated, though poorly, in air-ventilated lungs, but not in lungs ventilated with 3% O2 and 7% CO2 in nitrogen; this suggests that a common factor may operate to increase both blood flow and blood volume in the fetal lung following the introduction of air.

Diaphragmatic activity and lung liquid flow in the unanesthetized fetal sheep.

For some time it has been suggested that breathing movements are made "in utero" and recently measurements of tracheal pressure and lung liquid flow in chronic fetal preparations have led to the hypothesis that rapid changes in these parameters are the result of respiratory muscle activity. To test this hypothesis diaphragmatic electrical activity was measured in seven chronic unanesthetized fetal sheep preparations and correlated with lung liquid flow and tracheal pressure. Diaphragmatic activity led to a fall of tracheal pressure and movement of a small volume of lung liquid into the lung. After the activity ceased, tracheal pressure returned to normal and flow diminished to zero or was directed out of the lung. The breathing pattern was unassociated with the net movement of lung liquid out of the lung. A histogram of the interval between breaths revealed a changing pattern of activity throughout gestation. The pattern was significantly altered after premature delivery of one animal with a respiratory problem. These observations provide evidence that respiratory muscles are active "in utero" and that the pattern of activity changes throughout gestation.

Lung liquid production and composition in the "in utero" foetal lamb.

Experiments were carried out on foetal lambs in utero from 103 to 133 days' gestation, to measure the daily flow and solute composition of liquid from the foetal lung. The mean daily flow from foetuses with a tracheal fistula was 231 ml/day (9.6 ml/h), while the mean hourly flow in foetuses with a tracheal loop was 5.1 ml/h. The pattern of flow of lung liquid was intermittent and irregular, with short periods of rapid flow interspersed with longer periods of slow and no flow. The Na+, Ca2+, Mg2+, Cl- and urea concentrations showed no significant change with increasing gestational age, but the K+ concentration showed a significant rise. It is concluded that the lung of the foetal lamb behaves as an exocrine gland, secreting a substantial volume of liquid of a relatively constant composition.

Development of patterns of respiratory activity in unanesthetized fetal sheep in utero.

Respiratory activity (diaphragmatic electromyogram) was recorded in six unanesthetized in utero fetal lambs, between 0.7 of gestation and term. Respiratory patterns generated by the fetus showed developmental changes that included 1) an emergence of a periodic modulation of respiratory rate producing alternating active and quite phases (mean cycle length of 37 min between 130 and 140 days' gestation; 2) an increase in percentage apnea (expiratory time greater than 10 s) from 20% at 110 days to 60% at 140 days; and 3) a linear decrease in the 2-h average respiratory rate, while mean rate during active phases showed no consistent gestational decline. Electrocortical and electroocular activity was monitored in three of six fetuses; however, discrete sleep state patterns could not be consistently identified. The results demonstrate a gestational change in the respiratory patterns of the developing fetus and suggest an orderly maturation of the mechanisms controlling respiratory neuronal output.

Hypercapnic stimulation of respiratory activity in unanesthetized fetal sheep in utero.

Respiratory responses to hypercapnia were studied in seven chronic in utero fetal lambs between 105 and 138 days' gestation (16 expts). Fetal arterial CO2 tension was raised (mean increase 9.9 Torr) by altering maternal inspired gas concentrations. Diaphragmatic electromyogram (EMG) was recorded as the index of respiratory activity. Electrocortical and electroocular activity (3 fetuses) were monitored in an attempt to define sleep state. Average respiratory rate increased (90%) and fetal apnea decreased (60%) during hypercapnia. Mean respiratory rate during "on" periods (greater than 6 EMG bursts/min) increased significantly during hypercapnia throughout the gestational epoch studied. Mean duration of the inspiratory time (TI) showed no significant change. Variability in both rate and TI decreased in response to CO2 at all gestations. Integrated EMG activity per burst divided by TI increased significantly at all gestations; however, no gestational increase in responsiveness to CO2 was seen. Sleep states were not able to be consistently identified, and a quantifiable electrocortical response to CO2 was not observed. These results indicate a relatively early functional maturation of fetal respiratory responses to CO2.

Increased arterial pressure variability after arterial baroreceptor denervation in fetal lambs.

Baroreceptor reflexes can be demonstrated during fetal life, but whether baroreceptors normally regulate fetal arterial pressure is unknown. This problem was addressed directly by measuring arterial pressure and analyzing its variation in eight unanesthetized fetal lambs throughout the last third of gestation, and comparing these data with similar measurements made in seven fetal lambs with denervated arterial baroreceptors. Measurements were made at 5-minute intervals over 24 hours in a total of thirty-three experiments. The coefficient of variation of mean arterial pressure (standard deviation of mean arterial pressure/mean value of mean arterial pressure) expressed as a percentage was used as an index of blood pressure variability. Coefficients averaged 7.0% in intact lambs and 12.1% in barodenervated lambs (P less than 0.001), signifying considerably increased variability of mean arterial pressure after barodenervation. Mean arterial pressure averaged over 24 hours was not different between the two groups prior to 120 days (0.8) of gestation. Between 120 days and term, mean pressure was significantly greater in the denervated fetuses (65 cm H2O) than in the sham-operated controls (60 cm H2O, P less than 0.025). These data demonstrate that a baroreceptor-blood pressure reflex functions during late gestational development in lambs and signify an important role of arterial baroreceptors in regulating fetal arterial pressure. Failure to regulate arterial pressure in the barodenervated fetus could result in significant alterations in placental perfusion and exchange, and in the regional delivery of oxygen and substrates to developing organs in these animals.