The use of computerized tomography in the diagnosis of cerebral hydatid cysts.

Eleven cases of cerebral hydatid cyst, diagnosed by computerized tomography (CT), are presented. The importance of CT in minimizing the possibility of accidentally tapping or tearing the cyst membrane is stressed. Repeat CT scanning after removal of the cyst revealed atrophy in the affected hemisphere.


Clearance of macromolecular and particulate substances from the cerebrospinal fluid system of the rat.

Arachnoid villi in the intracranial dural sinuses constitute the principal sites for absorption of proteins and particulates from the cerebrospinal fluid (CSF) system. Although arachnoid villi in the rat are morphologically less complex than those found in other mammals, their resistance to CSF outflow, as assessed by a graded series of contstant flow manometric infusions, is similar to that found in other species. Moreover, inulin and polystyrene beads, when infused into the spinal subarachnoid space of rats, are rapidly cleared from the CSF system into intracranial dural sinuses. Inulin appeared in sinus blood 3 minutes after onset of infusion and reached concentrations 26 times greater than those found in the systemic circulation; particulate matter in the form of 0.5 micrometer polystyrene beads showed similar efflux characteristics. Hence, the CSF system of the rat is functionally similar to that found in other mammalian species, with arachnoid villi constituting a major efflux route for clearance of macromolecular and particulate substances.


Effect of vasodilators and myelotomy on recovery after acute spinal cord injury in rats.

The effect of papaverine, nitroprusside, or myelotomy on the recovery of spinal cord function was studied in rats after acute cord-compression injury. Spinal cord recovery was measured by a quantitative method of clinical assessment previously developed in our laboratory. Neither papaverine nor nitroprusside improved recovery of cord function. Dorsal midline myelotomy extending anteriorly as far as the central canal did not produce significant improvement (p greater than 0.05). However, when the myelotomy extended completely through the cord in the anteroposterior plane significant improvement (p less than 0.01) was obtained.


Spinal cord blood flow and conduction during experimental cord compression in normotensive and hypotensive dogs.

Spinal cord blood flow (SCBF) and dorsal column conduction, as assessed by the dorsal column evoked potential (DCEP), were measured during subacute cord compression in dogs. Ventral, midline balloons were used to produce compression and a dorsally situated strain gauge transducer measured the cord pressure. In normotensive animals there was autoregulation of SCBF to perfusion pressures (PP) of 65 to 70 mm Hg, and up to cord pressures of 55 to 60 mm Hg. The DCEP amplitude  was significantly decreased even during this autoregulatory period. Conduction failure occurred at PP of 20 to 30 mm Hg. Chemically produced hypotension (74 mm Hg) did not affect either SCBF or DCEP. Minimal compression superimposed on hypotension decreased both flow and DCEP amplitude. The results indicate that ischemia is probably not the cause of the impaired conduction although, as the degree of compression increases, the cord will become ischemic once the autoregulatory limit is passed.


Acute hydrocephalus and death one month after non-surgical treatment for acute cerebellar hemorrhage. Case report.

Acute cerebellar hemorrhages, treated medically with subsequent complete recovery, have been designated "benign cerebellar hemorrhages." Ordinarily, acute cerebellar hemorrhage does require early surgical intervention and reported surgical mortality is relatively low (17%) in awake patients with this lesion. Clinical studies have shown that, after a period of approximately 2 weeks, the predicted mortality for this disorder becomes less than the operative mortality, and patients are then expected to recover. The author reports a case, with serial computerized tomography scanning, in which deterioration and death occurred 4 weeks after acute cerebellar hemorrhage. It is concluded that surgical intervention should be considered early in the clinical course of all cases of acute cerebellar hemorrhage.


Superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. Pathological study of two cases.

Superficial temporal artery to middle cerebral artery (STA-MCA) anastomoses were examined at autopsy in two patients who survived 2 years and 5 1/2 years, respectively, after the cerebral revascularization procedure. Identification of the actual anastomotic sites at autopsy was rendered impossible because of marked fibrosis in the region of the surgery. However, in both patients intimal fibrosis and medial damage were noted in the STA immediately adjacent to the anastomosis. In the patient who survived 2 years, the lumen of the STA was only slightly compromised by these changes, but in the patient who survived 5 1/2 years, the artery was almost totally occluded. The MCA's adjacent to the anastomosis were widely patent and showed focal areas of intimal hyperplasia with no abnormalities of the media.


Swan-neck deformity secondary to osteomyelitis of the posterior elements of the cervical spine. Case report.

A case of osteomyelitis is described, involving the posterior elements of the cervical vertebrae in a 7-year-old girl and resulting in swan-neck deformity. Treatment was initiated with antibiotics, and the patient was placed in halo traction. Eventually posterior cervical fusion was performed, which provided excellent stability and correction of the deformity.


Percutaneous restoration of a kinked shunt. Case report.

A thin-walled atrial catheter used in shunting for hydrocephalus may become curled or kinked in the neck after it has been in normal position and functioning for years. The usual cause is a bout of severe coughing. Such a case is described together with a percutaneous method of restoration of the shunt by transfemoral catheterization utilizing a wire loop.


Early and late results of intracranial direct surgery of anterior communicating artery aneurysms.

During the 14-year period up to September, 1975, 346 patients with a single anterior communicating artery aneurysm, including eight with unruptured aneurysms, were operated on by direct intracranial procedures. There was an early operative mortality of 5.5%. Follow-up studies, an average of 3 years 11 months after surgery, revealed that about 85% of the survivors, excluding those who could not be followed, had regained their working capacity, and that the late mortality and morbidity rates were 9.6% and 2.0%, respectively. The rationale for performing the intracranial operation and factors influencing postoperative results are discussed, with particular emphasis on the techniques for accurate treatment of aneurysms that help to prevent postoperative rebleeding and therefore give better overall surgical results.


Transient ischemic attacks due to increased platelet aggregation and adhesiveness. Ultrastructural and functional correlation.

The authors report 22 cases of transient ischemic attacks (TIA's) manifested by amaurosis fugax or hemiparesis or paresthesia of less than 24 hours' duration. None of the patients demonstrated 1) evidence of atherosclerotic cerebral vascular disease on angiography, 2) evidence of intracranial lesion on brain scan, 3) cardiac source of emboli, 4) arteritis or collagen disease, or 5) history of migraine. The only abnormalities found to explain the TIA's were abnormally increased platelet adhesiveness and/or aggregation. All of these patients were followed from 1 to 5 years, and had repeated coagulation studies. Treatment with antiplatelet drugs showed an excellent clinical response with associated decrease in platelet adhesiveness and aggregation. Discontinuance of the antiplatelet drug resulted in a recurrence of the TIA's which coincided with an increase in aggregation and adhesiveness. In two cases the platelet morphology was studied by transmission and scanning electron microscopy. It appears that there is a specific group of patients with TIA's in whom the sole cause of the attack is an abnormality of platelet function. For these people there is a specific therapy and a method monitoring the treatment.


Neurosurgical management of acromegaly. Results in 82 patients treated between 1972 and 1977.

A consecutive series of 82 acromegalic patients who underwent transsphenoidal surgery during a 5-year period is presented. Preoperative and postoperative values for human growth hormone (HGH) were available in 80 cases. Microadenomas were present in 18 patients with a mean preoperative HGH value of 25.2 ng/ml, diffuse adenomas in 39 patients with mean of 53.8 ng/ml, and invasive adenomas in 25 with mean of 68.0 ng/ml. There was no operative mortality. The results reflected the classification of the tumors, with apparent cures accomplished in 87.5% of previously untreated patients with microadenoma, all of whom had anterior pituitary function preserved. The percentages of apparent cures in cases of diffuse adenoma (68%) and invasive adenoma (54%) were much less satisfactory. Transsphenoidal microsurgery is capable of achieving good results, particularly in patients with microadenoma.


Prolactin suppression of leukocyte chemotaxis in vitro.

Leukocyte chemotaxis in vitro was studied for cells from patients with pituitary adenomas. Leukocytes obtained preoperatively from two of three patients with elevated serum prolactin levels demonstrated chemotaxic alterations described in other malignant disease. Statistically significant suppression of chemotaxis occurred in the leukocytes of four of 12 specimens from normal donors at concentrations of 1000 ng/ml, and in four of eight specimens at 2000 ng/ml of prolactin in preincubation media. Thus prolactin concentration may influence the motility of leukocytes. The variable neoplastic behavior of morphologically similar pituitary adenomas may, in part, reflect a neurohormonally altered host response to the presence of these lesions.


Empty sella and rhinorrhea. A report of eight treated cases.

The association of an empty sella with rhinorrhea is an unusual finding. Of 29 cases of empty sella observed by the authors, eight underwent surgery for rhinorrhea. None of the patients showed clinical evidence of increased intracranial pressure or hydrocephalus. Seven were cases of primary empty sella, the eighth was an acromegalic patient, who had received radiotherapy 4 years before. Except for this patient, the others showed no clinical signs of a previous tumor. In the surgical treatment of these patients, the authors used both the transfrontal and transsphenoidal approaches. In spite of generally accepted good results following surgical closure of this type of fistula, four patients needed more than one operation. The fistula closed in only three of them; in the last patient rhinorrhea persisted after three operations.


Cerebral hemodynamic changes during plateau waves in brain-tumor patients.

The plateau wave, one of the wave forms observed in patients with increased intracranial pressure, has previously been extensively investigated, but its pathophysiological aspect is as yet unclear. The authors undertook a study of cerebral hemodynamic changes while the plateau waves were observed in five brain-tumor patients. Although the number of cases studied was small, a remarkable decrease in cerebrovascular resistance was seen in all patients during the plateau waves. It is suggested that the plateau waves are caused by a marked cerebral vasodilatation. The present results support the thesis that cerebral blood volume is increased during the plateau waves. The plateau waves are closely related to the intrinsic vasomotor control of cerebral circulation, and can occur as long as cerebral vasodilating ability is maintained, irrespective of the existence of cerebral autoregulation.


Intracranial pressure and conductance to outflow of cerebrospinal fluid in normal-pressure hydrocephalus.

Forty patients with clinical evidence of normal-pressure hydrocephalus were studied by monitoring intraventricular pressure during a 24-hour period, and by a lumboventricular perfusion test for measurement of the conductance to outflow of cerebrospinal fluid (CSF). The purpose of the study was to investigate whether there is a relationship between intraventricular pressure and conductance to outflow of CSF, and whether it is possible to use the results from pressure monitoring in the selection of patients who may be expected to benefit from shunting therapy. The conductance to outflow was used as an evaluation factor in the selection of patients to be treated by a shunt. The conductance to CSF outflow differed by twelvefold between the lowest and highest values. The level of resting intraventricular pressure was within normal limits in all patients. Accordingly, there was no evidence of a relationship between conductance to outflow and intraventricular pressure. So-called B-waves were seen more frequently in patients with decreased conductance to outflow, but were also present in patients with high conductance to outflow. Therefore, the presence of B-waves does not imply a low conductance to outflow of CSF.


Motion of bones and volume changes in the neurocranium after craniectomy in Crouzon's disease. A roentgen stereometric study.

Craniectomy was performed on a boy with Crouzon's disease at 22 months of age. Metallic implants (tantalum balls, 0.5 mm in diameter) were inserted in the calvaria during surgery, and the child was examined postoperatively by roentgen stereometry at intervals of about 100 days (total observation time, 309 days). The thyroid radiation dose was 250 muGy for one examination. The effect of craniectomy was recorded with a high degree of accuracy in terms of motion of bones and volume changes in the calvaria. Expansion occurred almost entirely through motion of free bone flaps in the frontal region, while a linear craniectomy in the region of the sagittal suture caused small changes. The rate of expansion decreased rapidly and stabilization was recorded about 250 days after surgery.


Estrogen-receptor protein in intracranial meningiomas.

The increased frequency of meningiomas in women compared with men, and the rapidly progressive course of these tumors in pregnant patients suggest that hormones may be involved in this disease. Tumor tissue from six patients with meningiomas was analyzed for estrogen-receptor protein. Two patients had tumors with very high concentrations of this protein, approaching that found in hormonally sensitive breast carcinoma. The biochemical and possible clinical significance of these findings is discussed.


Depressed skull fracture in the neonate. Report of three cases.

The authors describe three cases of neonatal depressed skull fracture that were elevated by means of an obstetrical vacuum extractor. In one case, a transparent breast pump shield replaced the metal vacuum extractor cup, permitting direct observation as the depression was elevated. Neonatal depressed skull fractures not associated with neurological signs may be safely elevated without surgery using the obstetrical vacuum extractor.


Dural-cortical anastomosis in pial arteriovenous malformation. Case report.

A patient is reported with a purely pial arteriovenous malformation (AVM) supplied from the posterior parietal artery. The prominent middle meningeal artery contributed to opacification of the angular branches distal to the AVM, but did not contribute to the AVM. After total removal of the AVM, the angular branches became opacified from the middle cerebral artery. Review of the literature suggests that hypertrophied dural arteries which do not contribute to the AVM's but which do opacify the cortical branches distal to the AVM's are rare.


Subdural tension pneumocephalus. Report of two cases.

Two patients developed subdural tension pneumocephalus after undergoing posterior fossa surgery performed in the sitting position. The mechanism for entry of air into the intracranial compartment is analogous to the entry of air into an inverted soda-pop bottle. As the fluid pours out, air bubbles to the top of the container. We have thus referred to this as the "inverted pop-bottle syndrome." Computerized tomography provided prompt diagnosis and confirmed brain displacement. Twist-drill aspiration of the air resulted in improvement in both patients, although one patient subsequently died from an intracerebellar hemorrhage. Tension pneumocephalus appears to be another potential complication of posterior fossa surgery in the sitting position. This condition is easily diagnosed and treated, and should be considered whenever a patient fails to recover as expected following posterior fossa surgery.


A new self-drilling skull traction device with flexion-extension modification. Technical note.

A new tong has been designed that can be attached to the skull using the three-prong principle. It may act as a rigid integral part of the skull, or may simply swivel in the same manner as all contemporary tongs. This ability to function as a rigid attachment allows for flexion or extension of the patient's neck if indicated. The need for incisions or extra drills has been eliminated.


Pulmonary function in children with a history of laryngotracheobronchitis.

Baseline, postexercise, and postisoproterenol lung function was studied in 27 children, 8 to 18 years of age, with a past history of laryngotracheobronchitis (croup) and in ten children without such a history. The LTB subjects were divided into two groups, based on the presence or absence of allergies. Baseline flow tests were similar in all groups but small airway function was mildly abnormal in several members of each group. There was no consistent response to isoproterenol inhalation among those who had had croup and normal subjects. Following exercise, however, a significant (P less than 0.05) number of subjects (14 of 27) in both LTB groups demonstrated bronchoconstriction with a greater than 10% drop in peak expiratory flows. From these studies, it appears that children with a past history of croup have a higher prevalence of increased bronchial reactivity, which occurs irrespective of allergy and baseline lung function abnormalities.


Cell-mediated immune response to respiratory syncytial virus infection: relationship to the development of reactive airway disease.

The possibility that cell-mediated immunity might play a role in the pathogenesis of infection with respiratory syncytial virus was evaluated in a study of 39 infants. Infection with RSV was confirmed by identification of virus in nasopharyngeal secretions using immunofluorescence, and by tissue culture infectivity. CMI, as determined by a whole blood lymphocyte transformation technique, was evaluated in samples taken 0 to 10 and 20 to 60 days after the onset of illness. Patients diagnosed as having RSV-induced bronchiolitis or recurrence of asthma had evidence of significantly (P less than 0.01) higher degree of CMI in the 0 to 10-day period than patients with RSV pneumonia or upper respiratory illness. Higher CMI activity in the 20 to 60-day period was also seen in patients with more severe illness, with moderate-to-severe degree of hypoxia. A positive correlation was observed between the degree of LTF activity in samples taken 20 to 60 days after the onset of illness ard subsequent episodes of wheezing. Eleven patients had one or more episodes of wheezing in the first six months after RSV infection. LTF activity in samples taken during the 20 to 60-day period from these patients was significantly higher (P less than 0.02) than LTF activity in corresponding samples from six patients who were free of wheezing in the six months after RSV infection. The results suggest that alterations of RSV-specific cell-mediated immune mechanisms may result in an increased tendency toward airway reactivity on primary and subsequent exposure to RSV and possibly to other agents.


Allergic bronchopulmonary aspergillosis in pediatric practice.

Twelve cases of allergic bronchopulmonary aspergillosis in the pediatric age group are reported. The average age of diagnosis was 14.5 years with a range from 6 to 18 years. All patients had a history of pulmonary infiltrations or atelectasis or both documented by chest radiographs. Eight patients had bronchograms or tomograms, and seven of them showed proximal bronchiectasis. Total serum IgE concentrations were elevated in all patients. Preciptitating antibodies against Aspergillus fumigatus were positive in all patients at the time of diagnosis, and became negative in some after therapy. The specific IgE or IgG antibody activity agaist Af was elevated in all 12 patients. After prednisone was started the total serum IgE sharply declined to a plateau and remained at this level until a flare of allergic aspergillosis occurred. A flare of allergic aspergillosis is characterized by an increasing total serum IgE concentration followed by pulmonary infiltration. Clinical and roentgenologic improvements were observed after steroid therapy. The importance and methods of early diagnosis in the pediatric population are discussed.


Benign subdural collections of infancy.

During the past two years we studied six infants with subdural collections of fluid. All patients had macrocrania and excessive transillumination of the head. Rapid head growth was common but five patients were otherwise asymptomatic. Subdural taps performed on five children confirmed the presence of abnormal fluid over the cerebral convexities. Subdural fluid in four patients was compatible with effusion and in another with a hematoma. Computerized tomographic evaluation of all infants showed ventricular enlargement, wide cerebral sulci, decreased density in the anterior temporal regions, large sylvian cisterns, prominent interhemispheric fissures, and decreased density over the cerebral convexities. The CT findings resembled cerebral atrophy but psychomotor development and neurologic examinations have been norma.


Uterine malformation and fetal deformation.

Beyond the enhanced miscarriage and prematurity associated with the structurally abnormal uterus, we have found 14 examples of fetal deformation secondary to uterine malformation with its consequent uterine constraint. In several instances the constellation of deformations had been misinterpreted as a multiple malformation disorder. One patient died of pulmonary hypoplasia, but all the survivors showed restoration toward normal form postnatally. Recognition of the basic problem allows for surgical reconstruction of the uterus, which is generally accompanied by an improved outlook for subsequent pregnancies.


An inherited defect of neutrophil mobility in Shwachman syndrome.

Selected immunologic functions were assessed in 14 patients with the Shwachman syndrome. Nine patients were neutropenic and four had low levels of IgA or of IgM. Neutrophil mobility was significantly defective in the group of patients as a whole (in 12 it was below the lower limit of normal) and in their parents. No other consistent abnormality in immunity was found. These results suggest that the defective neutrophil mobility is a feature of Shwachman syndrome which may contribute to the vulnerability of these patients to frequent infections. The defect appears to be a primary genetic one, inherited as an autosomal recessive characteristic consistent with the assumed inheritance of Shwachman syndrome.


Noninvasive assessment of surgical systemic to pulmonary artery shunts by range-gated pulsed Doppler echocardiography.

Suprasternal range-gated pulsed Doppler echocardiography was used to evaluate surgical shunt patency in children with cyanotic congenital heart disease and right ventricular outflow obstruction following systemic artery to pulmonary artery anastomoses. Normal patients had laminar Doppler auditory signals and time interval histogram flow patterns because right pulmonary artery turbulence was not present during systole or diastole. Patients with pulmonary valvar stenosis had turbulence during systole only. In all nine postoperative patients with surgical shunts, turbulent systolic and diastolic time interval histograms and abnormal auditory signals were present. A typical shunt murmur was not audible to auscultation in six of the postsurgical patients at the time of the study. Suprasternal range-gated pulsed Doppler echocardiography affords an accurate, safe and simple noninvasive bedside means for confirming shunt patency in patients who have undergone surgical systemic artery to pulmonary artery anastomoses.


Muscle relaxation in mechanically ventilated infants.

We evaluated the effect of muscle paralysis on gas exchange and incidence of pneumothorax in 35 severely ill infants on mechanical ventilation. Pancuronium (0.1 mg/kg) was given repeatedly until spontaneous respirations ceased in infants with inadequate gas exchange with FIO2 greater than 0.60, or peak inspiratory pressure greater than 30 cm H2O, or who were breathing out of phase with the respirator. Of 27 infants who had an alveolar-arterial oxygen gradient greater than 300 torr before paralysis, AaDO2 improved by greater than 100 torr within one hour of paralysis in only two infants; it worsened in two infants within the same period. By six hours postparalysis, 12 of 27 infants had improved, five of whom had had a worsening AaDO2 before administration of pancuronium. Changes in oxygenation were unrelated to changes in arterial carbon dioxide tension in most infants. Peak transpulmonary pressures after paralysis were lower than during spontaneous breathing, and may explain the low incidence of pneumothorax (3 of 35) during paralysis. Since those who improved could not be distinguished by birth weight, gestational age, or diagnosis, pancuronium might be worthy of trial in a mechanically ventilated infant with severe lung disease who is at risk for pneumothorax.


Effects of maternal isoxsuprine administration on preterm infants.

A retrospective study of all inborn infants at 26 to 35 weeks' gestational age delivered from August, 1976, through July, 1977, was undertaken to determine the effects on the neonate of maternal isoxsuprine therapy for premature labor. Mothers of 43 infants received ISX within 48 hours of delivery and mothers of 107 received no ISX. Hypocalcemia, hypoglycemia, evidence of ileus, hypotension, and neonatal death were all significantly more common in infants whose mothers received ISX. Hypotension and death occurred predominantly in infants of 26 to 31 weeks' gestation and in infants whose mothers developed hypotension or tachycardia during ISX infusion. The frequency of hypotension and death decreased as the time interval from the loading dose of ISX to delivery increased.


Neonatal hypoglycemia after beta-sympathomimetic tocolytic therapy.

The effect of oral beta-sympathomimetic tocolytic therapy on neonatal serum glucose concentrations in the first several hours after delivery was examined in 12 babies. Hypoglycemia was noted in eight babies, and was sustained over at least a 30-minute period in five. The group with sustained hypoglycemia had a higher cord serum insulin concentration, a lower serum glucose nadir, and a more rapid initial rate of serum glucose disappearance than those babies with normoglycemia or transient hypoglycemia. Sustained hypoglycemia was observed in five of six babies delivered within two days of the termination of tocolytic therapy, but was not present in any of six babies delivered five or more days after the end of tocolytic therapy. Speculations as to the interaction between beta-sympathomimetic tocolytic drugs administered to the mother and fetal and neonatal glucose metabolism are made.


Hyperglycemia in stressed small premature neonates.

The metabolic responses to a constant glucose infusion were measured in 30 premature infants, 700 to 1,550 gm. The study included 18 stressed premature infants who needed assisted ventilation, and 12 control premature infants. Metabolic measurements were similar in both groups in the cord and preinfusion samples. In the first postinfusion sample, glucose, cortisol, and glycerol values were higher in stressed than in control premature infants. Hyperglycemia was seen in 13 of stressed and in only one of control premature infants. Stressed infants who became hyperglycemic in the first postinfusion sample were then compared to stressed euglycemic infants. Insulin levels were higher, glycerol levels similar, but cortisol levels lower in stressed hyperglycemic than in stressed euglycemic premature infants. The etiology of hyperglycemia in stressed premature infants cannot be attributed to hypoinsulinemia or to hypercortisolemia, and is not associated with increased glycerol levels. There was no difference in mortality between stressed hyperglycemia and stressed euglycemic infants; stress, rather than hyperglycemia, was related to mortality.


Serum concentrations of 25-hydroxyvitamin D in rickets of extremely premature infants.

Nine premature infants developed radiographic and biochemical rickets at a mean +/- SD of 12.6 +/- 2.8 weeks of age. Serum 25-hydroxyvitamin D concentrations were all low, with a mean of less than 3.6 +/- 2.1 ng/ml. The mean average daily intake of vitamin D since birth had been 300 +/- 181 IU, and the mean average daily intake during the week of diagnosis was 587 +/- 313 IU. All of the infants were extremely premature (mean weight 948 +/- 153 gm, mean gestation 27.7 +/- 1.1 weeks), and were being fed either a low-calcium "human milk-like" formula or a soy formula. It is postulated that low-calcium intake may have increased 25-OHD utilization in the face of a decreased ability of the extremely premature infant to produce 25-OHD. Because of multiple factors leading to both decreased production and possible increased utilization of 25-OHD, such infants have an increased requirement for vitamin D to maintain normal serum 25-OHD concentrations, and daily intakes of at least 400 IU vitamin D orally must be assured. Serum 25-OHD measurements and radiographs may be important in following infants at risk.


Intestinal absorption of bile salts: immature development in the neonate.

The intestinal absorption of sodium taurocholate was studied in fetuses, neonates, infants, children, and adults. Absorption rates were measured in vitro in everted rings of jejunum and ileum. Mucosal accumulation of 3H-taurocholate against a concentration gradient was consistently demonstrated in rings of ileum from adults, children, and infants older than 8 months, whereas fetal and neonatal ileal mucosal concentrations were not significantly above those in the incubation medium after exposure of the mucosa to 0.003, 0.03, and 0.3 mM taurocholate. There were no significant differences in mucosal uptake of taurocholate by perinatal jejunal and ileal rings. Incubations of mucosa from older infants, children, and adults in 0.3 mM taurocholate exhibited saturation phenomena. It is concluded that the ileal mechanism for active transport of taurocholate is undeveloped in the fetus and newborn infant. It is probable that the enterohepatic circulation of bile salt during the perinatal period is limited to that fraction of bile salt absorbed passively. The results suggest that losses of bile salt from the immature intestine may contribute to the steatorrhea and so-called diarrhea of newborn infants.


Reverse tri-iodothyronine to tri-iodothyronine ratio and gestational age.

The biologic significance of reverse tri-iodothyronine is not yet identified. Cord blood values reflect the fetal thyroid state, with rT3 excess and tri-iodothyronine deficiency. In an attempt to correlate thyroid function and gestational age, T3 and rT3 concentrations were measured by radioimmunoassay on 64 cord blood samples. Infant gestational ages ranged from 29 to 42 weeks; birth weights from 650 to 3,870 gm. The results show a significant positive correlation between gestational age and T3 and a significant negative correlation between gestational age and rT3. The rT3/T3 offers the best correlation.


Pharmacology and use of muscle relaxants in infants and children.

Succinylcholine is a short-acting depolarizing neuromuscular blocker used to facilitate intubation; pancuronium is a longer-acting, nondepolarizing agent commonly employed to control ventilation in pediatric patients. The neuromuscular block produced by both drugs may be modified by patient age, acid-base and electrolyte status, body temperature, and drugs such as aminoglycoside antibiotics; adjustment in dose or in technique of administration may be required. Cardiovascular side-effects, primarily arrhythmias, are occasionally associated with the use of either agent. In contrast to that of succinylcholine, the paralysis from pancuronium is pharmacologically reversible with the combination of atropine and neostigmine.


The effect of cimetidine on maldigestion in cystic fibrosis.

Ten patients (6 to 27 years of age) who had severe pancreatic exocrine insufficiency due to cystic fibrosis were studied to determine whether cimetidine would improve dietary fat and nitrogen absorption. When a constant diet was consumed and oral pancreatic enzymes were administered, the addition of cimetidine (150 or 200 mg taken orally one-half hour before meals) signficantly reduced fecal fat excretion from 25.3 +/- 2.9 to 17.3 +/- 2.1 gm/24 hours and fecal nitrogen excretion from 4.5 +/- 0.6 to 3.4 +/- 0.5 gm/24 hours (P less than 0.05). Lower doses of cimetidine resulted in less significant reductions of steatorrhea and azotorrhea. Cimetidine may be a useful adjunct to oral pancreatic enzyme therapy in patients with cystic fibrosis who continue to have steatorrhea and azotorrhea with enzyme therapy alone.


Abnormal choledocho-pancreatico ductal junction related to the etiology of infantile obstructive jaundice diseases.

According to our current radiologic, histopathologic, and experimental studies, the congenital stenosis associated with anomalous choledocho-pancreatico ductal junction is considered to be the most important etiologic factor in congenital biliary dilatation. Furthermore, the possibility of pancreatic juice reflux into the biliary tract due to the abnormal choledocho-pancreatico ductal junction, which could lead to obstructive cholangiopathy, was suggested in relation to the pathogenesis of congenital biliary atresia.


Distal spleno-renal shunt for portal decompression in childhood.

Successful portal decompression presents a unique challenge in children. The meso-caval shunt, utilizing the large caliber iliac vein in constructing the anastomosis, has been accepted as the standard operative procedure for treating these patients. Technical and anatomic difficulties, however, often prevent the successful performance of this shunt. The proximal spleno-renal shunt, advocated by many as an alternative in children, incurs the penalty of splenectomy. Furthermore, in both techniques, portal venous blood is preferentially shunted from the liver, posing a potential for subsequent development of hepatic encephalopathy as the patients mature. The distal spleno-renal shunt avoids these problems by selectively decompressing the esophageal venous plexus through the spleen. With this procedure, the majority of portal venous blood flow is maintained and the spleen is preserved. The present report describes three children in whom the distal spleno-renal shunt has been successfully employed for portal decompression. The youngest of these patients was 2 1/2 yr of age at the time of operation and has a patent portal-systemic shunt 18 mo postoperatively. This experience confirms the effectiveness of the distal spleno-renal shunt as an alternative to the meso-caval shunt, especially in children with inflammatory involvement of the superior mesenteric vein.


Recent experience in the treatment of rhabdomyosarcoma.

Twenty-two patients with rhabdomyosarcoma have presented in the years 1970--1977. Of 8 patients who had inadequate postoperative chemotherapy and radiotherapy, or none at all, only 2 patients with small completely resectable tumors are alive and well at 6 and 4 yr after surgery. Fourteen patients had intensive combination chemotherapy in addition to appropriate surgery and radiotherapy. Five have died and the remaining nine are well and free of disease at follow up ranging from 9 mo to over 5 yr. A continued place in the treatment regime is advocated for early surgery aimed at total excision of the primary tumor where this is feasible.


Chest trauma in children.

A series of 94 children with chest trauma is reviewed. Mortality is related to age and the number of major systems involved. Closed chest injuries were preponderent and were most often caused by road traffic accidents that accounted for all fatalities. The most frequent injury was pulmonary contusion. Fractures of ribs in children are more common than is generally supposed.


Pulmonary burns in children.

Basic concepts have evolved from a 15-yr experience in the management of 101 children with inhalation injuries. Progression through three distinct clinical stages--bronchospasm (1--12 hr post-burn), pulmonary edema (6--72 hr), and bronchopneumonia (after 60 hr)--was often noted. Success in outcome appeared to depend upon treatment that conformed to the pathophysiologic state present, a pulmonary toilet being both thorough and aseptic, tracheotomy being reserved for true glottic or supraglottic airway obstructions, the sharp division of strangulating or suffocating constrictions caused by cervical or thoracic eschars, use of ventilators primarily to maintain arterial pO2 above 60 mm Hg and to reverse otherwise intractable pulmonary edema, corticosteroids being administered as a single intravenous bolus and only for overt bronchospasm, and parenteral antibiotic therapy being based upon sputum smears and cultures for established pneumonia alone, never as prophylaxis.


Incidence and significance of gastroesophageal reflux following repair of esophageal atresia and tracheoesophageal fistula and the need for anti-reflux procedures.

Patients with esophageal atresia and/or tracheoesophageal fistula are known to have disordered esophageal motility, but the incidence of significant gastroesophageal reflux requiring anti-reflux surgery remains undocumented. We have studied a series of patients from 2 wk to 13 yr post-repair, utilizing manometric motility and acid reflux techniques. All demonstrated abnormalities of esophageal motility, including aperistalsis, low amplitude contraction, and simultaneous contractions. Lower esophageal sphincter pressures ranged from 7 to 50 mm Hg. Fourteen patients demonstrated signifcant reflux and six patients required anti-reflux surgery for recurrent pneumonia or recurrent stricture. The incidence of significant gastroesophageal reflux requiring antireflux surgery appears significant following repair of esophageal atresia and/or tracheoesophageal fistula.


Pulmonary arteriovenous malformations in children.

Pulmonary arteriovenous malformations are a life-threatening, but curable, cause of persistent cyanosis in children. Abnormal communications may be single or multiple and are usually in the lower lobes. Three patients with pulmonary arteriovenous malformations have recently been managed at this hospital. Ranging in age from 2 to 4 yr, all were female, all were from families with Rendu-Osler-Weber syndrome, and all underwent pulmonary angiography with confirmation of diagnosis. All have had uneventful resection, one of the left lower lobe, one the right upper lobe, and the other the right middle and lower lobes.


Anterior resection combined with anorectal myectomy in the treatment of Hirschsprung's disease.

During the period October 1974 to November 1977, six children with Hirschsprung's disease have undergone anorectal myectomy followed by anterior resection. The procedure was carried out in a group of older children who presented late, where the aganglionic segment was thought to be confined to the rectum alone. In these cases, when the initial myectomy specimen revealed total aganglionosis and serial biopsies revealed that the aganglionic segment extended beyond the reach of myectomy, it was decided to carry out anterior resection. The rationale, methods, and results are discussed. It is suggested that this type of procedure is most suitable to those older patients who are diagnosed late, with disease located in the rectum.


The injection treatment of rectal prolapse.

The injection of 5% phenol in oil into the rectal submucosa cured persistent rectal prolapse in 91 of 100 young children. This result supports the view that the common form of rectal prolapse in otherwise-healthy children primarily involves the mucosa and the muscular wall is only secondarily involved.


The management of a fistula between the rectum and the lower urinary tract.

Ten boys with a fistula between the rectum and the urinary tract are presented. Six resulted from complications of imperforate anus surgery, three were various congenital abnormalities, and one was associated with an inflammatory pelvic mass. The management of these patients is described and the problems are discussed.


Ureterosigmoidostomy in childhood: the quality of life.

Thirty-one patients in whom ureterosigmoidostomy had been performed between 1952 and 1974 for a variety of conditions are presented. Twelve patients, or 39%, were subsequently rediverted, mainly for upper tract deterioration. Nineteen patients retaining their ureterosigmoidostomy were evaluated after 3 to 22 yr. Growth was normal in all. Twelve patients required regular alkali and three intermittant antibiotics. In 14 patients, the I.V.U. remained perfect. Each patient was interviewed. Voiding was on average three hourly. Some urgency was common, but soiling was rare. Sleep was disturbed in nearly half the patients but this was usually around dawn. Lessons were rarely interrupted and nearly all took part in sports. The large majority felt no different from their peers. In spite of close initial supervision and significant rediversion rate, ureterosigmoidostomy can provide a very acceptable form of urinary diversion in children.


A case of fibrous hamartoma of infancy.

An instance of fibrous hamartoma of infancy (FHI) in the perianal region of an 8-mo-old infant, a hitherto unreported location, is described. The majority of the reported cases occur in the torso and upper extremities. The differential diagnostic features which aid differentiating FHI from other conditions is discussed. Although the tumor may recur after excision, a conservative surgical management appears adequate since all reported cases ultimately have proven to have an excellent prognosis.


Gastric duplication.

Vomiting and failure to thrive were the presenting complaints of a patient with gastric duplication. The case is presented and features of gastric duplication are summarized with other cases reported in the literature.


Retroperitoneal lipoma in children.

A case of retroperitoneal lipoma in a 23-mo old girl is reported together with a brief review of the 11 previously documented cases. It has been encountered through age 8 yr and twice as frequently in girls. The majority had an enlarged abdomen of long duration. The others were asymptomatic and found incidentally or at the time of examination for abdominal pain. Most lipomata were large. The possibility of their being congenital cannot be excluded. None have recurred.


Congenital biliary tract dilatation and anomalous junction of the pancreatico-biliary ductal system.

Anomalous junction of the pancreaticobiliary ductal system (AJPBDS) was found not only in 6 of 28 children with congenital dilatation of the bile duct, but in 3 of 57 children with congenital biliary atresia, in 2 of 17 children with infantile hepatitis and in one child with chronic pancreatitis during the past 17 yr at the Kagoshima University Hospital. A new technique of selective choledochopancreatography has been developed in which the mid-choledochus is clamped and dye is selectively injected into the distal choledochus to demonstrate the pathology of the bile duct. This technique has been successful even in small children when other cholangiographic techniques have failed to show AJPBDS. AJPBDS can be divided into two main types: (1) with biliary tract dilatation and (2) without biliary tract dilatation. The preferred treatment for type 1 is considered to be Roux-en-Y limb hepaticojejunostomy with primary excision of the choledochal cyst in order to prevent reflux of pancreatic juice flow into the choledochus, postoperative gall stone formation, or cancer from arising in the remaining choledochal cyst. Hepatic portocholecystostomy for biliary atresia with patency between gall bladder and papilla duodeni associated with AJPBDS can not be recommended since it may cause dilatation or obstruction of the bile duct postoperatively. Further studies concerning the etiology or therapy for AJPBDS are necessary.


Lingual rhabdomyoma (adult variant) in a child.

A case of rhabdomyoma of the adult variant arising in the tongue of an 11-yr-old male is presented. Fifteen previously reported cases were reviewed and compared to our case. This patient is believed to be the only child with this lesion.


Intensive care for sick neonates, the earlier the better: improved survival rate of IRDS children, referred by means of a mobile neonatal intensive care unit.

A mobile intensive care unit has been used since september 1976 in the region referring sick neonates to the two University Hospital NICU's of Amsterdam. The present study compares two groups of neonates (suffering from the I.R.D.S.) i.e. a group that had been referred by non specialized transport teams (N S T-group) and a group admitted after institution of the neonatal-transport service (S. T.-group). Significant difference is found in the temperature on admission (S T group greater than N S T group). In the N S T-and the S T-group the need for ventilatory assistance was not significantly different but in the S T-group it was started significantly earlier. Survival after institution of ventilatory assistance and overall-survival are significantly better in the S T-group. These conclusions point to the fact that administering intensive care to sick neonates as early as possible and transportation of this group by means of special "neonatal"-transport services increases their survival rates.


Kinetics of absorption and elimination of pralidoxime chloride in dogs.

The kinetics of the absorption and elimination of pralidoxime chloride were investigated in the dog. Similar apparent elimination rate constants were obtained after intravenous, intramuscular, and oral administration. Although oral absorption occurred slowly, intramuscular absorption proceeded rapidly. With in situ techniques, it was found that no absorption occurred from the isolated stomach and duodenum but that absorption did take place from the jejunum and ileum.


Metabolism, plasma or serum levels, and elimination of phenformin in guinea pigs, rats, and dogs.

14C-Phenformin hydrochloride was used for investigating the metabolism, plasma or serum levels, and elimination of the drug following 1.5-mg/kg po or iv doses to guinea pigs, rats, and dogs. The amounts of individual metabolites and unchanged drug were assessed in urine as well as in plasma or serum. The glucuronide of 1-(p-hydroxyphenethyl)biguanide was a major metabolite in the blood and urine of all three species. Guinea pig serum and urine contained a sizable quantity of unchanged drug. Dog plasma and urine had significant amounts of nonconjugated 1-(p-hydroxyphenethyl)biguanide and of an unidentified major metabolite. In all three species following intravenous drug administration, unchanged drug contributed significantly to the radioactivity found in blood and urine. The apparent half-lives of phenformin eliminateion were 0.3-0.8 day for guinea pigs and rats and 1-1.5 days for dogs. Urinary excretion data indicate apparent half-lives of approximately 1.3-1.5 days for the elimination of each of the three major metabolites in dogs.


Plasma levels following single and repeated doses of erythromycin estolate and erythromycin stearate.

The pharmacokinetics of erythromycin and erythromycin 2'-propanoate were studied in healthy male volunteers following single and repeated doses of erythromycin stearate tablets, erythromycin estolate capsules, and a suspension. Estolate dosages gave rise to higher plasma levels of total drug than the stearate. However, the stearate yielded higher plasma levels of erythromycin base. Absorption of all dosage forms, except the suspension, was delayed, and pharmacokinetic interpretation of both single- and multiple-dose data required incorporation of an absorption lag time. The absorption of erythromycin stearate was inhibited by food and also by low fluid volumes in fasted subjects. Absorption of erythromycin estolate was increased in the presence of food and was not greatly affected by fluid volume. Although single-dose data poorly predicted circulating levels of erythromycin following repeated doses, trends observed after single doses were maintained during chronic treatment.


Fluorocarbon aerosol propellants XII: Correlation of blood level of trichloromonofluoromethane to cardiovascular and respiratory responses in anesthetized dogs.

Anesthetized mongrel dogs were exposed to various concentrations of trichloromonofluoromethane. Before, during, and after the inhalation, arterial and venous blood samples were obtained for fluorocarbon analysis. After the cessation of fluorocarbon inhalation, a multiexponential decline for the blood was observed. This finding was similar to that of previous study in which the fluorocarbon was administered intravenously to unanesthetized dogs. The half-life calculated from the terminal phase was about 280 min, and the pseudodistribution equilibrium was reached about 100 min after dosing. Study of the relationship between blood fluorocarbon levels and effects on the respiration rate and arterial blood pressure indicates that the sites of these pharmacological activities are located in the blood or central compartment rather than in the peripheral compartment. The effect on the heart rate appears to be quite instantaneous after inhalation. These results might shed some light on the fast effect of the fluorocarbon propellants, which caused sudden deaths after inhalation of a large quantity.


Solution rate of crystals at fluid-fluid interface.

A model system was developed in which the dissolution behavior of a single crystal of potassium ferricyanide was studied at a liquid paraffin-water interface. Since the equilibrium position of a crystal at the interface is independent of its size, the lifetime of a crystal dissolving at the interface is determined entirely by its initial size and its dissolution rate in the water phase. The dimensions of every crystal were measured microscopically before dissolution. A continuous-flow recording dissolution apparatus was used to measure spectrophotometrically the mass flow of dissolved potassium ferricyanide. The dissolution cell in this system was mounted in an optical bench, making it possible to follow dissolving crystals visually by projecting them on a screen. The results show that the lifetime of a crystal is proportional to the shortest length of the crystal face in contact with the liquid paraffin and is rather independent of its form. Furthermore, crystal shape changes during dissolution, which is explained partly by the nonisometric dissolution of potassium ferricyanide crystal faces and partly by the nonconstancy of film thickness.


Flupenthixol dihydrochloride decomposition in aqueous solution.

Flupenthixol dihydrochloride in aqueous solution oxidized to trifluoromethylthioxanthone, ethanol, and piperazine via aldehydic and epoxidic intermediates in the presence of air. The formation rate of trifluoromethylthioxanthone increased with increases in pH and oxygen concentration. Buffer ions also affected the decomposition rate. Micelle formation by the drug markedly influenced its oxidation rate.


High-performance liquid chromatographic analysis of cyclophosphamide.

A reversed-phase high-performance liquid chromatographic technique is described for the analysis of cyclophosphamide in the presence of its hydrolysis products. The drug was quantified using a UV detector at a low wavelength. A single band was observed for the intact drug, which was well separated from tis hydrolysis product(s). Quantificaiton was obtained with adequate precision by the use of an injector loop or a suitable internal standard (hydrocortisone). The technique requires no extraction of the drug from aqueous solution or derivatization for analysis. The method was applied to partially hydrolyzed and to known solutions of cyclophosphamide. With suitable modification, the method may be useful for analysis of dosage forms but probably lacks the sensitivity necessary for analysis of the drug in biological samples.


Thermodynamic relationship between alpha- and beta-forms of crystalline progesterone.

Thermodynamic properties such as the latent heat of fusion, aqueous solubility, heat of solution, and interchange energy with water were determined for single crystals of progesterone in alpha- and beta-forms. The differences in the properties between the polymorphic crystals arise from a dissimilar mode of molecular packing, rather than of molecular conformation, in the unit cells, as reflected in the IR spectral and X-ray crystallographic results..


New in vitro dissolution test apparatus.

A new in vitro dissolution test apparatus was designed and evaluated. Compressed tablets of drugs representing different solubility characteristics were tested at various air pressures and compared to dissolution patterns of similar tablets by the Levy beaker and USP methods. Air pressure of 46 mm generally was suitable for determining the dissolution rates of tablets. This new dissolution tester possibly can be useful in determining drug release from solid dosage forms and correlating it with in vivo bioavailability because dissolution rate can be controlled easily with the adjustment of air pressure without complicated changes in the apparatus, there is no excessive settling of particles, and complete drug dissolution can be achieved with no clogging of the screen.


Synthesis and antimicrobial activity of 3H-1,2,4-thiadiazolo fused heterocycles.

Various fused 3H-1,2,4-thiadiazoles were prepared. Significant in vitro Gram-positive antibacterial and antifungal activities were observed fro certain members of the series.


Potential CNS antitumor agents VI: aziridinylbenzoquinones III.

Thirty-one aziridinylbenzoquinones were compared against five murine tumor models in vivo. Two intracerebral (ependymoblastoma and L-1210 leukemia) and three intraperitoneal (P-388 and L-1210 leukemia and B16 melanoma) systems were utilized. Excellent activity was observed for many compounds. Multiple long-term survivors were produced in the ependymoblastoma, P-388, and intraperitoneal L-1210 systems. Diethyl 2,5-bis(1-aziridinyl)-3,6-dioxo-1,4-cyclohexadiene-1,4-dicarbamate demonstrated superior activity in all five test systems. This compound also was reproducibly active against two colon tumors, a mammary tumor, and the intracerebrally implanted P-388 leukemia model.


Synthesis and therapeutic testing of mono- and dialkyl esters of pentetic (diethylenetriaminepentaacetic) acid for decorporation of polymeric plutonium.

The synthesis, characterization, and therapeutic evaluation of a series of partially esterified derivatives of pentetic (diethylenetriaminepentaacetic) acid are reported. These compounds were prepared in an attempt to promote increased decorporation of insoluble colloidal forms of plutonium, which are removed by pentetic acid alone. The dimethyl, diethyl, dibutyl, dioctyl, monoethyl esters were synthesized by reaction of the appropriate alcohol with the dianhydride of pentetic acid. These esters were injected intravenously into mice as their calcium chelates in saline. None of the esters was effective in removing plutonium from the liver. All esters removed approximately 20% of the plutonium in the skeleton. However, when the esters were given together with pentetic acid, only the dioctyl ester showed enhanced removal of plutonium compared to pentetic acid alone. The small increase in effectiveness and the increased acute toxicity make these esters of limited practical interest in plutonium decorporation therapy.


Metal-binding abilities of radioprotective aminoalkyl disulfides and thiosulfates.

Mental-binding stability constants for several heterocyclic aminoalkyl disulfides and thiosulfates with Ni(II) and Al(III) were determined. The data obtained indicated that both classes of compounds were acting as bidentate chelating agents and that the heterocyclic rings apparently prevented tridentate behavior of the disulfides because of steric hindrance. The magnitude of the constants indicated that metal complexes of these compounds could exist in a cellular environment, but no correlation with radiation-protective activity was apparent.


Effect of microcrystalline cellulose on liquid penetration in and disintegration of directly compressed tablets.

The penetration of isooctane and water into tablets of microcrystalline cellulose, dibasic calcium phosphate dihydrate, spray-crystallized maltose-dextrose, and blends of microcrystalline cellulose with one of the other excipients were studied. The isooctane penetrations occurred according to the Washburn equation and were not affected by the presence of 0.5 or 1.0% magnesium stearate. The inhibition of aqueous penetration into tablets resulting from hydrophobic magnesium stearate was less pronounced for vehicles like dibasic calcium phosphate, which exhibited extensive brittle fracture under compression. Microcrystalline cellulose tablets, both with and without magnesium stearate, exhibited extremely fast aqueous penetration even at low porosities, caused by breaking of the hydrogen bonds and subsequent widening of the pores. Ratios between water uptake and original pore volume up to 20 were obtained for microcrystalline cellulose tablets. This unique property was, however, suppressed by the presence of fast dissolving and highly soluble excipients like dextrose, resulting in an antagonistic disintegration behavior of tablets compressed at pressures over 10,000 N/cm2. Improved disintegration properties were obtained by blending microcrystalline cellulose with an insoluble vehicle such as dibasic calcium phosphate dihydrate.


Preparation and evaluation of microencapsulated ion-exchange resin beads.

Ion-exchange resin beads in the benzoate form were coated by several microencapsulation techniques to alter and improve characteristics, especially the control of drug release, of this type of drug delivery system. The most successful techniques included polymer-polymer interaction, temperature change, and nonsolvent addition. The microencapsulated beads then were studied with respect to the release rate of the organic anion to determine the effects of microencapsulation. The release rate of the organic anion could be controlled over a wide range, depending on the encapsulating material characteristics. Factors affecting the extent and rate of release as result of microencapsulation are discussed.


GLC analysis of loxapine, amoxapine, and their metabolites in serum and urine.

A GLC analysis is presented for loxapine, amoxapine, and their major metabolites in serum and urine. Electron-capture detection is employed for serum analysis, and flame ionization is used for urine analysis. The procedure includes trifluoroacetylation of secondary amine functions, followed by trimethylsilylation of phenolic groups after ethyl acetate extraction of the sample. Urine requires prior enzymatic hydrolysis of conjugates. Data indicating the utility of the procedure in hospitalized patients and normal volunteers are presented.


Determination of guanfacine in biological fluids by electron-capture GLC.

A quantitative electron-capture GLC method with good sensitivity is described for the determination of guanfacine in human plasma and urine. By condensing its amidino group with hexafluoroacetylacetone, guanfacine is converted to a pyrimidino derivative with better GLC properties than the parent drug. This method allows the determination of guanfacine in plasma and urine at concentrations as low as 0.5 ng/ml and was applied successfully to measurement of plasma levels in humans after therapeutic dosing.


Electrical conductance of directly compressible materials under pressure.

An electrometer that allowed direct recording of resistance changes during compression was used to measure the conductances of sodium chloride, potassium chloride, ammonium chloride, and sodium citrate. The effects of initial particle size, lubricant level, moisture content, and compaction pressure were determined. Direct compression tableting diluents also studied were dextrose, sucrose, lactose, microcrystalline cellulose, and dibasic calcium phosphate. Distinctive conductance patterns were observed and are rationalized in terms of previously proposed bondign machanisms.


Effect of hydroxyl group substituents on pyran ring on hydrolysis rate of benzoates: 2-tetrahydropyranyl benzoate.

The hydrolysis of 2-tetrahydropyranyl benzoate was followed spectrophotometrically at 240 nm and was first order with respect to the compound, independent of pH, and very sensitivie to solvent polarity and had an isotope effect (kD2O/kH2O) near unity. The pH-independent hydrolysis rate was about 1 X 10(6) times faster than that of the corresponding glucosly benzoate. The results suggest that the presence of hydroxyl groups on the pyran ring has tremendous effect on the hydrolysis rate of these compounds.


Quantitation of sodium in human albumin solutions.

An osmolatity method is described for quantitating sodium in isotonic solutions of diafiltered albumin and diafiltered plasma protein fractions. The proposed method shows comparable results with a reference procedure bases on atomic absorption spectrometry.


Quantitative determination of hexylresorcinol in commercial antiseptic solution by high-pressure liquid chromatography.

High-pressure liquid chromatography was used with a 5-micron silica gel column to quantitate hexylresorcinol in a commercial antiseptic solution following extraction with methylene chloride. This method shows linearity to at least 0.025% hexylresorcinol. A mobile phase consisting of 63% heptane, 34% chloroform, and 5% methanol was used with a UV detector (254 nm) and a flow of 3 ml/min. No interfering substances were observed.


Potential antineoplastics I: substituted 3,5-dioxo-and 3-thioxo-5-oxo-2,3,4,5-tetrahydro-1,2,4-triazines.

The synthesis of some 6-substituted 3,5-dioxo- and 3-thioxo-5-oxo-2,3,4,5-tetrahydro-1,2,4-triazines for possible antineoplastic activity is reported. The assigned structures were substantiated by IR, NMR, and mass spectral studies of representative members of the series. Four compounds were tested against P-388 lymphocytic leukemia and were inactive.


Antihypercholesterolemic studies with sterols: beta-sitosterol and stigmasterol.

Stigmasterol, which differs from beta-sitosterol by unsaturation at C22, was tested for antihypercholesterolemic activity under an experimental protocol that gave the results expected with beta-sitosterol and cholestyramine. In terms of serum cholesterol, stigmasterol had a barely significant antihypercholesterolemic effect while exhibiting no obvious effect on the heart or liver. It was concluded that saturation of the side chain, at least at C22, is important in conferring antihypercholesterolemic activity on a sterol.


Chemical constituents of Echites hirsuta (Apocynaceae).

A phytochemical investigation of an ethanolic extract of the whole plant of Echites hirsuta (Apocynaceae) resulted in the isolation and identification of the flavonoids naringenin, aromadendrin (dihydrokaempferol), and kaempferol; the coumarin fraxetin; the triterpene ursolic acid; and the sterol glycoside sitosteryl glucoside.


Fluorescamine use in high-performance liquid chromatographic determination of aminocaproic acid in serum.

A sensitive and specific high-performance liquid chromatographic determination of aminocaproic acid in serum is described. omega-Aminocaprylic acid is used as an internal standard. To 10 microliter of serum, 10 microliter of the internal standard solution and 50 microliter of ethanol are added. After centrifugation, a portion of the supernate is evaporated. The residue is dissolved in 750 microliter of 50 mM dibasic sodium phosphate, and then 250 microliter of fluorescamine in acetonitrile (35 mg/100 ml) is added. The reaction mixture is chromatographed using a column of octadecylsilane bonded to silica and 44% acetonitrile in 0.5 mM phosphoric acid as the eluent. Quantitation is achieved by monitoring either the absorbance of the effluent at 405 nm or the fluorescence of the compounds with a fluorometer equipped with a flowcell. The method is reproducible, simple, and fast and has a precision of 4.4%.


Theophylline protein binding in humans.

Theophylline protein binding was 58-82% in serum from six normal adults and 42 asthmatic patients, 1-25 years old, who were given 5 mg of theophylline/kg. The binding range was greatest in young patients, but the proportion of protein-bound drug did not correlate with age. Theophylline protein binding was higher than previously reported. The effect of binding should be considered in patients who do not have optimal bronchodilation from theophylline despite total serum theophylline concentrations of 10-20 microgram/ml.


Liquid chromatography in pharmaceutical analysis X: Determination of chlorzoxazone and hydroxy metabolite in plasma.

A method for the high-pressure liquid chromatographic determination of chlorzoxazone and its hydroxy metabolite in human plasma samples is presented. The separation of the compounds is achieved on an octadecylsilane column with a mobile phase of absolute methanol-distilled water (40:60) at a flow rate of 2.0 ml/min (3100 psig). The chromatographic separation is achieved within 10 min. The overall analysis time is about 45 min, which includes extraction of the drug and metabolite from plasma followed by high-pressure liquid chromatographic separation and quantification. The accuracy of the procedure is in the 1-5% range.


Antimicrobial activity of chlormerodrin.

A radiochemical study for antimicrobial activity of chlormerodrin was performed using some commonly occurring nonpathogenic and pathogenic microorganisms. Chlormerodrin concentrations of 15-35 and 20-45 microgram/ml of the culture medium were microbiostatic and microbicidal, respectively. The microbiostatic effect was reversible in the presence of cysteine, an amino acid containing a sulfhydryl group.


Effect of obtrusive measures on antibiotic compliance.

The influence of compliance measurement activities on patient behavior was studied. The project measured the relationship among physical capsule counts, patient interviews, and the amounts of excreted ampicillin. The capsule counts and patient interviews were conducted in a manner that disguised their intent. Sixty college-age patients were assigned to one of three experimental groups: a telephone interview, a personal interview and capsule count, or a control group. Stimulation (interviews) occurred on the 2nd day of the prescribed regimen, and urine was collected on random days thereafter. Results indicated that both stimulation types were associated with more positive compliance rates. The influence diminished rapidly. The reactive influence of experimentor intervention associated with personal and phone communication was demonstrated.


Effects of polyoxypropylene 15 stearyl ether and propylene glycol on percutaneous penetration rate of diflorasone diacetate.

Theoretical models for percutaneous penetration are described, and a diffusion apparatus useful in the evaluation of transport kinetics of drugs applied to skin is discussed. Experimental data are presented for: (a) the flux of diflorasone diacetate through hairless mouse skin, (b) the percutaneous penetration profile of propylene glycol, (c) the effects of vehicle concentrations of polyoxypropylene 15 stearyl ether and propylene glycol on the percutaneous flux of diflorasone diacetate, (d) skin--vehicle partition coefficients of diflorasone diacetate, (e) the solubility profile of diflorasone diacetate as a function of solvent concentration, and (f) the alteration of the skin's resistance to the penetration of diflorasone diacetate due to propylene glycol. Excess solvent in a vehicle caused a decrease in the percutaneous flux of diflorasone diacetate. Formulations containing 0.05 and 0.1% diflorasone diacetate had similar penetration rates when the solvent concentration was optimized for each percentage of diflorasone diacetate.


High-pressure liquid chromatographic assay of benzoyl peroxide in dermatological gels and lotions.

A high-pressure liquid chromatographic method for the assay of benzoyl peroxide in dermatological preparations is described. Degradation products such as benzoic acid and perbenzoic acid do not interfere. The method is simple, precise, accurate, and stability indicating.


Identification and synthesis of a methylated catechol metabolite of glutethimide isolated from biological fluids of overdose victims.

Urine samples from victims severely intoxicated by glutethimide were hydrolyzed enzymatically. TLC, GLC, and mass spectral analyses revealed a methylated catechol metabolite of the parent drug. Two synthetic pathways are described for the preparation of 2-ethyl-2-(3-methoxy-4-hydroxyphenyl)glutarimide and 2-ethyl-2-(3-hydroxy-4-methoxyphenyl)glutarimde. Comparisons of GLC and mass spectral data to a compound isolated from the body fluids of glutethimide overdose victims conclusively identified a new 3-methoxy-4-hydroxyphenyl metabolite of glutethimide in humans.


Beneficial effects of methionine and histidine in aspirin solutions on gastric mucosal damage in rats.

Amino acids methionine and histidine, which are soluble in propylene glycol, were investigated for their purported beneficial effects on aspirin-induced gastric mucosal damage in the rat. The pathognomonic changes observed microscopically in the fundic region of the stomach of animals administered daily doses (100 mg/kg), for up to 15 days, of aspirin solutions (0.36 M) in propylene glycol incorporated with the amino acids were compared with those of animals given equivalent quantities of aspirin in an aqueous suspension combined with an aluminum hydroxide antacid. A "delayed" onset of aspirin-induced cellular damage due to the presence of amino acids, analogous to that associated with the use of antacids, was found as determined partly by differences in the staining ability of injured cells with hematoxylin and eosin.


Kinetics and mechanism of reaction of m-nitrobenzhydrazide and other hydrazines with acetic acid.

A comprehensive kinetic study was conducted of the reactions of m-nitrobenzhydrazide and some other hydrazines with acetic acid. The overall reaction rate for all of the compounds studied followed pseudo-first-order kinetics. The temperature dependence of the m-nitrobenzhydrazide degradation reaction was determined. The reaction rate dependence on the acetic acid concentration was found to be close to first order. High-pressure liquid chromatography was used extensively in identifying and measuring the appearance or disappearance rates of m-nitrobenzhydrazide degradation products in acetous solution. With m-nitrobenzhydrazide, the major degradation products were N,N'-bis(m-nitrobenzoyl)hydrazine, N-acetyl-N'-m-nitrobenzoylhydrazine, diacetylhydrazine, and hydrazine. The concentration profiles of these products in solution suggested a complex mechanism by which hydrazides react with acetic acid. All eight rate constants at 61 degrees in the suggested mechanism were calculated by an approximation method based on experimental data. The findings in the present study indicate that acetic acid is to be avoided as a solvent for hydrazine derivatives.


Separation and quantitation of esterified estrogens in bulk mixtures and combination drug preparations using high-performance liquid chromatography.

A high-performance liquid chromatographic method for esterified estrogens is described. By using a facile acid hydrolysis extraction procedure for the sample preparation, the compounds are chromatographed as their free phenolic forms. The separation of structurally similar compounds, such as equilenin, equilin, estrone, and estradiol, was achieved with a reversed-phase column and a methanol--water mobile phase. Several samples of bulk mixtures and tablets were assayed; the results compared favorably with those obtained using the USP XIX method. The method was rapid, and the detector response was linear over a wide concentration range. A relative standard deviation of +/- 5% indicates the reliability and accuracy of the proposed method.


Synthesis of substituted 2-aminopyrrole analogs of lidocaine I.

The synthesis, local anesthetic, and antiarrhythmic properties of nine 2-diethylaminoacetamido-3-cyano-4-methyl-5-substituted pyrroles are described. All compounds showed local anesthetic activity by the guinea pig wheal test and antiarrhythmic activity for chloroform-induced ventricular arrhythmias in mice.


Indolizine derivatives with biological activity IV: 3-(2-Aminoethyl)-2-methylindolizine, 3-(2-aminoethyl)-2-methyl-5,6,7,8-tetrahydroindolizine, and their N-alkyl derivatives.

In a continuing search for new biologically active agents derived from indolizine, 3-(2-aminoethyl)-2-methylindolizine, 3-(2-aminoethyl)-2-methyl-5,6,7,8-tetrahydroindolizine, and some mono- and di-N-substituted derivatives were prepared. Initial pharmacological screening showed that these compounds possess anti-5-hydroxytryptamine, antihistamine, antiacetylcholine, and CNS-depressant activities.


Structure--activity studies on tetrahydro- and hexahydrocannabinol derivatives.

A series of tetrahydro- and hexahydrocannabinol derivatives was prepared in which the substituents at position 9 were varied. These compounds were evaluated in mice for their effects on locomotor acitivty, body temperature, muscle tone, and analgesia. Depression of body temperature and locomotor function was demonstrated by several compounds, but all were devoid of any significant analgesic activity.


Synthesis of 4-substituted aminobenzoate quaternary salts as potent antispasmodic agents.

N-(Diethylaminoethyl)-4-substituted aminobenzoate quaternary salts, N-(diethylaminoethyl)-4-substituted aminobenzamide quaternary salts, 4-substituted acylaminobenzamide quaternary salts, and 4-substituted acylaminosalicylamide derivatives were prepared and tested for antispasmodic activity. Preliminary pharmacological tests on isolated guinea pig ileum revealed that the new compounds possess nonspecific inhibitory action on smooth muscles.


6-substituted 1-methylquinolinium-2-dithioacetic acid zwitterions: antileukemia activity.

Condensation of the anhydro bases derived from 6-substituted 1-methylquinaldinium iodides with carbon disulfide provided the 2-dithioacetic acid zwitterions. Since 1.6-dimethylquinolinium-2-dithioacetic acid zwitterion previously showed appreciable activity against P-388 lymphocytic leukemia in mice, a series of analogs with other 6-substituents was synthesized to assess the importance of substitution in this position. Both electron-donating and electron-attracting 6-substituents gave compounds with antileukemia activity. The 6-unsubstituted analog had only marginal activity.


Differential pulse polarographic analysis of thyroid hormone: determination of iodine, thyroxine, and liothyronine.

A differential pulse polarographic method for the analysis of thyroid and thyroid tablets for total iodine, thyroxine, and liothyronine is described. The procedure for iodine, which is also applicable to individual tablet assay, consists of ashing the sample, coverting iodide to iodate, and analyzing by differential pulse polarography. The procedure for thyroxine and liothyronine involves hydrolysis of the sample with barium hydroxide and isolation and separation of the iodoamino acids using ion exchangers, followed by differential pulse polarographic determination in a supporting electrolyte composed of 0.5 N Na2CO3 in 20% 2-propanol containing 1% tetrabutylammonium bromide. The differential pulse polarographic results for iodine agree with values obtained using the USP XIX procedure, and the quantities of thyroxine and liothyronine found agree with literature values.


Nonlinear model for acetazolamide.

Intravenous bolus injections of 14C-labeled acetazolamide were made in rabbits. Plasma, urine, and washed red blood cell concentrations were measured, the latter indicating bound drug. AUTOAN and NONLIN were used to fit the plasma data to a linear two-compartment model. However, utilization of the urine and red blood cell data suggested that a nonlinear model was more appropriate. The developed nonlinear system uses a one-compartment model with two tissue-binding parameters. The system simultaneously fits three equations describing drug in the plasma, in the body, and bound to red blood cells, Six parameters were estimated. The initial plasma concentration and the maximum amount bound to tissue protein (minus red blood cell protein) correlated with dose. The dissociation constant from this protein fraction suggested that it is composed mainly of the enzyme, carbonic anhydrase. The dissociation constant for the red blood cell fraction suggested that the drug binds to other protein in addition to carbonic anhydrase. The elimination constants were quite similar, indicating little variation from one animal to another. Utilization of the concepts of site and mechanism of action in this model should be of considerable help in relating drug concentration to pharmacological resonse.


Relationship of pharmacokinetics to pharmacological response for acetazolamide.

Acetazolamide concentration values derived from a nonlinear model system were related to two pharmacological responses in the rabbit. Kidney response was measured by monitoring urine flow and sodium elimination. Ocular response was followed using an applanation tonometer. Maximum urine flow and sodium elimination occurring immediately after injection correlated with log dose. Urine flow dropped below control values along with a rise in osmolality, suggesting the involvement of antidiuretic hormone. Sodium elimination was correlated with plasma levels. Urine pH is thought to be involved in reducing accessibility of drug to carbonic anhydrase in the kidney. Maximum ocular response also was correlated with log dose. Ocular response was related to a protein fraction, which is believed to be mainly carbonic anhydrase. However, the duration of ocular response was related to the red blood cell protein fraction. Thus, drug activity could conceivably be regulated by monitoring a tissue that is not the site of action and can be sampled readily.


Synthesis of alpha-methylenebeutyrolactams as potential antitumor agents.

A series of 1-aryl-3-methylene-2-pyrrolidinones was synthesized via a three-step reaction sequence. 1,4-Bis-[N-(3-methylene-2-oxopyrrolidino)]benzene, which can undergo alkylation at two sites, was also prepared. These compounds are related to the known antitumor agents alpha-methylenebutyrolactones. Attempts to prepare bis-alpha-methylenelactams, in which the heterocyclic rings are joined through their nitrogen atoms by an alkylene bridge, were unsuccessful. All of the alpha-methylenelactams were screened in B16 melanocarcinoma and P-388 lymphocytic leukemia tumor systems but failed to show significant activity.


Crystal structure of 1:1 complex of barbital with 1-methylimidazole.

The prediction of a strong hydrogen-bonding interaction between barbital and 1-methylimidazole was confirmed. Two crystal complexes were obtained, 1:1 and 2:1, and the X-ray structure was determined for the 1:1 complex, which is monoclinic, space group P21/c, with a = 12.236(3) A, b = 11.332(4) A, c = 12.495(4) A, and beta = 120.67(1) degrees. The structure contains disk-shaped hydrogen-bonded tetramers with two molecules of each kind. There is a short NH...N hydrogen bond (2.82 A) in which barbiturate provides the NH donor.


TLC determination of biotin in a lyophilized multivitamin preparation.

A TLC method for the determination of biotin was developed. The method is selective and sensitive and permits the determination of biotin in the presence of all water-soluble vitamins as well as glycine, edetate sodium, and methylparaben. The main steps are: dissolution of the lyophilized multivitamin preparation in water, addition of the internal standard, application on a thin-layer plate, separation from interfering components, visualization by spraying with 4-dimethylaminocinnamaldehyde, and in situ determination by reflectance measurements. Spraying the plate with paraffin after the coloring procedure increases the sensitivity of the method. The coefficient of variation is 2.3% with 0.15 microgram of biotin/spot. Quantities as low as 10 ng/spot can be determined.


Determination of ketoprofen by direct injection of deproteinized body fluids into a high-pressure liquid chromatographic system.

A rapid, sensitive, and specific determination of ketoprofen in human and animal deproteinized body fluids by reversed-phase high-pressure liquid chromatography is presented. The acid is detectable in amounts as low as 0.1 microgram/ml. Limits of error are in the range of +/- 5.1% of the sample mean.


Light stability of norethindrone and ethinyl estradiol formulation with FD&C colorants.

In general, light-sensitive tablets exhibit discoloration in the surface layer(s) only. A case is discussed where a quantitative interaction between a drug, ethinyl estradiol (in a combination tablet containing norethindrone and ethinyl estradiol), and a dye (FD&C Red No. 3) occurs, and discoloration exists throughout the tablet. The data suggest that accelerated light studies should be carried further than those dictated by predictive periods so that equilibrium levels can be deduced.


Quantitative structure--activity relationships and carminative activity II: steric considerations.

The unexplained variation in the relationships between carminative activities and octanol--water distribution coefficients of various classes of compounds was explained. The steric substituent constant (Es) value, van der Waals volume, and molecular connectivity were introduced into a previously derived correlation. Each parameter brought about an improvement, and molecular connectivity was the most successful. Correlations containing molecular connectivity was the most successful. Correlations containing molecular connectivity terms explained the excess variation. The results were in agreement with a mechanism in which carminative activity depended on the availability of the oxygen atom in the functional group of the molecule and was reduced when the substituent attached to the oxygen hindered the interaction between the oxygen atom and the receptor.


Metabolic studies with nonnutritive sweeteners cyclooctylsulfamate and 4-methylcyclohexylsulfamate.

The nonnutritive sweeteners cyclooctylsulfamate and 4-methylcyclohexylsulfamate were fed separately to female Wistar albino rats, and the urine was examined for the possible metabolites cyclooctylamine, cyclooctanone, cyclooctanol, 4-methylcyclohexylamine, 4-methylcyclohexanone, and cis- and trans-4-methylcyclohexanols. The average percent conversions to cyclooctylamine, cyclooctanone, and cyclooctanol were 0.127, 0.08, and 0.092, respectively. The average percent conversions to 4-methylcyclohexylamine and 4-methylcyclohexanone were 0.007 and 0.0013, respectively. No cis- or trans-4-methylcyclohexanol metabolites were found. With cyclooctylsulfamate, 42% was recovered unchanged from the urine. Cyclooctyl- and cycloheptylsulfamates were metabolized to a greater extent than cyclopentylsulfamate, which, in turn, was metabolized to a greater extent than cyclohexylsulfamate (cyclamate) and 4-methylcyclohexylsulfamate.


GLC determination of purity of Schiff bases bakrine and saddamine.

GLC methods were developed for the investigation of impurities in bakrine and saddamine. The method used for bakrine was unsuitable for saddamine since two possible saddamine impurities, benzylamine and salicylaldehyde, reacted very readily in solution to form saddamine, thus giving a false low value for the original concentration of these impurities. The method devised for saddamine involved silylation, which greatly reduced the possibility of saddamine formation from its precursors and also enabled the detection of another possible impurity, salicylic acid. The method described has an obvious application to the determination of other Schiff bases.


Synthesis of 1-phenyl-2-(phenylcarbamoyl)pyrazolidines as potential anticonvulsant agents.

Twelve 1-phenyl-2-(phenylcarbamoyl)pyrazolidines were synthesized from 1-arylpyrazolidines and aryl isocyanates. These adducts showed little anticonvulsant activity in the maximal electroshock seizure and pentylenetetrazol seizure assays.


Sensitive high-pressure liquid chromatographic determination of propranolol in plasma.

A high-pressure liquid chromatographic method is presented for the determination of propranolol in human plasma. A reversed-phase cyanopropylsilane column was utilized with a liquid phase consisting of 70% acetonitrile and 30% 0.02 M acetate buffer, pH 7.0. A spectrofluorometric detector with an excitation wavelength of 276 nm and an emission filter with a 340-nm cutoff provided a detectable peak for 0.8 ng of propranolol/injection with this system. The reproducibility and precision of the method are shown from the analyses of samples containing 10--150 ng/ml of plasma.


Electron-capture GLC assay of dichlorphenamide.

GLC with electron-caputre detection was applied to the assay of the carbonic anhydrase inhibitor dichlorphenamide and demonstrated a sensitivity of 10 ng in 0.5 ml of rabbit serum or whole aqueous humor (congruent to 0.25 ml) from one rabbit eye. After extraction of the drug and internal standard (monochlorphenamide) from the biological fluid, these compounds were converted to their tetramethyl derivatives by a nucleophilic alkylation method. Dichlorphenamide contents of aqueous humor and serum of rabbits treated with this drug are reported.


Comparison of in vitro activity of undecylenic acid and tolnaftate against athlete's foot fungi.

Undecylenic acid and tolnaftate were tested in an in vitro test system to evaluate their relative "killing time" efficacy against Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophyton floccosum. Commercial products containing these active agents were tested similarly. The pure active agents were equivalent in activity. The commercial product containing undecylenic acid appeared to be more effective against the test organisms than did the product containing tolnaftate.


Rapid, sensitive GLC determination of pentobarbital and other barbiturates in serum using nitrogen-specific detector.

A GLC method for the analysis of pentobarbital in serum was developed. After extraction from serum, a methyl derivative was prepared and quantitated by nitrogen-specific detection. The method has a senstivity of 0.08 microgram/ml for pentobarbital with only 0.1 ml of serum. Secobarbital was the internal standard. Derivatives of other barbiturates also were prepared.


Separation, identification, and quantitation of anthralin and its decomposition products.

Anthralin and its decomposition products were separated by both column chromatographic and TLC techniques. Two decomposition products were characterized by TLC, melting-point data, and UV and IR spectroscopy. Pure anthralin and its decomposition products also were determined quantitatively.


Semantic disorders of auditory language comprehension in right brain-damaged patients.

A test of auditory language comprehension was given to 110 right brain-damaged patients and to 94 normal controls in order to check if patients with lesions of the right (nondominant) hemisphere make a significantly higher number of semantic errors than normals. Confirmation of the hypothesis was obtained, but the relationship between semantic errors and lesion of the right hemisphere did not seem a simple and direct one. In fact, most of the lexical-semantic errors were due to associated variables (such as unilateral spatial agnosia and general mental deterioration) and not to the lesion of the right hemisphere per se. These data do not suggest a specific semantic capacity of the nondominant hemisphere but rather stress the fragility of the lexical-semantic organization at the cortical level.


Fertilizing capacity and ultrastructure of fowl and turkey spermatozoa before and after freezing.

The fertilizing capacity, motility and ultrastructure of fowl and turkey spermatozoa were examined at various stages of the freezing process. For both species, fertility and motility were depressed after equilibration with dimethyl-sulphoxide at 5 degrees C. After freezing, motility was maintained at 55% for fowl spermatozoa and 40% for turkey spermatozoa; however, fertility was 55% for the fowl and 0% for the turkey. Qualitatively, the damage to the spermatozoa of both species was nearly identical, as revealed by scanning and transmission electron microscopy. The plasmalemma was the primary site of damage. 'Bent' spermatozoa, coiled tails and swollen mitochondria were also present. Damage to the acrosome was only observed in spermatozoa which had been frozen to -180 degrees or -196 degrees C. These changes were attributed to adverse osmotic conditions. Binding of cationic ferritin to the plasmalemma of spermatozoa from both species remained unaltered.


Substrate specificity of the lactate dehydrogenase isoenzyme C4 from human spermatozoa and a possible selective assay.

The activity of lactate dehydrogenase (EC 1.1.1.27) in normal human sperm lysates and in human heart and liver homogenates was determined by using a variety of 2-oxoacids as substrates. Sperm preparations were active with pyruvate, 2-oxobutanoate, 2-oxopentanoate and 2-oxohexanoate, while heart and liver extracts utilized only pyruvate and 2-oxobutanoate. Selective staining after gel electrophoresis indicated that the fraction corresponding to lactate dehydrogenase C4, the sperm-specific isoenzyme, was responsible for the utilization of substrates with a linear chain of 3 to 6 carbon atoms. The use of 5 mM 2-oxohexanoate allowed the selective determination of isoenzyme C4 in preparations containing different lactate dehydrogenase molecular forms.


Correlation of lactate dehydrogenase isoenzyme C4 activity with the count and motility of human spermatozoa.

The activity of lactate dehydrogenase isoenzyme C4 was determined on 90 human semen samples. The correlation between the isoenzyme activity and sperm count and motility was good (r = 0.74 for values of U/ml semen against sperm count).


Varying effects of an IUD on decidualization in mice.

Chronically implanted IUDs consisting of silk suture threads induced decidualization in regions of the uterus remote from the suture site in ovariectomized mice treated with a regimen of progesterone and oestrogen which sensitizes the uterus to a decidual stimulus. In these conditions the IUDs did not inhibit decidualization induced by instilled oil, although they did so in pregnant animals of the same strain. Varying the dose of progesterone and oestrogen did not produce conditions in which IUD's inhibited oil-induced decidualization in ovariectomized mice and progesterone treatment did not prevent IUDs inhibiting decidualization in pregnant animals. However, when ovariectomized mice, sensitized as before, were primed repeatedly with oestrogen to simulate continuing oestrous cycles after IUD insertion, the IUD's inhibited oil-induced decidualization. This involved the premature loss of instilled oil from the uterine lumen and was associated with heavy infiltration of leucocytes into the luminal epithelium. Numbers of leucocytes free in the uterine lumen did not appear to be critical. It appears that contact between the oil and the luminal epithelial surface must be sustained for some length of time to induce a decidual reaction; brief contact is not sufficient to trigger the response.


Early cellular changes and circular muscle contraction associated with the induction of decidualization by intrauterine oil in mice.

Intrauterine instillations of oil or saline distended the uterus in ovariectomized mice treated with progesterone + oestrogen to sensitize the uterus to a decidualizing stimulus. Saline does not induce decidualization, and therefore uterine distension per se is not the trigger to decidual induction. Oil induces decidualization, but does not involve gross damage to the epithelium, penetration of oil into the stroma or release of epithelial lipid into the stroma. Instillation (oil, saline or sham) induced a contraction of the circular muscles along the length of the uterus which closed the uterine lumen, expelled most of the oil and located the remainder primarily in the antimesometrial cleft of the lumen. Progesterone inhibited longitudinal muscle contraction and facilitated circular muscle contraction. These effects are discussed in relation to the spacing and implantation of blastocysts.


Symplasma formation and decidualization in the pseudopregnant rabbit after intraluminal instillation of tricaprylin.

A pure neutral triglyceride, tricaprylin, was injected (Day 0) into isolated segments of the uterus of rabbits in which pseudopregnancy had been induced by i.v. injection of hCG 6 days before. The animals were killed in groups of 3 on Days 1, 2, 3, 4 and 6. Saline, simple ligation of the uterus or uterine trauma were used as control treatments in other uterine segments in the same animals. Extensive symplasma formation in the uterine epithelium of the tricaprylin-treated segments was observed on Days 2 and 3; this had degenerated by Day 4 and was absent by Day 6. Decidualization of the stroma began on Days 3 and 4 and was absent by Day 6. The symplasma formed earlier on the antimesometrial side than it did laterally or mesometrially. Decidualization was maximal mesometrially, intermediate laterally, and absent antimesometrially. Ligation with saline and trauma, but not ligation alone, produced symplasma formation. Decidualization occurred after trauma but not after saline injection or ligation alone.


Thromboxane B-2 in the plasma and amniotic fluid of late pregnant and periparturient sheep.

The concentration of thromboxane (TX) B-2 was similar in plasma from all sources but was significantly greater (P less than 0.01) in amniotic fluid. Fetal hypophysectomy was without effect on maternal or fetal levels of TXB-2 (P greater than 0.1). Neither normal parturition at term nor prematurely induced delivery was associated with any significant trend in TXB-2 levels. During late pregnancy (105--145 days of gestation) the concentrations of TXB-2 and 13, 14-dihydro-15-keto-prostaglandin F (PGFM) in maternal and fetal plasma were significantly correlated (P less than 0.001). There was, however, no correlation between TXB-2 and PGFM levels in samples taken during the 36 h before delivery. These data suggest that thromboxanes play little part in the mechanism of parturition in sheep.


The estimation of sperm motility in semen, on a membrane slide, by measuring the area change frequency with an image analysing computer.

A simple slide is described in which the base is a permeable membrane so that a suspension of spermatozoa (or other cells) may be examined under controlled conditions with a microscope. An objective method of assessing the motility of spermatozoa in undiluted or diluted semen from a wide variety of species including cattle, horse, pig, rabbit, rat and sheep is described. It is shown to be well correlated with other methods of assessing motility and also with the non-return rate obtained with frozen cattle semen.


Measurement of the motility of rat spermatozoa collected by micropuncture from the testis and from different regions along the epididymis.

Spermatozoa from the testis and various regions along the epididymis of the rat were collected by micropuncture and their motility after dilution was estimated over a 15-min period by using a Quantimet image analyser. The motility of sermatozoa from the rete testis and seminiferous tubules was too low to be measured. The estimate of motility of spermatozoa from the proximal caput epididymidis was much lower than that of spermatozoa from the other regions. Spermatozoa from the distal part of the caput showed sustained motility for 15 min, whereas those from the caudal region and ductus deferens, although active initially, became less active during this period.


Hormonal and physical changes associated with bovine conceptus development.

Conceptus (placental membranes, fetal fluids and fetus) development was characterized between Days 27 and 111 of gestation. Progestagens, oestrone, oestradiol, oestrone sulphate and prostaglandins (PG) F were measured in maternal plasma and allantoic and amniotic fluids. Protein concentrations are described for fetal fluids. The early increase in placental membrane weight from 1.12 g (27 days) to 58.45 g (50 days) was associated with oestrogen production presumably of conceptus origin. Oestrogens increased significantly in allantoic and amniotic fluids throughout the period studied with oestrone being the primary free oestrogen, rising from 2 pg/ml (Day 33) to 144 ng/ml by 111 days in allantoic fluid. Changes in plasma oestrogens of the maternal circulation were not detected until after Day 70 at which time oestrone concentration was greater than that of oestradiol. Fetal fluid concentrations of progestagens, oestrone sulphate and PGF were not related to maternal plasma levels and a sequestration of these hormones by the allantois is postulated.