Prevalence of hepatitis B e antigen and its antibody as detected by radioimmunoassays. A solid-phase radioimmunoassay (RIA) for the detection of hepatitis B e antigen (HBeAg) and antibody (anti-HBe) was developed. The RIA was approximately 1,000-fold more sensitive than rheophoresis for HBeAg, and approximately 6,000-fold more sensitive than rheophoresis for anti-HBe. Generally, less than one-fifth of hepatitis B antigen (HBsAg)-positive sera from blood donors were positive for either HBeAg or anti-HBe by rheophoresis; in contrast, more than 90% of the samples were positive by the RIA method. The ratio of HBeAg to anti-HBe among HBsAg carriers varied in different geographic localities. Also, the presence of HBeAg correlated directly with the titer of HBsAg and the presence of Dane core particles. Anti-HBe was associated with lower titers of serum HBsAg.


Abstract reasoning in a specific group of perceptually impaired children: namely, the learning-disabled. The present study was designed to investigate whether learning-disabled children differ from normal achievers in terms of logical thought and wheter they exhibit décalages intheir acquisition of Piagetian concepts. The Ss comprised 35 learning-disabled boys attending full-time remedial schools and 35 matched normal achievers. The group mean was 9 years 1 month and the mean IQ was 109. S s were tested on a measure of visual perception and on 11 Piagetian tasks measuring conservation of quantitiy and number, seriation, and classification. Results indicated a significant difference between the groups in terms of perception but not in terms of logical thought. The rank order of the 11 Piagetain tasks was significantly correlated for the two groups (r = .89). It was concluded that the perceptual problems of the learning-disabled reside at a functional rather than at an organizational level, thus effecting only specific congnitive activities.


Reactions of infants and young children to a stranger in an unfamiliar setting. Reactions of infants and young children to a stranger in an unfamiliar laboratory setting were examined to determine (a) variability in responses at six, 12, 24, and 36 months; (b) consistency of six and 12 month infants' responses to specific stranger behaviors; and (c) possible determinants of responses to strangers. The reactions of 136 male and female infants and children to a female stranger were recorded both when the stranger was actively trying to interact with the child and when the stranger sat quietly nearby after giving him a toy to play with. Both positive and negative reactions were observed at all ages, with one-year-olds showing greater distress than other age groups. Consistency was found in infant reactions to intrusive stranger behaviors. It was suggested that stangers are more likely to elicit curious-affiliative than cautious-avoidance behaviors from chidren if they are both attentive and appropriately to the child on the basis of his communications.


Some developmental aspects of infants cry. Respiratory activity during crying was measured in a semilongitudianl study of 10 normal infants aged two days to eight months. Temporal aspects of respiration during crying showed marked change with age: athe duration of the expiratory phase steadily increased, while the duration of the inspiratory phase remained remarkable constant, producing an ever-lower I-fraction. A previous study reported no developmental changes in the temporal aspects of the acoustic cry signal from one to seven months of age. Reasons for the divergent findings of the present study arepresented, and it is suggested that respiratory behavior may be a better indicator of developmental changes in the crying act thanthe acoustic signal.


Continuous tracking of behavioral development in infants. Infant development scales provide a one time measure of the number of scale items an infant performs and his standing relative to his age group. Repeated assessment indicates how many more items he can perform and whether his relative status has altered but does not measure actual changes in the same behaviors as development progresses. This paper discusses the importance of continuously measuring the same behavior over time as an alternative strategy. The developmental information is exemplified by the behavioral records of two infants observed over a 25-week period for changes in frequency and duration of three prone position motor responses.


On some complexities in the application of conflict theory to psychotherapy. The present paper discusses several complications which arise in applying Dollard and Miller's analysis of conflict to the study of psychotherapy. Discussed are problems associated with recent theorizing on the nonunitary nature of fear; considerations relevant to the question of why individuals exposed to partial cues for anxiety do not show extinction of the anxiety, generalization of extinction, and increased approach behavior; the role of interpersonal feedback in maintaining neurotic behavior; and the issue of changing golas as therapy proceeds.


Chronic neurotic encopresis as a paradigm of a multifactorial psychiatric disorder. Chronic neurotic encopresis (CNE), a childhood psychiatric disorder characterized by inappropriate fecal soiling, necessitated the formation of the following specific etiological factors: a) a neurologically immature developmental musculature, an organic condition which may complicate toilet training; b) premature or harsh toilet training; c) a family constellation in which the father is frequently absent and the mother erratic, emotionally inappropriate, and distant; d) the child's formation of a noncommunicative, passive, dependent personality. All of these factors are helpful in explaining the occurrence of CNE, which is thus seen as the result of a synergistic interaction among them. The complexity of etiological agents dictates a multifactorial rather than unicausal model of mental illness. Future research and tactics of psychotherapeutic intervention should focus on the interplay among these factors rather than attempting to single out one primary predisposing factor.


Spironolactone prophylaxis in manic-depressive disease. Lithium is now recognized as the drug of choice for the prophylactic control of manic-depressive disease, but its mechanism of action is the nonspecific inhibition of adenyl cyclase and subsequent cAMP formation which produces many undesirable side effects. However, the effect that lithium has on the central nervous system is compatible with all three theories regarding the basis of affective disorders, i.e., the biogenic amine theory, the electrolyte theory, and the membrane theory. Fluctuations of the hormone aldosterone during the various stages of manic-depressive disease could account for an etiological mechanism, that also is compatible with all three theories. Both spironolactone and lithium can inhibit the action of aldosterone. Therefore, when six manic-depressive patients, who had been well maintained on lithium, requested discontinuance of this drug because of side effects, spironolactone was substituted. On a minimum 1-year follow-up study, five of the six patients were well maintained on this new drug regimen.


On conscious primal scene fantasies.

On conscious primal scene fantasies. Pertinent literature concerning the pathogenicity of the primal scene is reviewed. Two psychoanalytic cases, both of whom had conscious primal scene fantasies prior to beginning psychoanalysis, are discussed. These fantasies did not represent significant ego or superego deficits. The authors suggest that conscious primal scene fantasies, in these patients, represented screen memories. Both patients were successfully analyzed.


Papilledema following therapeutic dosages of lithium carbonate. A patient with diagnosis of manic-depressive illness, circular type, and receiving therapeutic dosages of lithium carbonate, developed papilledema that seemed to be directly related to the drug. Although this is an extremely rare complication, the authors suggest that fundal exams may be considered in patients treated with lithium.


Short-lasting memory in lower nervous centers in Octopus. Octopuses with the supraesophageal lobes split and the subesophageal centers isolated by cutting the cerebrobrachial connective on one or both sides were trained by food and shock rewards to discriminate between rough and smooth balls. Because there is a greater tendency to take the rough ball, training was done with the smooth ball positive for half the animals, and the rough ball positive for the others. In the animals with the cerebrobrachial connective cut only on one side, the subesophageal lobes showed no capacity to use the information gained by their opposite, intact, half-brains, which learned well. In animals with isolated subesophageal lobes, there was a decrease during each training session in the tendency to take both types of ball; however, this decrease did not persist from day to day. During each training session there were signs of discrimination between the balls by animals with isolated subesophageal lobes, but these also did not survive from day to day. In a series of training sessions spread over seven weeks, there was no change in results in animals with isolated subesophageal lobes when the smooth ball was positive. When the rough was positive the discrimination in its favor was slightly increased at later sessions.


Spasmodic torticollis: a combined clinical study. The prognosis in 30 patients with spasmodic torticollis proved to be unexpectedly bad, only one patient making a full and sustained recovery. Investigation did not confirm previously reported reflex influences on the degree of spasm. Detailed otological investigation did not suggest that spasmodic torticollis originates in vestibular dysfunction. Psychological assessment of the patients showed no deviation from normal in premorbid personality but confirmed the severe adverse effects of the condition.


Visual evoked responses and visual symptoms in multiple sclerosis. Absolute latency, interocular difference in latency, and waveform of visual evoked responses (VER) to checkerboard reversal stimuli recorded from the midline of the skull were studied in 104 multiple sclerosis patients, 25 to 50 years of age, classified according to visual symptomatology. Group 1 had strong evidence of past or present optic neuritis. Patients with blurring of vision, diplopia, and undefined visual complaints were assigned to group 2, while group 3 contained patients with no visual symptoms but suspected diagnosis of multiple sclerosis on other grounds. The three parameters explored showed consistent association with the degree of visual involvement, as assessed by clinical impression, but their discriminatory power was diverse. Absolute latency was significantly longer in group 1 patients compared with groups 2 and 3, but it did not discriminate between the last two, whereas interocular difference in latency proved to be sensitive to differences between symptomatic (diplopia, blurring) and asymptomatic groups (2 and 3). Waveshapes were grouped into three categories based upon degree of distortion of the major positive peak, and their relative distribution among the three patient groups was found to be associated with symptomatology. We suggest that, in the production of symptoms such as diplopia, a temporal disparity of afferent impulses might be involved in much the same way that spatial incongruities between both eyes lead to impaired function. In this regard, interocular difference in latency rather than absolute latency would be a more accurate predictor of symptom development. The analysis of VER waveshape suggests, in addition, the importance of inhomogeneous involvement of the visual pathways in the production of symptoms during the evolution of multiple sclerosis.


Visual evoked responses in multiple sclerosis: comparison of two methods for pattern reversal. Visual evoked responses have been elicited by reversal of a black and white checkerboard pattern and also by a display of light-emitting diodes (LED) generating a reversal of a pattern of illuminated red circular areas. In a control group the LED display produced responses of lower amplitude and shorter latency compared to responses to checkerboard stimulation. In patients with a definite or probable diagnosis of multiple sclerosis the stimulators were equally effective in evoking pathological responses; in patients with a possible but less certain diagnosis abnormal responses were found in a higher percentage when the LED stimulus was used. Differences in stimulus field size and in stimulus colour are discussed as possible reasons for this result.


Diagnosis of infantile neuroaxonal dystrophy by conjunctival biopsy. Conjunctival biopsy and ultrastructural examination of conjunctival nerves, showing the presence of spheroids within axons, led to the confirmation of the diagnosis of infantile neuroaxonal dystrophy in two children with progressive mental deterioration. Conjunctival biopsy, which is simple to perform, even in young children, and does not require general anaesthesia or admission to hospital, is presented as a reliable and very convenient technique for the diagnosis of infantile neuroaxonal dystrophy.


Chronic brainstem encephalitis with mental symptoms and ataxia: report of three cases with necropsy. Three necropsied cases of chronic, sporadic brainstem encephalitis of unknown aetiology are presented. Since their outstanding symptoms were dementia and ataxia of a progressive nature, a noninflammatory disease of the central nervous system was suspected. Neuropathological studies showed chronic inflammatory changes mainly in the brainstem without the presence of inclusion bodies or viral particles. Compared to cases previously reported as brainstem encephalitis, the clinical and pathological findings observed in these cases have rather peculiar characteristics.


Does transient blocking of axonal conduction occur in uraemic neuropathy? In uraemic and other patients with neuropathies, motor unit spike intervals were analysed using a special computer program to detect prolonged intervals of twice the normal duration, so-called "double intervals." These may have different causes--trigger failure, double discharge, or a transient fall in the firing rate of coactive motor units. There was not sufficient evidence that transient conduction blockings will occur in the main axon in uraemic neuropathies.


Effect of continuous vibration on nociceptive flexor reflexes. The effects of continuous segmental vibration on the biceps femoris (BF) nociceptive flexor reflexes elicited by painful electrical stimulation of the sural nerve at the ankle were investigated in 25 normal subjects. During vibration of 100 Hz frequency, applied either on ipsilateral or contralateral foot skin, the nociceptive BF flexor reflexes increased in amplitude. Marked facilitation was prolonged even 20 minutes after vibration ceased. Pain sensation described by subjects did not change significantly except that radiation of pain was reduced in some cases. The results could not be explained by current views of reflex sensitisation, dishabituation, or the gate control theory.


Study of anosognosia.

Study of anosognosia. Anosognosia (denial of weakness) and "anosognosic phenomena" (other abnormal attitudes to a weak limb) were studied in 100 acute hemiplegics. Both conditions were associated with lesions of either hemisphere. Apathy, visual field defect, and impaired picture identification were particularly prominent in anosognosia. A failure to integrate information from one side of the body was regarded as fundamental to the condition; explanations in terms of "unilateral neglect" and "agnosia" are discussed.


Dissociated disorders of speaking and writing in aphasia. Of 500 left brain-damaged patients with educational level above elementary school investigated with a standard quantitative battery for dissociation between oral and written expression, speech was found to be selectively impaired in seven (three with "pure anarthria," two with anarthria in the context of Broca's aphasia, and two with fluent aphasia with remarkable sparing of writing), and writing in another seven (two with "pure" agraphia, two with "agraphia with mild alexia," and three with "agraphia with mild fluent aphasia.") The nature of three conditions (pure anarthria, fluent aphasia with sparing of writing, and pure agraphia) is discussed, with evidence of a selective association between pure agraphia and lesions of the upper left parietal lobule.


Linguistic correlates of pantomime recognition in aphasic patients. Aphasic patients were given tests assessing pantomime recognition, reading comprehension, aural comprehension, and naming ability to determine whether defective pantomime recognition could be the result of a disturbance of symbolic thinking also affecting linguistic functioning. Defects in pantomime recognition always occurred in conjunction with reading defects of at least comparable severity, but reading defects sometimes occurred without comparable defects in pantomime recognition. The relationship of pantomime recognition with both aural comprehension and naming ability was significantly weaker than that between pantomime recognition and reading comprehension. The implications of the findings with regard to other nonverbal aphasic symptoms and the role of sensory modality factors are discussed.


Category-specific naming preservation: a single case study. The report of this single case study describes the preservation of a simple semantic category in a severely anomic patient. The implications for the organisation of semantic knowledge are discussed.


Selective impairment of topographical memory: a single case study. We describe a patient who developed topographical memory loss after a closed head injury. His symptoms and the psychological test results indicate a selective deficit of topographical memory, his perceptual and spatial skills being relatively unimpaired.


Pituitary adenomas in childhood and adolescence. This report describes a group of 25 children and adolescents with biopsy-proven pituitary adenomas. They were found in 33% of patients encountered in our recent study of 74 parasellar tumor detected in patients under 20 years old. Earlier detection accounts for this apparent increase in frequency. This interpretation is supported by the rarity of signs of intracranial hypertension at presentation, as well as decreased incidence and severity of visual failure. More than 70% of patients have evidence of pituitary hypersecretion at presentation. Increased awareness of these endocrinological signs as well as improved hormonal assays facilitate both diagnosis and management. Hypopituitarism is rare; the important exception is suppression of gonadotrophic function that is known to occur early in the natural history of intrasellar pituitary adenomas. The low incidence of suprasellar and extrasellar extension is documented by both radiographic and operative findings. Transsphenoidal resection was employed in 92% of patients, with an estimated total resection in 73% of cases. Follow-up studies show a high quality of survival; no patient has severe neurological deficit and less than half of them require replacement therapy. The recurrence rate is 8%. Our findings do not support a previous report that pituitary adenomas in this age group are frequently extrasellar and invasive.


Long-term prognosis in children with benign cerebellar astrocytoma. In 44 children with benign cerebellar astrocytoma, operated on between 1935 and 1959, two histological types could be distinguished, namely, a so-called juvenile type (31 children) and a diffuse type (13 children). All the children were followed to April, 1976, and the histological review was performed without knowledge of the survival in the single patient. For children with the juvenile type of cerebellar astrocytoma the 25-year cumulative survival rate was 94%, as against 38% for children with the diffuse type. It has thus been demonstrated that the morphological difference between the two types corresponds to a marked difference in survival rate.


Civilian gunshot wounds of the brain.

Civilian gunshot wounds of the brain. The authors report on 42 fatal gunshot wounds to the brain in civilians. The firearms used were those commonly available to civilians, ranging from a .22 revolver to a .45 semiautomatic pistol. Missle tracks were measured and the volume computed. The relatively low-velocity missles produced by these weapons to not create the devastation that characterizes wounds from high-velocity military firearms. Instead, there is much variation in the size of the missle tracks, and they cannot be directly related to caliber. Pressure marks and contusions, impaction of bone chips, internal richochet, and cerebral edema occurred frequently. The missle passed through the brain completely in very case but was retained by the skull or soft tissues in a large percentage of cases. The mechanism of death may be acute pressure on the brain stem from the passage of the missle through the brain.


Experience with multiloculated brain abscesses. The author reports his experience with 10 consecutive multiloculated brain abscesses diagnosed by computerized tomography and successfully treated by excision (primary or early secondary) or repeated aspiration.


Microsurgical anatomy of the distal anterior cerebral artery. The microsurgical anatomy of the distal anterior cerebral artery (ACA) has been defined in 50 cerebral hemispheres. The distal ACA, the portion beginning at the anterior communicating artery (ACoA), was divided into four segments (A2 through A5) according to Fischer. The distal ACA gave origin to central and cerebral branches. The central branches passed to the optic chiasm, suprachiasmatic area, and anterior forebrain below the corpus callosum. The cerebral branches were divided into cortical, subcortical, and callosal branches. The most frequent site of origin of the cortical branches was as follows: orbitofrontal and frontopolar arteries, A2; the anterior and middle internal frontal and callosomarginal arteries, A3; the paracentral artery, A4; and the superior and inferior parietal arteries, A5. The posterior internal frontal artery arose with approximately equal frequency from A3 and A4 and callosomarginal artery. All the cortical branches arose more frequently from the pericallosal than the callosomarginal artery. Of the major cortical branches, the internal frontal and paracentral arteries arose most frequently from the callosomarginal artery. The distal ACA of one hemisphere sent branches to the contralateral hemisphere in 64% of brains. The anterior portions of the hemisphere between the 5-cm and 15-cm points on the circumferential line showed the most promise of revealing a recipient artery of sufficient size for an extracranial-intracranial artery anastomosis. The distal ACA was the principal artery supplying the corpus callosum. The recurrent artery, which arose from the A2 segment in 78% of hemispheres, sent branches into the subcortical area around the anterior limb of the internal capsule.


Radiographic diagnosis of meningioma of the lateral ventricle. Review of 22 cases. Review of 22 cases of meningioma indicates that this lesion occurs slightly more frequently on the left but without predilection for sex or age of the patient. The presenting symptoms were nonspecific. Plain radiographs of the skull sometimes demonstrated calcification in the tumor, but more often did not. Cerebral angiography frequently showed enlargement and displacement of the anterior choroidal artery on the side of the tumor; the lateral posterior choroidal artery on the side of the tumor was also enlarged and displaced in seven of nine patients who underwent vertebral arteriography. Pneumoencephalography accurately demonstrated the site and size of the lesion, as did radionuclide scanning if the lesion was vascular. Computerized tomographic (TC) scanning also determined the location and size of the tumors, as well as their mass effect and vascularity; CT scanning also demonstrated calcification that was not visible on the plain skull radiographs in two of six patients who underwent CT scanning and had calcification.


Long-term intracranial pressure recording in the management of pseudotumor cerebri. Long-term monitoring of intracranial pressure (ICP) was used as an aid for the management of four patients with pseudotumor cerebri. After the implantation of a small experimental pressure sensor in the skull, most of the subsequent (ICP measurements were made noninvasively by an external interrogator. During the initial study of the patient, baseline ICP recordings were made in the hospital before treatment. Pressure recordings on a 24-hour basis were continued during treatment, which, depending on the case, was with Diamox (acetazolamide), steroids, or the coperitoneal shunting. After discharge these patients returned weekly over 10 to 22 months for ICP measurement and for ophthalmological examination. Intracranial pressure before treatment showed irregular variations ranging from 100 to 500 mm H2O over a 24-hour period. The efficacy of treatments could be assessed in a few hours by the degree of ICP stabilization. Shunt malfunction was detected by a slow but continuous rise in pressure before full clinical signs were evident.


Assessment of the effects of cinglulate gyrus lesions by neuropsychological techniques. Nineteen psychiatric patients undergoing bilateral cryogenic cingulate cortex lesions were extensively evaluated pre- and postoperatively with objective measures of intelligence, higher cortical functions, memory, and emotional status. Following surgery the patients as a group revealed no significant deterioration of functions; rather, they demonstrated improvement that could be interpreted as the result of decline in anxiety. Investigations of individual revealed that the overall test performance was improved in 13 and substantially unchanged in three, whereas three demonstrated some decline in performance. These results were discussed in terms of the characteristics of the changes across the various tests.


Treatment of fusiform aneurysms of the peripheral cerebral arteries. Report of two cases. Two patients with fusiform aneurysms and at least one previous subarachnoid hemorrhage were treated by excision of the aneurysms and reconstruction of the arteries. The first case presented with two fusiform aneurysms, the larger of which involved the angular and the smaller one the temporal branch of the left middle cerebral artery (MCA). Both aneurysms were totally excised. The angular artery was reconstructed with a 1.5 cm long arterial graft taken from the left superficial temporal artery. Excision of the temporal aneurysm was followed by an end-to-end suture of the central and distal parts of the vessel. The second case had a fusiform aneurysms involving the temporal branch of the left MCA. The aneurysm was excised and an arterial graft 1 cm long cut from the superficial temporal artery was used in reconstruction of the affected vessel. In each case left carotid angiography was done 1 week postoperatively. In the first case the angiogram showed that the angular artery reconstructed with a graft was patent, whereas the temporal artery reconstructed without a graft was not visualized. In the second patient, whose temporal artery was reconstructed with a graft, angiography did not show the reconstructed artery. Left carotid angiography was repeated 1 year after the operation in both cases, and all the reconstructed vessels were well visualized.


Giant thrombosed aneurysm associated with an arteriovenous malformation. Case report. The authors describe a case of giant anterior cerebral artery aneurysm associated with an anatomically related arteriovenous malformation (AVM). The aneurysm was almost completely thrombosed and was resected along with the AVM.


Symptomatic pituitary tumor enlargement after induced pregnancy. Case report. A case is presented and 11 others are reviewed in which symptomatic pituitary tumor enlargement occurred during pregnancies that resulted from induced ovulation. The syndrome is usually characterized by headache and visual disturbances with bitemporal visual field abnormalities, but may present with ocular muscle palsies. The cases are divided into two groups. The patients in one group had a shorter duration of amenorrhea (3.8 years), developed symptoms before the 14th week of pregnancy, and were usually treated by tumor removal. Patients in the second group had a longer period of amenorrhea (10.2 years), developed symptoms after the 24th week of pregnancy, and their symptoms regressed with delivery of the infant. Tumor removal or termination of the pregnancy both resulted in resolution of symptoms. All pregnancies resulted in normal infants. This series provides guidelines for management of future cases.


Postoperative epidural hematoma as a complication of anterior cervical discectomy. Report of three cases. In three cases, anterior cervical discectomy was complicated by acute postoperative paraplegia secondary to epidural hematomas at the operative sites. Prompt evacuation of the hematomas was followed by recovery in each instance. The source of bleeding was an arterial arcade that may be encountered during the course of removing the posterior longitudinal ligament. As a result of this experience, the authors suggest steps to be taken to avoid this uncommon complication.


Teratomatous cyst of the spinal canal. Case report. A search of the English literature revealed 46 cases of primary intraspinal teratomas, of which 22 were teratomatous cysts of spinal cord. To clarify the confusion regarding this rare lesion, the definition, origin, presentation, and histological features of the lesion are discussed. An additional case is presented.


Metastatic melanoma simulating subdural hematoma. Case report. Metastatic melanoma tends to be found in subcortical white matter and this localization may produce clinical or radiological features that are unusual in metastatic disease. A case is described that closely simulated a subdural hematoma both clinically and radiologically.


Diffuse cerebrospinal gliomatosis. Case report. A case of diffuse cerebrospinal gliomatosis is presented, with widespread involvement of the brain, cranial nerves, and spinal cord. This showed a far more extensive distribution of tumor cells than previously reported cases of gliomatosis cerebri. The clinical picture and oncogenesis of gliomatosis cerebri is briefly discussed.


Angiographic changes to induced hypertension in cerebral vasospasm. Case report. A case of cerebral vasospasm complicating intracranial aneurysm surgery is presented. Angiographic findings under hypertension and normotension revealed a paradoxical response of involved vessels suggesting that normal autoregulation is either lost or overcome by spasm.


Surgery of the carpal tunnel. Technical note. The authors describe a modified technique for surgery of the carpal tunnel. The primary cause of the carpal tunnel syndrome is the same as other entrapment neuropathies: an enlarged nerve within a tight tunnel. Electrical studies have shown that the area of compression is in the middle of the tunnel. Treatment is surgical: a palmar incision, which begins at the wrist medial to the palmaris longus, to avoid damage to the sensory branch of the median nerve; and selection of the retinaculum from the exit of the tunnel toward the entrance.


Cerebral angiography of the rat. Technical note. An open technique of right retrograde brachial arteriography of the rat is described. With the aid of magnification radiography, this method permits high quality examinations of the extracranial and intracranial circulations. The muscular branches of the brachial artery are preserved at the initial study to allow repeat examination. A four-vessel study is also attainable by injection of contrast material immediately after death of the animal.


The effects of aminoethyl phosphonic acid on hepatic microsomal drug metabolism and ultrastructure of normal and cholesterol fed rats. The effects of parenteral administration of aminoethyl phosphonic acid (AEP) on the liver microsomal drug metabolism and ultrastructure were studied in normal and 1% cholesterol-fed albino rats. AEP administration to rats fed a stock-diet resulted in decreased demethylation of aminopyrine with a concomitant fall in cytochrome P-450 level. Aniline hydroxylation remained unaltered. AEP injection to cholesterol-fed rats, caused marked reduction in both aminopyrine demethylation and aniline hydroxylation, with a significant increase in cytochrome P-450 level. AEP injection to both control and cholesterol-fed animals produced a modest increase in Bilirubin UDP-glucuronyl transferase. RNA:DNA ratio showed remarkable elevation in rats fed the cholesterol diet with AEP injection. AEP injection caused an atypical smooth endoplasmic reticulum and a marked loss of nuclear euchromatin. Effect of AEP was more pronounced in rats receiving the cholesterol-diet. AEP administration thus induces structural and drug metabolic enzyme alteration in liver.


Effects of vitamin B-6 deficiency on the developing central nervous system of the rat. Gross measurements and cytoarchitectural alterations. The effects of different levels of dietary pyridoxine (1.0, 1.2, 1.4, and 20.0 mg/kg diet) fed to dams from weaning through lactation on gross measurements and cytoarchitectural alterations of brains of progeny were investigated. Progeny of the 1.0 and 1.2 groups died between 15 and 21 days of age due to the severe vitamin deficit. Differences were observed in brain and body weights and brain: body weight ratios. Vitamin B-6 concentrations in brain ranged from 498 to 713 ng/g in the three lower groups and were markedly lower than for the 20.0 group (2,256 ng/g). Protein concentrations were not different. Changes in cytoarchitecture, as seen by light microscopy, included reduced area in the neocortex and, to a greater extent, in the cerebellum of the deficient groups. Molecular and granular layers, but not medullary layer, of the cerebellum were significantly reduced. Significantly greater granular layer/molecular layer area ratios (GMR) in the 1.2 and 1.4 groups indicated that the molecular layer was more affected in these groups while both layers were affected in the 1.0 group. Purkinje cells were dispersed from the usual monocellular layer in the 1.0 and 1.2 groups. The results indicated that central nervous system development in the progeny is altered parallel to the maternal vitamin B-6 intake levels.


Effects of vitamin B-6 deficiency on the developing central nervous system of the rat. Myelination. The effects of different levels of dietary pyridoxine (1.0, 1.2, 1.4, and 20.0 mg/kg diet) fed to dams during growth, gestation and lactation on myelination in progeny were investigated. Degree of myelination at 15 days, postnatally, was determined from closely matched micrographs of the four dietary treatment groups. Electron micrographs showed markedly less myelination in the 1.0 group as compared with the 1.4 and 20.0 groups with the 1.2 group appearing intermediate in the number of myelinated axons. Some myelinated axons of the 1.0 group exhibited an "unusual" appearance of whorls of lamina separated by cytoplasmic space occupied by widely separated lamina. The results indicate that brain development, particularly myelination, was affected by a deficiency of vitamin B-6 prior to and including the period of rapid myelination.


Changes in organ growth with feeding pattern. The influence of feeding frequency on the circadian rhythm of protein synthesis in the rat. The effect of eating one large meal rather than several small meals per day on protein metabolism and the growth of individual organs was investigated in young male rats. Meal-eating did not affect the rate of protein catabolism in liver, kidney, small intestine, or spleen in vivo compared with continously fed control animals that consumed the same total amount of food. A circadian rhythm of protein synthesis was found in liver and kidney slices taken from normal rats killed at various times; starvation reduced the magnitude of protein synthesis but did not alter its cyclical nature. Consumption of the daily food all in one meal distorted the circadian rhythm, particularly when it was taken in the morning, and a morning meal increased the total 24 hour synthesis of protein in liver whereas an evening meal did not. Meal-feeding in the morning increased the weights of the liver, small intestine and tibia compared with continuously fed rats, but meal-feeding in the evening did not.


Effect of a low protein diet on in vitro protein synthesis in thymus, spleen, and bone marrow in young adult rats. Young adult rats (body weight 90 g) were given a low protein (3% casein) diet for 6 days. Under these conditions, thymus and spleen organ wet weights and DNA content decreased as compared with control rats given a high protein (20% casein) diet. The in vitro incorporation of amino acids into protein was followed using leucine as the radioactive precursor. Ribosomes of tissues from the dietary rats were incubated together with soluble enzymes from liver of rats fed a stock diet, and cofactors. Ribosomal capacity for leucine incorporation into protein diminished in thymus by 33% per mg ribosomal RNA, 77% per total ribosomal RNA, and 43% per mg DNA. In spleen the corresponding reductions were 29%, 81%, and 31%; in bone marrow the decrease was 29% per mg ribosomal RNA, 56% per total ribosomal RNA, and 19% per mg DNA. A reduction in physiological activity is thus evident in these tissues soon after protein restriction.


Analysis of fecal bile acids and diet among the Japanese in Hawaii. Fecal samples of 165 Japanese men in Hawaii, age 43 to 74, were analyzed for bile acid content by their conversion to the methyl ester and the trimethylsilyl ether derivative followed by separation on a gas chromatograph. The arithmetic mean of total bile acids for the 165 specimens was 10.96 mg/g dry weight feces. Each of the following bile acids was detectable in over 77% of the fecal specimens: cholic, deoxycholic, lithocholic, and cholanic acid. The intake of Western foods was not positively correlated with the fecal content of secondary or modified bile acids, even though other workers have observed that these bile acids predominated in persons from Westernized countries. Two of the Japanese foods were negatively correlated with the levels of modified bile acids, which suggested that these foods contributed to a decrease in modified bile acids in fecal specimens. Fecal bile acid measurements appeared to be associated with age, but not with weight, height, or serum cholesterol levels.


The influence of zinc-deprivation on the mast cell population of the bone marrow and other tissues. Five groups consisting of 72 young male Sprague-Dawley rats were submitted to dietary Zn deprivation (1 ppm versus 50 ppm for controls) for periods of 1 to 6 weeks with ad libitum or pair feeding. After 1 week of Zn deficiency, growth was almost arrested, the oesophageal epithelium became hyperplastic. After 3 weeks, the mast cell population of the bone marrow increased rapidly in ad libitum fed and also in pair-fed rats. Between 3 and 5 weeks, the thickness of the proximal epiphyseal plate of the tibia decreased by 33%. Contrary to Mg-deficient rats, Zn-deprived rats maintained their skin and thyroid mast cell populations after 5 weeks. The mast cell population of the metaphysis of the tibia increased from 1 to 5 weeks in both Zn-deficient and Zn-supplemented rats. In the Zn-deprived rats however, the mast cell population became increasingly higher than in the Zn-supplemented, from 1 to 5 weeks. In the pair-fed group, the mast cell population of the marrow was also significantly higher after 3 weeks. The special response of the bone marrow cells to Zn-depletion points to this tissue as a renewal site. Zinc may also be a maturation factor for mast cells.


Phosphate absorption and excretion in the young turkey, as influenced by calcium intake. Phosphorus absorption in the young turkey, measured with the aid of yttrium-91 as a reference substance, was linear with phosphorus intake. This observation suggested the lack of adaptation of the phosphorus transport mechanism to changes in the phosphorus needs. Phosphorus retention and bone ash initially increased with increased intake to plateau at a dietary phosphorus concentration of about 0.8%. The excess phosphorus absorbed from diets higher in phosphate, was eliminated in the urine. Plasma inorganic phosphate was linear with absorbed phosphate. The apparent phosphorus absorption from the basal vegetable diet was 45% of the intake and that of the inorganic supplement, sodium phosphate and calcium monophosphate, was about 100%, at low calcium intakes. Increasing the calcium intake above 440 mg/day progressively depressed the absorption of phosphate. This inhibitory action of calcium on phosphate absorption was resolved into a linear coefficient.


Effect of low lysine diet on rat liver nuclear metabolism. Prolonged dietary lysine deficiency induced by feeding male weanling rats a diet low in lysine for 6 weeks resulted in substantial impairment of growth as compared with control rats and in alterations in the morphology of the nucleus of hepatocytes. Electronmicrographs of liver nuclei from lysine deficient rats showed an increased incidence of binucleated cells, reduction in numbers of nucleoli, changes in the position and size of nucleoli within the nucleus and altered patterns of chromatin aggregation in lysine deficient rats. Mass ratios of nonhistone proteins to DNA in liver chromatin from lysine deficient rats were higher than those of controls and electrophoretic patterns of chromatin nonhistone proteins were altered. In particular, one high molecular weight fraction of these proteins showing the same mobility as myosin was substantially enriched. The histone: DNA ratio and histone electrophoretic patterns, however, appeared to be unchanged. Incorporation of [3H] thymidine into DNA was increased, but the nuclear content of DNA was unchanged in lysine deficient animals.


Lipogenesis in the brain of thiamine-deficient rat pups. (1) The effect of thiamine deficiency during pregnancy and lactation on lipogenesis in the brain of rat pups was determined. (2) Acetate incorporation to brain lipids in thiamine-deficient rats in vivo was no less than in pair fed control rats, apart from slightly reduced fatty acid synthesis in the cerebrum. (3) Glucose incorporation to brain lipids in vivo was considerably reduced in thiamine-deficient pups. (4) The inducible NADP dependent malic enzyme activity was increased in thiamine-deficient pup brains. (5) The synthesis of acetyl-CoA appears to be the rate limiting step in lipogenesis in thiamine-deficient pup brains.


Electrocyclization reaction of higher conjugated polyenals: photochemical behaviors of retinal (vitamin A1 aldehyde) homologues. During the studies on a photoreaction of retinal, involving various kinds of (Z)-(E) isomerization, a heretofore unknown photoproduct of retinal was isolated in a pure state and was characterized unambiguously. Thus, direct irradiation of all-(E)-retinal (I) and of all-(E)-beta-ionylidenecrotonaldehyde (II) in acetonitrile solution gave the corresponding 6e-electrocyclized photoproducts, (III) and (IV), both via the possible 7-(Z)-isomer intermediates of the parent conjugated polyenals. Unlike the lower members in the retinal series, it was also confirmed that sigmatropic rearrangement or photo-Diels-Alder reaction hardly proceeds in these higher members of the series mentioned above.


A cause of hypercholesterolemia in alloxan diabetic rat. In studies on the cause of hypercholesterolemia in alloxan diabetic rats, the pool size and basal daily synthesis of conjugated bile salts were measured by the washout method and neutral sterols in the luminal contents were determined using cholestyramine. The results showed that in diabetic rats: 1) the biliary excretions of cholesterol and bile salts were significantly increased; 2) the pool size of conjugated bile salts was increased and its rate of synthesis was higher than in controls; 3) the amount of neutral sterols in the luminal contents doubled when cholesterol absorption was inhibited by administration of cholestyramine; 4) the amount of neutral sterols excreted in the feces was the same as in controls. Thus, it was concluded that hypercholesterolemia may be partly caused by an increased rate of intestinal absorption of cholesterol, derived mainly from sloughed off epithelial cells and bile, and due to facilitated micellar formation by the increased amount of bile salts in the intestine.


Effect of nicotinic acid on catecholamine synthesis in rat brain. Effect of nicotinic acid on the formation of catecholamine has been studied. Norepinephrine and dopamine concentrations in brain were 30 per cent higher and brain catecholamine formation was 50 per cent higher in the nicotinic acid-supplemented rats than the nicotinic acid-deficient rats. However, these catecholamine levels of the nicotinic acid-deficient rats were recovered by the administration of nicotinic acid. The concentration of brain tyrosine was unaltered after administration of nicotinic acid to the nicotinic acid-deficient rats. Therefore, the changes catecholamine formation by the nicotinic acid supplementation were not due to the difference of tyrosine concentration in the brain which is the precursor for catecholamine biosynthesis. As the difference of catecholamine concentration between the nicotinic acid deficient and the nicotinic acid supplemented group was smaller than that of catecholamine formation of these groups, the turnover of catecholamine was supposed to be decreased in nicotinic acid deficiency.


Mode of binding of pyridoxal 5'-phosphate in rat liver ornithine aminotransferase. 1. Pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate were effective for the association of apo-form II of ornithine aminotransferase [EC 2.6.1.13]; whereas other B6 derivatives, such as pyridoxal, pyridoxamine, pyridoxine and pyridoxine 5'-phosphate, had no effect on form II of this apoenzyme. 2. The pyridoxal 5'-phosphate contents of the native enzyme, and reconstituted forms I and II were determined by two different methods to be 1.5 moles, 2.5 moles and 3.3 moles of pyridoxal 5'-phosphate/mole of enzyme, respectively.


The effect of homocysteine, methionine, serine and glycine on DNA synthesis by human normoblastic and megaloblastic bone marrow cells. Both glycine and methionine, when added to a suspension of human bone marrow cells, impaired the utilization of deoxyuridine for DNA synthesis, using either the uptake of 3H-deoxyuridine or the subsequent uptake of 3H-thymidine as an index. Homocysteine reduced the uptake of both 3H-deoxyuridine and 3H-thymidine, indicating interference with DNA synthesis after the stage of thymidylate synthesis. Another explanation that the decreased uptake of both substances by homocysteine was due to cell damage caused in vitro was suggested by the trypan blue viability test. Serine generally did not produce significant effects. No difference could be detected between the results in normoblastic and megaloblastic marrow.


Analysis of physical fitness and coronary heart disease risk of Dallas area police officers. Two hundred thirteen male police officers between 21 and 52 years of age volunteered to participate in a physical evaluation and conditioning program. Information concerning the physical fitness status and risk of coronary heart disease (CHD) of police officers were shown. Younger police officers (less than 30 years of age) were average in physical fitness levels and CHD risk compared to the population of the same age. Middle-aged police officers were shown to be lower in physical fitness levels and higher in CHD risk compared to their cohorts. The results from this investigation support the need for physical fitness and preventive medicine programs for police officers.


Mortality of female workers in rubber manufacturing plant. The ten-year mortality experience of a cohort of white female production workers in a large rubber manufacturing plant is presented. An analysis of the observed and expected numbers of death from numerous causes revealed a slightly elevated overall standarized mortality ratio with an excess of deaths from both lung cancer and myocardial infarction, and a deficit of deaths from breast cancer. About two-thirds of all women in this cohort had worked, for the longest period of employment, in the manufacture of industrial products, while the remainder were engaged mostly in the manufacture of tires. Some preliminary associations between type of job and mortality experience are discussed, but a more detailed analytic investigation is required before nonoccupational risk factors can be ruled out.


Occupational pharmacology.

Occupational pharmacology. Occupational pharmacology is defined as a subdiscipline important to occupational safety and health, in which specialized information is gathered and evaluated. Occupational pharmacologist study and evaluate drugs used to combat or prevent occupational diseases. They also perform studies on occupational chemical-drug interactions. Specialized training programs are needed to produce qualified individuals for expected future needs.


Mesothelioma in the United States. Incidence in the 1970's. Mesothelioma is a rare neoplasm, the occurrence of which has been clearly related to asbestos exposure. Data recently collected by population based cancer registries in Washington, Hawaii, New Mexico, Connecticut, Michigan, Utah, Louisiana and Iowa were obtained for the determination of mesothelioma incidence rates. These registries represent a total population of over 16 million persons. Crude incidence rates were found to range from 3.0 to 7.1 per million per year. Age specific incidence rates showed a steady increase from the third through the eighth decade, with a more rapid increase for males than females. Sex specific incidence rates, age adjusted to the 1970 U.S. population, were found to range from 4.4 to 11.1 per million per year for males and from 1.2 to 3.8 per million per year for females. The highest rates for both males and females were found in the New Orleans area of Louisiana and the Puget Sound area of Washington state, both with significant shipbuilding activity.


Geographic patterns of industry in the United States. An aid to the study of occupational disease. The geographic location of 18 major manufacturing industries within the United States is illustrated by a series of computer-generated county maps. The metal and machinery industries, the two largest employers, an the transportation and rubber industries are concentrated in the northeastern quadrant of the United States, while most counties with textile, apparel, tobacco, and furniture manufacturing are in the South. Other industries had different patterns. The counties where industry was concentrated tended to be more urban and to have higher levels of income and education. The maps and associated demographic data on industrial counties may prove a useful adjunct to county maps illustrating mortality patterns for cancer and other diseases. Despite obvious limitations, the visual patterns and correlation analyses may help to generate and formulate hypothese concerning occupationally induced diease.


A study of three preventive approaches to low back injury. The prevention of low back injuries in industry has traditionally been attempted by (1) careful selection of workers, (2) good training in safe lifting, and (3) designing the job to fit the worker (ergonomics). One hundred ninety-one low back injuries were analyzed to determine the effectiveness of each preventive approach. The results indicate that the common selection techniques, as they are being used today, are not an effective control for low back injuries. Similarly, training on safe lifting procedures, as it is being administered today, is not an effective control for low back injuries. It was determined that a worker is three times more susceptible to low back injury if exposed to excessive manual handling tasks. The ergonomic redesign of these tasks to reduce the manual handling exposure represents a partial control for low back injuries.


Urinary cytologic examinations of laboratory workers. Useful medical surveillance tool or clinician's nightmare? An apparent excess of abnormal urine cytological findings in crime laboratory workers exposed to potentially carcinogenic aromatic amines was investigated by a cross-sectional epidemiologic study comparing these workers with an unexposed control group. The prevalence of atypical findings in the laboratory workers exceeded that in the control group; however, the results were not statistically significant. A number of serious problems were identified including a high prevalence of inflammatory changes (25% to 26%) and a moderately high percentage of atypical changes (2.5% to 5.4%) in the control population, failure to detect (on urological workup) evidence of neoplastic disease of the urinary tract in any of the laboratory workers whose urine examinations were cytologically interpreted as either atypical or neoplastic cells, and difficulty in determining proper referral criteria for urological workup.


Toxicology: assessing the hazard.

Toxicology: assessing the hazard. Some of the fundamentals of toxicology that are used by the toxicologist in assessing the toxic properties of compounds have been discussed. It is easy to see that a large amount of keen professional judgment must enter into the toxicologist's decisions. It is not a job that can be done by an amateur, even though some well meaning lay and political associates may believe they are capable of doing so. The toxicologist's job is not finished when he has determined the toxicological properties of a compound. He then has to assess the hazard of the compound, an infinitely more complex and complicated task. In the end, as stated by Dr. Mrak, "There are no harmless substances, there are only harmless ways of using substances" (quoted in Reference 1, p. 11).


Spatial summation effects on two-component grating thresholds. Some experimental studies of subthreshold summation between sinusoidal grating components have been interpreted as showing very narrow channel bandwidths in human visions. This paper discusses an alternative interpretation of these experiments based on consideration of probability-summation effects among spatially distributed detectors. We conclude that frequency-selective channels must still be hypothesized in order to fit the data, but the channel bandwidth may be much wider than earlier interpretations suggest.


Brightness exponent for the periphery in the Bloch region. Using a method of direct magnitude estimation, perceived brightness was measured in the dark-adapted eye with brief flashes of varying duration in the Bloch region (1-100 ms) and retinal lock (0 degrees-40 degrees) for the photopic luminance levels covering the range between 140 and 0.14 cd/m2 in steps of 1 log unit. Perceived brightness increased as a function of flash luminous energy (product of luminance and duration) up to critical duration of approximately 100 ms. The brightness power exponent for brief flash was found to be 0.48 +/- 0.01 in the fovea, whereas about 0.44 +/- 0.01 in the periphery.


A visual system model and a new distortion measure in the context of image processing. Underlying many techniques of image restortation, quantization, and enhancement is the mathematically convenient, but visually unsuitable distortion measure of squared difference in intensity. Squared-intensity differences has an indirect phenomenological correspondence in a model of the visual system. We have undertaken, therefore, an experiment that derives a new distortion measure from an acceptable visual system model and compares it in a fair test against squared difference in intensity in an image restoration task. We start with an eye-brain system model inferred from the works of current vision researchers, which consists of a bank of paralles spatial frequency channels and image detectors. From this model we derive a new distortion criterion that is related to changes in the per-channel detection probability and phase angle. The optimal linear (Wiener) filters for each distortion measure operate in turn on the same noisy incoherent images. The results show that the filter for the new distortion measures yields a superior restoration. It is more visually agrreable, more sharply detailed, and truer in contrast compared to the squared-difference filter, and impressive in its own right. Its mathematical properties suggest that significantly increased efficeincy in the storage or communication of images my be gained by its use.


Subjective Lorentz transformations and the perception of motion. It has been known for some 40 years that the perceived velocity of a moving object does not correspond to its physical velocity. It is also known that the perceived length and temporal duration of a moving objects is affected by its physical velocity. In this paper it is argued that such phenomenal distortions can be embedded in a model for motion perception that involves the concepts of moving frames, Lorentz transformations, perceived length contractions, and time dilations. Experimental results support this model and indicate that c, the maximum perceivable velocity of movement, plays a crucial role in determining motion effects.


Complementary afterimages and the unequal adapting effects of steady and flickering light. Prolonged exposure to flickering chromatic light of moderate intensity produce a much weaker complementary afterimage than that produced by exposure to stead light of the same average intesity. This difference in adapting effectiveness was investigated by determining theretinal illuminance of the study adapting field required to produce an afterimage equal to that produced by the flickering adapting field. In a variety of conditions, the greater effectiveness of the steady adapting field was confirmed; in several instances a steady field having an average retinal illuminance of only 0.05 times that of the flickering field gave rise to an equally saturated afterimage. The results are taken as evidence that complementary afterimages produced by extended moderate intensity exposure are primarily a consequence of neural adaption.


Steroscopic acuity for moving retinal images. Stereoscopic acuity in the human fovea remains unimpaired with retinal image motions of up to 2 deg/s. These findings apply to lateral motion of the test target alone, and to simultaneous lateral motion of both test and comparison targets. For good steroscopic acuity, depth motion can be tolerated only so long as the configuration does not move outside the disparity zone for optimal stereoscopic acuity, within 2-3 arc min of either side of the fixation plane. The presence during a short exposure of some stimulus components lying outside this zone leads to an overall reduction of stereoscopic acuity, either by dilution through summation, or by active inhibition of the best achievable depth resolution.


Convexity theorem for subthreshold stimuli in linear models of visual contrast detection. Under the general assumption that visual contrast detection occurs by a parallel array of linear detectors, either without probability summation or with probability summation of a commonly assumed type, it is shown that the set of functions representing subthreshold stimuli must be convex. Thus, for example, a planar plot of the threshold locus using multiples of any two functions as axes, must be convex (cannot bulge inward). If experimental evidence to the contrary were discovered, it would rule out detection by parallel linear detectors of the above type. One possible kind of such evidence would be an inward cusp of the threshold locus corresponding to one of a special class of stimuli to which the visual system might be specifically sensitive.


Accommodation and color.

Accommodation and color. Previous studies of the effects of color on the accommodation response are reviewed. The monocular, steady-state response to targets under various colors of illumination is investigated. It is shown that trained observers change their level of accommodation, when viewing a target at a constant distance, to compensate for the varying ocular longitudinal chromatic aberration as the color of the target is changed. Untrained subjects, however, may initially show inconsistent responses. Results in white and greeen are closely comparable. Dynamic aspects of these effects are illustrated and it is shown that the ocular longitudinal chromatic aberration increases slightly with accommodation. The results are related to current ideas on the accommodative system.


Laser Doppler measurements of blood velocity in human retinal vessels. We have measured Doppler shift frequency spectra (DSFS) of laser light scattered from red blood cells (RBC's) flowing through individual human retinal vessels. Each spectrum exhibits a cutoff frequency which is directly related to the maximum RBC velocity at the measurement site. Meaningful DSFS can be measured in times as short as 0.1 s. DSFS obtained from suspensions of polystyrene spheres and RBC's flowing through glass capillary tubes are used to illustrate the basic principles of the technique and to aid in the interpretation of the in vivo measurements. Our measurements show that maximum RBC velocities in retinal arteries vary markedly during each cardiac cycle.


Need for iron supplementation in infants on prolonged breast feeding. Iron status, as measured by blood counts and indices, serum iron, transferrin saturation, and serum ferritin values, was studied longitudinally in 56 infants on prolonged breast feeding, and compared to that of 29 infants receiving cow milk formula prepared at home and of 47 infants receiving a proprietary infant formula. The first two groups received no iron supplementation, whereas the proprietary formula was supplemented with iron. Although breast feeding was found to be sufficient to meet iron needs during the first 6 months of life, supplemental iron would be necessary during the second half of infancy in order to guarantee the optimal iron status.


Ductal remnants in extrahepatic biliary atresia: A histopathologic study with clinical correlation. Atretic ducts were studied in 34 infants undergoing the portoenterostomy procedure for biliary atresia. The specimens were grouped into three categories on the basis of the size of the lumen at the proximal margin: Type I with a lumen 150 mu or greater, Type II with single to multiple ductal structures measuring less than 150 mu, and Type III with no identifiable epithelium-lined structures in fibrous connective tissue. A significant correlation existed between postoperative bile drainage and the duct type; bile drainage occurred in all five patients with Type I ducts, 18 of 21 patients with Type II ducts, and one of eight patients with Type III ducts. Furthermore, the duct type was the only feature that correlated with the ultimate outcome. Ductal inflammation and hepatic histology did not correlate with postoperative bile drainage or clinical course.


Human neonatal and maternal monocyte-macrophage and lymphocyte-mediated antibody-dependent cytotoxicity to cells infected with herpes simplex. We recently have described destruction of cells infected with herpes simplex virus by the combination of specific antibody and either lymphocytes or monocyte-macrophages. Because of the role of these cells in viral immunity and the severity of HSV in neonates and pregnant women, cord blood from 11 healthy neonates and peripheral blood from seven of their postpartum mothers were analyzed for MP and lymphocyte antibody-dependent cellular cytotoxicity against cells infected with HSV. Cord blood yielded more lymphocytes and maternal blood fewer lymphocytes than did blood from adult female control subjects. Baseline cytotoxicity of cord MP and lymphocytes and maternal lymphocytes was significantly lower than control values. There was no significant difference in MP or lymphocyte ADCC, although maternal ADCC tended to be lower than that of control subjects. Analysis of cord plasma indicated that antibody able to participate in lymphocyte and MP ADCC crosses the placenta. These data demonstrate intact ADCC but possible defects in baseline cytotoxicity with leukocytes obtained from neonates and pregnant women. Further consideration of the use of HSV antibody for prevention and therapy of neonatal HSV infection is suggested.


Chronic recurrent multifocal osteomyelitis and pustulosis palmoplantaris. Based on nine patients 4 to 26 years of age, we describe the clinical characteristics of chronic recurrent multifocal osteomyelitis. This disorder was characterized by an insidious onset of fever, local swelling and pain in affected bones, and radiologic findings suggesting osteomyelitis. The lesions were mainly localized to the clavicles and the metaphyses of tubular bones. The clinical course was characterized by intermittent periods of exacerbation and improvement over several years. Six of the patients had recurrent pustulosis palmaris and plantaris, which closely parallelled the exacerbations of the bone lesions. Biopsies from the bone lesions showed nonspecific inflammatory changes with granulocytic infiltration. Repeated bacterial and fungal cultivations from blood, bone biopsies, and pustules were negative. Immunologic investigation revealed no abnormality common to the patients. There was no indications of a genetic etiology. The pathogenesis of the disorder is unknown. Antibiotic treatment had no obvious effect but corticosteroid therapy appeared to be of benefit in some patients. The long-term prognosis appears to be relatively good.


Spontaneously acquired factor IX inhibitor in a nonhemophiliac child. A 2 1/2-year-old, previously healthy child developed progressive swelling of the left leg and a hematoma of the anterior chest wall associated with a falling hemoglobin concentration, as a result of a spontaneously acquired Factor IX inhibitor. Successful management of her condition required a four-volume exchange transfusion and immunosuppressive therapy consisting of cyclophosphamide for four days and prednisone for one month. A brief review of the literature regarding the occurrence and nature of acquired coagulation factor inhibitors and the role of immunosuppressive therapy is also presented.


Thiamine-responsive megaloblastic anemia, sensorineural deafness, and diabetes mellitus: A new syndrome? A 6-year-old girl is described who has congenital megaloblastic anemia which completely responded only to pharmacologic doses of thiamine. Relapse was observed twice when the drug was discontinued. The reintroduction of thiamine caused a prompt reticulocytosis and a rise in hemoglobin concentration. Other abnormalities included latent diabetes mellitus, sensorineural deafness, and "situs inversus totalis." Her parents are first cousins, both with partial deafness. Her father has an abnormal oral glucose tolerance test. A single similar case has been reported; the combination of almost the same anomalies seems to represent a newly recognized syndrome. This case reinforces the proposal that thiamine has a role in hematopoesis.


Confirmation of the Cohen syndrome.

Confirmation of the Cohen syndrome. In 1973 Cohen et al reported a new syndrome in two siblings and an unrelated individual, consisting of obesity, mental retardation, hypotonia, limb abnormalities, and a characteristic craniofacial appearance. Since then no similar cases have appeared in the literature. This report firmly establishes the Cohen syndrome as a distinct clinical entity by presenting four additional patients, including a sibling pair of normal parents, suggesting autosomal recessive inheritance. One of our four patients has normal intelligence, indicating that mental deficiency is a variable feature of the syndrome.


Noninvasive estimation of arterial oxygenation in newborn infants. Two noninvasive methods of estimating arterial oxygenation were compared in a group of 48 infants ranging in birth weight from 870 to 4,000 gm, with diagnoses including apnea of prematurity, hyaline membrane disease, meconium aspiration, and congenital heart disease. Both transcutaneous oxygen measurements and ear oximetry gave reasonably accurate estimations of arterial oxygen levels within commonly used clinical ranges (PO2 50 to 70 mm Hg, arterial saturation 90 to 98%). Infants with shock demonstrated a wide range of values for transcutaneous oxygen levels, suggesting that this method has limited usefulness in this situation. Ear oximetry had limited ability to distinguish high, but safe, levels of arterial oxygen from excessively elevated levels. While neither method can be recommended for replacement of arterial oxygen sampling, both methods may be useful in a clinical setting if care is exercised in interpretation of the results and if the values obtained are checked against those from arterial blood.


Plasma levels, half-life values, and correlation with physiologic assays for growth and immunity. Plasma prednisolone levels have been measured hourly in children receiving a single dose of oral prednisone. Peak prednisolone levels occurred one to two hours after ingestion; half-life studies gave a mean value of 132 minutes in most children. Some children had marked variability in absorption and metabolism of prednisone. Somatomedin activity and cell-mediated immunity were inhibited by plasma prednisolone values which were achieved by single doses of prednisone of 0.5 mg/kg or higher. Monitoring prednisolone levels may be of value in identifying those children who accumulate excessively high levels on moderate dosage regimens.


Voiding cystourethrography in infants and children: a new technique. A technique for voiding cystourethrography utilizing a small caliber (3.5 Fr.) catheter that is left in place during the entire examination is described and illustrated. Urethral pathology is not obscured. The contrast is infused under pressure applied with a blood administration set. Visualization of voiding can be achieved in all cases.


Evaluation of ischemic bowel viability with a fluorescent technique. Clinical estimations of bowel viability after ischemic insult are unreliable. Accurate criteria are essential to avoid unnecessary resection. This study describes a safe technique using fluorescein that predicts bowel viability with increased accuracy.


Congenital diaphragmatic hernia: the hidden mortality. From 1969 to 1975, 33 cases of congenital diaphragmatic hernia (CDH) were treated at the National Hospital of Norway with a "visible" or operative mortality of 30%. At least 37 additional infants with CDH who died soon after birth and did not come to the attention of a major referral center were identified retrospectively from a comprehensive survey of neonatal deaths. CDH occurred at least once in every 5455 live births and the "true" mortality was 66%. More than half of the infants born with CDH during this 6-yr period died before they could be treated, contributing to a substantial "hidden" mortality.


Open thoracotomy and pleural abrasion in the treatment of spontaneous pneumothorax in cystic fibrosis. The various treatments of spontaneous pneumothorax in cystic fibrosis are examined over a 15-yr period. Open thoracotomy with pleural abrasion is compared to observation, tube thoracostomy, and tube thoracostomy with instillation of quinacrine. Open thoracotomy with pleural abrasion has been performed 31 times in 20 patients. Discussion centers around selection of patients, preoperative preparation, operative technique, and postoperative care and follow-up, including analysis of pulmonary function studies. In our experience, open thoracotomy with pleural abrasion is a safe and effective method that should be utilized in the management of pneumothorax in patients with cystic fibrosis.


A new nonoperative treatment of large omphaloceles with a polymer membrane. The management of a huge omphalocele that cannot be primarily closed presents many difficulties. When surgery is technically impossible, the application of a Silon pouch carries a serious risk of infection and painting the sac with tinctures has its own peculiar problems. A newborn baby with a large unruptured omphalocele was successfully treated by covering the sac with a skin-like polymer membrane that is flexible, elastic, and impervious to bacteria and water. The covering did not adhere to the underlying tissues and did not interfere with gastrointestinal function. Infection was not a problem. This material was wrapped around the trunk and covered with a dry sterile dressing. The entire dressing was removed after 3 wk, revealing a small residual area of granulations that subsequently healed at home. This baby was not operated upon. We have also used this technique in a second newborn in whom the sac had ruptured. The rent was repaired and the membrane applied. This method does not eliminate later closure of the large ventral hernia, but ccertainly eliminates the necessity for surgery in the newborn period.


Plication of the diaphragm for symptomatic phrenic nerve paralysis. Paralysis of the diaphragm in infants may produce severe respiratory difficulty because of the paradoxic motion of the affected diaphragm and shift of a mobile mediastinum to the contralateral side. Six infants with diaphragmatic paralysis and severe respiratory distress underwent plication of the diaphragm by a simple technique. Five of the six infants had significant improvement in respiratory effort and were ultimately weaned from ventilatory support. One patient with bilateral paralysis had only minimal improvement. Diaphragmatic function returned in two patients after plication. Plication of the diaphragm is a safe and useful procedure to improve ventilation in infants with a paralyzed diaphragm. Since this technique does not prevent return of diaphragmatic function, it should be employed prior to the development of sequelae of prolonged assisted ventilation and sooner if the phrenic nerve is permanently injured.


Subclavian flap aortoplasty for treatment of coarctation in early infancy. In a 2-yr period 12 infants less than 2 mo of age underwent surgery for critical coarctation of the aorta. All had severe congestive failure with unsatisfactory response to medical therapy. In all patients the coarctation was located in the preductal or preligamentous region. Eleven patients had an associated ventricular septal defect (VSD). Early (1-mo) survival in the patients with VSD was 82%. Two early deaths occurred; there have been five late deaths on follow-up of up to 30 mo. In all patients who expired, the cause of death was unrelated to the coarctation repair. Recurrent coarctation has occurred in one patient. Early aggressive surgical intervention is indicated in the management of coarctation of the aorta both with and without VSD.


Esophageal atresia with double tracheoesophageal fistula. Ninety cases of esophageal atresia (EA) with double tracheoesophageal fistula (TEF) from the literature and 4 new cases are examined. The incidence may be more common than is generally recognized with incidences up to 5.3% reported. The pre-, intra-, and postoperative diagnosis may be difficult, and half have been missed initially with almost half of these being first recognized at autopsy. During repair of EA and TEF the proximal esophagus should be mobilized looking for a proximal fistula. Many proximal TEF are missed at the initial operation and discovered in the postoperative period. The symptoms, diagnosis and treatment of the unrecognized proximal TEF are similar to that for isolated TEF. Results should be good since this problem occurs in large babies with fewer and less complex associated conditions.


True hermaphroditism: a clinical description and a proposed function for the long arm of the Y chromosome. True hermaphroditism is a very rare form of ambiguous genitalia characterized by the presence of both ovarian and testicular tissue in the same individual. Sixty percent of these patients have a 46,XX karyotype; however, most have H-Y antigen detectable. Since H-Y antigen is thought to be the gene product of the short arm of the Y, then the short arm must be present somewhere in the karyotype. Products of the short arm loci are thought to initiate testicular differentiation and male determination. The long arm of the Y has not been detected in true hermaphrodites. Testicular histology in true hermaphrodites is characterized by spermatogenic arrest, causing us to speculate that the long arm of the Y might be essential for germ cell maturation beyond the spermatogonia state.


Management of large skin defects in newborn children with myelodysplasia: a new method. A method successfully used in closing a large skin defect in each of three children with myelodysplasia is described in detail. Full thickness skin closure was achieved in 7--10 days without skin grafts or rotation flaps.


Prepyloric gastric antral web: a puzzling epidemic. Antral webs and diaphragms are considered a rare cause of gastric outlet obstruction in infants and children. A radiographic diagnosis of antral web was made in 28 children during a 26-mo period. Nonbilious, often projectile vomiting was the predominant presenting symptom in 24 infants who were less than 6 mo of age. The older children complained of pain, vomiting, fullness after eating, and eructation. The characteristic radiologic finging was a wirelike transverse septum 1--2 cm proximal to the pylorus. Poor antral filling was an important early clue in the radiographic search for the webs. Pyloroplasty was performed in 20 patients, frequently after failure of medical management of symptoms. Coexistent congenital abnormalities were present in 28% of patients. A search for environmental and familial factors has failed to elucidate any teratogenic influences in this population.


Paracentesis and lavage for diagnosis of intestinal gangrene in neonatal necrotizing enterocolitis. A study to evaluate peritoneal fluid as an index of intestinal gangrene in infants with necrotizing entercolitis (NEC) was begun in 1974. Twenty samples of peritoneal fluid were obtained by paracentesis or lavage from 15 infants with nonperforated NEC. A brown color in the peritoneal fluid was noted in all 8 patients found to have intestinal gangrene at subsequent operation. Gram stain showed bacteria in 6 of these 8 patients and bacterial cultures were confimatory in all but one. In 12 samples of peritoneal fluid in patients without intestinal gangrene, the fluid was straw-colored or pink and Gram stain showed no bacteria. The decision to operate on an infant with intestinal gangrene and impending perforation may be aided by analysis of the peritoneal fluid.


Small bowel reversal procedure for treatment of the "short gut" baby. An increasing number of infants have undergone massive intestinal resection for various reasons: uncontrollable diarrhea, malabsorption, and failure to thrive makes these babies a difficult management problem and threatens their survival and later "quality of life." Five short gut babies have had a 3-cm small bowel reversal operation as part of the total salvage effort. It is recognized that very skilled care by dedicated personnel and parents, utilizing i.v. nutrition and special feeding techniques, is probably the most significant factor in achieving success with these babies. It is believed small bowel reversal helps in keeping these infants alive while their intestinal tract is making the adjustments necessary for long-term survival.


Determination of fetal maturity from the measurement of the sedimentary fraction of the amniotic fluid (amniocrit). A simple technique is described for evaluating foetal maturity. This consists in measuring the sedimentary fraction of the amniotic fluid (amniocrit). The amount of sediment, expressed in percent of the total liquid volume varies between 0.33% at 36 weeks of amenorrhea and about 2.22% at 40 weeks. These values are correspond to arithmetical means. The differences between pre-term and term pregnancy are highly significant (p less than 0.001). The mean at 32--36 weeks of amenorrhea is 0.27, and at 37--41 weeks is 1.45. A close correlation between gestational age and the fraction of sediment in amniotic fluid is shown in Fig. 1. The correlation coefficient was 0.726. This technique of measuring the sediment combines simplicity and reliability and can be employed where minimal resources are available, and in rural hospitals. The feasibility of using this procedure in institutions with limited resources is emphasized.


An eight channel telemetry system for the transmission of biomedical signals. An eight channel telemetry system is presented which has low dimensions, low weight and is easy to use. The transmission is in the 430 MHz band on the basis of pulse-width modulation in a time-multiplex mode. A standard 9 volt battery offers a minimum of 15 hours operation with an accuracy of 1%. The upper limit frequency is currently at about 100 Hz. A 9th channel serves to monitor the function of the system.


Salience of ethnicity in the spontaneous self-concept as a function of one's ethnic distinctiveness in the social environment. How likely people are to think of themselves in terms of a given personal characteristic is predicted from the distinctiveness postulate that the person, when confronted by a complex stimulus (such as the self), selectively notices and encodes the stimulus in terms of what is most peculiar about it, since these peculiar characteristics are the most informative in distinguishing it from other stimuli. This partial view of the person as an information-encoding machine (one is conscious of oneself insofar as, and in the ways that, one is different) is used to derive four predictions implying that ethnic identity is salient in children's spontaneous self-concepts to the extent that their ethnic group is in the minority in their social milieu at school. Our measure of salience of ethnicity was its being spontaneously mentioned by the children in response to a nondirective "Tell us about yourself" question. All four predictions were confirmed, though for several of the findings there are plausible alternative explanations.


Effect on retaliation of causal attributions concerning attack. In two studies, men were defeated on either 17%, 50%, or 83% of reaction time trials, received aversive noise, and could ostensibly retaliate by delivering shock to their partner. The noise level delivered was described in Experiment 1 as typical of most other people (high consensus) or atypical of most other people (low consensus) and in Experiment 2 as from a partner who knew (high foreseeability) or did not know (low foreseeability) the kind and level of stimulation controlled by the switches delivering reinforcement to the recipient. Hypotheses were based on the notion that retaliation increases as more personal causality is attributed to a provoker and that more personal causality is inferred in highly foreseeable--or low consensus--50% defeat conditions. As expected, greater differences in aggression between high and low consensus and between high and low foreseeability were displayed in the 50% defeat condition than in the other defeat conditions. Anticipated differences in inferences were obtained.


Distractibility in dieters and nondieters: an alternative view of "externality". Two experiments were performed in an investigation of the effects of distraction and emotional arousal on the proofreading performance of dieting female subjects. In Experiment 1, it was found that distraction initially impaired the performance of dieters and facilitated the performance of nondieters, a pattern previously shown by Rodin to apply to obese and normal weight subjects, respectively, and interpreted as evidence of greater externality in the obese. Subsequent retesting of the same subjects in succeeding months, however, revealed a complete reversal of the original results. In Experiment 2, the reaction to distraction found in the first phase of Experiment 1 was obtained when subjects were in a situation of minimal threat. In a situation of high threat, the relative distractibility of dieters was reversed, as in the latter phases of Experiment 1. An explanation is offered for these data in terms of the greater emotionality of dieters, the susceptibility of cognitive performance to arousal (distraction, anxiety) manipulations, and the potentially competing effects of distraction and anxiety. Implications for the prevailing "trait" view of externality (stimulus binding) are discussed.


Facilitation of social interaction through deindividuation of the target. It was hypothesized that actors want their perception of a target to be consistent with the type of interaction they expect. It was predicted that subjects expecting to aggress would deindividuate their target through the selective recall of deindividuating information. Conversely, subjects expecting a prosocial interaction should individuate the target. Further, angry subjects should deindividuate the individual who angered them. Male subjects were either angered or not angered by an experimental confederate and then given the opportunity to either shock, reward, or have no interaction with him. Subjects recalled information about the confederate either prior to or after the learning task. Subjects expecting to aggress deindividuated the target, whereas subjects expecting a prosocial interaction individuated him. Angry subjects deindividuated the target, nonangry subjects did not. Since the selective recall of information occurred prior to the interaction, the deindividuation (individuation) was aimed at facilitating future behavior rather than justifying it.


Effects of federal human subjects regulations on data obtained in environmental stressor research. A series of experiments on environmental noise was performed over a 3-year period. Those experiments in the series that incorporated federal subjects guidelines concerning informed consent failed to replicate the negative aftereffects of noise found earlier by Glass and Singer. The experiments that were performed before implementation of the federal guidelines, however, successfully replicated the Glass and Singer findings. To clarify this pattern of results, a final experiment was performed on two groups of subjects treated identically except that one group gave informed consent while the other did not. The results confirmed that the subject procedures involving informed consent as defined by the federal guidelines prevent the emergence of negative aftereffects of noise, possibly because these procedures give the subjects what amounts to control over the stressor. Similar phenomena may occur in research on other environmental stressors, such as crowding and electric shock, in which subject's perception of control is a critical variable. Possible techniques for performing future research of this type are discussed.


Controlled delivery of theophylline: chemistry of 7-acyl- and 7,7'-acylditheophylline derivates. 7-Acyl- and 7,7'-acylditheophylline derivatives were prepared from the reaction of theophylline with acid chlorides. In addition, a novel synthesis of these compounds was developed, which proceeds through an acylonium ion generated under mild conditions. The physical properties and stability of the derivative of choice, 7,7'-succinylditheophylline, depend on the synthetic procedure employed. This compound is a useful controlled-release prodrug of theophylline.


Assays and statistical analyses for antibiotic standards. Some microbiological assays and statistical analyses of test results used by the National Center for Antibiotics Analysis are described for the establishment of offical antibiotic reference standards. Examples are given of both cylinder plate agar diffusion assays and turbidimetric assays. Formulas providing simple and quick analyses of data are shown for calculating potency, determining limits for the potency, and performing validity tests on the results.


Equilibrium penetration of monolayers VI: cholesterol-cetrimonium bromide system. Equilibrium surface pressure-area isotherms for the penetration of cholesterol monolayers by the surfactant cetrimonium bromide are presented. From these isotherms, the saturation adsorptions of surfactant for various surface concentrations of cholesterol were calculated. Plots of adsorption against the inverse of the area per cholesterol molecule revealed two linear revealed two linear regions, corresponding to penetration at high and low monolayer areas. At high monolayer areas, surfactant adsorption into accessible areas of the surface was similar to adsorption at a monolayer-free surface. In this region, packing of cholesterol and surfactant molecules on the surface lowered the effective cross-sectional area of the cholesterol molecule. However, at low monolayer areas, adsorption was determined by the size of the surfactant ion and the effective area of the cholesterol molecule was equal to the collapse area of a pure cholesterol monolayer.


Pharmacokinetics of intravenous erythromycin. Erythromycin pharmacokinetics were examined following intravenous infusion to male subjects. The biological half-life of erythromycin in serum was 2 hr in individuals with normal renal function. The half-life varied in cases of reduced renal function, with values of 3.9 and 7.0 hr occurring in two subjects with severe renal impairment. Postinfusion serum erythromycin levels were adequately described by two-compartment model kinetics, and values for the distribution volume of the central compartment and the overall distribution are described. Estimated erythromycin distribution volumes in normal individuals may facilitate calculation of absorption efficiencies of erythromycin and its salts after oral doses.


Determination of salicylic acid and aspirin in multicomponent tablets by liquid chromatography on a nonionic resin. Aspirin and free salicylic acid were determined in combinations containing caffeine, phenacetin, salicylamide, and acetaminophen by liquid chromatography on poly(methyl methacrylate) resin. Precision and accuracy were +/- 2% for salicylic acid, the latter at levels corresponding to 0.02% of the aspirin content.


Correlation of aspirin excretion with parameters from different dissolution methods. The cumulative urinary excretion of four different aspirin products (two tablets, a capsule, and a timed-release tablet) was determined in a crossover study using five subjects. Comparison of in vivo results showed a significant difference in cumulative urinary excretion levels at only 1 hr. The excretion from the two regular tablets was significantly different from the timed-release tablet, but the capsule showed no significant difference from the other three products. Each product was tested in the USP, Levy beaker, and the regular and large magnetic basket dissolution apparatus. Analysis of variance of the in vitro results showed a significant difference between the aspirin products and the dissolution methods at selected times. In vitro comparison with in vivo results for the four products showed that a regression analysis can be used to determined which dissolution methods produce a significant correlation with urinary excretion.


Sensitive electron-capture GLC determination of metoclopramide in biological fluids. A highly sensitive and specific electron-capture GLC assay capable of detecting picogram quantities of metoclopramide, a procaine derivative, in biological fluids was developed. This assay consisted of extracting metoclopramide from an alkalinized aqueous layer into benzene. A portion of the organic phase was derivatized with heptafluorobutyric anhydride. Quantitative estimation of the derivative was accomplished by adding diazepam, the internal standard, in bezene (750 ng/ml). A calibration curve was prepared for the plasma extracts. Linearity was observed in the range studied (91-825 ng/ml). No interference from endogenous substances was observed. The minimum detectable amount was 1 pg/injection. The structure of the derivative was confirmed by electron-impact and chemical-ionization mass spectrometry. The applicability of this method was shown by a preliminary study of the elimination kinetics of metoclopramide in rats after a 10-mg/kg iv dose.


Interaction of sulindac and metabolite with human serum albumin. The binding of the newly developed nonsteroidal anti-inflammatory agent sulindac and its principal active metabolite, sunlindac sulfide, to human serum albumin was investigated. With the methods of dialysis, fluorescence quenching, and difference spectrophotometry, it was found that both agents were extensively bound to albumin. The binding affinity of the metabolite was considerably higher than that of sunlindac and this effect may be related to its prolonged plasma half-life versus the parent drug. Sulindac binding was albumin concentration dependent, which gave rise to an unfamilar Scatchard analysis of the dialysis data.


Physical characterization of erythromycin: anhydrate, monohydrate, and dihydrate crystalline solids. Hot-stage microscopy, thermoanalytical methods, and X-ray powder diffraction were used to demonstrate that crystalline erythromycin dihydrate converts to the crystalline anhydrate via a noncrystalline intermediate. X-ray powder diffraction, IR spectral, thermogravimetric, and differential thermal analyses were used to characterize the monohydrate material. The flow interrupt technique, a procedure recently developed to deal with low surface area samples, was employed successfully in obtaining isotherms and specific surface areas for the monohydrate and anhydrate. The relative dissolution rates of the various hydrates were determined in an aqueous solution (0.01 M phosphate buffer, pH 7.5) at 37 degrees. The results showed a significant difference in the dissolution rate of the dihydrate compared to the monohydrate and anhydrate.


GLC determination of caffeine in plasma using alkali flame detection. A rapid, specific, and sensitive GLC assay for caffeine in plasma was developed utilizing alkali flame-ionization detection. The procedure involves the addition of mepivacaine as an internal standard, alkalinization of the sample, and extraction with chloroform. Peak height ratio measurements produced linear standard curves in the 0.25-10.0-microgram/ml range. Absolute sensitivity from a 1.0-ml plasma sample was 0.1 microgram/ml. The relative standard deviation of a 2.0-microgram/ml pooled plasma standard run repeatedly over several months was 5.2%. The method is applicable to time-concentration studies in human and animal plasma following typical oral doses of caffeine.


GLC determination of ticrynafen and its metabolites in urine, serum, and plasma of humans and animals. A sensitive GLC assay for ticrynafen, a diuretic agent with uricosuric properties, and its two metabolites in urine, serum, and plasma is described. The method employs methylation of carboxylic acid groups and trimethylsilyation of the hydroxyl group on one metabolite that cannot otherwise be separated readily from ticrynafen as a simple methyl ester. Urinary output and serum or plasma levels of ticrynafen and its two metabolites were measured in specimens from human volunteers receiving one 250-mg tablet.


Chromatographic separation and assay of morphine in tablets. A method specific for the determination of morphine sulfate in tablets was developed. Morphine is separated from the excipient and degradation products by a column chromatographic method. The eluate containing morphine is extracted into an acid solution and determined spectrophotometrically. Recovery from standard solutions is greater than 99%. This method is more specific for the separation and determination or morphine in tablets than is the USP XVIII procedure.


Multicompartment pharmacokinetic model of 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-beta-D-glucopyranoside) in humans. The formation and elimination of the metabolite of 4'-demethylepipodophyllotoxin 9-(4,6-O-ethylidene-beta-D-glucopyranoside) (I) were studied in seven patients with advanced cancer who received I intravenously. The plasma concentration-time data best fit a triexponential equation. The volume of the metabolite compartment (27.5 liters) was calculated as a fraction of the extrapolated volume. A larger body clearance (111.7 ml/min) of metabolite as compared to the renal clearance (31.3 ml/min) indicates that the metabolite is lost from the plasma equivalent space by another elimination route. The combination of metabolite data presented here with previously published data for unchanged I leads to a multicompartment model for the distribution, metabolism, and excretion of I and its metabolite. A comparison of algebraically derived model transfer constants with those evaluated by computer fitting the system of differential equations is presented.


Solid dispersion of pharmaceutical ternary systems I: Phase diagram of aspirin-acetaminophen-urea system. The phase diagram of an aspirin-acetaminophen-urea system was constructed. The data obtained by the thermomicroscopic method showed that the binary systems of aspirin-acetaminophen, aspirin-urea, and acetaminophen-urea are simple eutectic mixtures with negligible formation of solid solutions or molecular compounds. The equilateral triangular phase diagram of the ternary system revealed that it forms, upon solidification, solid dispersions of the mechanical mixture type. The ternary eutectic corresponded to a composition of 60% aspirin, 20% acetaminophen, and 20% urea at 72 degrees. The method of calculating the composition finally solidified melts, lying within any area of the phase diagram, is presented. Use of the phase diagram in selecting the optimum ratio of components to enhance dissolution rates of these drugs may be possible.


Fluorometric assay for urinary indapamide. A sensitive fluorescence method for the determination of indapamide was developed. Reaction of indapamide with sodium hydroxide at 100 degrees yielded a fluorescent product, and addition of formaldehyde to the fluorescent product increased its fluorescence intensity by a factor of three. The assay is sensitive to levels of indapamide of 0.025 microgram/ml in an aqueous solution, and a linear response between 0.025 and 2.0 microgram/ml was observed. The procedure was adapted to the analysis of intact indapamide in urine. Concentrations of indapamide of 0.05 microgram/ml can be detected in dogs given 20 mg of the drug.