Intravenous therapy and EEG monitoring in prolonged seizures.

Attempts were made to control prolonged seizures with rapid intravenous administration of either diazepam or methohexitone in relatively small doses under electroencephalographic (EEG) monitoring. The clinical and EEG features are discussed in relation to 65 episodes which occurred in 51 infants and children. Both clinical and EEG effects may become apparent in half a minute when the drug is administered with this technique and no undesirable side-effects were observed. The return of consciousness was not impaired by the small amounts of these drugs and the cumulative effects were negligible, allowing repeated injections if necessary. This technique avoids the disadvantages of larger doses of drugs given by slow intravenous infusion.


Upper limb involvement in cervical spondylosis.

Analysis of 200 cases reveals that the two neurological syndromes, brachial neuritis and myelopathy, associated with cervical spondylosis are distinct with relatively little overlap. While upper limb motor and sensory loss are doubtless due to nerve root compression in cases of "pure' brachial neuritis, they are more likely to be due to cord damage in cases with myelopathy (with spastic paraparesis of lower limbs). In either group of cases, neurological features in the upper limbs are not very helpful in localizing the level of significant intervertebral disc pathology. Contrast radiology (myelography and possibly discography) is a reliable guide judging by the excellent results obtained by anterior route (Cloward's) operation at specific disc levels in a series of cases with longstanding complaints unrelieved by conservative treatment. Pathological data provide a rational basis for interpretation of clinical observations and for surgical treatment.


Investigation of cranial and other nerves in the mouse with muscular dystrophy.

In the muscular dystrophic mouse mutant there is an absence of Schwann cells over circumscribed lengths of all cranial nerves except for II (I was not examined) and the lesion involves the sympathetic system. Where present, Schwann cells do not produce myelin of normal thickness. The lesion is similar to that described for the spinal roots. Causation is discussed.


Familial type I fiber atrophy.

An 11-year-old boy and his 40-year-old mother with congenital, non-progressive muscular weakness and wasting are described. Muscle biopsies from both cases showed a selective atrophy of Type I fibers without any structural change except for very few nemaline bodies. Probably, the neuromuscular disorder in this family is identical to the congenital fiber type disproportion described by Dubowitz and Brooke, but familial Type I fiber atrophy (hypotrophy, or hypoplasia) is considered to be a more appropriate descriptive term for a family with such distinct histochemical characteristics.


Influence of thyroid hormones on myelin proteins in the developing rat brain.

This communication describes developmental changes in myelin proteins prepared from control, hypothyroid, and hyperthyroid rat brain. In the 10- to 37-day postnatal period studied, total myelin protein was found to double, and this change mainly reflected the increase in proteolipid and basic protein constituents. Thyroid states affect differentially the various myelin proteins. Hypothyroidism decreases the proteolipid and slow-moving basic protein, but has no effect on the fast basic or minor proteins. In hyperthyroidism, an increase was observed in proteolipid as well as both slow- and fast-moving proteins. The protein alterations were correlated to the changes previously found in lipid composition of myelin consequent upon hypo- and hyperthyroidism, and the role of thyroid hormones in brain development.


The ultrastruct of normal human muscle in relation to fibre type.

A quantitative analysis using a stereological point-counting method was made of the volume fractions of the components of healthy human muscle in an attempt to distinguish between Type I and Type II fibres ultrastructurally. The Z-line widths of each fibre were also measured using the 38.5 nm axial periodicity in the I-band as a reference measurement. There was a wide range of values for the parameters measured. The volume of mitochondria was 5.14 plus or minus 1.85% (mean plus or minus standard deviation, n=24 fibres), the volume of the membrane systems was 1.59 plus or minus 0.31%, the volume of the sarcoplasm was 9.37 plus or minus 2.50% and the volume of lipid was 0.63 plus or minus 0.43%. The width of the Z-lines was 89.0 plus or minus 18.65 nm. The results show that no single feature can be used to distinguish fibre types reliably. If 2 factors are measured and certain assumptions are made, it is possible to classify about 50% of the fibres examined. These conclusions are discussed in relation to other workers' findings on the effects of age, sex and athleticism on the ultrastructure of muscle.


An unusual form of spinal muscular atrophy with mental retardation occurring in an inbred population.

Three sibs are described suffering from hereditary non-progressive spinal muscular atrophy with non-progressive mental retardation. One of them had in addition signs of pyramidal tract involvement. Muscular weakness was more pronounced proximally than distally and the neck muscles were severely involved. Th.ey all had small skulls and several associated congenital malformations were observed including syndactyly of the left hand in 1 patient. The patients belong to a small inbred community in the Netherlands. Erythropoietic protoporphyria was also present in the family but segregated independently. This combination of "congenital" mental retardation with "congenital" non-progressive spinal muscular atrophy is believed to represent a new syndrome, caused by a rare recessive gene.


On the relationship of brain vasculature to production of neurological deficit and morphological changes following acute unilateral common carotid artery ligation in gerbils.

The known susceptibility of the Mongolian gerbil to cerebral infarction following unilateral carotid artery ligation has been attributed in the past to the demonstrated absences of an anastomotic supply between the anterior and posterior cerebral circulations. In a study of 34 adult gerbils exposed to such a procedure, 11, or 33%, developed severe neurological sequelae and succumbed to the procedure in less than 30 hr, whereas 23 animals survived with only minor or transient neurological signs. All animals displayed the expected lack of an anastomosis between the anterior and posterior circulations, but in addition the animals which survived the procedure were found to have a prominent early cross-connection between the anterior cerebral arteries, whereas the animals which succumbed had no such connection. Neuropathological changes in susceptible animals were apparent as early as 3 and one-half hr after ligation and consisted of edema, initially perivascular and then intraneuronal, slowed by acute necrosis. A variety of other vascular anomalies was encountered. We conclude that the peculiar susceptibility of Mongolian gerbils to cerebral infarction following acute unilateral common carotid artery ligation is not related primarily to lack o adequate collaterals between the anterior and the anterior cerebral arteries, but to the degree of adequate adequacy of communication between the anterior cerebral arteries. The critical difference may be more one of degree, i.e. the point at which the medial branches of the anterior cerebral artery fust to become anazygos vessel, rather than an actual difference in the pattern of distribution of the anterior cerebral arteries. The presence of other variation in vascular supply in a relatively small series suggests that results of similar studies of infarction and response to treatment be interpreted with caution.


Reversible central nervous system dysfunction in folate deficiency.

An epileptic patient on chronic anticonvulsant drug therapy is described, in whom anaemia and neurological abnormalities including progressive dementia, bilateral pyramidal tract signs, incontinence and ataxia developed. Vitamin B12  serum levels and absorption were normal, but serum folic acid levels were low. Both the neurological disturbances and anaemia resolved following oral folic acid administration. This sequence of events in our patient suggests a cause and effect relationship between the folate deficiency and the coexistent, transient neurological syndrome.


Progressive demyelination and reparative phenomena in chronic experimental allergic encephalomyelitis.

Chronic experimental allergic encephalomyelitis (EAE), produced in inbred guinea pigs given a single inoculation during the juvenile period with isologous spinal cord in complete Freund's adjuvant, has been studied by light and electron microscopy. Most animals showed a delayed onset of nurologic signs from 12 to 68 weeks post-inoculation (PI), while several were asymptomatic up to 74 weeks PI. Two animals showed a relapsing clinical course. Examination of the spinal cords of all animals revealed chronic demyelination, remyelination, and recent demyelination. Marked perivascular inflammation, including plasma cells, was seen within demyelinated plaques. The usual type of central nervous system (CNS) remyelination was documented but in addition, remyelination of CNS axons by invading Schwann cells was noted. This Schwann cell invasion, not previously seen in EAE, was predominantly in the area of the root entry zone, and occasionally involved extensive areas of the dorsal or ventral horns. The extent of Schwann cell invasion, as well as the usual CNS-type remyelination, demonstrates the reparative capacity of the CNS. The recurrent clinical and morphologic changes in these long-term animals provides further evidence that this model of chronic EAE has many features reminiscent of multiple sclerosis. The underlying immunologic mechanisms responsible for the recurrent disease in these animals are unknown. The presence of plasma cells in the inflammatory exudates might suggest a role for B cells in these chronic animals. The possibility of an intermittent release of loculated adjuvant/antigen accounting for the recurrent disease was considered.


Ultrastructure of axonal reaction in red nucleus of cat.

Described here are ultrastructural changes in neurons of feline red nucleus exhibiting axon reaction after unilateral rubropsinal tratotomy at the C-2 level and surviving 2 to 65 days. Ultrastructural alterations included neurofilamentous hyperplasia; proliferation of smooth ER; temporary disappearance of organized granular ER with partial substitution by haphazardly arranged, broad cisternal profiles; loss of rosette ribosomes and occurrence of single ribonucleoprotein granules or an intercisternal amorphous density; increased numbers of subsurface cisterns and allied structures, often disposed in stacks; vesiculation and vacuolation of Golgi cisternae; prevalence of autophagic bodies derived in part from Golgi complexes; probable mitochondrial hyperplasia and various qualitative changes in these organelles; an increase in lipofuscin. Dendritic changes paralleled those of perikarya save that proliferation of subsurface cisterns and autophagic bodies was absent. Abnormalities of myelinated axons and boutons occurred and may have originated from retrograde degeneration of cortical neurons induced by lateral funiculotomy. Some perikarya were devoid of axosomatic boutons. Ultrastructural changes varied with the length of postoperative survival and were, at least partly, reversible. Chromatolysis was detectable light microscopically before ultrastructural abnormality appeared. The bearing of transneuronal mechanisms on axon reaction of central neurons and the protective effect of section of axons beyond the site of origin of collaterals are discussed.


Scanning electron microscopy of the ventricular system in normal and hydrocephalic rabbits. Preliminary report and atlas.

The author used the scanning electron microscope to study the ependyma in six control rabbits and six rabbits made hydrocephalic by infusion of silicone oil into the cisterna magna. The ependymal lining of the third ventricle, head of the caudate nucleus, superior angle of the caudate, and atrium of the lateral ventricle was examined. In the hydrocephalic animals, clusters of cilia emanating from the ependyma over periventricular white matter become separated; the author believes this is secondary to ingrowth of new ependymal cell processes covered with microvilli. The addition of these cells to the ependymal surface permits ventricular dilatation without ependymal disruption and provides more surface containing microvilli, presumably capable of increased transventricular fluid transfer. No such changes occur over gray matter masses since their surfaces are not deformed by moderate ventricular dilatation. The morphological alterations in the ependyma that occur in moderate hydrocephalus do not appear to be simply manifestations of ependymal destruction but rather suggest a modification in its function from that of a surface capable of propelling cerebrospinal fluid to one capable of increased transfer of transventricular fluid. As hydrocephalus progresses, compensation may fail because of the relative decrease in microvilli so that the cell surface provides a less efficient mechanism for absorption.


Formation of cerebrospinal fluid. Relation of studies of isolated choroid plexus to the standing gradient hypothesis.

After a brief summary of current views on the origin of cerebrospinal fluid (CSF) and the processes underlying its elaboration, the author discusses studies of isolated choroid plexus in extracorporeal perfusion systems and flux chambers. The results suggest that transependymal water flow is secondary to the electrically silent pumping of sodium. The author presents evidence in support of the standing gradient hypothesis as the structural basis of CSF secretion.


Follow-up analysis of ventriculoperitoneal and ventriculoatrial shunts for hydrocephalus.

The authors report an analysis of 300 patients in whom primary treatment for hydrocephalus was either a ventriculoperitoneal (VP) or ventriculoatrial (VA) shunt. Although differences in primary and total revision rates between placements were not statistically significant, the VA shunt failures carried a higher morbidity than the VP placements.


Experimental effects of steroids and steroid withdrawal on cerebrospinal fluid absorption.

The authors studied the effects on cerebrospinal fluid (CSF) absorption of chronic administration and acute withdrawal of steroids in dogs. CSF absorption was measured by determining the amount of isotope (indium 111DTPA) recovered over a 4-hour period after injection into the cisterna magna. Resistance to CSF absorption was estimated by determining rates of low of Ringer's lactate infusion into the cisterna magna over a range of pressure gradients between CSF and sagittal sinus. Steroid withdrawal was associated with a marked reduction in CSF absorption and an increase in resistance to CSF flow. Dogs on steroids also showed reduced CSF absorption although the reduction was not statistically significant when compared with controls. The results are discussed in terms of possible mechanisms of action of steroids on CSF absorption, the etiology of the benign intracranial hypertension syndrome and the use of steroids and in the control of intracranial hypertension.


Sinus pericranii.

Five cases of sinus pericranii are presented, four congenital and one traumatic. All five cases were successfully treated with extirpation and reinforcement with Gelfoam and silk thread over the skull openings. The literature on this rare symptom-complex is reviewed and a new definition of sinus pericranii proposed.


Pupillary sparing in oculomotor palsy from internal carotid aneurysm. Case report.

The authors report a patient with a carotid-posterior communicating artery aneurysm; although the oculomotor palsy accompanying such an aneurysm is almost universally recognized as being complete, with pupillary involvement, this patient had pupillary sparing the absence of subarachnoid bleeding. A few similar cases have appeared in the literature. The mechanism of pupillary sparing appears to be based on the position of the parasympathetic pupilloconstrictor fibers within the subarachnoid portion of the third nerve and on the anatomic relationship between the third nerve and the junction of the carotid and posterior communicating arteries.


Thrombectomy of the middle cerebral artery. Case report.

A case is described in which thrombectomy of the middle-cerebral artery by way of one of its side branches successfully restored blood flow in the artery and resulted in marked regression of neurological disturbances.


Spontaneous elevation of a depressed skull fracture in an infant. Case report.

This is a report of an infant with a depressed skull fracture that apparently elevated spontaneously within a period of 4 hours.


Ultrasound determination of cerebrospinal fluid shunt patency. Technical note.

A technique employing a Doppler ultrasound flowmeter in determining cerebrospinal fluid shunt patency is described. The technique has proven to be a valuable aid in the elevaluation of the patient in whom shunt function is in question.


Endotracheal intubation in patients with fractures of the cervical spine. Technical note.

The author presents a safe method of endotracheal intubation for anesthesia without moving the neck in patients with fractures of the cervical spine.


Memory clip for intracranial aneurysm surgery. Technical note.

The authors have devised a malleable V-shaped removable clip with mechanical memory effect of shape memory. This clip is easily removed by heating part of it to 79 degrees to 107 degrees C, causing the closed clip to return to its original V shape.


Concurrent intracranial and spinal cord arteriovenous malformations. Case report.

The authors report the case of a patient with subarachnoid hemorrhage in whom an intracranial dural arteriovenous malformation coexisted with a spinal arteriovenous malformation. The latter was considered to be the source of the hemorrhage by clinical and radiographic criteria. It is concluded that patients with subarachnoid hemorrhage who show no suitable intracranial source for their bleed in some instances should be investigated for a spinal origin of hemorrhage.


Perforation of the intestine by a Raimondi peritoneal catheter. Case report.

The authors report a case in which the cut end of a Raimondi peritoneal catheter apparently caused intestinal perforation and contamination of the shunt system. The authors advise that if this type of catheter is to be divided the cut should be distal to the end of the sharp wire contained in it, which otherwise will protrude.


Clinical, arteriographic, and cisternographic observations after removal of acute subdural hematoma.

The authors review 47 patients with closed-head injuries requiring treatment for acute subdural hematoma and report that 21 (45%) survived for 5 days or more. Follow-up study of these 21 survivors led to the following observations: that clinical evaluation of these patients is the most reliable index of their postoperative progress; that the diagnostic usefulness of postoperative cerebral arteriograms is limited because immediate postoperative changes tend to persist; that craniotomy is preferable to burr holes for removal of an acute hematoma; and that the value of cisternography, unless done serially, is limited since posttraumatic hydrocephalus develops rapidly and may persist indefinitely.


Catecholamine content of cerebral tissue after occlusion or manipulation of middle cerebral artery in cats.

The authors determined by fluorimetry the norepinephrine-epinephrine content (NE-E) of cerebral tissue from 38 cats, to ascertain whether constriction of hypersensitive arterial vessels by vasoactive agents in ischemic cerebral tissue could cause extension of cerebral infarcts and worsening of neurological deficits. Twenty-three cats had the left middle cerebral artery (MCA) occluded transorbitally, and 10 cats had sham operations. Five cats had only the surgical procedures necessary for obtaining tissue; mean NE-E content was 0.30 mug/gm (SD=0.041). For the other 33 cats, including those with sham operations, values were variable, ranging from 0.07 to 0.60 mug/gm. Low values usually were obtained for ischemic hemispheres 24 hours and 7 days after MCA occlusion, but at other times values could be high or low on either side. Many factors unrelated to tissue damage, including arterial manipulation, influence the catecholamine content of cerebral tissue.


Craniosynostosis.

The authors review the embryopathology and clinical manifestations of craniosynostosis and analyze a series of 27 children. The operative procedure of linear craniectomy and immediate cranioplasty is described and evaluated. Since few children with craniosynostosis have neurological deficits that can be ascribed to the skull anomalies, surgery to prevent neurological complications is only rarely justified. However, it is often possible to ameliorate the cosmetic deformity in many of these patients if operative intervention is undertaken in early infancy.


Quality of survival following direct surgery for anterior communicating artery aneurysms.

The authors describe a series of 32 patients with ruptured aneurysms of the anterior communicating artery who were admitted during a 3-year period. In 28, the aneurysms were treated by direct surgery with no deaths; 26 of these patients were studied psychometrically from 4 to 33 months after operation. There was no evidence of postoperative intellectual impairment; however, there were personality changes associated with loss of interest, initiative, and energy. Analysis of the different factors involved suggests to the authors that the outcome of surgery depends mainly on preoperative clinical condition which, in turn, reflects the severity of the hemorrhage.


Giant occipital hemangioendothelioma with thrombocytopenia, anemia, and hypofibrinogenemia. Case report.

The authors describe the total excision of a huge occipital hemangioendothelioma in an infant with thrombocytopenia, hypofibrinogenemia, and anemia; treatment was followed by normalization of platelet count, blood cell count, and level of fibrinogen. Histological and clincial studies support the concept the disseminated intravascular coagulation was related to the thrombocytopenia and coagulation deficits found in this case.


Late appearance of meningioma at the site of partially removed oligodendroglioma. Case report.

A case is presented in which a meningioma and a glioma grew in the region where, 23 years before, a glial tumor had been partially removed and irradiated. The authors suggest that surgical trauma and ionizing radiation may have influenced the tumor's development.


Cloverleaf skull syndrome. Case report.

The authors report a case of cloverleaf skull syndrome (Kleeblattschädel) and describe how early surgical management of this condition appears to offer hope for a reasonable cosmetic results, as well as improvement in cerebral function to the point where children with this syndrome may avoid institutional care.


Experimental cervical myelopathy. Effects of ischemia and compression of the canine cervical spinal cord.

The authors report experiments designed to test the effect of regional ischemia induced by selective vascular ligations and anterior compression of the cervical cord at two adjacent segments (C-4, C-5) in the same dog. They conclude that local ischemia of the cervical cord, caused by local deformation, when superimposed on a regional reduction in spinal cord blood flow, accounts for the myelopathy of cervical spondylosis whether produced experimentally in animals or occurring naturally in man.


Bilateral aberrant regeneration of the third cranial nerve following trauma. Case report.

This 6-year-old boy, after recovery from prolonged coma following head trauma, exhibited the rare phenomenon of bilateral oculomotor nerve misdirection manifested by ipsilateral eyelid elevation on adduction of either eye.


Intracerebellar "fibroma". Case report.

The authors report a unique case of intracerebellar fibroma; the tumor was well circumscribed and was treated by complete excision.


Cholesterol kinetic analysis in normal and cholesterol-fed rabbits; effects of saturated versus polyunsaturated fat and of cholestyramine.

A model for cholesterol metabolism in rabbits has been demonstrated based on kinetic analysis and total carcass analysis.  As has been shown for humans and primates, the model conforms to a two-exchangeable pool model with a third pool not exchangeing during the time interval studied.  Alterations in turnover rate, sizes of pools, and exchange rates were demonstrated when rabbits were fed diets containing increased amounts of cholesterol and fat.  Evidence was presented that indicated that the there may be differences in tissue distribution of cholesterol, dependent on whether the fat fed with choleserol is saturated or polyunsaturated.  These differences include: in rabbits fed cholesterol plus coconut oil is compared with those fed cholesterol plus corn oil, the ratio of the amount of cholesterol in plasma to the amount of cholesterol in pool B was higher, and the rate constant for transfer from pool B was higher.  The serum cholesterol concentration of rabbits fed cholesterol plus coconut oil was lowered slightly by feeding cholestyramine.  Cholestyramine administration at the dose fed  failed to produce statistically significant alterations in pool sizes or serum cholesterol concentration in control rabbits; it did lower serum cholesterol concentration in rabbits fed cholesterol plus coconut oil.


Studies of nutritional safety of some heavy metals in mice.

Heavy metals have been proposed as nutrient markers to allow the accurate determination of the time of passage, nutrient intake, or apparent utilization of multiple nutrients. In order to evaluate possible toxic effects of scandium, chromium, lanthanum, samarium, europium, dysprosium, terbium, thulium, and ytterbium oxides, and barium sulfate upon growth, general development, reproduction, and lactation, mice were fed different levels of these compounds for three generations. The amount of elements fed were 0,110, 100, and 1000 times the use amount. The use amounts were (in ppm2.) : Sc, 0.12; Cr, 0.02; La.0.40;; Sm. 0.80; Eu, 0.036:TB, 1.20; Dy, 1.20; Tm. 0.08; Tb, 0.12; and Ba, 0.008. The use amount was one-fifth of the concentration required for activation analysis. Mortality and morbidity were negligible. No consistent growth rate changes were observed; however, different groups showed different growth rates during different generations. The number of mice born showed no significant differences amoung treatment groups. Survival, growth rate, hematology, morphological development, maturation, reproduction, and lactational performance were comparable in mice fed the different levels of 10 heavy metal oxides to those mice fed the basal diet.


Dietary effects of the esters of butyric, caproic, caprylic, capric, lauric, myristic, palmitic, and stearic acids on food intake, weight gain, plasma glucose, and tissue lipid in the male white rat.

Eight saturated fatty acid esters were fed to male white rats for 30 days in a 1/81 fractional factorial experiment in which diets contained 12-38% of their total energy as lipid.  Marked increases in food intake, feed efficiency, and weight gain were achieved when lipid provided 36% of diet energy, and when that lipid was more than half caproate, caprate, myristate, and/or stearate.  Caproate was the only saturated fatty acid to increase plasma glucose levels.  The feeding of stearate or caprylate decreased plasma and liver cholesterol.  Caprate increased liver fat.  The short-chain fatty acids (butyrate to myristate) increased the concentration of fat in the carcass.


Effect of exercise on lipid metabolism of rats fed high carbohydrate diets.

Two experiments were conducted to determine whether high carbohydrate diets or exercise would have a greater influence on certain parameters of lipid metabolism.  Male Fischer rats were used in both experiments, separated into exercise and sedentary groups, and fed either a high sucrose (63%) or a high starch (63%) diet. There were no differences in body weight or food consumption between the two diets. Exercise resulted in a highly significant increase in food consumption in both experiments.  Rats fed sucrose had a higher serum cholesterol value than rats fed starch. Diet did not influence serum triglycerides but the rats on excercise had significantly lower serum triglycerides than the sedentary rats.  Liver weight was significantly larger in rats fed sucrose.  Sucrose caused an increase in the activity of both glucose-6-phosphate dehydrogenase and malic enzyme activities in liver tissue, whereas exercise caused an increase in the activity of these enzymes in adipose tissue.


Influence of genetic differences in feed efficiency of young chickens on derivation of metabolizable energy from the diet and nitrogen retention.

The relationship of efficiency of efficiency of feed utilization with metabolizable energy derived from the diet and nitrogen retention was studied in broiler strains and in lines selected for divergence in feed conversion ratio. Individual feed conversion (g feed/g gain) and metabolizable energy derived from the diet and nitrogen retention (determined by chromic oxide method) of these strains and lines were measured, and correlations were determined at various intervals from 4 to 9 weeks of age to determine the effects of age, sex, strain, feed conversion, growth, and feed consumption on the metabolizable energy derived from the diet and nitrogen retained. Although there were significant differences in feed conversion between sexes, strains, and lines selected for divergence in feed conversion, there were no associated differences in metabolizable energy derived from the diet or in nitrogen retention. There were no significant correlations of consumption, growth, or feed conversion with metabolizable energy derived from the diet or nitrogen retention. Nitrogen retention of the White Plymouth Rock strain was significantly higher for all ages. These results show that differences observed in growth, consumption, or feed conversion do not influence derivation of metabolizable energy from the diet or nitrogen retention.


Effect of calcium and phosphorus on fluoride metabolism in man.

The effect of orally administered calcium and phosphorus on the fluoride balance was studied in man during a low fluoride intake of about 4 mg/day and a high fluoride intake of 14 mg/day. Three calcium intake levels averaging 223, 1,481, and 2,312 mg and two phosphorus intakes averaging 915 and 1,430 mg/day were used. Calcium or phosphorus used singly or combined did not affect the urinary fluoride. Increasing the calcium intake from an average of 223 to 1,481 and to 2,312 mg/day during the low fluoride intake increased the fecal fluoride only slightly, from 0.13 to 0.17 and 0.20 mg/day, respectively, and during high fluoride intake from 0.31 to 0.58 and 0.56 mg/day, respectively. The addition of phosphorus to the low calcium intake did not change the fecal fluoride excretion during either low or high fluoride intake, but the fecal fluoride increased during the two higher calcium intakes by a factor of 1.5. As the fecal fluoride was very low in the control study and was still relatively low in the experimental studies, the increase in fecal fluoride did not change the fluoride balances. The studies have shown that the increased levels of calcium and phosphorus used had little effect on fluoride metabloism in man.


Modification of a selenium toxicity in chicks by dietary silver and copper.

Studies were conducted to determine the effects of high levels of dietary silver nitrate and copper sulfate on the response of chicks to toxic levels of dietary selenium. Adding 5 ppm or more selenium to a basal stock diet significantly reduced growth rate, and 40 ppm or high significantly increased mortality during the 2-week experiments. Deitary silver or copper (1,000 ppm) counteracted the growth depression and prevented mortality at the higher levels of selenium. Hepatic selenium reached a maxiumum in chicks fed the basal diet with 10 ppm dietary selenium. Hepatic selenium of chicks fed silver was less  than that of the control chicks when diets containing 10 ppm or less selenium were fed. Adding copper to the diet resulted in considerable accumulation of selenium in the liver, which was evident even at the lower levels of added selenium. Rseults of an experiment to determine the effects of deitray silver and copper on the distribution of 75-Se administered either orally or in tramusculary showed that silver interfered with absorption of selenium. The results of these experiments suggest that silver modifies selenium toxity both by interfering with selenium absorption and by causing the accumulation of a nondeleterious selenium compound in the tissues. Copper modifies selenium toxicity primarily by causing the accumulation of a nondeleterious compound in the tissues.


Efficiency of alpha-ketoisocaproic acid as a substitute for leucine in the diet of the growing rat.

Immature male albino rats (70-80 g), eating a diet furnishing all nutrients for optimal growth and containing 84.6 mumoles of leucine/g, gained weight at an average rate of 5.9 g/day.  Removal of leucine caused an average daily weight loss of 1.3 g.  Addition of leucine to the diet in graduated amounts corrected this weight loss, the improvement in body weight (BW) being proportional to the dietary content of leucine.  Addition of alpha-ketoisocaproic acid in place of leucine to the leucine-free diet also prevented loss of BW.  Percentage efficiency of alpha-ketoisocaproic acid as a dietary substitute for leucine was calculated as: (see article).  Efficiency of such substitution varied from 27% for a diet containing 84.6 mumoles of alpha-ketoisocaproic acid/g to 20% for a diet containing 169.2 alpha-ketoisocaproic acid/g.


Effect upon brain weight and cholesterol content of maintaining rats of various ages at constant weight.

Rats weighing 400 g were maintained at constant weight for 500 days. Their diet consisted of 14 g/day for the first 150 days and 13 g/day thereafter. A second group of rats weighing 350 g was fed 11.5 g/day for 400 days; at the end of the experiment, these rats weighed 382 g. Under these conditions, the increase in brain weight and in quantity and concentration of cholesterol in the brain as a function of time was identical to that observed in the control rats fed ad libitum. Rats weighting 250 g fed 8.5 g/day for 200 days showed a body weight increase of 16 g. Up to the age of 115 days, the evolution of brain weight in terms of time did not differ from that observed in control rats. Rats weighting 100 g and fed 4.5 g/day showed an increase of 28 g after 300 days. The increase in brain weight and in brain cholesterol content as a function of time was less than that observed in the control rats. A curve deduced from these results has the practical interest of indicating the daily energy requirement for maintaining rats at a chosen constant weight. Expressed in terms of body surface area, the daily energy intake appears constant. It was also observed that, when conditions of minimal economy are imposed upon the adult rat, brain nutrition is not modified. But for young rats (100 g),brain development under these nutrtional conditions is affected.


Effects of D-, DL-and L-glutamic acid on chicks.

Studies were conducted to investigate the effects of D-, DL-, or L-glutamic acid on the chick. Supplementation of levels of L-glutamic acid to an amino acid mixture containing adequate levels of all the indispensable amino acids plus cystine and tyrosine resulted in increased growth up to 10% L-glutamic acid in the diet. Chicks tolerated as much as 15% L-glutamic acid with no growth retardation. Supplementation of D-glutamic acid at levels of 3.75 or 5% resulted in growth depressions of 18 and 38%, respectively, at the end of a 2-week experiment. Significant growth-depressing effects of these levels of D-glutamic acid and 7.5% of DL-glutamic acid were also observed with an amino acid diet as well as an isolated soybean protein diet. The growth-depressing effect was most severe during week 2 of the experiment. Additional vitamins and amino acid supplements failed to reverse the growth-depressing effect. Plasma glutamic acid concentration was not altered by the inclusion of D-glutamic acid in the diet, but generally, plasma free amino acid concentrations were increased. This was especially true of arginine. Free glutamic acid increased in the kidney and was lowered in the liver. Free ammonia was increased in both the liver and kidney when the D form was included in the diet. Implications of these findings are discussed.


Dietary and hormonal regulation of pancreatic xanthine dehydrogenase in the chick.

Chick pancreatic xanthine dehydrogenase (PXDH) is synthesized in response to feeding. Its induction generally correlates with growth; in the absence of growth, induction is observed uniquely when pure glucose is fed. This study attempted to determine what events after feeding lead to PXDH synthesis. When chicks were fed diets providing equal numbers of calories/gram of diet and varying only in the major energy source (carbohydrate, protein, or fat), PXDH response was high in the carbohydrate-fed, low in the protein-fed, and minimal in the fat-fed chicks. A unique, transitory increase in plasma glucose occurred in the carbohydrate-fed chicks within day 2 after feeding. These unique effects of dietary glucose indicated that the induction of PXDH after feeding was linked to carbohydrate metabolism. Effects of injected insulin on PXDH were examined. Insulin doses between 0.001 and 10.0 IU induced PXDH 25-60% above the activity found in carbohydrate-fed chicks. The initiation of PXDH accumulation may be the result of a sequence of metabolic responses to dietary carbohydrate beginning with an increase in plasm glucose, which induces an insulin response.


Selenium levels in human blood and tissues in health and in disease.

The levels of selenium in human sera and pancreatic, hepatic and synovial tissues were measured. An attempt was made to correlate the selenium level with certain disease states. Selenium was determined by nerutron activation analysis, using the 17.4 second half-life isotope 77mSe with a sensitivity of 2ppb. Serum-bound selenium was determined in normal individuals and individuals with various malignancies, and medical and surgical disorders. Tissue selenium was assayed in diseased and normal pancreases, livers, and synovial membranes. A wide variation was observed both in the serum selenium content of patients with a malignancy and in postmoren pancreatic and synovial showing histopathological changes. Significantly lower selenium values were observed in sera from cancer patients than from normal individuals. Higher values were generally observed in patients with primary neoplasms of the reticuloendothelial system. Higher tissue concentrations were obtained in synovia from patients with rheumatoid arthritis and in pancreatic tissues associated with histopathological changes.


Changes in the intestinal lactase activity in the small intestine of two breeds of swine from birth to 6 weeks of age.

Total and specific lactase activities in the small intestine of Chester White and Hampshire pigs were measured at 1, 8, 15, 22, 29, and 43 days of age. The small intestine was divided into 10 segments of equal length, the proximal 10 cm of each segment was scraped, and the scrapings were homogenized for use in the lactase determinations. Significant breed, age, and segment differences were observed for both specific and total activities. In both breeds, the total lactase activity at 1 day of age was lower than that at any other age. After reaching maximal levels at 15 days of age, the total activity declined with the loss of activity occurring primarily in the ileum. At 1 and 8 days of age, the total lactase activities for the two breeds were similar, but the Chester White pigs had higher activities at all other ages. The pattern of changes in specific activity with age was similar for both breeds. The mean specific activity was highest at 1 and 8 days of age and then fell progressively to minimal levels at 43 days of age. Chester Whites had higher specific activities than Hampshires during the first 4 weeks of life, but at 6 weeks of age there was little difference between the breeds. The peak lactase activity, expressed as total or specific activity, occurred in the proximal one-third of the small intestine of both breeds, and the distal one-third of the gut had relatively low activities as the animals matured.


An evaluation of the nutritive value of new high protein oat varieties (cultivars).

Studies were conducted to evaluate the nutritive value of new high protein oat varieties using chicks and rats. Oat groats studied were Lodi, Dal, and Goodland; protein contents were 16.0, 18.0, and 20.5%, respectively. Increases in protein content were accompanied with an increase in indispensable amino acids. The lysine contents of Lodi and Goodland oat groats were 0.60 and 0.72%, respectively. With amino acid supplementation the 80% oat groats diets supported a growth rate of chicks comparable with that of a practical diet for up to 2 weeks. To correct amino acid deficiency, Goodland, Dal, and Lodi oat groats diets were supplemented with 0.55, 0.60, and 0.65% lysine and 3.2, 5.1, and 6.6% of a mixture of other amino acids. Omission of lysine from the amino acid supplement resulted in retarded growth and marked reduction of plasma free lysine concentration. For Goodland oat groats, the chemical score was 51. Protein efficiency ratio with rats was 2.2, which was increased to 2.4 by lysine and methionine supplementation, while protein efficiency ratio for whole egg protein was 3.4. The slope-ratio assay rendered a relative nutritive value of 59 for Goodland oat groats, assuming 100 for whole egg protein. This value was increased to 67 by lysine and methionine supplementation.


Effects of nutritional copper deficiency on the biomechanical properties of bone and arterial elastin metabolism in the chick.

Increased bone fragility was observed in chickens fed diets containing less than 1 ppm copper. Using a device that was designed to measure torsion during fracture, it could be demonstrated that bone from copper-deficient chicks fractured with less deformation and torque than bone from control chicks. The collagen of bone from copper-deficient chicks appeared to contain fewer cross-links than normal bone. The introduction of artificial cross-links into collagen from copper-deficient chick bone by formaldehyde and NaBH4 treatments improved bone strength and strain (deformation) so that it was comparable with normal bone. Copper deficiency blocks the formation of cross-links in collagens and elastin from various tissues. It is felt that the bone fragility related to nutritional copper deficiency is the result of decreased bone collagen cross linking. Arterial elastin metabolism was also investigated. By radioactively labeling arterial soluble elastin (tropoelastin) in vivo by an intraperitoneal injection of [G-3H]valine, it could be demonstrated that copper deficiency appeared to reduce its rate of metabolic turnover. Soluble elastin or tropoelastin is assumed to be the precursor of mature or insoluble elastin. The observations presented here are consistent with the view that by retarding the steps associated with elastin cross-link formation, the incorporation of soluble elastin into mature elastin may be retarded as well.


Essential dietary amino acids for growth of larvae of the yellow mealworm, Tenebrio molitor L.

Larvae of the yellow mealworm, Tenebrio molitor L., have been used to evaluate nutritional quality of proteins and protein isolates. However, such investigations have been complicated by lack of knowledge of dietary requirements of the larvae. To determine essential dietary amino acids for growth of Tenebrio molitor, single amino acids were deleted from the amino acid mixture of the diet. Diets were maintained isonitrogenous with supplementary glycine and, in the case of deleted glycine, with glutamic acid. Growth, as measured by gain in weight, and survival were observed over a 4-week period at 27 plus or minus 0.25 degrees and 65 plus or minus 5% relative humidity. The results indicate that larvae of Tenebrio molitor require a dietary source of the same 10 amino acids essential for growth in rats, other vertebrates, and some protozoa. They also showed that serine, tyrosine, glutamic acid, and possibly glycine were dispensable for growth in this insect. Alanine, cystine, proline, and aspartic acid appeared semidispensable. Survival over the 4-week experimental period was unaffected by deleting amino acids from the diet. The results are discussed in relation to amino acid requirements of other insects and to suggested improvement of the diet of the present investigation.


Influence of meal frequency on in vivo hepatic fatty acid synthesis, lipogenic enzyme activity, and glucose tolerance in the chicken.

Chicks were allowed access to food for 2 hours per day (meal-fed) or were fed ad libitum. Tritiated water was administered intravenously, and the incorporation of tritium into fatty acids was used to estimate in vivo rates of fatty acid synthesis. Allowing the meal-fed chick access to a meal increased the hepatic rate of fatty acid synthesis up to 50-fold. Hepatic activities of malic enzyme and fatty acid synthetase were similar before and after the meal. The rate of fatty acid synthesis was greater in the fed meal-eater than in the ad libitum-fed chichen. Plasma free fatty acid levels were decreased and plasma triglyceride levels were increased when the meal-eater was fed. Oral and intravenous glucose tolerance tests were conducted. Meal-feeding did not impair glucose tolerance in the chicken, as has been reported in meal-fed humans. Unlike in the rat, intravenous glucose tolerance was not greatly influenced by meal pattern in the chicken. Oral glucose tolerance was improved in one of two experiments as a consequence of meal-eating. These results suggest that the chicken does respond to a shift in meal pattern.


Effects of vitamin K deficiency, warfarin, and inhibitors of protein synthesis upon the plasma levels of vitamin K-dependent clotting factors in the chick.

Two-week-old chicks adequate in vitamin K showed a relative lack of vitamin K-dependent clotting factors when compared with the rat, cow, and man. Chick prothrombin was 50%, IX 8%, and X 6% of respective levels in the rat. Factor VII was not detectable in chick plasma. When 1-day-old chicks were fed a vitamin K-deficient diet, prothrombin levels fell to 5% in 5 days, whereas factors IX and X fell to only 60% of normal. After warfarin administration to normal chicks, prothrombin levels fell to 20% in 6 hours, whereas factors IX and X fell to 60%. When cycloheximide was given to normal chicks, all vitamin K-dependent factors fell at the same relative rate with a half time of 2 hours. Cycloheximide also completely blocked the effect of physiological doses (10 mug) of phylloquinone upon prothrombin synthesis, but only partially blocked the effect of pharmacological doses (2.5 mg) of phylloquinone, suggesting an antagonism between cycloheximide and vitamin K at the ribosomal level. Puromycin was effective in blocking the action of vitamin K at both physiological and pharmacological doses. In the chick, unlike the rat, it appears that (1) cycloheximide is fully effective in blocking the action of physiological doses of vitamin K and (2) the regulatory systems for factors IX and X appear to have a higher affinity for vitamin K and a lower affinity for warfarin than the regulatory system for prothrombin.


Lipid composition of brown adipose tissue as related to nutrition during the neonatal period in hypotrophic rats.

Animals with intrauterine growth retardation (IUGR) were obtained by artery clamping of one uterine horn of the rat on day 17 of gestation. Body weight reduction was at least 30% as compared with the control animals that originated from the other horn. Brown adipose tissue (ISBAT), which plays a role in nonshivering thermogenesis, was greatly reduced during the period studied (fetuses from the day before up to 10 days after birth). Total lipids were very low after birth and increased rapidly up to age 3 days. Nevertheless, lipids of IUGR rats were lower during 48 hours and became identical to the controls only at 3 days. This deficiency could play a role in the high mortality rate observed just after birth. The developmental pattern of fatty acid methyl esters of ISBAT studied by gas chromatography method was identical in both groups of animals. On the other hand, a change from mainly saturated to a greater proportion of unsaturated fatty acids occurred just after the first suckling. This switch was closely correlated to the fatty acid composition of the rat milk. Incorporation of 14C from [14C]glucose into lipids of ISBAT was lower in IUGR rats up to 48 hours as compared with control values and overlapped the control value after. This could explain the catching up in lipid content in IUGR at 3 days of life. Also it could be correlated with the hypoglycemia observed in the IUGR rats during the neonatal period.


Nutritional consequences of the Maillard reaction. The absorption of fructose-L-tryptophan in the large intestine of the rat.

The absorption of fructose-L-tryptophan, an early Maillard reaction product formed from tryptophan and glucose, in the large intestine of the rat was examined. The possible involvement of cecal microflora of the rat in the absorption of fructose-L-tryptophan was investigated. Fructose-L-tryptophan was degraded by the cecal microflora (in vitro) after a 12-hour incubation at 37 degrees. Experiments with rat colonic rings and everted sacs indicated that a passive diffusion of this compound occurs in vitro in the colon of the rat. In vivo absorption was determined by introducing fructose-L-[3-14C]tryptophan directly into the cecum. Twenty percent of the total radioactivity injected was recovered in the urine after 24 hours. Fructose-L-tryptophan was detected in the urine, which suggested that this compound was absorbed by the large intestine but excreted without being metabolized. Approximately 1% of the total radioactivity was recovered in the expired air within 24 hours after injection. The small recovery of fructose-L-tryptophan in feces might indicate that this compound was degraded by the action of microorganisms in the large intestine of the rat.


Linoleate enrichment of diet and prostaglandin metabolism in rats.

Evidence that biosynthesis of prostaglandins (PG) in tissues of animals deficient in essential fatty acids is dependent on the availability of their precursors has been demonstrated. The purpose of this study was to determine the following: (1) effects of dietary linoleate enrichment on PG biosynthesis in rats; (2) effects of exogenous PGE2 and dietary linoleate on plasma free fatty acids and serum cholesterol in fed and fasted rats. Rats were fed three different concentrations of dietary linoleate as beef tallow, hydrogenated vegetable fat, or corn oil. The concentrations of PGE1 and PGF2a measured by radioimmunoassay were higher in rats fed the fed the beef tallow diet independent of energy status. A decrease in the concentration of PG between fasted and fed rats receiving hydrogenated vegetable fat is discussed in respect to the possible influence of trans isomers of unsaturated fatty acids on the biosynthesis of PG. There were significant effects of fasting on serum cholesterol concentration regardless of diet and significant interactions among effects of PGE2, fasting, and diet, suggesting regulatory effects of PGE2 on serum cholesterol concentration. The increase in plasma free fatty acids associated with fasting was prevented by PGE2 for all diets, but had the most marked effect on rats fed hydrogenated vegetable fat.


Mortality of lead workers.

The mortality of 7,032 men employed for one or more years in lead production facilities or battery plants was followed over a 23-year period, 1947 to 70. Lead absorption in many of these men was greatly in excess of currently accepted standards based upon urinary and blood lead concentrations available for a portion of the group. There were 1356 deaths reported; death certificates were obtained for 1267. The standardized mortality ratio (SMR) for all causes was 107 for smelter workers and 99 for battery plant workers. Deaths from neoplasms were in slight excess in smelters, but not significantly increased in battery plants. There were no excess deaths from kidney tumors. The SMR for cardiovascular-renal disease was 96 for smelter workers and 101 for battery plant workers, i.e. roughly the same as for the general population, but not as good as would be expected in a population that had been employed. There was definitely no excess in deaths from either stroke or hypertensive heart disease. However, deaths classified as "other hypertensive disease" and "unspecified nephritis or renal sclerosis" were higher than expected. The actual numbers of deaths in these last-named categories combined (41 where 19.5 were expected) represented about 3% of all certified deaths. The life expectancy of lead workers was calculated to be approximately the same as that of all U.S. males. Considering the high levels of exposure in this population of workers and the small deviations from expected mortality, one can be optimistic in predicting no detectable effect on the mortality of male adults from occupational exposures to lead controlled in conformity to currently recommended environmental and biologic standards.


Transparency of pair-correlated, random distributions of small scatterers, with applications to the cornea.

We consider transmission through pair-correlated random distributions of lossless dielectric (globular, cylindrical, or plate-like) scatterers with length parameter a and average spacing small compared to wavelength. Each optical particle is centered in a tough adherent transparent coating whose outer surface (sphere, cylinder, or slab) has radius b smaller than or equal to a. The corresponding attenuation coefficients beta varies directly as WM involve an integral of the appropriate radial-distribution function. Using the scaled-particle equations of state and statistical-mechanics theorems, we evaluate WM explicitly as a rational function of the volume fraction W of the fluid of rigid b particles. We obtain betaM = betaO WM with betaO as the uncorrelated value; W3(W) for spheres decreases more rapidly with increasing W than W2 for cylinders, and W2 decreases faster than W1, the result for slabs. We apply the results for cylinders in terms of W2 to the problem of the transparency of the cornea (whose collagen fibers are the scatters), as posed by Maurice. The value W APPROXIMATELY 0.6 GIVES GOOD ACCORD WITH THE ESSENTIALS OF THE Data for the transparency of the normal cornea, and the opacity that results from swelling is accounted for by corresponding smaller values of W. Thus, the normal cornea is modeled as a very densely packed two-dimensional gas, with gas-particle (mechanical) radius about 60% greater than the fiber (optical) radius.


Cross talk in absorbing optical fibers.

Cross talk between neighboring optical fibers is shown to alter the absorption spectrum of the fibers. There is an enhancement of absorption at shorter wavelengths and a consequent shift of the absorption peak towards the short-wavelength end of the spectrum. Curves are presented to illustrate the effect. Results are given in a dimensionless form, applicable to fibers with arbitrary physical parameters.


Visual fourier-transform spectroscopy with a single crystal plate.

This paper shows how a single Z-cut plate of uniaxial crystal can be used as a two-beam interferometer of Fourier-transform spectrometer. As a visual device, it permits easy identification of a set of achromatic fringes that can be seen in any two-beam interferometer when a white-light source is observed through it. These fringes apparently have not been described previously. They are expected when we understand that the white-light fringe pattern is in fact the Fourier transform of the spectral-sensitivity curve of the eye.


Visual acuity in the presence of retinal-image motion.

Resolution thresholds for Landolt C's and for vernier targets remain the same whether the target is stationary or moving with horizontal or vertical velocities of up to 2.5 degrees for foveal presentations lasting 0.1 and 0.2 s. Oblique target motions are tolerated only up to 1 degree. Because visual pursuit is ruled out by randomization of direction of motion and by the short exposure, it is concluded that a stationary retinal image is not a prerequisite for good acuity.


Experience with clinical and operative staging of Hodgkin's disease in children.

Accurate staging is critical for the proper treatment of Hodgkin's disease. In the past 5 yr, 60 children with Hodgkin's disease were staged by celiotomy which included splenectomy and biopsy of liver, retroperitoneal lymph nodes, and bone. Fifty children underwent staging celiotomy at initial diagnosis (Group I). Ten others were staged surgically because of suspected reactivation of disease diagnosed and treated before current staging methods were employed (Group II). Forty-one of 50 children in Group I had Stage I or II disease, seven Stage III, and two Stage IV. As a result of operation, therapy was altered in seven children. Three had a higher stag e and four a lower stage than that suspected by clinical evaluation, including two with liver involvement. Of the two patients in Group II, celiotomy revealed unsuspected splenic disease in seven, including one with liver involvement. Celiotomy and splenectomy were well tolerated and no long-term complications have been noted (average follow-up 2 yr). Forty-nine of 50 children in Group I and six of ten in Group II are alive without disease. No cases of sepsis attributable to splenectomy have been observed.


Position of rectal fistula in relation to the hymen  in 46 girls with imperforate anus.

Forty-six records of infant girls with so-called imperforate anus have been reviewed to determine the position of the rectal opening in relation to the hymen. Eight of these children proved to have the cloacal deformity, in which the rectum enters high into a single tube and just behind the opening of a double or septate vagina, with the urethra entering anteriorly at the same level. No normal hymen was  visible in these eight children. Seventeen patients had a normal-appearing hymen, and no rectal opening on the perineum. In each of these 17 children the rectal opening was found above the tissue flap overlying the posterior vestibule. In the remaining 21 patients, the hymen was visible and appeared normal, and there was a rectal opening somewhere on the perineum between the vestibule and the normal position for the external sphincters. These findings suggest that in the presence of a normal-appearing hymen, and in the absence of a normal anus, the rectal opening will be either in the posterior part of the vestibule or on the perineum. Where no hymen was visible, we have found in a limited experience that the rectal opening was high in the pelvis in some degree of the so-called cloacal deformity.


Nonrefluxing colon conduit for temporary or permanent urinary diversion in children.

Colon conduit, with nonrefluxing ureterosigmoid anastomoses, was performed upon 21 children in the past 3 1/2 yr for the following indications: (1) previously unoperated exstrophy of the bladder; (2) exstrophy of the bladder with prior ileal conduit; (3) previously unoperated neurogenic bladder; (4) neurogenic bladder with prior ileal conduit; and (5) with anterior pelvic exenteration for sarcoma of the prostate. In some of these patients the conduit will be a permanent diversion; in others it will be anastomosed later to the colon, providing a staged method of ureterosigmoid urinary diversion. Nine patients have undergone the second stage of anstomosis of the conduit to the colon with satisfactory outcome. Colon conduit diversion is a more time-consuming procedure than ileal loop diversion. It can require 6-8 hr in a patients with a prior ileal diversion, particualarly if the ureters require tapering. Our experience with this procedure leads us to the following conclusions: (1) this is a better method than ileal conduit for permanent diversion; (2) it offers an alternative way for treating patients with bladder exstrophy; (3) it is useful in patients with pelvic cancer; and (4) it should be considered for those patients with ileal conduits who are not doing well, i.e., who have infection and renal deterioration.


Liver trauma in children.

A review of our experience with urban children who sustained blunt abdominal trauma revealed that liver trauma occurred in one-third of all children. The cause of trauma, predominantly blunt in nature, led to a multitude of associated injuries which not only caused visceral and skeletal injury endangering the patient, but, more apparent even though less significant injuries delayed diagnosis and therapy of the underlying sever liver injury. Awareness of the possibility of liver injury in children with blunt abdominal trauma, prompt operative intervention wil injuries should significantly increase the salvage of these pediatric trauma victims.


Cervical lymphadenopathy from atypical mycobacteria: diagnosis and surgical treatment.

Cervical lymphadenopathy due to atypical mycobacteria was an easily identifiable clinical entity in 45 children. A 3-wk history of lymphadenopathy associated with positive atypical acid-fast mycobacterium skin test is highly suggestive of the diagnosis. Surgical extirpation is recommended for cure. The results of operative excision in 40 children were excellent.


Naturalistic studies of aggressive behavior: aggressive stimuli, victim visibility, and horn honking.

Three studies extended laboratory research on aggression to a naturalistic setting which involved horn honking from drivers as a measure of aggression; the studies were adapted from Doob and Gross. The results from a survey (Study 1) of 59 drivers suggested that they were frequently irritated by and aggressive toward other drivers. A second study (using a 3x2 factorial design with 92 male drivers) indicated that manipulations of a rifle in an aggressive context and victim visibility (dehumanization) both significantly influenced horn honking rates subsequent to obstruction at a signal light. A third study with 137 male drivers and 63 female drivers examined the interactive effects of a rifle, an aggressively connotated bumper sticker, and individual subject characteristics (sex and an exploratory index of self-perceived status) on horn honking. The results for three studies in naturalistic settings offer possible extensions of laboratory based findings on aggression. The role of inhibitions in modifying the pattern of results was also discussed.


Perceptions of and reactions to stressful situations.

Two approaches to the study of the psychological significance of situations were compared, one using data for individuals' perceptions of situations and the other using data for individuals' reactions to situations. Perception and reaction data for 40 subjects were used for multidimensional classification of 12 situations, which were selected so as to cover four different types of stressful situations. For three of the a priori groupings of situations the congruence in outcomes between the two methods was high. The implications of the congruence and the discrepancies in outcomes for the two approaches are discussed. The main conclusion is that one should distinguish clearly between situation perception factors and situation reaction factors in further research on the psychological significance of situations.


Selection of a reference partitioning system for drug design work.

Consideration of the structural, polar, and transport properties of water-saturated solvent and solvent-saturated water phases of three general and eight specific binary systems leads to the conclusion that the n-octanol-water system is a very good all-round compromise for use as a reference system for biological partitioning in drug design work.


Effect of various alcohols on intestinal net water flux and theophylline absorption in rats.

Previous studies in this laboratory demonstrated that the rate of intestinal absorption of theophylline in rats is increased significantly by ethanol in low concentrations and that this absorption enhancing effect is associated with an increased net water flux from the intestine. It is now shown that other alcohols, namely methanol, n-propanol, n-butanol, glycerin, propylene glycol, and, to a lesser extent, mannitol and sorbitol, can also increase net water flux from the small intestine of anesthetized rats. Polyethylene glycol 200 and 400 had no such effect, suggesting that these compounds do not penetrate to a site of action that elicits the increased net water flux. At initial concentrations of 0.1 and 1.0 M, glycerin and propylene glycol increase significantly the intestinal absorption rate of theophylline from the small intestine of anesthetized rats. The results show that the theophylline absorption enhancing effect of ethanol is not limited to that particular alcohol.


Convective diffusion model for a transport-controlled dissolution rate process.

A mathematical model based on convective diffusion was developed to describe the rate of dissolution form the surface of a compressed compact. Experimental studies were carried out to test the model. The basic experimental apparatus consisted of a modified rotating-filter-stationary basket dissolution test apparatus. Dissolution rates from rectangular and circular surfaces of an homologous series of p-aminobenzoate esters permitted testing the theory with respect to solubility, geometry, and agitation conditions. The correlation between experimental results and theory was reasonalby good considering that the test conditions were somewhat less than ideal.


Biosynthesis, isolation, and identification of 6-beta-hydroxynaltrexone, a major human metabolite of naltrexone.

Chemical reduction of naltrexone is described in an attempt to synthesize 6-beta-hydroxynaltrexone. Only the epimer, 6-alpha-hydroxynaltrexone, was produced. Pilot metabolic studies on naltrexone in the dog, rat, and guinea pig were made to determine which animal produced the greatest amount of 6-beta-hydroxynaltrexone. The guinea pig was selected and used to produce the metabolite. Isolation and purification methods are described, and spectral data are presented for structural confirmation of the metabolite.


Systems approach to study of solute transport across membranes using suspension cultures of mammalian cells III: steady-state diffusion models.

General physical models are derived for the diffusional transport of drugs across membranes of mammalian cells in culture suspension. These models represent different sets of possible physical processes taking place during the transport of a drug molecule. Once the diffusing species reaches the cell barrier, it may gain entrance to the cell kinetically by one of the principal quasisteady-state mechanisms, all of which assume the cell membrane to be an integral part of the total barrier.


Systems approach to study of solute transport across membranes using suspension cultures of mammalian cells V: Uptake and release kinetics of cardiac glycosides by Burkitt lymphoma cells.

Mass transport studies with three cardiac glycosides in the Burkitt lymphoma cell system have provided significant examples of the factorization and quantification of the influences of serum-drug binding, membrane-drug binding, cell interior binding, and intrinsic membrane permeability upon the uptake and release kinetics of drugs in living cell systems. All of the data from the glycosides are in agreement with the general physical model involving the rapid equilibration of the solute within the cell after permeation through the rate-determining plasma membrane barrier. The transport of digitoxin was influenced by membrane and serum binding and that of digoxin was influenced by membrane binding. There was no binding of ouabain to the plasma membrane and serum. The variables in the uptake and release kinetic studies at pH 7.3 included the use of viable and heat-inactivated cells, fetal bovine serum levels, and temperature.


Antiarrhythmic activity of 3-amino-3-methyloxindoles.

A series of 3-amino-3-methyloxindoles was synthesized from indoles by modification of previously described procedures. All compounds showed activity against chloroform-induced arrhythmias in mice. One member of the series, 3-methyl-3-piperidinooxindole, displayed activity equal to that of lidocaine while showing only one-third the acute toxicity.


Determination of 17-monochloroacetylajmaline and its metabolite in plasma by TLC fluorescence detection.

A sensitive and specific method is described for the determination of 17-monochloroacetylajmaline (I) and its metabolite, ajmaline (II), in plasma. Method specificity is accomplished by combining an ion-pair extraction with chromatography followed by development and utilization of reaction product fluorescence of the isolated species on silica gel. Recovery of I and II added to plasma or water averaged 70%. The major loss in the assay resulted during a solvent evaporation step and was reproducible over the concentration interval studied. The limit of detectability for I is 0.06 mu-g/2 ml of plasma. The method was used to determine plasma levels of I and II in the dog following a dose of 10 mg/kg iv of I.


Biochemorphology of cyclobutanecarbonylureas.

Ten urea derivatives of cyclobutanecarboxylic acid were synthesized and examined for general CNS depressant properties, barbiturate potentiation, and myorelaxant, antitremorine, and anticonvulsant potencies. Although water solubility plays an important role in the activity of these compounds, other factors also appear to be involved. 1-Cyclobutanecarbonyl-3,3-dimethylurea appears to be the most active CNS depressant, whereas 1-cyclobutanecarbonyl-3-(alpha-naphthyl)thiourea is the most active barbiturate potentiator. 1-Cyclobutanecarbonyl-3,3-dimethylurea, 1-cyclobutanecarbonyl-3-phenylurea, and 1-cyclobutanecarbonyl-3-tert-butylurea, 1-cyclobutanecarbonyl-3-allylurea, and 1-cyclobutanecarbonyl-3-phenylurea apparently are the most active against pentylenetetrazol-induced convulsions. 1-Cyclobutanecarbonyl-3-tert-butylurea, 1-cyclobutanecarbonyl-3,3-dimethylurea, and 1-cyclobutanecarbonyl-3-phenylurea are also slightly active tremorine antagonists.


Biopharmaceutic factors in parenteral administration of vitamin E.

When properly formulated, micellar-type aqueous dispersions of tocopheryl acetate are administered intravenously or intramuscularly to dogs, the rate-limiting step in the bioavailability of the physiologically active free tocopherol is the rate of hydrolysis of the acetate ester. A similar dispersion of free tocopherol yields blood levels of tocopherol many fold higher than those obtained with the acetate ester after intravenous injection and also yields much greater increases in blood levels of free tocopherol after intramuscular injection than the acetate ester formulation, particularly in the early period after the dose.


Effect of inorganic additives on solutions of nonionic surfactants II.

The effect of electrolytes and urea on the cloud points of the following three nonionic polyoxyethylated surfactants was studied: cetyl, stearyl, and oleyl alcohol adducts containing 10 ethylene oxide units. The results were similar to those obtained previously with polyethylene oxide and with a polyoxyethylated alkylphenol. Nitrates of cations capable of forming stable solid complexes with model ethers like dioxane raised the cloud points in proportion to their concentrations by up to 35 degrees. They salted the surfactants in through complexation with the ether oxygens. The order of effectiveness in raising the cloud points was lead nitrate greater than hydrochloric acid greater than cadmium nitrate greater than sulfuric acid approximately equal to to magnesium nitrate greater than aluminum nitrate greater than nickel nitrate greater than lithium nitrate greater than calcium nitrate. Only the nitrates of sodium, potassium, ammonium, and cesium lowered the cloud points, salting the surfactants out. These cations do not form complexes with ether oxygens. Urea, sodium perchlorate, and sodium iodide, which break the structure of water, raised the cloud points. This salting-in process is ascribed to increased hydration of the ether groups of the polyoxyethylated surfactants due to depolymerization of water by urea and the perchlorate and iodide anions. The bromide, chloride, and sulfate of sodium lowered the cloud points. The surfactant with the alkylaryl moiety was salted in more extensively but salted out only slightly more than the three surfactants with the linear hydrocarbon chain. The data indicate the need for revising the theories of the effects of salts on the solubility of nonelectrolytes in water. None of the theories takes into account the interaction between electrolytes and nonelectrolytes, even though many nonelectrolytes compete with water as ligands for the cations.


In vivo method for monitoring polysorbate 85 effect on epidermal permeability.

An in vivo method of monitoring the rate of water desorption from human forearms, using "dry" nitrogen gas passed over approximately 1 cm-2 of skin was investigated with the aid of a commercial electrolytic moisture analyzer. The assembled apparatus was used to evaluate the differences in water loss rates from treated and untreated (control) forearms following surfactant application. The changes in the differences were also monitored after cessation of treatment, i.e., during the healing process. The apparatus provided an accurate, rapid, and painless method of monitoring relative water loss rates and, as such, could prove a useful tool in routine testing in experimental dermatology and cosmetology. The results confirm the earlier finding from an in vitro method with excised rabbit skin that the tested surfactant increases the permeability of the epidermis.


Determination of acetaminophen in pharmaceutical preparations and body fluids by high-performance liquid chromatography with electrochemical detection.

A sensitive and very rapid assay for acetaminophen was developed based on the combination of high-performance chromatographic columns with a thin-layer electrochemical detector. Application to liquid and solid dosage forms and body fluids has been demonstrated. Great advantage derives from the detector selectivity, which permits discrimination against many potentially interfering substances without need for extensive separations or formation of derivatives. As little as 0.005% of the hydrolysis product, p-aminophenol, can be detected in the presence of the intact drug following cation-exchange chromatography. Acetaminophen can be quantitatively determined in serum on the 50-ng/ml level by liquid chromatography using a pellicular polyamide packing.


Automated procedure for determination of free aromatic amine in water-soluble radiopaques.

The determination of free aromatic amine in water-soluble radiopaques by diazotization in 2-methoxyethanol-water, coupling with naphthylethylenediamine, and colorimetry of the azo dye has been automated. Sensitivity, precision, and accuracy are satisfactory for purity testing and stability studies.


Syntheses and tissue distribution of 99m-Tc-sulfonylureas.

Four new tolbutamide analogs were prepared and evaluated as hypoglycemics. Hypoglycemic action was observed in two members of the class, and 99m-Tc-chelates were tested as potential radiopharmaceutical imaging agents.


Utility of fasting essential amino acid plasma levels in formulation of nutritionally adequate diets III: lowering of rat serum cholesterol levels by lysine supplementation.

A lysine-supplemented ration lowered the serum cholesterol levels of rats. The level of lysine supplementation was derived from the fasting plasma essential amino acid profile.


Utility of fasting essential amino acid plasma levels in formulation of nutritionally adequate diets IV: lowering of human plasma cholesterol and triglyceride levels by lysine and tryptophan supplementation.

The administration of capsules containing L-lysine monohydrochloride (0.205 g) and L-tryptophan (0.069 g) three times daily after meals resulted in a significant drop in plasma cholesterol and triglyceride levels. The proportion of amino acids in the blend was derived from the average fasting plasma essential amino acid profile.


Topical mosquito repellents VII: alkyl triethylene glycol monoethers.

Normal and branched-chain aliphatic monoethers of triethylene glycol are effective topical mosquito repellents. In terms of duration of protection, they are generally superior to the corresponding diethylene glycol analogs and some are superior to diethyltoluamide. The n-heptyl monoether of triethylene glycol affords double the protection time of diethyltoluamide under controlled laboratory conditions and appears to be a useful new mosquito repellent.


Complex formation between menadione and cetylethylmorpholinium ethosulfate: effect on UV photodegradation of menadione.

The process of menadione photodegradation can be enhanced or diminished by other compounds. The presence of the quaternary ammonium compound cetylethylmorpholinium ethosulfate (I) in solutions of minadione was found to slow the rate of photodegradation by UV light (253.7 nm). The mechanism of this effect may be due to complex formation between menadione and I. Complex formation was demonstrated by a shift in the absorption peaks of menadione from 245 and 260 nm to 251.5 and 261.5 nm, respectively. The equilibrium constant of this complex was calculated to be 1.647 M.


Synthesis and evaluation of antitumor activity of 1-[N, N-bis(2-chloroethyl) sulfamoylphenyl]-3,3-dialkyltriazenes.

Twenty-two 1-p-sulfamoylphenyl-3,3-dialkyltriazenes, 1-p-dialkylsulfamoylphenyl-3,3-dialkyltriazenes, and 1-p-[N,N-bis(2-chloroethyl) sulfamoylphenyl] -3,3-dialkyltriazenes were synthesized from their corresponding amines. Six of the compounds tested were devoid of antitumor activity.


Excretion of the active principle of of Catha edulis (Miraa) in human urine.

d-Norpseudoephedrine, a central stimulant present in Catha edulis, is excreted unchanged in human urine. The alkaloid was detected in urine 30-50 min after ingestion of synthetic d-norpseudoephedrine, and trace amounts of the drug could still be detected 24 hr later. Approximately 40% of ingested d-norpseudoephedrine was recovered in urine in the first 6 hr.


New compounds: fatty acid and long chain hydrocarbon derivatives containing a strong chelating agent.

Fatty acid and long chain hydrocarbon analogs that contain a strong chelating group were synthesized as part of an effort to determine if the biological function of the fatty acid can be used to transport metallic isotopes to the myocardium.


Effect of isoproterenol and D-600 on calcium movements in rat myometrium.

The effects of two smooth muscle relaxants, isoproterenol and D-600, on calcium movements in rat myometrium were investigated. Both relaxants caused a nonspecific increase in 45-Ca efflux due to changes in mechanical tension but the additional net loss expected on the basis of previous studies with isoproterenol could not be demonstrated due to a high background of calcium exchange. Analysis of 45-Ca and 40-Ca residual in the muscle after efflux experiments and washing of the tissue in a Ca-deficient solution containing LaCl3 (2.0 mM) showed that the specific activity ratio 45-Ca/40-Ca was unaltered with isoproterenol and, thus, the net loss of calcium occurred equally from slowly and rapidly exchanging compartments. "Pulse label" experiments in which 45-Ca and either isoproterenol or D-600 were added simultaneously for a 2-minute period demonstrated that both relaxants decreased the 45-Ca space; however, the specific activity ratio 45-Ca/40-Ca in the tissue was reduced while 40-Ca remained unchanged in the presence of D-600. With isoproterenol, the 45-Ca/40-Ca ratio was increased while 40-Ca was reduced. These data support the hypothesis that isoproterenol stimulates a net efflux of calcium whereas D-600 inhibits the influx of calcium. Since previous studies have demonstrated that relaxants which increase cyclic3,5-adenosine monophosphate (cyclic AMP) (isoproterenol, dibutyryl cyclic AMP and papaverine) produce consistent decreases in tissue Ca but others (D-600) do not, it is concluded that relaxants which increase tissue cyclic AMP stimulate a net efflux of calcium but other antagonists may act by inhibiting calcium influx into rat myometrium.


Neural mechanisms involved in acetylstrophanthidin-induced bradycardia.

The role of neural sites in the bradycardia produced by acetylstrophanthidin (14.1, 22.5 and 35.5 mug/kg) was studied in chloralose-anesthetized cats with efferent vagal tone blocked by atropine. The sites were: carotid sinus baroreceptors, aortic arch baroreceptors, cardiac sensory receptors, nodose ganglion receptors and central nervous system structures. The role of each site was determined by selective ablation of all sites except the one under study. Significant slowing in heart rate occurred when: 1) only carotid sinus baroreceptors were intact; 2) only aortic arch baroreceptors were intact and 3) only cardiac sensory receptors were intact. No cardiac slowing was observed when only nodose ganglion receptors, central sympathoinhibitory sites and beta adrenergic receptors were intact. These results indicate that in atropine-treated cats, the further slowing in heart rate produced by acetylstrophanthidin arises from activation of reflex sites located in the carotid sinus, aortic arch and myocardium.


Renal hemodynamics and electrolyte excretions after reserpine and ethanol.

The participation of the peripheral nervous system in the renal response to an acute ethanol administration was investigated in dogs. The animals received water or ethanol (3 g/kg), with and without 2 days pretreatment with reserpine. Each group was examined 18 hours after the water or ethanol administration. In comparison to water controls, both reserpine and ethanol produced similar increases with respect to renal hemodynamics. The combined treatment produced a further significant increase in effective renal plasma flow. Reserpine alone produced increases in the rates of filtration and reabsorption of sodium and chloride; ethanol and reserpine-ethanol treatments produced further increases but did not alter the excretory rates. Although all three treatments produced increases in the rate of filtration of potassium, only ethanol and reserpine-ethanol treatments increased the excretory rate. Magnesium excretion was decreased by reserpine and reserpine-ethanol in comparison to water and ethanol, respectively; but calcium excretion was elevated in all the treatment groups. Zinc excretion was increased in the ethanol group. The results suggest that the secondary action of ethanol to produce release and possible depletion of peripheral catecholamine stores is not primarily involved with its renal effects, except in the case of magnesium and zinc metabolism.


Nicotine-induced relaxation in isolated canine cerebral arteries.

Nicotine in concentrations ranging from 5 times 10- minus 6 to 10- minus 4 M caused a transient relaxation in strips of isolated canine basilar, middle cerebral and posterior cerebral arteries contracted with prostaglandin F2a (PGF). Transmural neural stimulation did not produce changes in the tension of these arteries. Tyramine contracted the arterial strips. Relaxation induced by nicotine was markedly attenuated by hexamethonium (10- minus 5 M), cocaine (10- minus 5M), bretylium (2 times 10- minus 5 M), sotalol (5 times 10- minus 5 M), propranolol (10- minus 6 M) and removal of Ca-++ from the bathing media. Relaxation was not significantly influenced by atropine, physostigmine, ouabain, tetrodotoxin, aminophylline and sotalol (10- minus 5 M). In cerebral arterial strips, the addition of K-+ also elicited a transient relaxation which was abolished by treatment with ouabain but not with other blocking agents. In mesenteric arterial strips, nicotine caused a transient contraction as did transmural stimulation. The nicotine-induced contraction was markedly attenuated or completely abolished by hexamethonium, cocaine, bretylium and phentolamine and also high concentration of sotalol (5 times 10- minus 5 M), and propranolol. Tetrodotoxin did not affect the contractile response to nicotine but did abolish the response to transmural stimulation. It is strongly suggested that  relaxation induced by nicotine in cerebral arterial strips is the result of a specific action on nicotinic receptors as is the contraction observed in mesenteric arteries. It appears that beta adrenergic and cholinergic mechanisms do not play major roles in the genesis of nicotine-induced relaxation nor does it appear that an electrogenic Na-+ pump mechanism is involved.


Analysis of the effect of 5-hydroxykynurenamine,, a serotonin metabolite, on isolated cerebral arteries, aortas and atria.

In helically cut strips of dog and human cerebral arteries, the addition of 5-hydroxykynurenamine (5-HK) caused dose-related contractions, and this contractile response was attenuated by methysergide and lysergic acid diethylamide (LSD). Treatment of the strips with 5-HK in concentrations higher than 2 X 10- minus 6 M shifted the dose-response curve of serotonin to the right and downward. The inhibitory effect of 5-HK was reversed only partially by repeated washings, whereas the inhibition caused by methysergide and LSD was completely reversed. The contractile response to K-+ (30 mM) was reduced only slightly even at the highest concentration of 5-HK used (5 X 10-minus 5 M). In strips of rabbit aortas, the contractile effect of serotonin was markedly attenuated by 5-HK, whereas that of norepinephrine was reduced only slightly. In isolated rabbit right atria, 5-HK produced a transient increase in the rate as did serotonin, 5-HK being approximately 1/20 as potent as serotonin. The positive effect was not influenced by methysergide but was markedly attenuated or abolished by 10-minus 6 M propranolol and 3 X 10-minus 6 M cocaine. Treatment with 5-HK (5 X 10-minus 5 M) did not modify the chronotropic response to isoproterenol. It appears that 5-HK produces vascular contractions via serotonergic receptors, inhibits specifically the contractile response of arteries and aortas to serotonin and causes a tachycardia in rabbit atria by liberating catecholamines from adrenergic nerves.


Differential inhibitory effect of neomycin on contractile responses of various canine arteries.

The influence of neomycin on vascular smooth muscle contractile responses was examined in different isolated arterial preparations of the dog. Prior exposure (5 minutes) to 7 mM neomycin decreased contractile responses elicited with norepinephrine (NE, 0.6 muM) or KC1 (K-+, 80 nM) in helical strips of canine aortae (Ao) and femoral (F), carotid (Cd), renal (R), superior mesenteric (Sm), terminal mesenteric (Tm) and coronary (Cr) arteries. Addition of neomycin subsequent to NE-induced contractile responses depressed tension responses of the F, Cd, R, Sm and Tm arteries but had little or no effect on the Ao. However, after contractions had been elicited with K-+, neomycin had no effect on tension responses of the Ao, F, Cd, R or Sm arteries but depressed contractions of the Cr and Tm arterial strips. Preincubation with neomycin (0.7-3.5 mM) produced a concentration-related inhibition of contractile responses elicited in Tm arterial strips by addition of calcium ions (Ca-++; 1.6 mM) to a Ca-++-free depolarizing solution; conversely, subsequent addition of neomycin had no effect on maintained Ca-++ contractures. In constant flow-perfused terminal mesenteric arterial branches, neomycin (0.5-4.0 mM) produced a concentration-related antagonism of pressor responses elicited with NE (1-8 mug) or K-+ (40 mM). The inhibitory action of neomycin on K-+-induced pressor responses was inversely related to the Ca-++ concentration of the perfusion fluid. However, inhibition of NE pressor responses by neomycin did not appear to be related to the Ca-++ concentration. The differential inhibitory action of neomycin on contractions induced by NE and K-+ in various canine arteries suggests that different vascular beds vary in the manner in which Ca-++ is bound and subsequently utilized by stimulatory agents to elicit tension changes.


Sex and estrogens and responsiveness of terminal arterioles to neurohypophyseal hormones and catecholamines.

It has been generally assumed that reactivity (or responsiveness) of mammalian microcirculatory blood vessels to vasoactive hormones is not influenced by sex. In view of the paucity of knowledge in this area, the present in vivo studies were initiated to determine the quantitative dose-response relationships (by means of a high magnification image-splitting television microscope recording system) of catecholamines, selected sympathomimetics, neurohypophyseal hormones (NHPH), serotonin and angiotensin on mesenteric arterioles of unpretreated male and female rats and male rats pretreated with single low doses of 17 beta-estradiol (2 and 10 mug/100 g s.c.). The results indicate: 1) dose-response curves for the constrictor catecholamines (epinephrine and norepinephrine) and NHPH (vasopressin, oxytocin, vasotocin) in female rats are significantly shifted in parallel manner to the left of those obtained in male rats; 2) pretreatment of male rats with estrogen results in an enhancement of the constrictor actions of catecholamines, NHPH and phenylephrine; 3) the maximal arteriolar contractile responses (i.e., lumen narrowings) to norepinephrine and phenylphrine were enhanced by pretreatment with estrogen; and 4) dose-response curves for arteriolar constrictions induced by dopamine, serotonin or angiotensin were not affected by sex or estrogen pretreatment. The sex-linked differences, observed in this study, thus appear to be specific for NHPH and certain alpha adrenergic agonists. Overall, these findings reinforce the concept that sex hormones may play a role in control of peripheral blood flow and reactivity of arteriolar smooth muscle.


Effect of castration on the smooth muscle cells of the internal sex organs of the rat: influence of the smooth muscle on the sympathetic neurons innervating the vas deferens, seminal vesicle and coagulating gland.

Wet weights of vas deferens, seminal vesicle and coagulating gland were reduced by almost 80 to 90% 10 weeks after castration. Endogenous norepinephrine content and dopamine-beta-hydroxylas activity of these tissues were also reduced to the same degree. One week after castration there was approximately a 50% loss in the weight of all three organs. However, this was accompanied by an equal reduction in norepinephrine content and dopamine-beta-hydroxylase activity only in the vas deferens. Two weeks later the degree of reductions in wet weight, norepinephrine content and dopamine-beta-hydroxylase activity was almost identical for all three organs. Treatment of 40-day castrate rats with testosterone (10 mg/kg s.c.) not only restored the wet weights of the internal sex organs to normal but their norepinephrine content and dopamine-beta-hydroxylase activity as well. Castration of immature rats (10-14 days old) resulted in retardation of growth of the vas deferens and seminal vesicle by 90-95%, and similar reductions in norepinephrin content and dopamine-beta-hydroxylase activity, when compared to the tissues of control littermates on the 90th postoperative day. Histological examination of normal and castrate rats indicated that, along with a reduction in epithelial cells, the smooth muscle cells of the vas deferens, seminal vesicle and coagulating gland was markedly reduce in size as well. Administration of testosterone completely reversed these changes. Furthermore, deoxyribonucleic acid content of the seminal vesicle and coagulating gland was reduced by 50% after castration and then restored to control level after testosterone treatment. Taken together, it seems that atrophy of the internal sex organs following castration is a combined effect of reduction in size and number of smooth muscle cells. Therefore, it is concluded that any alteration in the size of smooth muscle cells or loss of such cells of the internal sex organs indirectly influences their sympathetic nerves in such a manner that norepinephrine concentrations, and thereby the density of innervation, are maintained at normal levels.


Characterization by cyproheptadine of the dopamine-induced contraction in canine isolated arteries.

Spirally cut strips of isolated canine femoral and carotid arteries were used to characterize the vasoconstrictor effect of dopamine. A serotonin antagonist, cyproheptadine, 10- minus 7, 3 X 10- minus 7 and 10-minus 6 M, inhibited dopamine (pA2 = 7.46 plus or minus 0.11), tryptamine (pA2 = 7.38 plus or minus 0.09) and serotonin-induced contractions (pA2 = 7.59 plus or minus 0.09). Cyproheptadine shifted the threshold concentration of dopamine 2 log units to the right without altering norepinephrine response. In protection experiments, preincubation with serotonin (10-minus 5 M) for 10 minutes protected serotonin and tryptamine receptors from cyproheptadine (3 X 10-minus 7 M) and phenoxybenzamine (10-minus 6 M) blockade. Serotonin cross-protected dopamine receptors also. Reciprocally dopamine (10-minus 4 M) protected its own receptors as well as those for serotonin and tryptamine. Norepinephrine did not afford any protection of dopamine, serotonin or tryptamine receptors but did protect its own receptors from phenoxybenzamine blockade. The attempt to characterize the receptor subserving dopamine-induced contraction failed to confirm a relationship between dopamine and alpha adrenoceptors. Since dopamine, tryptamine and serotonin, unlike norepinephrine, were sensitive to cyproheptadine blockade, dopamine-induced contraction appeared to be mediated by a receptor closely related to serotonin receptors. Therefore, alpha adrenoceptors may not be exclusively involved in the vasoconstriction evoked by dopamine on canine vasculature.


Pressure-dependent factors in edema formation in canine forelimbs.

Acetycholine (10 mug/min) infused intra-arterially for 30 minutes into naturally perfused forelimbs increased forelimb weight 23 g. largely due to edema formation. The weight gain was associated with markedly elevated skin and skeletal muscle blood flows and small vein pressures, suggesting that the edema was attributable, in part, to a rise in microvascular pressures. Mechanically increasing venous pressure and blood flow to similar levels for 30 minutes in pump-perfused forelimbs produced a weight gain of 27 g. The rate of weight gain for the acetylcholine and mechanical alterations was nearly identical. Acetylcholine and mechanical alterations both increased forelimb lymph flow rate but failed to increase lymph total protein concentration significantly. These studies indicate that in the dog forelimb elevated microvascular pressures result in edema formation by increasing the transcapillary hydrostatic pressure gradient without producing an important decrease in the transcapillary colloid osmotic pressure gradient. Increased pressure is not associated with a large increase in microvascular permeability to plasma proteins as is seen with the administration of high doses of histamine and bradykinin.


Experimental evidence for calcium independent catecholamine secretion from the bovine adrenal medulla.

The purpose of this investigation was to establish the existence of a calcium-independent mechanism for catecholamine secretion from the adrenal medulla. Concentration-effect curves were obtained using isolated perfused (5 ml/min; 25 degrees C) bovine adrenal medullae stimulated with acetaldehyde (1-64 mM). Catecholamine secretion was the same in presence and in absence of calcium in the perfusion medium and was not diminished by the addition of magnesium (5 X 10-minus 3 M) to the calcium-free medium. Stimulation of 45-Ca-labeled adrenals with 23 mM acetaldehyde evoked secretion of catecholamines but not 45-Ca. Furthermore, examination of the distribution of 45-Ca and catecholamines in subcellular fractions (cytosol, nuclei, microsomes, mitochondria and chromaffin granules) from acetaldehyde-stimulated and nonstimulated glands showed that acetaldehyde stimulation caused no mobilization of 45-Ca from any of the intracellular pools, but significantly decreased the catecholamine content of a chromaffin granule fraction with a concomitant increase of catecholamines in the cytosolic fraction. These results establish an adrenomedullary secretory mechanism independent of both extracellular and intracellular calcium and indicate that acetaldehyde evokes catecholamine secretion by this calcium-independent mechanism, releasing the intragranular hormones into the cytoplasm prior to their extrusion from the chromaffin cell.