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A new fine-wire microelectrode made from tungsten wire is described. The electrode design provides for strength as well as flexibility due to the stiffness of tungsten wire and a gradually tapering profile. Unlike previously-used fine wire electrodes, microelectrodes of the new design can be singly implanted under electrophysiological control into deep brain structures of larger animals such as cats. The flexibility of the fine diameter terminal portion of the microelectrode permits stable recording from caudal brain stem single units during vigorous behavioral activity.

Using the Nottingham introducer and diazepam sedation, 93 of 100 patients with oesophagogastric malignancy have been successfully intubated, 67 with Celestin tubes and 26 with Atkinson tubes. Their mean age was 72 years (range 36-91). Six of the failures were in patients with fundal adenocarcinoma. Sixty-nine patients were discharged from hospital after initial intubation (74%). Nine patients developed a perforation, 6 died and there were 5 deaths from aspiration. Nine patients are alive up to 11 months later. The mean survival after discharge was four months with a maximum of 18 months. Later 11 tubes obstructed and 12 Celestin tubes displaced upward. Endoscopic insertion of oesophageal prosthetic tubes provides satisfactory palliation for inoperable oesophagogastric malignancy. The development of the Atkinson tube with a distal flange has eliminated tube displacement upwards.

Previous research has shown that bilateral deep tectal lesions in golden hamsters abolish the lordosis response, whereas unilateral lesions selectively impair lordosis elicitation by contralateral flank stimulation. The present study analyzed the neural basis of these lesion effects by assessing the somatosensory responsiveness of midbrain neurons in three groups of urethane-anesthetized hamsters: animals with lordosis-abolishing bilateral tectal lesions, animals with lordosis-impairing unilateral lesions, and intact animals. Animals with bilateral lesions differed from the other groups in three aspects of unit sensory responsiveness by showing: (1) the highest percentage of neurons responsive to somatic stimulation, (2) the highest incidence of unit responsiveness to flank stimulation, and (3) the greatest proportion of responsive neurons in the ventral tegmentum. Hamsters with unilateral lesions showed basically normal unit responsiveness apart from elevated unit response to face stimulation. The results suggest that bilateral tectal lesions may eliminate lordosis by the combined effects of enhanced ventral tegmental somatosensory responsiveness and tectal destruction. Unilateral lesions appear to impair lordosis without changing the somatosensory excitability of remaining midbrain neurons.

Concentrations of histamine were quantified by an enzymatic isotopic assay in different regions of the brain and pituitary gland of gonadal-intact and chronically ovariectomized ewes during the anestrous season. Sera concentrations of LH were confirmed to be elevated in ovariectomized compared with intact animals immediately before tissues were obtained. Areas of the brain that were examined included cerebral cortex, thalamus, pineal gland, hypothalamus (rostral, medial basal, median eminence), midbrain, cerebellum and brain stem. Concentrations of histamine were greatest within the thalamus, pineal gland, medial basal hypothalamus and median eminence. Histamine within the medial basal hypothalamus was greater (P less than .05) in ovariectomized than in ovarian-intact animals. Further experiments were designed to determine the effect of antihistaminic drugs on secretion of LH. Ovariectomized ewes were treated every 6 h (i.m.) for 24 h with diphenhydramine (an antagonist of the H1-receptor for histamine), cimetidine (an H2-receptor antagonist), a combination of the drugs, or vehicle. Twelve hours after initiation of treatments, animals were injected with estradiol. Diphenhydramine depressed (P less than .01) basal serum concentrations of LH and the positive feedback effect of estradiol on serum concentrations of LH. Cimetidine did not influence the pattern of secretion of LH. Diphenhydramine did not alter LHRH-induced release of LH in ovariectomized ewes or basal serum concentrations of LH in ovarian-intact anestrous ewes. We suggest that histamine acts at the level of the central nervous system through an H1-receptor mechanism to control secretion of LH in female sheep.

Midbrain single units in anesthetized female hamsters were examined for pronounced, sustained responses to types of somatic stimuli which control the display of lordosis during periods of sexual receptivity. Units showing strong responses to lordosis trigger stimuli were widely distributed, but tended to be most concentrated in th deep superior colliculus, ventromedial midbrain and central gray, brain regions previously implicated, by other methods, in the control of hamster lordosis.

Previous studies have demonstrated the importance of the midbrain, especially the tectum, in the sensorimotor control of the sexually-receptive posture, lordosis, in female golden hamsters. In the present study, midbrain single unit activity was recorded during hormonal induction of lordosis, to identify neuronal activity mediating the sensorimotor control of the response and to observe functional changes in these neurons associated with the hormones' behavioral effect. Progesterone administration to estrogen-primed hamsters initiated pronounced changes in neuronal activity levels, somatosensory responsiveness and movement-related firing. These changes began in some neurons within 10 min of subcutaneous hormone injection and affected progressively more neurons until lordosis was elicitable 2-4 hr later. The pattern of these changes, including increased neuronal responsiveness to lumbosacral stimuli, appearance of lordosis-related firing (especially in the tectum) and reduced incidence of firing associated with lordosis-incompatible behaviors, constituted a transformation, or reconfiguration of midbrain sensorimotor function. It is proposed that this reconfiguration enables the elicitation and maintenance of lordosis by lumbosacral stimuli. Neural effects of comparable magnitude didn't result from control progesterone injections which failed to induce lordosis.

During the induction of lordosis responses in golden hamsters, the joint actions of estradiol (E) and progesterone (P) have been found to produce major changes in the activity levels, sensory responsiveness and movement-related firing of neurons in the dorsal midbrain, a region vital for lordosis in this species. The present study investigated the possibility that these effects of E and P on dorsal midbrain neurons might arise through changes in transsynaptic excitability or spike-generating processes. Single dorsal midbrain neurons were orthodromically or antidromically activated by ventromedial midbrain tegmental stimulation in ovariectomized, urethane-anesthetized hamsters before and after subcutaneous injection of P in propylene glycol vehicle. P injection produced two neurophysiological effects: (1) a strong depression of transsynaptic activation, and (2) in antidromically invaded neurons, a change in the amplitude (either an increase or decrease) of the soma-dendritic spike component. Both of these effects appeared rapidly (i.e. within 10-20 min) after P injection. The P effect on orthodromic neuronal excitability was contingent upon E priming of the hamsters, but, in contrast, the P effect on antidromic spike amplitude was not. Several features of these neurophysiological effects of P imply that the hormone may have been acting through nongenomic mechanisms, possibly involving receptors in neuronal membranes.

Certain derivatives containing the 1,2-dihydropyrido[3,4-b]pyrazine (1-deaza-7,8-dihydropteridine) ring system are active against experimental neoplasms in mice. The mechanism of action of these agents has been attributed to the accumulation of cells at mitosis. Identification of the structural features that are necessary for activity was accomplished by evaluation of modified 1-deazapteridines and ring and ring-opened analogues. Relative to ethyl 4-amino-1-deaza-7,8-dihydro-6-[(N-methylanilino)methyl]pteridine-2-carbamate (11) and the corresponding 6-phenyl compound (12), no antitumor activity was observed with 7,8-dihydropteridines, 3-deaza-7,8-dihydropteridines, and the corresponding heteroaromatic compounds. Also, activity was diminished or destroyed when 1-deaza-7,8-dihydropteridines were oxidized to 1-deazapteridines or reduced to 1-deaza-5,6,7,8-tetrahydropteridines. In addition, replacement of the 4-amino group with other substituents destroyed activity. The presence of a 6-substituent containing an aryl group appeared to be necessary for activity, which was increased when a methyl group was substituted at the 7-position.

Current theories of the causes of somatic symptoms in depression neglect evidence for a general inhibition of Na,K-ATPase. Experimentally, sodium pump inhibition is associated with depolarization of electrically active tissue: the threshold of peripheral nerves is decreased and smooth muscle function altered. Symptoms compatible with these changes are found both in depression and intoxication with digoxin, which inhibits Na,K-ATPase. The hypothalamus contains inhibitors of Na,K-ATPase which are capable of producing depolarization. In depression, changes in hypothalamic activity may increase endogenous inhibition and contribute to the somatic symptoms.

We report the presence of an unusual systolic murmur associated with a traumatic left ventricular pseudoaneurysm. Echophonocardiographic studies showed the murmur to begin at the first heart sound, but end well before the second heart sound. It seems likely that the murmur is caused by the systolic flow of blood from the left ventricle into the relatively noncompliant pseudoaneurysm. The echocardiographic scan of the left ventricle demonstrated a relatively echo-free space posterior to the left ventricular wall, supporting the diagnosis of pseudoaneurysm, which has confirmed with angiographic studies and at surgery. These findings indicate that a combination of noninvasive techniques is useful in establishing this diagnosis.

In female golden hamsters, vomeronasal organ removal disrupts the elicitation of lordosis by lumbosacral tactile stimulation. A similar disruption occurs if the nasopalatine ducts are closed, without removing the vomeronasal organ. Injection of luteinising hormone-releasing hormone reverses the effect of vomeronasal organ removal. These findings suggest that chemosensory signals from the male hamster act via the accessory olfactory system, to facilitate the triggering of lordosis by somatic stimulation.

Movement-correlated firing was studied in 111 midbrain neurons recorded in freely behaving hamsters. For 42% of these cells, most of which lay in the deeper laminae of the superior colliculus, firing occurred principally or exclusively in association with head movements. In 38% of the neurons, most of which were in subtectal regions, activity was greatest during locomotion, but also occurred in correlation with other types of movement.

Forty patients with bleeding oesophageal varices were studied during treatment by endoscopic sclerotherapy to discover what factors determine successful outcome. Large varices required more injections than small varices for obliteration, and rebleeding during treatment occurred only in patients with large varices. Radiological studies with sclerosant contrast mixture showed that in two groups of varices of comparable size, intravenous sclerosant was significantly more effective, leading to thrombosis in 8/10 as opposed to only 3/10 after paravasal injection (p less than 0.05). Intravenous contrast was rapidly cleared upwards, whereas paravasal contrast formed a rounded opacity alongside the vein that persisted for approximately 90 minutes, responsible for the complications of oesophageal ulceration and stenosis.

Radiological and endoscopic shrinkage of the antrum of the stomach may occur in the elderly and following gastroenterostomy. We describe this in 18 subjects, of whom 17 had a gastroenterostomy with or without vagotomy. Shrinkage can appear within two years of operation and is usually associated with a well-functioning stoma. Reflux biliary gastritis occurred in almost all and in nine out of ten tested the acid secretion in response to pentagastrin was virtually nil. Dyspepsia and bile vomiting were frequent indications for endoscopy. No patient had jejunal ulceration. In the majority radiological interpretation was correct.

Of 565 febrile patients examined in the emergency room of a metropolitan hospital, 210 had blood samples cultured (37.1%). Bacteremia was present in 9 of 86 patients who were admitted to the hospital but in only one of 124 patients who were not admitted (P less than .005). Thus, approximately 5% of febrile adult outpatients had bacteremia, and these patients were usually admitted before the results of the culture were known. Since positive cultures were found so infrequently in patients not admitted and were, therefore, of little value in guiding the treatment of these patients, we conclude that use of routine blood cultures to screen for bacteremia in unnecessary for febrile adult outpatients who are not admitted to the hospital.

Fifteen patients, whose oesophageal varices had been obliterated by injection sclerotherapy, were examined by double-contrast barium swallow. In nine patients (60%) the oesophagram was abnormal and demonstrated sharp-edged, longitudinal tramline filling defects and an irregular, patchy nodularity with loss of the normal longitudinal folds. These appearances represent redundant epithelial folds, epithelial tags and healed ulcers produced by endoscopic sclerotherapy.

Single midbrain neurons were examined for effects of ovarian hormone administration on responsiveness to an array of lordosis-controlling types of somatosensory stimuli in anesthetized, ovariectomized Syrian hamsters. Neuronal responses were recorded under four different hormonal treatment conditions: 1) estradiol benzoate (EB) followed by progesterone (P), 2) EB alone, 3) P alone, or 4) no hormone administration. Only the hamsters receiving both EB and P showed lordosis in a mating test immediately prior to preparation for recording. The joint administration of EB and P strongly facilitated unit responsiveness to lordosis-eliciting (e.g., lumbosacral tactile) forms of stimulation. The incidence of units showing sustained changes in firing of at least +/- 30% in response to these stimuli was highest in animals having received EB and P (69%) and lowest in those given P alone (37%), with the occurrence of responsive units significantly different across the four hormonal conditions. The magnitude of the median unit response to lordosis-trigger stimuli in hamsters given EB and P was significantly higher than unit responses in hamsters receiving either P alone or no hormone. Bilateral shoulders stimulation, a weak stimulus for lordosis elicitation, produced the most responses in units from animals given EB and P (42%) and the fewest in hamsters given EB alone (12%), with a significant difference in responsiveness across the hormonal conditions. The incidence of units responding exclusively to facial stimulation, which is strongly antagonistic to lordosis in behaving animals, was greatest in hamsters injected with P alone (22%) and least for cells from the animals given both EB and P (6%). The difference in unit responsiveness to this stimulus across the four hormone conditions was significant. Analysis of unit-response patterns by the multivariate technique of discriminant analysis revealed that neuronal responses to most stimuli, especially flanks, back, shoulders, and face, were differentially affected by the hormone treatments such that these response patterns could be used to identify the four hormonal conditions from which the neurons were sampled. In addition, the hormonal treatments were found to have influenced the incidence of accelerative or decelerative unit responses to somatic stimuli. Discriminant analysis of unit responses as a function of location of the cells within the midbrain showed that neurons in the tectum and central gray had response patterns highly distinguishable from each other as well as from those of cells in the central and ventromedial tegmental regions.(ABSTRACT TRUNCATED AT 400 WORDS)

The incidence of Crohn's disease in Cardiff between 1931 and 1985 has been examined using hospital diagnostic indices supplemented in recent years by records from clinicians, and the departments of pathology and radiology. Four hundred and seven new patients were confirmed after all notes had been reviewed. There has been a large increase from 0.18 cases/10(5) of the population per year in the 1930s to current values of 8.3/10(5)/year. The incidence continues to rise and shows an increasing proportion of patients with colorectal disease. Peak age specific incidences occur in the third and eighth decades of life.

Reaction of 5,6,7,8-tetrahydrofolic acid (THF,7) with phosgene, thiophosgene, and cyanogen bromide gave the bridged derivatives, 5,10-(CO)-THF (8), 5,10-(CS)-THF (9), and 5,10-(C = NH)-THF (11), respectively. Catalytic hydrogenation of 10-(chloroacetyl)folic acid (2) gave 5,10-(CH2CO)-THF (12). A similar reaction with 10-(3-chloropropionyl)folic acid (3) gave 10-(ClCH2CH2CO)-THF (14) rather than 5,10-(CH2CH2CO)-THF (13). In the catalytic hydrogenation of 10-ethoxalylfolic acid (5), the initial product 10-(EtO2CCO)-THF (22) rearranged readily to give 5-(EtO2CCO)-THF (21). Acylation of THF with chloroacetyl chloride gave a N5,N10-diacylated product (18 or 19), which could not be converted to 5,10-COCH2)-THF (17). Reductive alkylation of THF with glyoxylic acid and 5-hydroxypentanal, respectively, gave 5-(HO2CCH2)-THF (24) and 5-[HO(CH2)5]-THF (25). Reductive dialkylation of THF with formaldehyde gave 5,10-(CH3)2-THF (27), whereas glyoxal gave 5,10-CH2CH2)-THF (10). Also, both folic acid and 5-(CHO)-THF were reductively alkylated with formaldehyde to give 10-methylfolic acid (6) and 5-(CHO)-10-(CH3)-THF (28), respectively. These compounds were tested as inhibitors of the enzymes involved in folate metabolism and for activity against lymphocytic leukemia P388 in mice.

Reinvestigation of the conversion of folic acid to leucovorin [L-(+/-)-5-CHO-THF] led to improved methods for the synthesis of this drug, which is suitable for clinical use. Also, methods were developed for the chromatographic and nonchromatographic purification of less pure samples of L-(+/-)-5-CHO-THF.

Previously, 8-deazafolic acid (17) was shown to be a potent inhibitor of the folate-dependent bacteria, Streptococcus faecium (ATCC 8043) and Lactobacillus casei (ATCC 7469), and to have activity against lymphoid leukemia L1210 in mice. To examine the 5,6,7,8-tetrahydro derivatives, a new synthesis of 17 was developed from 8-deaza-2,4-dichloro-6-methylpteridine. Treatment of the latter with aqueous base gave the corresponding pteridin-4(3H)-one, which was aminated with ammonia to give 8-deaza-6-methylpterin (9). Bromination of 9 gave mainly 8-deaza-6-(tribromomethyl)pterin, which on reaction with p-aminobenzoyl-L-glutamic acid resulted in the formation of the 9-oxo derivative of 17. In contrast, bromination of the 2-acetyl derivative of 9 gave mainly the corresponding 6-(bromomethyl)pterin, which was converted to 17 in 23% yield (from 9). Hydrogenation of 17 at atmospheric pressure and room temperature was unsuccessful either in a basic medium or formic acid. In trifluoroacetic acid, overreduction occurred to give a mixture containing 8-deaza-5,6,7,8-tetrahydro-6-methylpterin and the 5,6,7,8-tetrahydro derivative of 17. The latter was characterized by conversion to the methenyl analogue 21, which was also prepared by hydrogenation of the 10-formyl derivative of 17. Treatment of 21 with hydroxide gave 8-deaza-10-formyl-5,6,7,8-tetrahydrofolic acid. Compound 21 showed cytotoxicity to cultured H.Ep.-2 cells and was tested as an inhibitor of bovine dihydrofolic reductase. Lineweaver-Burk analysis indicated inhibition competitive with dihydrofolate.

During a one-year period 53 patients were referred for the investigation of epiphora. All underwent bilateral dacryoscintigraphy. Following the isotope study the patients had either bilateral or unilateral macrodacryocystography; a total of 66 tear ducts were shown by this procedure. The scintigraphs were more sensitive for obstruction (51/66 systems or 77%) than radiography (33/66 systems or 51%). Normal dacryoscintigraphy was always associated with duct patency on dacryocystography. We have concluded that scintigraphy should always be the first investigation and that, if this is normal, radiography is not necessary. The use of digital subtraction imaging for the lacrimal passages is discussed. It is suggested that this may provide information obtained at present only by combining dacryoscintigraphy with conventional contrast radiography.

The response properties and anatomical organization in the brain stem of 234 pontine and 60 medullary genitally sensitive (GS) neurons were studied by single-unit recording in acutely prepared estrous and anestrous cats which were decerebrated under sodium pentothal or anesthetized with urethane. Pontine unit responses to vaginal probing were very pronounced and stimulus-bound, and involved a variety of response patterns. Most of the pontine GS neurons also responded to nociceptive stimuli and to a lesser degree, to innocuous somatic, extragenital visceral, and auditory stimuli. Among pontine GS cells recorded in estrous cats, responsiveness to innocuous somatosensory stimuli was more prevalent than among units in anestrous preparations (71% vs. 40%), and on the average, the units in estrous cats responded to stimulation of more regions of the body than did comparable units in anestrous animals. In recordings from the medulla in the decerebrate preparations, exclusive responsiveness to vaginal stimulation was observed in 22% of the GS neurons, contrasting with earlier results from urethane-anesthetized animals in which a greater degree of specificity was found. A close anatomical proximity existed between some medullary GS neurons and cells of nucleus ambiguus, including antidromically identified recurrent laryngeal nerve motor neurons, and between pontine cells and the trigeminal motor nuclei. Antidromic responses of GS neurons to stimulation of the brain stem revealed a projection from medullary GS neurons to the lateral tegmental field of the pons. Relatively few pontine GS neurons projected to the ipsilateral medulla. A strong synaptic influence upon medullary GS neurons, possibly or midbrain origin, descends from the lateral tegmental field of the pons.

Reaction of alpha-aminoacetophenone oximes (2) with ethyl 6-amino-4-chloro-5-nitropyridine-2-carbamate (1) gave ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridine-2-carbamate oximes (3), which were hydrolyzed under acidic conditions to give the corresponding ketones (4). Related pyridines substituted with a keto side chain were prepared from 1 and 1,3-diaminopropanone oximes and by oxidation of the side-chain hydroxy group of ethyl 6-amino-4- [[3-(N-methyl-N-phenylamino)-2-hydroxypropyl]amino]-5-nitropyridine-7- carbamates (6). Catalytic hydrogenation of the nitro group of 4 over Raney nickel in a large volume of ethanol gave the 1-deaza-7,8-dihydropteridines (7). Several of the oximes 3 were successfully hydrogenated to give 7 directly. The resulting 1-deaza-7,8-dihydropteridines showed potent cytotoxicity against cultured L1210 cells and significant anticancer activity against lymphocytic leukemia P-388 in mice. These biological activities are attributed to the accumulation of cells at mitosis.

Although depression has been linked with both the irritable bowel syndrome and non-organic abdominal pain, which are common in gastrointestinal outpatients, the prevalence of depression in most surveys of outpatient practice has been low. Use of the Beck Depression Inventory to screen new referrals to a general medical and gastrointestinal clinic and to a minor surgical clinic showed that 50 of 100 medical patients were rated as having some degree of depression, compared with 14 of 75 (19%) of the surgical patients in whom abdominal pain and bowel dysfunction were rare (X2 = 9.6, p less than 0.01). In the medical clinic no organic disorder was detected in 64% of the depressed patients, the majority of whom presented with abdominal pain or irritable bowel syndrome. Depression was significantly commoner in this group of patients than in those with other conditions, (X2 = 6.63, p = 0.01). That depression is common in gastrointestinal outpatients is not always appreciated and its symptoms should be sought in all patients with bowel dysfunction and chronic abdominal pain.

Lesions in the ventromedial midbrain tegmentum of female golden hamsters produced various degrees of impairment of the lordosis response to male hamsters or manually delivered somatic stimuli. The most severe deficits were produced by anterior lesions, whereas larger, more posterior lesions sometimes produced no lordosis impairment. In tests where lordosis was not completely eliminated, the lesions tended to impair maintenance rather than elicitation of lordosis, thus constituting a different behavioral effect from that associated with deep tectal or central gray lesions in this species.

The isolation of citrovorum factor from a chemically prepared mixture of the L(+/-) diastereoisomers (leucovorin) is described. The natural diastereoisomer was at least twice as effective as leucovorin in reversing methotrexate toxicity in mice.