Organizing factors in the comprehension and recall of connected discourse.

This experiment is based on the theory that, in reading, one uses cues in order to activate an organizing system as an aid in reading the material. The variables introduced into the experiment include (1) the form of oragnization (meaningful, scrambled, and pseudo) and (2) the choice of material (descriptive, abstract, and technical). Having read a paragraph, subjects read a list of words including some from the paragraph and some not and were asked to check those words that they remembered as belonging to the paragraph. Accuracy is highest when subjects have been most successful in activating an appropriate organizing system.


The class-inclusion task: question form and distributive comparisons.

The class-inclusion task is regarded by Piaget as a measure of the child's mastery of the structure of hierarchical classification. Class-inclusion was improved by changing the wording of the question to conform to standard English usage. A theoretical argument is offered that the child's difficulties with this task derive from confusion of collective comparisons, in which properties of classes are compared, and distributive comparisons, in which properties of elements are compared. A grammatical constraint on expression of distributive comparisons--an element of a class cannot be compared to an element of an included subclass--is hypothesized to be overgeneralized to expressions referring to collective comparisons such as the class-inclusion task. This hypothesis accounts for the improvement in class-inclusion performance with changes in wording of the question and for the finding that young children's response to class-inclusion questions and to ungrammatical requests for comparison of an element of a class and an element of an included subclass are similar: the children respond readily but understand wrongly that the comparison involves coordinate classes.


Inversion of subject NP and Aux in children's questions.

Bellugi has proposed a stage of language acquisition in which children invert subject NP and Aux in yes-no but not wh questions. It was proposed that this stage would be found in a sampling of questions from young children. Cross-sectional samples of questions were collected from young children between 2:0 and 3:11. The results did not bear out this expectation. Based on percentages of inversion, none showed this stage. The results are discussed in terms of the importance of frequency in determining stages of acquisition and the use of children's data as psychological evidence for linguistic rules.


Clues to aural discrimination.

Five measures of the items of the Multiple-Choice Intelligibility Test were obtained: apparent aural similarity of the four words available to a listener on hearing a stimulus, interconsonantal differences among the prevocalic portions of these words, phonemic discrepancies among these words, distinctive feature differences among these words, and the pooled discrimination score of the four words that were available to the responder on hearing the stimulus. The last score was made the target in a multiple correlation problem, and the relative contribution, combined and separately, of the four remaining measures to the target measure was determined. These four measures accounted for approximately 45% of the variance among the scores of discrimination. The strongest contributors were apparent aural similarity of the available responses and the phonemic discrepancy among the available responses.


Distribution of the feature [+animate] in the lexicon of the child.

Piaget suggests that animistic thinking is a pervasive feature of children's cognition. To test this notion, 4- to 8-year-old children were shown several inanimate objects and asked to pick those which perform activities characteristic of living organisms. These activities were typified by six verbs: "ear," "sleep," "breathe," "grow," "die," and "be alive." Fifty percent of the younger children responded animistically, by misattributing life processes to inanimate objects, but only 18% of their total responses were animistic. Twenty percent of the older children responded animistically, but only 20% of their responses were animistic. In Experiment II, children were shown drawings singly and asked if the object could perform activities named by one of the six verbs. Results were similar to those of Experiment I but with somewhat less animism. Experiment III required children to spontaneously name things that are alive. There were no animistic responses. It was concluded that animistic thinking is not a genuine phenomenon but linguistic confusion elicited by novel objects and unfamiliar words.


A study of timing in a manual and a spoken language: American sign language and English.

A comparative analysis of the time variables in the production of speech and sign reveals that signers modify their global physical rate primarily by altering the time they spend articulating, whereas speakers do so by chaning the time they spend pausing. When signers increase or decrease their pause time, however little they do so, they alter the number and the length of the pauses equally, whereas speakers primarily alter the number of pauses and leave their pause durations relatively constant. An analysis of the durations of signs reveals that signs are longer at the end of sentences than within sentences and that the first occurrence of a sign is longer than the second when syntactic location is controlled (both these findings have already been reported for spoken language). The inherent duration of a sign can be accounted for almost totally by the movement characteristic; handshape, location, and number of hands in a sign are of little importance. Finally, signers retain their regular "quiet-breathing" respiratory pattern across signing rates and inhale at locations independent of syntactic importance. In this they are quite unlike speakers, who breathe at syntactic breaks.


Children's comprehension of relative clauses.

A review of the literature on children's use of relative clause constructions reveals many contradictory findings. The suggestion is that some studies fail to take into account the two factors of embeddedness (role of complex noun phrase within the sentence) and focus (role of head noun in the relative clause). The experiment reported here attempted to reconcile the disparate findings and extend the range of constructions examined. 114 children between the ages of 3 and 7 served as subjects in a test of comprehension using an act-out procedure of 9 different relative clause sentences that exhaust the possible combinations of 3 roles of the complex noun phrase in the sentence and 3 roles that the head noun plays within the relative clause (in each case, subject, direct object, and indirect object). All constructions were understood better with increasing age of the children; sex and sentence set were nonsignificant variables. The results reveal a difficulty in ordering of the 9 types of construction that is in keeping with a prediction based on surface structure processing strategies.


[The value of Mackenzie and Harries's technique in detecting pleural thickenings: results of a systematic study in 64 patients exposed to the risk of asbestosis (author's transl)].

The authors stress the difficulty of detecting pleural thickenings due to asbestos by radiography, before the late stage when calcification appears. Using Mackenzie and Harries's technique, they radiographed 64 subjects working in the naval shipbuilding yard in Nantes, who had previously been examined by radiophotography. Their results confirmed the superiority of the 45 degrees oblique incidence for demonstrating patches of pleural thickening in those areas where they occur most frequently. The value of this early detection is purely social and occupational at the present time, as it cannot be used to give a prognosis as to the possible appearance of a more serious lesion such as mesotheliomas.


[Experimental endovascular electrocoagulation. Use of alternating current and a bipolar electrode (preliminary study) (author's transl)].

Early experimental studies have shown that it is possible to obtain vascular obliteration and clot formation using monopolar direct current electrocoagulation. There is a major risk of rupture of blood vessels if alternating current is used. Using a co-axial bipolar electrode and high frequency alternating current it was possible to obtain valid, reproducible, and safe vascular obliteration in the distal digestive tract arteries in dogs. The obliteration is due to lesions of the intima and the formation of a clot in situ.


[Osteo-onychodysostosis. One more report about a family case (author's transl)].

A 9 year-old boy takes medical advice because of underdevelopment and intellectual insufficiency. The diagnosis of osteo-onychodysostosis (nail-patella syndrome) clinically expected is confirmed by X-ray examination. The main radiological signs of this disease are reminded of. You can also find a few remarks about family contex, frequency of the lesions and heredity.


[Above acetabulum aneurismal cyst. One case (author's transl)].

One case of above acetabulum aneurismal cyst is presented and the authors insist on the main features of this benign tumor supplied with radiology, clinic and evolution. Location of such cyst are uncommon: 4 cases upon 137. Medical team has to resolve two problems: on one hand, positive diagnosis of this benign tumor, on the other hand, treatment of this particular location.


[Unilateral oblique craniocaudal incidence of the sacro-iliac joint (author's transl)].

The author describes an oblique open-pelvis incidence, centered on the sacro-iliac of one side, carried out to study the anterior part of this joint. This incidence, which can be made on both sides for comparative purposes, easily complements standard sacro-iliac incidences.


[Computerized tomography in post-traumatic cerebral lesions (author's transl)].

A review of 108 cases of cranial injury, dating back for more than three months, and having had computerized tomography examinations, revealed 96 abnormalities in the results. These included overall, 65 times, and localized, 20 times, ventricular dilatations, generalized atrophy 27 times, porencephaly 27 times, enlargement of the sylvian fossa 28 times, chronic subdural hematomas 8 times, intracranial calcification 3 times, meningiomas 3 times, and a cerebral abscess in 1 patient. The computerized tomography results were normal in 12 patients. Very good correlations were found between clinical and computerized tomography results in patients with psychic disturbances and disorders of the higher centers. They were variable in cases of epilepsy and neurological deficiency states. The greatest number of normal results was found in so-called subjective syndromes.


[An experimental study to evaluate mineralization of vertebral bone by computerized tomography (author's transl)].

Computerized tomography ("tomodensitometry") should, in principle, be able to calculate the linear attenuation coefficient of a compact or spongy bone volume. This coefficient is related to the amount of mineralization, enabling the use of the Scanner X to measure the density of the bone. Thirty vertebrae from the vertebral columns of 14 subjects who died after acute infections were examined by C.T. and by standard methods, and then calcinified. The correlation between ashes weight-Houns-field number was positive but only moderate (r = 0.54), and lower than the result obtained (r = 0.84) with standard methods. Errors occur with presently used apparatuses which are related to: polychromatism, too high an energy of the beam, artefacts, and the effects of "partial volume". Futhermore, the mineral concentration by unit of vertebral volume is very low, and large variations must occur for it to be detectable. Finally, considerable errors arise from the intravertebral bone fat. Suggestions are made with the objective of improving the quality of C.T. as a measuring instrument.


[Duplication of the digestive tract in adults. 5 cases (author's transl)].

Five cases of duplication of the digestive tract are reported: oesophagus, stomach, duodenum, and colon. These patients were adults, in whom it is rare (5% of cases) to find such duplications. Two types of image are seen on barium meal examination: opacification of a lumen which may be abnormally blind and which can be easily diagnosed if it is short, but is sometimes more difficult to individualize if the duplication is long (colon); or an extrinsic type of compression which is a part of the wall and much more difficult to diagnose. Knowledge of these different types of radiological images in adults should avoid precipitous investigations and orientate possible surgical interventions.


[Apophyseal detachment of the anterior iliac spines: a radiological study of three cases (author's transl)].

The authors describe 3 cases of apophyseal detachment of the anterior iliac spines. This traumatic affection occurs mainly in adolescents during sporting activities, and is a rare disorder. It has to be borne in mind when a more or less typical clinical picture is present, and the diagnosis can be made by radiological examination.


[Hirtz's incidence in the study of the manducatory apparatus. Application to temporomandibular joint affections (author's transl)].

Radiological examinations have always been considered of secondary importance during diagnostic investigations of temporomandibular joint affections because of the frequency with which negative results were obtained. For most authors its only value has been to establish a differential diagnosis from other lesions of the manducatory apparatus in which clinical manifestations are comparable. A systematic study of the manducatory apparatus in patients with temporomandibular joint affections was carried out by taking two films, one with the month open, the other with the month closed, according to Hirtz's incidence. The results showed that abnormalities of varying degrees of severity were present relatively frequently. They usually involved the temporomandibular joint, either morphologically or physiologically. The multiplicity of the abnormalities observed, their character, and their frequency raise the problem of defining their role in the genesis of the disorders described and strongly suggests that the place of radiological investigations in the diagnostic tests for temporomandibular joint affections has to be reconsidered. The examination described would be, because of its simplicity, the basic investigation in the radiological study, with other studies possibly following on later to complement it.


[Computer tomography appearances of intracranial epidermoid and dermoid cysts as demonstrated by three cases (author's transl)].

The authors describe the computer tomography appearances of intracranial epidermoid and dermoid cysts as demonstrated by three cases, and review the published literature. Dermoid and epidermoid cysts can be distinguished from each other by their topography (dermoid cysts are found more medially while epidermoid cysts occur on the base of the skull and in the pontocerebellar angle), by the presence or not of calcification (found almost exclusively in dermoid cysts), and by their computer tomography appearances. Both tumors have low densities, below that of the cerebrospinal fluid, but dermoid cysts have lower densities than epidermoid cysts, which can be easily explained by referring to the anatomo-pathological appearance.


[Congenital arteriovenous communications. A report on three cases of systemic extravisceral fistulae (author's transl)].

Arteriovenous fistulae are rarely seen in children and are usually the result of malformations. Three cases are reported which were unusual because of their location and the manner in which they evolved. A simplified classification of these lesions is described and 582 cases from the published literature are reviewed.


[A critical review of the variations in size of the kidney caused by increased diuresis in hypertensive patients (author's transl)].

The authors studied the validity of Wolf and Dorph's test (increase in size of the kidney with increased diuresis) performed during intravenous urography in hypertensive patients. The technical procedure is described, and the results reported: 1 032 kidneys were measured, of which 84 had been also examined by arteriography. The results are analyzed and compared to those obtained after the standard method of early consecutive films, with the following conclusions: -- the test is not as valid as is suggested by the authors who described it; -- the information supplied by the standard method is more consistent and precise; -- the results of these two series are not completely superimposable; -- that even if Wolf and Dorph's test can sometimes supply useful information, it must not be relied upon completely.


[Radiographic appearances of a renin secreting renal tumor. A rare cause of hypertension (author's transl)].

Eleven cases of hypertension due to a renin secreting renal tumor have been reported since 1967. Here we are dealing with another case which appeared as hypertension and cerebro vascular accident in a thirty - year old woman an I.V. Pyélogram and a renal angiogram showed a tumor in the upper pole of the left kidney. Renal veins renin dosage showed hypersecretion on the side of the tumor. The tumorectomy was followed by a normalization of blood pressure. The microscopic study confirmed the diagnosis of renin secreting juxta-glomerular cell tumor.


[The value of embolization in severe epistaxis. Indications and methods (author's transl)].

When performed by a team who are experienced in the use of embolization of the external carotid region, this procedure is nowadays a safe and extremely effective method for treating severe, massive, uncontrolled, recurrent epistaxis. Arteriography shows the site of bleeding, the nature of the lesion, and the arteries affected. When carried out by the femoral or common carotid route, this method was effective in 52 cases of severe epistaxis of various origins: essential epistaxis, or from hypertension, trauma, Rendu Osler's disease, vascular malformations, carotidocavernous fistulae, benign or malignant tumors, hematological affections, or hemostatic disorders. To avoid risk it is essential that a perfect technique be used and a certain number of principles respected. The method is effective in cases were surgical hemostasis is insufficient, and its rapidity of action allows removal of packs immediately after embolization. This clearly underlines the value of constantly available vascular radiology units for treatment in this region as well as in other parts of the body.


[Double contrast radiography of the stomach. Technique and results in early gastric cancer (author's transl)].

A technique for examination of the stomach is described and includes: induction of hypotony with medication, thin layer study of the anterior wall, and double contrast and compression. If there is close collaboration between the radiologist and the surgeon performing the endoscopy, this method can considerably improve diagnosis. Its application enabled 21 "early" cancers (as defined by the Japanese Society of Gastro-Enterology and Endoscopy) to be diagnosed out of 8 000 exsminations performed between 1971 and 1977. The smallest lesion measured 0.5 X 0.8 cm. The diagnostic value of this examination technique is about equal to that of fibroscopy, and a comparison of the different methods of radiological examination clearly demonstrates the superiority of double contrast for detecting small lesions: 19 of the 21 early cancers were visible in the double contrast images, while only 10 produced irregulrities in the walls as seen when filling had been completed, and 6 of the 21 lesions appeared during compression. This method is also very useful for the differential diagnosis of ulcers, ulcer scars, and early cancer. The following signs favour a malignant lesion: clear but irregular edges of depressed area with a nodular surface, convergent but interrupted folds with club deformity, and fusioning of the two folds giving a typical appearance. Flat cancerous lesions with diameters less than 1 cm are still extremely difficult to diagnose.


[Diagnostic value of arteriography in a case of splenomegaly of unknown origin (author's transl)].

A 32 year-old patient was found to have a tender enlarged spleen with hardly any other signs apart from transient fever and moderate hepatomegaly. Coeliac arteriography was performed to eliminate the possibility of a splenic tumor. The splenic arteriography showed the presence of a great number of lacuna dispersed throughout the parenchyma and measuring 0,5 to 1 cm. Histopathological examination of samples of the spleen, removed by operation, and biopsies of the liver and lymphnodes confirmed the diagnosis of sarcoidosis of the liver, spleen and lymphnodes.


[Automatic calculation of the base dose in the Paris System (author's transl)].

The systematic dosimetric control after all endocurietherapy implantations considered to be in conformity with the Paris System is often made manually from tracings of the radioactive threads and a series of tables which gives the strength of the dose as a function of the distance from the thread. The authors describe a calculating programme, developed in a small Hewlett Packard calculator associated with a printing-out apparatus (without graph tracings), which can determine the strength of the base dose and the tracing of the isodoses in the central plane for all radioactive implantations belonging to the field of application of the Paris System. A schematic representation of the organization of the programme includes feeding of information in the form of Cartesian co-ordinates; the geometric determination of the points for calculating the base doses, the calculation of the strength of the base dose, the reference dose, and doses at particular points in the central plane, and finally, tracing the isodoses. Several examples are presented, after which the authors discuss the advantages as well as the limits of this method.


[Results of the radiotherapy in the non Hodgkin's lymphomas treatment (author's transl)].

In our 98 patients all treated by association chemotherapy + cobaltherapy, 37 cases were stages III and IV and 71 cases were of diffuse pathology classification. Meanwhile the results were not so poor: 66% at 5 years survival (all stages) and 69% for stages I and II. The curves of survival rate generally stabilize at 7 years. The prognostic depend of the pathology class: diffuse LBS and diffuse HBS have an evolution similar to acute leukemia (44.5% and 19% at 7 years survival), on the opposite nodular LBS, diffuse LCS have 100% survival at 7 years. Diffuse cases have visceral relapses (liver, bone marrow, Waldeyer ring) or generalized lymphatic involvement; nodular cases have generally localized and only lymph-nodes relapses. The best results by large fields irradiation suggest a contiguous extension of the disease, but there is also distant lymph nodes relapses. In the nodular cases, relapses can be generally cured by localized radiotherapy. In the diffuse case, we do not know if it is better to give total lymphnode irradiation (or to give more chemotherapy with economic irradiation). 10 gastro-intestinal cases were treated by moving strip technique with excellent tolerance and 67.5% at 5 years survival. These results show that interesting results may be obtained in non Hodgkin lymphomas by association of chemotherapy, with selective and moderately large fields irradiation, even in disseminated cases, even in diffuse cases.


[Cervical lymph nodes metastasis from an unknown primary: diagnosis, treatment and prognosis. A retrospective study of 127 cases observed from 1959 to 1973 (author's transl)].

Authors present clinical records of 127 patients bearing metastatic cervical lymph nodes of unknown origin and referred to the Cl. Regaud Cancer Center between 1959 and 1973. According the prognosis, it is possible to distinguish patients into three groups. In group I, patients (10%) have a lower neck involvement by an adenocarcinoma. The survival is dramatically bad. Group II includes also 10% of patients who have a fairly better prognosis, they are younger people bearing poorly differenciated squamous metastatic lymphonode(s) in the upper neck. Group III. The remaining eighty per cent of patients are heavy drinkers and smokers. Their upper neck is hurt by lymphatic metastases from a well or moderately differenciated squamous cell carcinoma. They have much about the same prognosis than people bearing a known primary carcinoma of the upper aerodigestive tract. After having excluded the first group of patients who is at high risk of having a widely disseminated illness, we can remark that about one half of relapses occurred in the cervical area. A well planned combination of neck dissection and whole cervical lymphatic areas irradiation may further reduce such recurrences and so may enhance the present results: 23% survival 3 years after completion of treatment.


[Stage I and II cancer of the cervix. Report on the results of treatment in 1,015 patients (author's transl)].

The results of treatment in 1,015 stage I and II patients with cancer of the cervix are presented. The 5 year survival and recurrence rates were calculated in relation to the treatment applied. Two groups of stage Ib and IIa patients were available, one of them having been treated with radiotherapy, and the other one with radical hysterectomy and pelvic lymphadenectomy after previous intra cavitary radiumtherapy. The difference in the survival rates between the two stage Ib groups is not statistically signficant. We did not try to make a statistical comparison between the two stage IIa groups because the combined therapy group includes only patients with very early lesions. Most stage IIb patients were treated with radiotherapy. The postoperative mortality was 2.2%. There were no deaths related to treatment in the group of patients treated with radiotherapy alone. Ninety percent of the recurrences appeared within 3 years after completion of treatment.


[Curietherapy in the carcinoma of the uterine cervix. Comparison of the obtained by computer dosimetric informations. Cooperative study by the European Group of curietherapists (author's transl)].

A cooperative study was taken to comparate the doses, obtained by the different institutes. The European Group had first defined the important points of the irradiated volume. This study has shown the great differencies between the doses of the institutes. First, the reference points for the surrounding structures were examined. The average of the doses at the inferior points of the Fletcher's lymphatic trapezium varies between 500 and 1 500 rads. This at the pelvic wall point is usually more important (10 or 15%). The doses at the delicate organs, the bladder and the rectum were studied in second. The average of the maximal vesical doses varies from 4 000 to 4 900 rads in the preoperative group; the average of the maximal rectal doses between 2 100 and 5 200 rads in the same group. The examination of the mean rectal dose was difficult. Every Institute has his own means of determining it. At last the size of the reference volume was considered. The 6 000 rads isodose was selected for the whole treatment. The height of this volume seems to be essentially dependent of the length of the uterine source. There seems existing some parallelism between the width and the thickness of the reference volume, but there are many differencies from an Institute to another. Now the Group has to determine a dosimetric methodology which may be transmissible.


[Diagnostic value of vaginal mouldings in uterine cancer (author's transl)].

Vaginal mouldings were originally introduced as applicators for uterovaginal radium therapy. After 13 years of experience with this method in the Gustave-Roussy Institute we have found that it is also of great value for diagnostic purposes: it enables the site of the uterine cervical and vaginal lesions to be determined in a more precise manner; areas of invasion of the vagina can be detected which would normally not have been found, either because of the difficulty of performing previous investigations, or because of the extremely superficial nature of certain vaginal lesions: the extent of invasion and the subsequent therapeutic approach can then be radically modified; objective records can be kept in the form of photographs which can be compared with any future mouldings. The vaginal moulding can, in fact, be used as a diagnostic tool during supervision of the patients, when there is the least suspicion of an abnormal finding.


[A projector of iridium 192 wires: motivations and preliminary studies (author's transl)].

Though the majority of procedures involved in curietherapy with Iridium 192 wires cause very few problems concerning radiation protection, this is not true in all cases: in elderly of debilitated patients, young children, or when using special techniques (curietherapy for prostate of bladder cancers for example). In these cases, the need for frequent treatments exposes the therapists to increased doses. The projector of Iridium 192 wires was conceived in order to reduce this irradiation hazard. A simple manipulation places the radioactive wires in a lead container during treatment, and then replaces them in the right position after therapy. This apparatus appears to offer the possibility of: an almost total protection of the therapists, and thus an opportunity for enlarging the indications for curietherapy; an improved quality of treatment to the patient during the application.


Lymphoid cells in the uterine cervix after electrocoagulation.

Lymphoid cells were observed in the healing cervix during the first week after electrocoagulation. The ultrastructure of these cells was similar to that of activated lymphocytes.


Giant condyloma acuminatum of the endocervix and lower uterine segment.

A 34-year-old woman presented with lower abdominal pain, dysmenorrhea, dyspareunia and vaginal discharge. A total abdominal hysterectomy was done for persistent, severe uterine pain unresponsive to medical management. Histologic examination of the surgical specimen revealed a large condyloma acuminatum of the endocervix and lower uterine segment. This represents a rare manifestation of a very common venereal disease.


Hysteroscopic oviductal blocking with formed-in-place silicone rubber plugs. I. Method and apparatus.

This method of nonsurgical female tubal sterilization involves the flowing of catalyzed silicone material into the oviduct through a silicone rubber obturator tip positioned at the tubal ostium. The method, described earlier as a fluoroscopic technique, has now been developed as a hysteroscopic procedure. Components include the obturator tip with retrieval loop, guide assembly, nonair-entraining mixer-dispenser, flow-actuation apparatus and plug-forming materials. Steps in the procedure include placement of the obturator tip in the tubal ostium, flow of the silicone, releasing of the tip (bonded to the cured plug) from the guide and removal of the guide.


Cytotoxic activity of cerebrospinal fluids (CSF's) against lymphocytes and phagocytes: comparison of normal and systemic lupus erythematosus CSF's.

Fifty cerebrospinal fluids (CSF), 24 normal, 26 from systemic lupus erythematosus (SLE) patients were tested for cytotoxic activity against human lymphocytes, granulocytes and monocytes. Normal and SLE CSF's frequently killed all 3 cell types. Lympho- and granulocytotoxins often reacted at both 4 degrees/24 degrees C, and at 37 degrees C. They were more active when no complement was added (p less than 0.01), whereas monocytotoxicity was complement-dependent (p less than 0.01). Normal CSF's more often contained cold-reacting lymphocytotoxins and SLE CSF's more often had warm-reacting monocytotoxins, but the differences were not significant (p = 0.03). Cytotoxins were easily absorbed to and eluted from lymphocytes and granulocytes, and when CSF's were toxic to both types of cells, the corresponding eluates usually retained this activity. Sometimes, only 1 type of cell was killed by the eluate, whereas cytotoxicity against another was retained by the corresponding supernatant. In SLE remarkable differences were noted between CSF cytotoxins and serum cytotoxins. The former were often more potent at 37 degrees C not requiring non-human complement. Preliminary characterization of CSF cytotoxins suggests they may be IgG, however, participation of non-Ig cytotoxic substances cannot be excluded.


Rheumatoid nodulosis. Sporadic and familial diseases.

Two patients are described with longstanding, multiple, subcutaneous nodules with the histopathological features of rheumatoid nodules. Neither patient had any clinical evidence of rheumatic disease. One patient had a family history of smiliar nodules transmitted as an autosomal dominant trait. Leukocyte function studies failed to reveal any defect to account for the nodule formation.


Rheumatoid markers in the absence of arthritis.

A 45-year-old man had high titer rheumatoid factor in his serum, marked elevation of his erythrocyte sedimentation rate, and a histologically proven rheumatoid nodule in the absence of other manifestations of rheumatoid disease. These findings are most unusual and emphasize that serologic and histologic markers of rheumatoid arthritis may be present without arthritis or other disease manifestations.


Alkenylidene bisphenols, a new class of bisphenol bactericide.

Alkenylidene bisphenols are prepared by condensation of an appropriate phenol with a haloacetaldehyde, followed by base-induced elimination, or by condensation of the corresponding aryl methyl ether, elimination, and deprotection of the phenol with boron tribromide. The resulting compounds may be further elaborated by reactions on the aromatic nucleus. A series of 13 such compounds showed activity against Staphylococcus aureus; the most active was 1,1-dichloro-2-(3-allyl-5-chloro-2-hydroxphenyl)-2-(5-chloro-2-hydroxyphenyl)ethylene (16), MIC 0.16 microgram/mL. 1,1-Dichloro-2,2-bis(5-chloro-2-hydroxyphenyl)ethylene (6) was similar in its activity and spectrum to hexachlorophene.


Radiological manifestations in 200 patients with ankylosing spondylitis: correlation with clinical features and HLA B27.

The radiological manifestations of 200 patients with ankylosing spondylitis were appraised, and correlated with the patient's sex, anterior uveitis, and HLA B27. Radiological findings in female patients were no different from male patients. Only syndesmophyte formation in the spine was found significantly more frequently in patients with uveitis and HLA B27. Osteoporosis of the spine correlated strongly with a later age of onset, longer duration of the disease, older age at the time of study, Romanus lesions, syndesmophytes, spinal fusion, osteitis pubis, and widespread radiological destructive peripheral joint disease. Syndesmophytes were most frequently present at the dorso-lumbar junction. Spondylodiscitis was present in 8 patients and was most commonly present in the thoracic spine.


Antecedent tonsillectomy and appendectomy in rheumatoid arthritis.

The prevalence of tonsillectomy and appendectomy was higher in 196 patients with rheumatoid arthritis (RA), prior to the onset of articular disease, than in their spouses and siblings. The estimated increased risk of developing RA with tonsillectomy was 1.5 and 3.5 times, with appendectomy 1.7 and 6.6 times, and with both surgical procedures 2.3 and 6.7 times, using patient-spouse and patient-sibling matched-pair data, respectively. However, only with patient-sibling data did the lower limits of the 95% confidence interval for the risk ratio exceed 1.0. Several hypotheses are offered to explain the possible association between these surgical procedures and RA.


Antimycotic imidazoles. part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent.

The preparation and antifungal properties of cis-1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine (I) are described. Ketoconazole has, at low oral doses, a high in vivi activity against vaginal candidosis in rats and against cutaneous candidosis in guinea pigs.


Temporal arteritis in Israel. A review of 47 patients.

We reviewed the charts of 47 patients with biopsy proven temporal arteritis, hospitalized in 9 major hospitals in Israel. The age of onset and clinical manifestations of this disease in Israel are similar to those reported from other parts of the world. The disease is more frequent (greater than x 3) in Ashkenazi than in Sephardic Jews and only 1 patient was Arab. More than half of the patients (20/32) had laboratory evidence of liver damage reversible with treatment. Follow-up of 19 of these patients revealed that the treatment with corticosteroids was continued in most patients for more than 2 years.


Adamantylthiourea derivatives as antiviral agents.

A series of nine 3-substituted 1-adamantylthioureas was prepared and tested for antiviral activity against influenza A2/Asian/J305 virus in vivo and in vitro. Protective dose 50 values were calculated for three of the compounds. One of these compounds, 7, has antiviral activity which compares favorably with that of amantadine.


Glomerulonephritis associated with polymyositis.

Five patients with primary idiopathic polymyositis developed proteinuria associated with urine sediment abnormalities. Renal biopsies disclosed a focal mesangial proliferative glomerulonephritis with deposits of immunoglobulin and complement. After treatment of the polymyositis with corticosteroids, proteinuria and urine sediment changes disappeared within 4 to 8 wk along with an improvement in the muscle disease. Although the pathogenesis remains to be determined, immune complexes may be implicated in the etiology of this renal lesion.


Partial synthesis of 6'-hydroxycinchonine and its antiarrhythmic activity in mice.

The synthesis of 6'-hydroxycinchonine [8R,9S)-cinchonan-6',9-diol] was achieved by demethylating quinidine with boron tribromide in dichloromethane at -75 degrees C. The antiarrhythmic activities of 6'-hydroxycinchonine and quinidine were compared following the infusion of aconitine into the tail veins of mice to induce arrhythmias. Comparative ED50 and LD50 studies for quinidine and 6'-hydroxycinchonine revealed equivalent antiarrhythmic potencies for the two drugs but a smaller acute toxicity for 6'-hydroxycinchonine.


Subluxation of the sacroiliac joints in a black female with ankylosing spondylitis.

A 55-year-old black female with ankylosing spondylitis (AS) is described. The patient had a severe flexion attitude secondary to a rotational subluxation at the sacroiliac joints with subsequent bony ankylosis. The sacroiliac abnormality has not been reported in AS patients. Sacroiliac joint laxity during multiple pregnancies might have contributed to the subluxation. The importance of this anatomic site in evaluating the surgical correction of the postural deformities of AS is stressed.


Hexofuranosyladenine nucleosides as substrates and inhibitors of calf intestinal adenosine deaminase.

A series of hexofuranosyladenine nucleosides have been tested as substrates and inhibitors of adenosine deaminase from calf intestinal mucosa. The nucleosides differed from each other in configuration at the various carbon atoms of the hexose and had either a methyl group or hydroxymethyl group at the terminal position. It has been confirmed that the best substrates have the beta-D or alpha-L configuration at the anomeric position and an hydroxyl group on the same side of the furanose ring as adenine. However, these properties are not minimal and other nucleosides will act as substrates even if they do not have the preferred configurations or groups available. The effect of having two hydroxyl groups in the same region of the molecule and in the preferred configurations was to greatly reduce Vmax. Most structural changes resulted in changes in Vmax, whereas KM values remained fairly close. Only a change in configuration of the hydroxyl group at C-5' caused a dramatic change in affinity, as reflected in the KM. All nucleosides exhibited competitive inhibitory kinetics. In the latter studies also, a change of configuration at C-5' greatly affected binding.


Adriamycin analogues. 3. Synthesis of N-alkylated anthracyclines with enhanced efficacy and reduced cardiotoxicity.

Reaction of daunorubicin (1) and adriamycin (2) with aldehydes and ketones in the presence of NaCNBH3 afforded N-alkyl- and N,N-dialkylanthracyclines along with their 13-dihydro derivatives. Product ratios depended upon the nature of the carbonyl reagent and the starting drug. The majority of these analogues retained in vivo antitumor activity comparable to 1 and 2. However, unlike the parent compounds, which inhibit DNA and RNA synthesis at comparable concentrations, several of these analogues inhibit RNA synthesis at markedly lower concentrations than required to inhibit DNA synthesis. In addition, in some cases the ability to bind to DNA in vitro was reduced while antitumor activity was retained. N,N-Dibenzyldaunorubicin was especially notable for increased efficacy (T/C 259, qd 1--9) against P388 leukemia in mice, despite reduction of DNA binding in vitro. It showed almost complete loss of mutagenicity vs S. typhimurium (Ames test) and it was tenfold less cardiotoxic by electrocardiographic measurements (Zbinden test) in the rat.


7-(Aminoethyl) ether and thioether of daunomycinone.

One-step treatment of daunomycinone with excess 2-aminoethanethiol and 2-aminoethanol in trifluoroacetic acid afforded at C-7 the thioether (77% yield) and ether (30% after recycling), respectively. Stereoselectivity for the natural 7S over the 7R configuration was greater for the ether (97:3) than for the thioether (2.5:1). Esterification of daunomycin at C-7 with beta-alanine was accomplished through the mixed anhydride of Z(OMe)-beta-alanine. Preliminary biological tests suggests that the antitumor and DNA interactive properties of the anthracyclines can be retained in such structures.


Synthesis of fused [1,2,6]thiadiazine 1,1-dioxides as potential transition-state analogue inhibitors of xanthine oxidase and guanase.

Ring closure of ethyl 3-aminopyrazole-4-carboxylate with sulfamoyl chloride gave 1,7-dihydropyrazolo[3,4-c][1,2,6]thiadiazine-4(3H)-one 2,2-dioxide. The corresponding 4-amino analogue of this new heterocyclic ring system was similarly prepared from 3-aminopyrazole-4-carbonitrile. Treatment of 4,5,6-triamino-2H-1,2,6-thiadiazine 1,1-dioxide with N-thionylaniline gave a derivative of another new ring system, 7-amino-4H-[1,2,5]thiadiazolo[3,4-c][1,2,6]thiadiazine 5,5-dioxide. These compounds and the corresponding 4-amino- and 4-hydroxyimidazol[4,5-c][1,2,6]thiadiazine 2,2-dioxides were examined as potential transition-state analogue inhibitors of xanthine oxidase and guanine aminohydrolase. Two of the compounds possessed Ki values of about 2x 10(-4) M with guanine aminohydrolase, but no inhibition of xanthine oxidase was observed by any at 5 x 10(-4) M.


Synthesis of arabinofuranosyl derivatives of 3-deazaguanine.

Synthesis of four arabinofuranosyl derivatives of the antitumor agent 3-deazaguanine is described. By the use of 13C and 1H nuclear magnetic resonance spectroscopy, the structures of these nucleosides were established to be alpha and beta pairs of N-7 and N-9 arabinosides of 3-deazaguanine. In contrast to 3-deazaguanine and its ribosyl derivative, the nucleosides described in this paper were found to be inactive against Sarcoma 180 in mice at 100 mg/kg.


Synthesis and antiestrogenic activity of [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]methanone, methanesulfonic acid salt.

Acylation of the sodio anion of beta-tetralone with phenyl anisoate, followed by a Grignard reaction of the resultant 4 with 4-methoxyphenylmagnesium bromide, gave rise to two novel dihydronaphthalene isomers 5 and 6. Regioselective demethylation of either 5 or 6 by NaSEt produced [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl](4-hydroxyphenyl)methanone (7). Etherification of the phenolic group of 7 by N-(2-chloroethyl)pyrrolidine and subsequent methanesulfonate salt formation provided [3,4-dihydro-2-(4-methoxyphenyl)-1-maphthalenyl]]4-]2-(1-pyrrolidinyl)ethoxy]phenyl]methanone, methane sulfonic acid salt (3). Potent antiestrogenic activity of 3 was demonstrated by both oral and subcutaneous administration to rats and mice. In vitro binding studies with rat uterine cytosol estrogen receptors indicate compound 3 has a very high binding affinity which exceeds that of estradiol.


Antileukemic activity of derivatives of 1,2-dimethyl-3,4-bis(hydroxymethyl)-5-phenylpyrrole bis(N-methylcarbamate).

A series of phenyl-substituted derivatives of 1,2-dimethyl-3,4-bis(hydroxymethyl)-5-phenylpyrrole bis(N-methylcarbamate) (1) were synthesized and tested for antileukemic activity against P388 lymphocytic leukemia in the mouse. All of the compounds tested, 1a--r, showed significant activity in this assay. Selected derivatives of 1 were tested against several bacteria and were found to have little or no antibacterial activity in the systems examined.


Distance geometry approach to rationalizing binding data.

A new method is presented for calculating a type of quantitative structure-activity relationship, given experimental data on the binding affinity of a series of ligands to a receptor site on a protein. All ligands are presumed to have known chemical structure but may be conformationally flexible, and all are presumed to bind to the same, single, fairly rigid site of the (pure) receptor protein molecule. Given the experimentally determined free energies of binding of the ligand molecules, possible binding sites are deduced in terms of geometry and the chemical character of the various parts of the site. A test of the method is given for a series of chymotrypsin inhibitors and for a series of dihydrofolate reductase inhibitors. The proposed dihydrofolate reductase site suggests that a quinazoline inhibitor may rock between two different binding nodes depending on the pK of the ring N(1).


Synthesis of Benzo-15-crown-5 polyethers, anticoccidial ionophore analogues.

Synthesis of eight benzo-15-crown-5 derivatives I (R = H, CO2Me, CO2H, Me; R1 = H, CO2H, CO2Me, CHO, CH=CHCO2H, CH2CH2CO2H) designed as rigid cyclic analogues of the anticoccidial ionophores is described. No anticoccidial activity was observed in chickens, but moderate activity in tissue culture was found for I (R = Me, R1 = H; R = R1 = H) and dibenzo-18-crown-6.


Antitumor agents. 1. 1,4-Bis[(aminoalkyl)amino]-9,10-anthracenediones.

The condensation of alkylenediamines with quinizarin or with 2,3-dihydro-1,4,5,8-tetrahydroxy-9,10-anthracenedione, followed by oxidation, gave 1,4-bis[aminoalkyl)amino]-9,10-anthracenediones. Some of these compounds and their 2,3-dihydro derivatives were markedly active against both leukemias and solid tumors in mice. Activity was maximal with 5,8-dihydroxylation and 1,4-bis[(2-aminoethyl)amino] substitution, in which the terminal nitrogen atoms were either unsubstituted (compound 50) or carried 2-hydroxyethyl groups (compound 40), indicating the importance of hydrophilicity. Against B-16 melanoma, 50 gave greater than 433% increase in median life span (ILS) with 7/10 80-day survivors. Against P-388 leukemia, 40 gave greater than 500% ILS with 4/5.60-day survivors; its efficacy and therapeutic index equaled or surpassed those of adriamycin, cyclophosphamide, daunorubicin, methotrexate, or 5-fluorouracil. Against L-1210 leukemia, B-16 melanoma, and colon tumor 26, 40 was generally as effective or more effective than adriamycin and is now undergoing preclinical toxicological evaluation.


Synthesis and biological evaluation of tetramisole analogues as inhibitors of alkaline phosphatase of the 6-thiopurine-resistant tumor sarcoma 180/TG.

Tetramisole and its analogues are potent inhibitors of alkaline phosphatase, including isoenzymes of Sarcoma 180/TG which appear to be involved in the mechanism of resistance of this neoplastic cell line to the 6-thiopurines. To determine the requirement for the thiazole ring system of tetramisole for inhibitor potency, 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]oxazole, 2,3-dihydro-6-phenylimidazo[2,1-b]oxazole, and 2,3,5,6-phenylimidazo[2,1-a]imidazole were synthesized and tested for inhibitory activity against alkaline phosphatase isolated from Sarcoma 180/TG. The results indicate that 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]oxazole caused 50% inhibition at 0.21 mM, while the other synthesized compounds were inactive at a concentration of 1 mM; in contrast, tetramisole required only 0.045 mM for 50% inhibition of alkaline phosphatase activity. The findings support the concept that the thiazole ring system of the tetramisole structure is required for maximum inhibitory potency of this series against alkaline phosphatase.


Structural analogues of L-glutamic Acid gamma-(4-hydroxyanilide) and gamma-(3,4-dihydroxyanilde) as potential agents against melanoma.

Nine heretofore unknown mono- and dihydroxyanilide analogues of the cytotoxic mushroom metabolites L-glutamic acid gamma-(4-hydroxyanilide) (1) and L-glutamic acid gamma-(3,4-dihydroxyanilide) (3, agaridoxin) were synthesized and tested as inhibitors of the growth of B16 mouse melanoma cells in culture. The naturally occurring anilides 1 and 3 had ID50 values of 0.10 and 0.27 mM, respectively. The analogue of 1 in which the gamma-L-glutamyl moiety was replaced by beta-L-aspartyl showed only a threefold decrease in activity, whereas attachment of the phenolic OH group to the meta instead of the para position resulted in a tenfold decrease. Other structural modifications, such as O-methylation or deletion of the carboxyl or amino group in the side chain, led to compounds of still lower activity (ID50 greater than 1.0 mM). The only analogue in the series with more activity than either 1 or 3 against B16 cells was L-glutamic acid gamma-(2,5-dihydroxyanilide) (14), which had an ID50 value of 0.051 mM. These data suggest that the gamma-L-glutamyl side chain in 1 or 3 plays a significant role in the biological action of these compounds, though some flexibility appears to exist insofar as the positioning of OH groups on the aromatic ring is concerned.


Angiotensin II analogues. 13. Role of the hydroxyl group of position 4 tyrosine in pressor activity.

In order to determine the features of the phenolic ring in position 4 of [Asn1,Ile5]angiotensin II that contribute to pressor activity, analogues with selected aromatic substituents were synthesized by the solid-phase method. They showed pressor activities in the rat: [Asn1,Phe(4-NH2)4]AII, 24%; [Asn1,Phe(4-NO2)4AII, 0.1%; [Asn1,Tyr(3,5-Me2)4]AII, 2.2%; [Asn1,D-Tyr(3,5-Me2)4]AII, 1.4%. These results indicate that the activity contributed by the aromatic character of the phenyl ring in the side chain of position 4 is enhanced by a group in the para position that may function as a proton donor in hydrogen-bond formation. Bulky substituents ortho to this hydrogen-bonding group decrease activity by steric interference with hydrogen-bond formation. Bulky groups than cannot act as hydrogen donors in the para position of the aromatic ring drastically decrease the activating effect of the aromatic ring on pressor activity.


Fluorinated retinoic acids and their analogues. 1. Synthesis and Biological activity of (4-methoxy-2,3,6-trimethylphenyl)nonatetraenoic acid analogues.

(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo in a chemically induced mouse papilloma test; the toxicities were assessed in an in vivo mouse hypervitaminosis A test. Antipapilloma activity greater than the parent nonfluorinated ester was found for 1c (ethyl 12-fluororetinoate) and 23 and 39 (aromatic 4- and 6-fluororetinoid esters, respectively). A similar increase in antipapilloma activity was observed for 71 and 72, the aromatic 4- and 6-fluororetinoic acids, respectively, relative to 2 and for 73 (aromatic 4-fluororetinoid amide) relative to 4.


(Aryloxy)[p-(aryloxy)phenyl]- and (aryloxy)[p-(arylthio)phenyl]acetic acids and esters as hypolipidemic agents.

A series of (aryloxy)[p-(aryloxy)phenyl]- and (aryloxy)[p-(arylthio)phenyl]acetic acids and esters of general structure 8 were prepared and tested for lipid-lowering activity in normal rats. At a dose of 0.1% of the diet (ca. 100 mg/kg), approximately half of the compounds reduced serum sterols in the range of 20--30% and lowered serum triglycerides by 40--60%. Over 35 analogues lowered serum sterols by 15--25% when fed at 0.03% of diet, and 15 of these maintained their activity at 0.01% of the diet (10 mg/kg). Synthetic methodology and structure-activity relationships are discussed.


Antiinflammatory agents. 1. Synthesis and antiinflammatory activity of 2-amino-3-benzoylphenylacetic acid.

The synthesis and antiinflammatory activity of 2-amino-3-benzoylphenylacetic acid are described. This compound was postulated to be an active metabolite of 7-benzoylindoline in order to explain the unexpected antiinflammatory activity of the latter compound. Metabolism studies on 14C-labeled 7-benzoylindoline did not confirm this hypothesis. Nevertheless, 2-amino-3-benzoylphenylacetic acid, its ethyl ester, and the sodium salt show potent antiinflammatory activity in pharmacological models.


Aromatic hydroxylation of beta-adrenergic antagonists. Formation of 4'- and 5'-hydroxy-1-(isopropylamino)-3-[2'-allyloxy)phenoxy]-2-propanol from oxprenolol.

The metabolic aromatic hydroxylation of oxprenolol [1-(isopropylamino)-3-[2'-(allyloxy)phenoxy]-2-propanol] in rats was examined. Synthesis of the isomeric ring methoxyoxprenolols (3b-6b) was accomplished from the isomeric methoxysalicylaldehydes by O-allylation, followed by Baeyer-Villiger oxidation. The propanolamine side chain was elaborated by O-alkylation of the Bayer-Villiger product with epichlorohydrin and subsequent oxirane opening with isopropylamine. Gas chromatography-mass spectra of the trifluoroacetyl derivatives of these standards was compared with urinary metabolites obtained from the rat, after methylation with diazomethane and derivatization with trifluoroacetic anhydride. Both 4'- and 5'-hydroxyoxprenolol (4a and 5a) were present in an approximate 4:1 ratio. No 3'- or 6'-hydroxyoxprenolol (3a and 6a) was detected. The metabolites obtained from a human urine treated in the same manner gave similar results with both 4a and 5a present.


Metabolism of beta-adrenergic antagonists. Evidence for an arene oxide-NIH shift pathway in the aromatic hydroxylation of oxprenolol.

The metabolic hydroxylation of 4'-deuteriooxprenolol [1-(isopropylamino)-3-[2'-(allyloxy)-4'-deuteriophenoxy]-2-propanol] prepared from the 4'-bromo compound was examined in the rat (in vivo). GC-MS analysis of the 4'-and 5'-hydroxyoxprenolol obtained showed 65% retention of deuterium in each of the metabolites. The results indicate that an arene oxide-NIH shift pathway is operative in these hydroxylation processes. The equal magnitude of deuterium retention is supportive of a 4',5'-arene oxide as a major contributor to their formation.


Synthesis of some carbon-3 substituted 1,4-benzodiazepin-2-ones and their central nervous system effects.

Starting from 3-hydroxy-1,4-benzodiazepin-2-ones 1--3, via 3-chloro derivatives 4--6, 13 new C(3)-substituted 1,4-benzodiazepin-2-ones were synthesized. Reaction of 4--6 with ethylene glycol yielded 3-(beta-hydroxyethyl) derivatives 7--9. Similar reaction with the isopropylidene derivative of glycerol afforded 10--12, which on hydrolysis of the isopropylidene group hielded glycerol derivatives 13--15. Reaction of trichloroacetyl chloride with oxazepam and temazepam yielded the corresponding trichloroacetyl esters 16 and 17. The beta-hydroxyethyl derivative 7 was conjugated with an acetylated glucopyranose derivative to give isomeric 18 and 19. Partition coefficients (log Poct) and central nervous system activities (in six stranded tests) were determined for 7--15 as well as several standard compounds. Most of the compounds exhibiting beneficial central nervous system activity had Poct values between 1.71 and 2.48. No correlation between lipophilicity and central nervous system activity could be discerned for these compounds.


Mechanism of the dealkylation of tertiary amines by hepatic oxygenases. Stable isotope studies with 1-benzyl-4-cyano-4-phenylpiperidine.

The microsomal oxidative dealkylation of 1-benzyl-4-cyano-4-phenylpiperidine has been studied and the source of oxygen shown to be molecular oxygen. The rate of debenzylation was decreased by substituting deuterium for hydrogen in the methylene portion of the benzyl group. The isotope effect was measured by comparison of the reaction rates of the d0 and d2 compounds 1a and 1b and also of the d5 and d7 compounds 1c and 1d. Determination of the reaction rates for various mixtures of labeled and unlabeled species allowed the rates for 0 (kH) and 100 mol % (kD) to be accurately obtained. A primary isotope effect of 1.46 was observed when the methylene hydrogens of benzyl were replaced by deuterium. No secondary isotope was observed when the aromatic hydrogens of benzyl were replaced by deuterium. The results of this study are consistent with a mechanism involving direct hydroxylation at the benzyl methylene position in a rate-determining step.


Nitrosoureidonucleosides.

3-Deoxyl-1,2-O-isopropylidine-3-(3-methylureido)-alpha-D-ribofuranose (2) was converted to 1,2,5-tri-O-acetyl-3-deoxy-3-(3-acetyl-3-methylureido)-D-ribofuranose (4) and the corresponding glycosyl chloride (7). These sugars were converted to the 3-deoxy-3-(3-methylureido)-beta-D-ribofuranosyl derivatives of adenine (6c), 2-chloroadenine (6d), cytosine (6f), and uracil (6g). Nitrosation of these nucleosides gave the corresponding 3-methyl-3-nitrosoureidonucleosides 8c,d,f,g. 5'-Amino-5'-doxyadenosine (10a), 5'-amino-5'-deoxyuridine (10b), and 5'-amino-5'-deoxycytidine (10c) were all converted to the corresponding 5'-(methylureido)-5'-deoxynucleosides 15a--c by reaction with methyl isocyanate. Nitrosation of these compounds gave the methylnitrosoureidonucleosides 16a--c. These nitrosoureas, potential active-site-directed irreversible enzyme inhibitors, showed little cytotoxicity or activity against leukemia L1210 in vivo.


Antiparasitic agents. 3. Synthesis and anthelmintic activities of novel 2-pyridinyl-5-isothiocyanatobenzimidazoles.

The preparation and anthelmintic activities of a series of 2-pyridinyl-5-isothiocyanatobenzimidazoles are described. In the primary oral mouse screen, six derivatives showed 100% taeniacidal activity at 0.2% in diet. The most active member in this series, 1c, is potentially an effective gastrointestinal nematocide in sheep at 50 mg/kg po.


Synthesis and antibacterial activity of 1-hydroxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide and related compounds.

A Free-Wilson analysis of the antibacterial activity found in a variety of quinoxaline 1,4-dioxides prepared and tested in these laboratories unexpectedly predicted that potent activity should be found in the case where the heterocyclic ring system was substituted with an acetyl group in the 2 position and a hydroxymethyl group in the 3 position (2). The synthesis and antibacterial activity of this compound, which was actually isolated in the hemiketal form (3), and of several of its derivatives are reported. 1-Hydroxy-1-methyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide (3) possesses exceptional activity in vivo against Escherichia coli, Salmonella choleraesuis, and Pasteurella multocida.


Synthesis of angiotensin II analogues by incorporating beta-homotyrosine or beta-homoisoleucine residues.

[1-Sarcosine,4-beta-homotyrosine]-(I), [5-beta-homoisoleucine]-(II), and [1-sarcosine,5-beta-homoisoleucine]angiotensin II (III) were synthesized by Merrifield's solid-phase procedure to study the effect of pressor activity and duration of action. The analogues I--III possessed, respectively, 1.98, 2.82, and 29.2% pressor activity of angiotensin II (vagotomized, ganglion-blocked rats by single-injection procedure) and duration of action of 5.5, 6.7, and 4.7 min; the comparative duration of action of an equipressor dose of angiotensin II was 5.2, 6.3, and 5.3 min, respectively. When incubated with leucine aminopeptidase, degradation of II was as fast as that of angiotensin II; this degradation became considerably slower when position 1 was replaced with sarcosine. Incubation of all these analogues with chymotrypsin showed very little or no degradation up to 3 h. The results indicate that an increase in the chain length by one carbon atom in position 4 or 5 of angiotensin II increased resistance to degradation by chymotrypsin without any increase in in vivo duration of action. Further, all analogues showed low pressor activity.


Stereochemical aspects of the metabolism of 5-(4'-fluorophenyl)-5-phenylhydantoin in the rat.

Racemic 5-(4'-fluorophenyl)-5-phenylhydantoin was synthesized to examine its metabolism in rat. This compound differs from the antiepileptic agent 5,5-diphenylhydantoin in that the normal site of hydroxylation in 5,5-diphenylhydantoin is blocked on one of the phenyl groups by a fluorine atom. The 4'-fluoro analogue gives a major metabolite, which was isolated and identified as (R)-(-)-5-(4'-fluorophenyl)-5-(4'-hydroxyphenyl)hydantoin of 37% enantiomeric purity. The absolute configuration and enantiomeric purity of the metabolite was determined by chemical conversion to (S)-(-)-5-(4'-hydroxyphenyl)-5-phenylhydantoin. A second metabolite of the catechol type, possibly as a mixture of 5-(3',4'-dihydroxyphenyl)-5-(4'-fluorophenyl)hydantoin, and the corresponding O-3'-methyl derivative was detected by gas chromatography-mass spectrometry after methylation.


Antiarrhythmic activity of some N-alkylbispidinebenzamides.

A series of aromatic ring substituted bispidinebenzamides, 2--10, was prepared by condensation of N-methyl- or N-n-butylbispidine with the appropriate acid chlorides. These compounds were initially evaluated in mice for acute toxicity and for their ability to protect against chloroform-induced ventricular fibrillation. All compounds had significant activity, which was optimized in 2, 3, and 5. These last compounds had potencies and LD50/ED50 ratios comparable to those of a standard antiarrhythmic, disopyramide. However, their potencies in increasing the effective refactory period in isolated rabbit atria were considerably less than that of disopyramide.


Synthesis of angiotensin II antagonists containing sarcosine in position 7.

Analogues of the type [1-sarcosine,7-sarcosine, 8-X]angiotensin II, where X = isoleucine, leucine, alanine, methionine, O-methylthreonine, or DL-alloisoleucine, were synthesized by the solid-phase method and purified by partition chromatography, cation-exchange chromatography, and high-pressure liquid chromatography. In the isolated rat uterus, these analogues had activities of less than 0.1, less than 0.1, less than 0.1, less than 0.1, less than 0.1, and 0.7%, respectively, of the hyotropic activity of angiotensin II and inhibited the contractile response to angiotensin II with pA2 values of 8.1, 7.2, 6.7, 7.7, 7.4, and 8.4, respectively. In the vagotomized ganglion blocked rat, the analogues had 0.7, 0.21, 0.06, 0.72, 0.13, and 12.5%, respectively, of the pressor activity of angiotensin II.


The general practitioner and the problems of battered women.

This paper discusses the responsibility of general practitioners who are consulted by women who have been physically injured by the men with whom they live. The paper draws on a study of 50 women who were interviewed at a refuge for battered women, and considers the help which they received, or did not receive, from their general practitioners. Such women are likely to face many difficulties: it is perhaps the essence of their problem that, because it is potentially the concern of so many people, it can so easily become the concern of nobody--except of the woman herself.


Self-ownership, abortion and infanticide.

Doctors have been placed in an anomalous position by abortion laws which sanction the termination of a fetus while in a woman's womb, yet call it murder when a physician attempts to end the life of a fetus which has somehow survived such a procedure. This predicament, the doctors' dilemma, can be resolved by adopting a strategy which posits the right to ownership of one's own body for human beings. Such an approach will generate a consistent policy prescription, one that sanctions the right of all pregnant women to abortions, yet grants the fetus, after it becomes viable as a potentially independent person, a right to its own body. The doctors' dilemma is surmounted, then, by requiring that abortions of viable fetuses be performed in a manner that will produce a live delivery. Hence, infanticide and termination of viable fetuses are proscribed.


Use of chromosomal translocations with in situ DNA hybridisation to confirm localisation of human 5S ribosomal RNA genes.

Two cases of chromosomal translocations involving the long arm of chromosome 1 were investigated for 5S ribosomal gene localisation using in situ hybridisation. In the first family, there was an interstitial translocation of 1q25-32 to chromosome 5; the 5S genes remained on chromosome 1. In the second family, there was a translocation of 1q42-44 to chromosome 21q12; the 5S gene locus in this case was translocated. This shows that the 5S ribosomal genes are at position 1q42-44, confirming a previous assignment based on adenovirus-induced uncoiling and on a partial trisomy (Steffensen et al., 1977).


A high incidence of chronic inflammatory bowel disease in patients with Turner's syndrome.

Four new cases of chronic inflammatory bowel disease in a series of 135 adult patients with Turner's syndrome observed over an average period of 11 years are reported. The diagnosis in 2 of the patients was ulcerative colitis; the other 2 had clinical and histological features consistent with a diagnosis of Crohn's disease. The incidence is considerably higher than any reported frequency of new cases of inflammatory bowel disease in the general population. Previously reported cases are described and attention is drawn to the severity of the bowel disorder. An apparent association with a karyotype abnormality which includes a structurally abnormal X chromosome is noted.


Meiotic and radiation studies in four oligochiasmatic men.

The meiotic findings in four oligochiasmatic males are described. Radiation studies on the somatic cells of three of them failed to provide evidence for a reduced facility to repair DNA which might also have accounted for the observed failure of chiasma formation at meiosis. The data support the idea that the 'low chiasma count' condition in sterile men is of mixed aetiology.


Further dicentric X isochromosomes and deletions, and a new structure i(X)(pter to q2102 to pter).

A new dicentric X isochromosome i(X)(pter to q2102 to pter) of similar size to a normal X is described in a girl with gonadal dysgenesis. In this non-mosaic case with an X short arm duplication, most of the stigmata associated with Turner's syndrome were absent. This structure was compared with that of six i(Xq) and three del(X). The del(Xq) structures all possessed a regular sized C band, but in the i(Xq) this was double sized in each case. Phenotypic comparisons are made in the Xq deletions, and some presumptive short arm isochromosomes are reinterpreted as Xq deletions. Incomplete centromeric suppression is suggested as the causal mechanism of mosaicism of sex isochromosomes with 45,X cells, and it is argued that an exchange event between homologoues is an unlikely mechanism to explain sex isochromosome origin.


Parental origin of triploidy and D and G trisomy in spontaneous abortions.

A cytogenetic study of 15 triploid spontaneous abortuses, 12 trisomic abortuses, and their parents was carried out using the Q-banding technique. Polymorphic regions in abortus chromosomes were compared to corresponding regions of parental chromosomes to determine the origin of the extra chromosomes. Using marker chromosomes it was found that 7 triploids and only one trisomy were informative. Three triploids arose by failure to shed the second polar body during oogenesis. One triploid arose by dispermy. The other three triploids inherited an extra haploid set of chromosomes from the father, either by dispermy or by failure of the second meiotic division during spermatogenesis. The only informative trisomy, a trisomy 22, inherited the extra 22 from the mother. Chromosome polymorphisms are useful in determining the parental origin of extra chromosomes in certain cases.


G gamma beta + type of hereditary persistence of fetal haemoglobin in association with Hb C.

This report describes a Negro family with the G gamma beta + type of hereditary persistence of fetal haemoglobin. Family members with levels of haemoglobin F of 17 to 23% had normal red cell indices, balanced globin chain synthesis, and a pancellular distribution of the fetal haemoglobin, showing that these subjects have a form of HPFH. The production of Hb A and C in addition to the large amount of Hb F in one family member showed that there was an active beta A gene in cis to the HPFH determinant, while structural analysis of the Hb F revealed the presence of only G gamma chains. The criteria for the diagnosis of G gamma beta + HPFH, and the relevance of such conditions to the control of globin gene expression, are discussed.


Globin chain synthesis in sickle beta-thalassaemic bone marrow and reticulocytes.

Globin chain synthesis was studied in reticulocytes and bone marrow erythroid precursors in four sickle beta-thalassaemic Greek patients. Significant globin chain imbalance was found in reticulocytes (alpha/gamma + beta A + beta S = 2.20 +/- SD 0.16) and bone marrow (alpha/gamma + beta A + beta S = 1.58 +/- SD 0.11) after two hours' incubation. There was evidence of contamination of the gamma, beta A, and, to a lesser extent, of the beta S chain by non-haem proteins. The contamination was more obvious in chromatograms obtained from whole cell bone marrow samples and could partially explain the lower alpha/non-alpha ratio found in bone marrow.


Gaucher's disease in South Africa.

The adult non-neuropathic form of Gaucher's disease has been identified in 32 patients in 25 Ashkenazi Jewish kindreds in South Africa. The minimum prevalence in this population is 1 in 5000, with a gene frequency of 0.014 and a carrier rate of 1 in 36. On correction for bias resulting from possible under-ascertainment, these minimum figures become 1 in 4000, 0.0166, and 1 in 30, respectively. Confirmation of autosomal recessive inheritance was obtained by segregation analysis by the 'a priori' and 'simple sib' methods. The Ashkenazin of South Africa have their origins in Lithuania and it is evident that the high gene frequency in South Africa is a reflection of the genetic constitution of the immigrant population. The localisation of the Gaucher gene to Lithuania represents a further step in the determination of the early geographic distribution of the genetic disorders of the Jewish race.


Congenital horizontal gaze palsy and kyphoscoliosis in two brothers.

In a sibship of 11, two brothers with a congenital complete horizontal gaze palsy developed severe kyphoscoliosis. No-one else in the family has a gaze palsy or comparable skeletal abnormalities. Since the parents are first cousins, an autosomal recessive mode of inheritance seems likely.


Re-evaluation of CHANDS.

A rare ectodermal dysplasia with the acronym CHANDS (Curly Hair, Ankyloblepharon, Nail Dysplasia Syndrome) was described by Baughman (1971) as being a new autosomal dominant condition. Additional pedigree data obtained after the original report indicate that the mode of inheritance is more likely to be autosomal recessive, with an instance of quasi-dominant transmission as a result of multiple consanguineous matings in the family. These data are provided in this report.


Trisomy 16q arising from a maternal 15p;16q translocation.

Trisomy 16q is reported in a malformed infant who died at 12 days of age. The karyotype was 46,XX,der(15)t(15;16) (p11;q11)mat. A balanced translocation was found in the mother. The consequences of various types of aneuploidy of chromosome 16 are discussed.


Two children with partial trisomy for 7p.

A second family in which a balanced translocation between 7p and 22q is segregating is described. The clinical features of 2 children with a resulting partial trisomy for 7p are described and compared with the previously described case.


A case of Turner's syndrome with familial balanced translocation t(1;2)(q32;q21)mat.

The first case of Turner's syndrome with the familial translocation not involving the X chromosome is described. The patient had a number of clinical signs of Turner's syndrome and her karyotype was 45,X,t(1;2)(q32;q2)mat. Though it is speculated that the altered structure of a chromosome may influence meiotic disjunction of a non-homologous chromosome, our case suggests that there may be no relationship between the two chromosomal abnormalities.


De novo interstitial deletion del(1)(p21p32).

A girl aged 14 years 9 months, overweight, with severe psychomotor retardation, short stature, a sheep-like face, malformed ears, skeletal and dermatoglyphic abnormalities, and partial deletion of the short arm of chromosome 1 is presented. The karyotype was 46,XX,del(1)(qter to p22::p32 to pter).


Legal medicine in medical schools: a survey of the state of the art.

American medical colleges are showing increased interest in acquainting their students with legal aspects of the practice of medicine. However, little is known about the role of legal medicine in the medical school curriculum. During the summer of 1978 the author sent a questionnaire to all U.S. medical schools. The 86% response rate suggests considerable interest in the subject matter. The results of the survey indicate that while 40% of the schools require their students to complete some course work in legal medicine, the curricula vary considerably among the schools. The topics most frequently covered are informed consent and malpractice.


Efficacy of cognitive/noncognitive measures in predicting resident-physician performance.

There has been relatively little research on the relationship between the clinical performance of physicians and the criteria used by medical school admissions and promotions committees. The studies which have been done primarily relate clinical performance to cognitive criteria. They have usually found only negligible relationships. By considering both cognitive and noncognitive variables, several investigators recently have improved the prediction of clinical performance in medical school. The present authors attempt to determine the increase in predictive efficiency attained by adding noncognitive variables to cognitive variables in predicting clinical performance of residents. The results of this investigation indicate that a combination of cognitive and noncognitive predictor variables functions much better than any individual variable or even any specific class of variables in predicting the postgraduate clinical performance of physicians.


A general medicine clinic: the dilemma and teaching implications.

An academic general medicine clinic (GMC) was studied to determine current patterns, shortcomings, and potential solutions. Retrospective medical record review of 349 randomly selected GMC patients from 1975 permitted profile generation. Only 11.5% of the patients had first visits in the study year. Almost 75% of the study group used the university hospital as their major source of care. Over two years only 58% continued in active care, while 5% died, 8% needed no further follow-up, and 29% were lost from care. The prevalence of hypertensive cardiovascular disease was disproportionately high. Patients exhibited chronic disease exclusively in 91% of return visits. The authors conclude that the GMC offers insufficient variety of patient presentations for optimal postgraduate medical education and inadequate accessibility for comprehensive medical care. Potential improvements include expanding the patient base, extending availability, and employing nonphysician clinicians.


Doctor-patient relationships in fetal/infant death encounters.

A study of concerns of 100 middle-class mothers and fathers who had lost infants revealed that the death of an infant or fetus (through miscarriage) was viewed as devastating because of inadequate community recognition of the loss. The impact of these deaths and the lack of community support forces the parents to turn to their physicians from whom they attempt to seek counsel and comfort. Many physicians, unfortunately, are unable to meet the parent's needs because they cannot deal with death on the personal level, and/or their training militates against their accepting a shift in responsibility from "healer" to "counselor-consoler." Thus, an impasse often is reached in which the expectations of parents exceed the service that the physician is able or willing to render. This detracts from the physician's ability to fulfill adequately his role of provider of total care.


Chart review skills: a dimension of clinical competence.

A study of undergraduate medical students' abilities to identify salient information in reviewing patient charts was conducted by members of the Department of Surgery at Southern Illinois University School of Medicine. Specific goals of the two-year study were to develop and test a method for assessing chart skills and to test the following hypotheses: (a) knowledge base is a component of chart review skill; (b) chart skills are related to basic observational skills; (c) performance on one chart is positively correlated with performance on other charts; (d) chart performance is affected by distraction and time pressure; and (e) chart performance improves with clinical experience. Evaluation instruments and methodology are described. Hypotheses a, b, and e and the time effect hypothesized in d were supported; hypothesis c was not supported. Results of the study provide a foundation for further research exploring the effect of instruction on chart performance and investigating the relationships between chart performance and other measures of clinical competence.


Evaluations of continuing medical education for chronic obstructive pulmonary diseases.

A continuing medical education program which linked primary care physicians to a source of needed appropriate clinical knowledge at a relatively low cost has been demonstrated. Chronic obstructive pulmonary disease was identified as the health problem; the reference patient population was comprised of coal miner health fund beneficiaries living in a 10-county region. Primary care physicians treating beneficiaries in this region were the eligible program participants. Content of the program was based on multiple sources of information about actual practice needs. Several educational techniques were used in combination to convey the knowledge identified as appropriate in the diagnostic stage. A quasi-experimental program evaluation indicated significant changes in physician knowledge, judgment, and self-reported behavior related to diagnosis and treatment of chronic obstructive pulmonary disease.


The use of a microprocessor in routine cardiac assessment.

Increasing use is being made of microprocessors in medicine to perform routine clinical measurements. Physiological parameters whose measurement involves data processing on the part of hospital technicians can in many cases be better obtained using such instrumentation. The application of a microprocessor to the measurement of ST-segment elevations in the electrocardiogram is described to illustrate the use of programmable instrumentation in medicine and demonstrate some of the ensuing benefits.


Education and certification of biomedical engineers in Canada.

The education of biomedical engineers in Canada is discussed, with reference to the Canadian health care system and related industry. Information on specific educational programmes, with enrollment data, is presented. The paper concludes with brief comments on the certification of clinical engineers in Canada.


Training for biomedical engineering in India.

There are biomedical engineers in India and a demand for their services, but there is an absence of trained technical staff to apply the subject within the hospitals. The current situation of the medical electronics aspect of biomedical engineering within Industry, the Hospitals and Educational Institutions is described and some of the problems identified. The particular problems of the growth of a complex technical subject within a developing country are also considered.


Electrical safety in dialysis.

Electrical hazards in dialysis equipment arise from the unintended passage of electric current through the patient. The main primary electrical hazards are described, and typical thresholds quoted. The complete dialysis installation is considered in some detail, bearing in mind the recently published British Standard on the Safety of Electromedical Equipment, BS 5724, Part 1. The microshock risk from leakage and fault currents flowing through the patient via the dialyser and lines is assessed and found to be of very little significance. Equipment that has been constructed to BS 5724 should not, by its design, give rise to primary electrical hazards. The continuing safety of dialysis installations can, however, only be ensured by regular routine testing, and suitable tests are described. It is concluded that, with regularly maintained and tested equipment, dialysis should be considered a relatively safe procedure as far as primary electrical hazards are concerned.


A simple radiation balance for measuring ultrasonic power.

The design and construction of a beam balance for measuring the power outputs of therapeutic and diagnostic ultrasonic instruments is described. Power outputs down to 4 mW have been measured using a low magnification microscope.


The derivation of elbow joint forces, and their relation to prosthesis design.

A literature review showed a lack of accurate data for upper limb joint forces. After discussing methods to determine muscle forces, the physiological cross-sections of muscles were used to estimate their strengths. Elbow joint forces were predicted for isometric actions which gave severe loading conditions. The predicted forces were discussed in relation to prosthesis design, and the use of a radial head replacement was recommended.


Microprocessor detection of electrocardiogram R-waves.

ECG monitoring devices for coronary care units require reliable R-wave dectors as a prerequisite for subsequent analysis. A simple algorithm has been developed for the detection of R-waves in an ECG signal with a microprocessor (Motorola MC6800). Detection criteria used were gradient and duration of a single upslope or downslope. Rejection of muscle noise and other artifiacts was achieved by setting system constants to optimum values which were determined by a short preliminary trial. This constant threshold system has been shown to cope with sudden changes of QRS complex amplitude better than some self adjusting systems. Assessment runs using patient tapes from a coronary care unit show total errors due to false positives and negatives are typically about 1% of the actual number of R-wave occurrences.


A flow and volume calibrator for respiratory measuring equipment.

The design of a simple calibrator for checking the performance of respiratory measuring equipment is described. It is particularly suitable for calibrating the equipment used for obtaining flow/volume curves.


Effect of plastocyanin and phycocyanin on the photosensitivity of chlorophyll-containing bilayer membranes.

Photovoltaic effects were studied in bilayer membranes constructed from phosphatidyl choline, monogalactosyl diglyceride, chlorophyll alpha and beta-carotene. It was demonstrated that the biliprotein C-phycocyanin enhanced the photosensitivity of these membranes. Plastocyanin, an important photosynthetic electron transfer protein, was also found to be effective in enhancing the membrane photovoltage. The C-phycocyanin and plastocyanin were effective on opposite sides of the membrane. Plastocyanin operates to transfer electrons into the membrane, while C-phycocyanin directs electron transfer from the membrane. Membranes containing monogalactosyl diglyceride were found to be extremely stable and were most susceptible to enhancement of photosensitivity by introduction of the proteins. The plastocyanin and C-phycocyanin when used together appeared to operate synergistically.


Stimulation by HCO3- of Na+ transport in rabbit gallbladder.

Bicarbonate presence in the bathing media doubles Na+ and fluid transepithelial transport and in parallel significantly increases Na+ and Cl- intracellular concentrations and contents, decreases K+ cell concentration without changing its amount, and causes a large cell swelling. Na+ and Cl- lumen-to-cell influxes are significantly enhanced, Na+ more so than Cl-. The stimulation does not raise any immediate change in luminal membrane potential and cannot be due to a HCO3(-)-ATPase in the brush border. The stimulation goes together with a large increase in a Na+-dependent H+ secretion into the lumen. All of these data suggests that HCO3- both activates Na+--Cl- cotransport and H+--Na+ countertransport at the luminal barrier. Thiocyanate inhibits Na+ and fluid transepithelial transport without affecting H+ secretion and HCO3(-)-dependent Na+ influx. It reduces Na+ and Cl- conentrations and contents, increases the same parameters for K+, causes a cell shrinking, and abolishes the lumen-to-cell Cl- influx. It enters the cell and is accumulated in the cytoplasm with a process which is Na+-dependent and HCO3(-)-activated. Thus SCN- is likely to compete for the Cl- site on the cotransport carrier and to be slowly transferred by the cotransport system itself.


Movement of thallous ion across the ascites cell membrane.

The movement of thallous ion (Tl+) across the ascites cell membrane has been characterized. Analogous to previous findings for 86Rb (used as a tracer for K+), 204Tl+-influx could be resolved into three components: a ouabain-inhibitable "pump" flux, a passive flux, and a furosemide- or NO-3-sensitive "exchange" flux. Although Tl+ moved approximately nine times faster across the membrane than K+, the pump/leak ratio was equal for the two ions. This suggests that the pump- and leak-pathways share a common rate-limiting step. The exchange mechanism was shown to provide close coupling between the Tl+- and K+-gradients.


Erythrocyte membrane proteins: a modified Gorter-Grendel experiment.

The pressure-area isotherm and shear resistance of spectrin-actin monolayers indicate a close-packed structure at about 1.0 m2/mg protein. This surface area is equivalent to a thickness of about two monolayers at the erythrocyte membrane inner face. The maximum elasticity (lowest compressibility) occurs at 0.7 mg2/mg protein, indicating the limit of reversible compression. The mechanical properties of the monolayers approximate those of the intact membrane, suggesting that the structures are similar and that these monolayers may account for many of the in vivo properties.


Chemically induced K+ conduction noise in squid axon.

Internal perfusion of tetraethylammonium ions (TEA) in squid axons produces a significant high frequency noise component. Although internal TEA suppresses the potassium conductance (GK) noise at relatively low frequencies, it induces high frequency noise which exceeds the intensity of the normal potassium and sodium noise. In addition, the induced noise is dependent on the presence of internal potassium ions (K+) suggesting that this source of noise arises from a modulation of the K+ conductance due to the blocking and unblocking of the K+ channel. The simplest model describing the TEA data is a two-step sequential, pseudo-unimolecular reaction where TEA binds during an open conductance state. A unit channel conductance of 2 pS is estimated from the TEA data as well as noise induced by triethyldecylammonium (TEDA) ions. Thus, these data are consistent with the hypothesis that the channel is blocked whenever the quaternary ammonium ion binding site, located near or within the K+ channel, is occupied.


Hemoglobin-depleted human erythrocyte ghosts: characterization of morphology and transport functions.

A method of preparing hemoglobin-depleted resealed ghosts with an extremely low hemoglobin content is described. The membrane morphology, the crossed immunoelectrophoresis pattern of the membrane proteins, and the transport function of these ghosts have been examined. Electron microscopic examination of the ghosts on hydrophilic as well as hydrophobic grid surfaces revealed a faint filamentous network (spectrin) associated with the membrane. The ghosts were found to have permeabilities towards small polar molecules (water and mannitol) and ions (chloride, sodium, and potassium) which are quantitatively very close to those of intact red cells. It is concluded that white ghosts prepared by the present method are well suited for simultaneous studies of morphology, membrane biochemistry, and membrane transport functions.


Effect of orthophosphate on the rate of calcium uptake by red and white muscle sarcoplasmic reticulum.

In the presence of added orthophosphate (Pi) there is a period during which sarcoplasmic reticulum vesicles (SR) accumulate calcium at a constant rate. This constant rate is increased and is reached sooner when the added Pi concentration is increased. A double reciprocal plot of rate and Pi concentration gives a straight line. The Pi concentration required for half-maximum rate of calcium accumulation is the same for SR preparations from red and white rabbit muscles, although the maximum rates are widely different. During the ageing of SR preparations the Pi concentration required for half-maximum rate increases, but the maximum rate remains the same.


Metabolic dependence of the offset of antidiuretic hormone-induced osmotic flow of water across the toad urinary bladder.

The elevated osmotic permeability to water induced by antidiuretic hormone (ADH) in the isolated urinary bladder of the toad is rapidly reversed by removal or washout of the ADH. This return to normal water permeability is delayed by the suppression of production of metabolic energy by any of three maneuvers: (i) low temperature (2 degrees C); (ii) inhibition of oxidative phosphorylation (10 mM azide or 0.5 mM 2,4 dinitrophenol); or (iii) inhibition of glycolysis (10 mM iodoacetate or 10 mM 2-deoxyglucose). Moreover exposure to cytochalasin B, 2.1 X 10(-5) M, either before or after initiation of the hormonal effect also delays the return of water permeability to normal following removal of ADH. When considered within constraints imposed by models which predict ADH's action on water permeability to be either via modulation of the fluidity of lipids in the membrane or via the figuration of proteins ("pores") in the lipid membrane, these observations on the inhibition of the reversal of ADH stimulation of water flow are more consistent with the protein (pore) theory and place limitations on the mechanisms by which proteins in such pores can return to the resting or impermeable state.


Inhibition of active strontium transport from erythrocyte ghosts by internal calcium: evidence for a specificity controlling site.

The inhibition of strontium transport from erythrocyte ghosts by internal calcium was investigated. When active strontium transport was measured in the presence of increasing levels of internal calcium it was found that the inhibition of strontium transport started at an internal calcium level of 0.3 mM and was virtually complete when this concentration reached 1.0 mM. It was also noted that calcium transport was virtually constant between concentrations of 0.3 and 1.0 mM. This experiment indicated that calcium did not inhibit strontium transport by competing for the active site of the transport system. This inhibition was partially reversed by increasing the internal magnesium concentration from 1 to 4 mM. A higher level of magnesium at the time of lysis and during incubation enhanced strontium transport. However, the inhibition remained noncompetitive with respect to calcium. Manganese was also found to support calcium and strontium transport. However, it could not reverse the inhibition of strontium transport by internal calcium at any concentration tested. In fact, manganese restored the inhibition of strontium transport by calcium in ghosts that were prepared and incubated in solutions that had high magnesium levels.


Triaminopyrimidinium (TAP+) blocks luminal membrane K conductance in Necturus gallbladder epithelium.

The effect of triaminopyrimidinium (TAP+) on the apical membrane of necturus gallbladder epithelial cells was investigated with intracellular microelectrode techniques. TAP+, added to the mucosal bathing solution only, produced the following effects (all rapid and reversible): (i) cell depolarization, (ii) increase of apical membrane resistance, and (iii) decrease of the apical membrane potential change produced by K for Na substitution on the mucosal side. These results can be explained by a decrease of apical membrane K conductance. The paracellular effects of TAP+ were similar to the ones previously described by Moreno (J.H. Moreno, 1974; Nature (London) 251:150; J.H. Moreno, 1975. J. Gen. Physiol. 66:97). These results indicate that the change of transepithelial potential produced by TAP+ cannot be ascribed solely to its effect on the paracellular pathway.


Species-specific effects on the optical signals of voltage-sensitive dyes.

The absorption changes of two merocyanine dyes in response to membrane potential changes were measured on several neuronal preparations to see whether the dyes would be useful in recording from these cells. We were able to record large signals without averaging from barnacle and leech neurons. The greatest signal with WW375 was seen at 750 nm. Much smaller increases in transmitted light intensity were seen at all other wavelengths between 500 and 780 nm. In contrast, vertebrate neuronal preparations produced much smaller signals with an entirely different action spectrum. Essentially the same spectrum was seen in cells of the sympathetic ganglion of the bullfrog, Rana catesbiana, dissociated chick spinal cord neurons, or dissociated rat superior cervical ganglion neurons. In each case an action potential was accompanied by increases in transmitted light intensity between 500 and 600 nm and 730 and 780 nm, and decreases in intensity between 600 and 730 nm with the dye WW375, the best dye tested. Similar results were obtained with dye NK2367 on both vertebrate and invertebrate preparations, except that the spectral properties were shifted 30 nm towards the blue. Both dyes caused some photodynamic damage to the cultured neurons after a few minute's exposure to the illuminating light. Several analogues of these dyes were also tried, but did not produce larger signals.


Binding of radioactively labeled saxitoxin to the squid giant axon.

The binding of saxitoxin, a specific inhibitor of the sodium conductance in excitable membranes, has been measured in giant axons from the squid, Loligo pealei. Binding was studied by labeling saxitoxin with tritium, using a solvent-exchange technique, and measuring the toxin uptake by liquid scintillation counting. Total toxin binding is the sum of a saturable, hyperbolic binding component, with a dissociation constant at 2--4 degrees C of 4.3 +/- 1.7 nM (mean SE), and a linear, nonsaturable component. The density of saturable binding sites is 166 +/- 20.4 micrometers-2. From this density and published values of the maximum sodium conductance, the conductance per toxin site is estimated to be about 7 pS, assuming sequential activation and inactivation processes (F. Bezanilla & C.M. Armstrong, 1977, J. Gen. Physiol. 70:549). This single site conductance value of 7 pS is in close aggreement with estimates of the conductance of one open sodium channel from measurements of gating currents and of noise on squid giant axons and is consistent with the hypothesis that one saxitoxin molecule binds to one sodium channel.


Dermatoglyphic findings in Rubinstein-Taybi syndrome.

The dermatoglyphics of seven patients with Rubinstein-Taybi syndrome and their seventeen family members were compared with those of 250 male and 250 female controls. The most striking dermatoglyphic findings of the patients were the increased frequency of arches, decreased frequency of ulnar loops and reduced ridge-counts on the finger-tips, particularly on the thumbs, lower a-b ridge-counts, increased frequency of I, Ir, II loops, e, f, and t'' triradii, decreased frequency of H loops and tb triradii on the palms, increased frequency of If loops, decreased frequency of I loops, f and p triradii on the soles. The relatives of the patients had more radial loops on the finger-tips, I and Hr loops and t' triradii on the palms, II, III, loops, f and z triradii on the soles.