[Studies on the circadian periodicity in patients with the awakening type of idiopathic epilepsy (author's transl)]. In 6 patients with idiopathic epilepsy of the awakening type and 3 control subjects, the heart rate, body temperature and urinary excretion of sodium, potassium and calcium were measured over 72 h. The patients and the control subjects stayed in the hospital under constant environmental conditions including a standard diet with a constant content of sodium, potassium and calcium. The diet began 2 days before the onset of data collection. No drugs were given during the whole period. The data obtained during the 72-hour period were scored visually concerning the position of the maxima and minima, whereas the period duration was calculated by means of power spectral analysis. The epileptic patients showed more inconstant results concerning the time of maxima and minima as well as the 24-hour periodicity. However, a constant deviation i.e. a constant phase shift or a constant change in period duration into the same direction could not be observed. The different parameters showed different behavior even in the same patient. Thus a constant difference in the circadian periodicity between normal subjects and patients with epilepsy of the awakening type could not be found in the data recorded in the present study.


Ultrastructural investigations of peripheral nerves in neuronal ceroid-lipofuscinoses (NCL). Specimens of brachial plexus, sural nerve and two cranial nerves of one patient with Jansky-Bielschowsky type and 3 patients with the Spielmeyer-Sjögren type of NCL were studied by electron microscopy. Significant light microscopic changes were absent in all specimens. Ultrastructurally, curvilinear and/or fingerprint inclusions were present in each case, located chiefly in Schwann cells. These diagnostic findings were, however, overshadowed by masses of lamellar pi-granule-like cytosomes, usually not mixed with curvilinear or finger-print profiles in the juvenile cases and only rarely associated with curvilinear profiles in the late infantile case. Since secondary changes of axons and myelin sheaths were mild, these lamellar cytosomes might indicate chronic damage to Schwann cells, perhaps by "wear and tear" as seen in aging as well as NCL. On account of the abundance of pi-granules in NCL, peripheral nerve biopsy appears less suitable for confirming this diagnosis than biopsy of skin, striated muscle and rectal tissue.


Myotonic dystrophy and multiple sclerosis. A 48-year-old man with myotonic dystrophy did well until the age of 37, when he developed the first of many remissions and exacerbations of multiple sclerosis. The only serum value done while the patient was infection free, revealed serum hypogammaglobulinemia. Three determinations of the relative concentration of gama globulin in the cerebrospinal fluid over 11 years, yielded markedly elevated levels. Previous work on the immunological abnormalities in both disease entities is discussed. This is the only published case in which these two diseases were manifested in the same patient.


Intrathecal cytostatic therapy of meningeal carcinomatosis. Autoradiographic investigations of the CSF cells. Autoradiographic investigations with 3H-thymidine were performed on cerebrospinal fluid (CSF) cells from a case of meningeal carcinomatosis following carcinoma of the breast. The cells were found to be anaplastic histologically. Within a period of 12 days 3 X 25 mg methotrexate were injected into the subarachnoid space by lumbar (2 X) or cisternal (1 X) puncture. The CSF cells were reduced from 283/3 to 19/3, while the proportion of tumour cells fell from 90 to 2%. The labelling index before onset of therapy was 33%; it increased to 70% after the first intrathecal administration of cytostatic and finally fell to 23%. The mitotic index, which was generally less reliable, behaved in a parallel way; the initial value of 1.5% increased to 3% and then declined to values less than 0.5%. Despite detailed histological investigation, carcinomatous cells could not be found anywhere on the surfaces of the central nervous system or meninges. Clinically, the patient had never shown significant neuropathological or psychopathological findings. However, the headache which had been very severe during the meningeal carcinomatosis vanished completely after the second application of methotrexate.


[N. interosseous anterior syndrome. Study in 4 cases of our own and in 49 cases from the literature (author's transl)]. The anterior interosseous nerve branches off from the median nerve distal of the pronator radii teres. It lies on the interosseous membrane, always innervates the flexor pollicis longus, usually the portion of the deep flexor belonging to the second, sometimes also the portion belonging to the third finger, then runs to the pronator quandratus. In 4 cases of our own and in 49 cases from the literature we could show that an isolated lesion of the motor division of the median nerve has been seen after fractures and in connection with dull traumas, unusual activities, pressure and medical procedures. A mechanical origin can be assumed also in the so-called "spontaneous" cases of paresis without any indication of exogenous influence. It is described twice as often on the right as on the left side and in 15 of 17 cases of operative revision fascial bands, adhesions, and similar compressions were found. Frequently, the only sign of the syndrome is paresis of the flexor pollicis longus. The diagnosis becomes clearer, when the flexor digitorum profundus is also affected, since the extension of the first two or three end phalanges during flexion of all fingers constitutes a characteristic clinical feature. Occasionally, pain is present on the outside of the forearm, and this can lead to differential diagnostic reflections. In spite of the convincing operative findings we find that the experience to date is not sufficient to give a general recommendation for operative treatment. The prognosis is favorable, apparently even without operative revision; in some cases, however, as in one of our patients, the paresis does not improve until the second year after onset.


Function and innervation of the involuntary m. retroauricularis. Beside the automatic, obligatory and tonic coinnervation of the involuntary m. retroauricularis in conjugate lateral gaze (oculoauricular phenomenon, nystagmus) several other physiological ways of accidental coinnervation are described. In talking, chewing, swallowing and during involuntary inspiration irregular bursts of innervation may be registered. In sleep regular rhythmic inspiratory innervation is demonstrated as well as myoclonic jerks. With reservation, an allusion is made to rem-sleep. In "nervous subjects" irregular involuntary innervation of the m. retroauricularis might serve as a measurement instrument for the involuntary somatomotor nervous system, i.e. the degree of neurotic tensity. An early myasthenic reaction is gained from the M. retroauricularis in patients with ocular forms of the disease. A common motor nucleus of abducens and facial nerve is discussed. Complementary studies are announced on the various forms of facial paralysis, strabismus and nystagmus. A further diagnostic use is presumed.


Genetic investigations on chronic forms of infantile and juvenile spinal muscular atrophy. A material of 247 cases selected from 260 cases of spinal muscular atrophy in the Warsaw Department of Neurology in 1960-1974 was analyzed. The size of sibships was established and calculations were made of the mean distribution of the age at onset, also according to sex, for the different clinical forms, genetical proportions by the method of siblings and of probands, and coefficient of sib-sib correlation for the material as a whole and separately for males, females and male-female pairs. The analysis shows the course of the disease to differ between the sexes and to be mild in males more often than in females, as is particularly noticeable in the higher age groups. Cases of Kugelberg-Welander's disease are predominantly male. The hypothesis is advanced that a proportion of male patients have a sex-linked modifying gene of a fairly high frequency (possibly of the range of 1 in 5 males, and 1 in 25, in the homozygous state, in females). Although it would not disprove conclusively the nosological distinctness of different forms of infantile and juvenile spinal muscular atrophy, the existence of the modifying gene, if proved, would tend rather to add to the likelihood of their constituting a single recessive autosomal disease.


The anterior interosseous nerve syndrome. A case of isolated anterior interosseous nerve palsy with its characteristic clinical picture of lack of function is described. The typical symptoms are the inability to flex the terminal phalanges of the thumb and index finger, possibly of other fingers too, and the inability to pronate the forearm when the elbow is flexed. The cases previously described in the literature are reported in comparison with the present case. Prognosis and treatment are discussed.


Plasma membranes of muscle in experimental myotonia in rats. Determinations of protein and phospholipid composition, as well as enzymatic activity, were carried out in plasma membranes isolated from the muscle of rats, after different periods of 20,25-diazacholesterol administration. A decrease in the level of phospholipids, and in the total amount of plasma membrane proteins, connected with a relative reduction in the amount of protein of a molecular weight of 100000 daltons, was found. The activity of (Na+ + K+)-ATP-ase gradually decreased while a reverse tendency was observed in the case of 5'-nucleotidase. Changes in ATP-ase and phospholipids appeared even prior to electrophysiologically recorded signs of the myotonia. The mechanism of these changes and their possible role in myotonia are discussed.


Sarcoplasmic reticulum in experimental myotonia in rats. Determinations of enzymatic activity, protein structure and phospholipid composition of sarcoplasmic reticulum isolated from the soleus muscle (S), extensor digitorum longus muscle (EDL) and gastrocnemius muscle (G) in rats were carried out after various periods of 20,25-diazacholesterol administration. The sarcoplasmic reticulum from G and EDL of myotonic rats exhibited a rise in basal ATP-ase activity and a fall of total phospholipids. The protein of molecular weight of 100000 daltons in G and EDL was slightly more pronounced.


Measles virus infection and multiple sclerosis: serological studies. In 159 patients out of 161 with multiple sclerosis (MS), a significant rise in the level of measles hemagglutination inhibition (HI) antibody was found in the serum and in 92 MS patients the occurrence of measles HI antibody in the CSF was significantly more frequent. MS patients showed CSF humoral response against measles virus by neutralizing test (NV) (76%) more often than by hemagglutination test (37%). CSF FA antibody was found in 60%. In the serum of MS patients the presence of NV, HAd, FA, and GP-RNP was observed. 87% of MS patients showed lowered serum: CSF NV or HI antibody ratios and 78% had a diminished FA antibody ratio. Longitudinal study of serum HI measles virus antibody showed no substantial changes over longer period of the disease. Higher CSF measles antibody titer was found in more disabled patients with a malignant course of the disease (P less than 0.001). It is concluded that either persistent infection with proviruses or nonspecific stimulation of certain clones in individuals with genetic susceptibility provides for an excessive synthesis of humoral viral antibodies in MS.


Anatomical analysis of ventrolateral thalamic input to primate motor cortex. 1. The origin and topographical organization of input to the arm area of the primate motor cortex from the ventrolateral thalamus were examined using the method of retrograde transport of horseradish peroxidase (HRP). 2. A thin, continuous slab of labeled neurons was found in the ventrolateral thalamus followingmultiple injections of HRP into the arm area of the motor cortex. The slab of labeled neurons was flanked, medially and laterally, by groups of unlabeled neurons. 3. The origin of ventrolateral thalamic input was more extensive than previously thought. Labeled neurons were found from A10.0 to A6.0 and occurred in three ventolateral thalamic subdivisions: ventralis lateralis pars oralis (VLo), ventralis lateralis pars caudalis (VLc), and ventralis posterior lateralis pars oralis (VPLo). For simplicity this region containing labeled neurons has been termed the ventrolateral thalamic (VL) arm area. 4. Injections of HRP into the somatic sensory cortex indicated that the thalamic regions which project to the somatic sensory cortex are separate from the VL arm area. 5. The distribution of labeled neurons following single injections of HRP into different regions of the motor cortex arm area indicated that the VL arm area is topographically organized, particularly its caudal part. Ventral regions of the VL arm area were labeled following HRP injections into motor cortex regions adjacent to the central sulcus where the representation of largely distal musculature is localized. Dorsal regions of the VL arm area were labeled following HRP injections into motor cortex regions more rostral to the central sulcus where the representation of more proximal musculature is localized. 6. A larger region of the VL arm area was labeled following HRP injections adjacent to the central sulcus than following the more rostral motor cortex injections. This suggests that, like the arm area of the motor cortex, more of the VL arm area is allotted to the representation of distal than proximal musculature. 7. Following very small cortical HRP injections, isolated labeled thalamic neurons were diffusely scattered throughout a 3-mm rostrocaudal extent of the VL arm area. In addition, a small focal cluster of labeled thalamic neurons was also seen. The labeled cluster was limited to 0.5 mm rostrocaudally and 300 mum in width. The focal distribution of labeled thalamic neurons suggests that aspects of a point to point organization may exist in the connection between VL and the motor cortex arm area.


A method of integrating family nursing in an undergraduate curriculum. The authors describe integrating theoretical content of families into an undergraduate curriculum based on the biopsychosocial spheres. Using audiovisual materials, and printed media, the student is introduced to independent learning and applies content to clinical settings in the community.


A plasma glycoprotein depressed in vitamin A deficiency in the rat: alpha 1-macroglobulin. Plasma glycoprotein synthesis in normal and vitamin A-deficient rats was investigated by injecting the rats with labeled carbohydrate precursors and then fractionating their plasmas on DEAE-Sephadex. Plasma from deficient rats showed a consistent depression of 30% in the uptake of label into a peak eluting with 0.23 M NaCl. The major component of this peak was identified as the rat alpha1-macroglobulin, based on its molecular weight (800,000), its mobility on cellulose acetate electrophoresis and its ability to bind trypsin. Although the alpha1-macroglobulin synthesis appeared to be depressed by 30%, its fractional turnover rate was not affected by vitamin A deficiency (t 1/2 = 18 hours). The trypsin-binding ability of this glycoprotein was used as a comparative measure of its concentration, and the results confirmed that serum levels of this glycoprotein were lower in deficient rats. In severe deficiency, alpha1-macroglobulin levels dropped to between 10% and 20% of normal levels.


Topographical distribution of sulphated glycosaminoglycans in human temporomandibular joint disks. A histochemical study of an autopsy material. The distribution of sulphated glycosaminoglycans (GAG's) in the human temporomandibular joint disk and its relationship to sex, age and osteoarthrosis was studied by histochemical methods in autopsy material from 18 individuals. The disks were embedded in paraffin and frontal sections, 5-7 mu thick, were cut at different levels. Two staining methods were used, toluidine blue at pH 0.5 and alcian blue with different concentrations of MgCl2. The two methods gave comparable results. The sulphated GAG's as represented by metachromatic staining with toluidine blue at pH 0.5 and staining with alcian blue in concentrations of MgCl2 above 0.55-M were found in the central load-bearing part of the disks evenly distributed in the medio-lateral direction. The findings from the alcian blue staining method indicated the presence of sulphated GAG's with characteristics similar to chondroitin/dermatan sulphate and keratan sulphate. The latter finding was most frequent in a surface zone )10-100 mu) located mainly in the central part of the disks. In macroscopically thin areas of the disks judged as early osteoarthrosis a significant reduction in the staining of sulphated GAG's could be observed. No age or sex differences were found in the distribution of GAG's, either in normal or in osteoarthrotic disks.


Chondromyxoid fibroma of the mandible.

Chondromyxoid fibroma of the mandible. A new case of chondromyxoid fibroma of the jaw arising in a 16-year-old white girl is presented. It is possible that unrepresentative biopsy specimens of this condition could be misdiagnosed as myxofibroma, chondrosarcoma, or mesenchymal chondrosarcoma.


An experimental kidney disease in dogs produced by injection of heterologous antisera to dog tubular fraction 3 antigen. Glomerular disease characterised by morphological alterations of the glomerular basement membrane and the mesangium was produced in dogs by injections of heterologous anti-dog renal tubular fraction 3 antibody. The renal lesion was characterised by irregular thickening of the glomerular basement membrane, with electron-dense deposits and loose granular material within it.


Exeriences with isoprenaline induced myocardial necrosis in the rat. An attempt has been made to quantify myocardial lesions produced in the rat by isoprenaline for use as a model to assess possible incremental effects of environmental and dietary factors. This was initially made difficult by variation in the cardiotoxicity of different samples of isoprenaline. Investigation of these samples failed to reveal the basis for the differences. Active preparations have, however, produced profound changes both clinically and pathologically. The earliest light-microscopic changes both clinically and pathologically. The earliest light-microscopic change was loss of fuchsinophilia of fibres in sections stained by the picro-Mallory technique. By 24 hr obvious necrosis, fragmentation and lysis of the fibres had occurred. Treatment of frozen sections to demonstrate succinate dehydrogenase showed early changes in the character of formazan, suggesting the possibility of a transient alteration in the hydrogen transport system. By 48 hr, this is reversed except in those fibres undergoing necrosis where there is a complete loss of formazan. This contrast in staining between normal and necrotic fibres constitutes the basis for quantification which has been carried out by point counting. The results show some differences in the amount of myocardial necrosis between different batches of animals but relatively small differences within individual batches, suggesting that the introduction of additional variants into the system should be capable of producing clear cut results.


Comparison of graphical and computerized methods for calculating binding parameters for two strongly bound drugs to human serum albumin. The determination of drug-protein binding parameters (n's and K's) can lead to important information on the required therapeutic dosage regimen and possible clinical complications associated with competitive displacement of one drug by a concurrently administered agent. Graphical and computer estimates of the data are often incorrectly formulated, and and seldom are adequate data obtained at low binding ratios. Commonly used graphical procedures, inadequately formulated computer methods, and a statistically correct computer method were used to compare results obtained from a circular dichroic examination of dicumarol-human serum albumin and fenoprofen-human serum albumin interactions. Literature binding constants for dicumarol-albumin range from 1 X 10(5) to 30 times that figure, and it is shown here that a wide range in parameter estimates may be obtained depending on the method of data analysis. The parameter estimates in the case of fenoprofen-albumin are even more variable.


Relationship between dicumarol distribution and the effect of enzyme induction on dicumarol elimination in rats. Pronounced intersubject differences in the apparent first-order elimination rate constant (kapp) for dicumarol in rats have been found to be due to corresponding differences in the distribution of dicumarol between the liver (the site of dicumarol biotransformation) and the rest of the body. From theoretical considerations and experimental results in animals given only dicumarol, it has been shown that kapp is linearly related to the fraction of drug in the liver (FL). The proportionality constant (k) for these variables was defined as the intrinsic elimination rate constant for dicumarol which should reflect the activity of the enzyme system(s) involved in the elimination of this drug. The purpose of this investigation was to determine the effect of enzyme induction on dicumarol distribution and on the relationship between kapp and FL in rats. It was found that pretreatment with phenobarbital caused a substantial increase in kapp, but that it had no apparent effect on the serum/liver and serum/kidney concentration ratios of dicumarol. The relative weight of the liver was significantly increased by phenobarbital treatment but the weight of the kidneys was not affected. Linear relationships between kapp and FL were found for both the control and the phenobarbital treated groups, but with a significant difference in the slopes of the regression lines. This study illustrates the application of a pharmacokinetic technique which permits a clear and quantitative distinction between the relative contributions of enzyme activity and body distribution to the in vivo elimination kinetics of a drug.


A novel chromosome abnormality in human neuroblastoma and antifolate-resistant Chinese hamster cell lives in culture. Four cell lines, SK-N-SH, SK-N-MC, SK-N-BE(2), and IMR-32, established in vitro from tumor tissue of patients with neuroblastoma were analyzed by trypsin-Giemsa banding methods. In two of the lines a large, abnormally staining chromosome region was observed. This "homogeneously staining region" (HSR) was considerably longer than any of the bands present in normal human cells and, as revealed by both G- and Q-banding, stained with an intermediate intensity. It was located on chromosomes No 6, 10, 17, or 19 of the SK-N-BE(2) cell line and on chromosome No 1 of the IMR-32 line. In concurrent studies, long HSR's were also observed in Chinese hamster sublines that had been exposed to and had developed high levels of resistance to methotrexate or methasquin and high levels of activity of target enzyme dihydrofolate reductase. For several sublines with the highest levels of enzyme activity, approximately 2% of the total cell protein was dihydrofolate reductase. Of 13 independently derived sublines with acquired resistance to antifolate, only those 7 with greater than 100-fold increases in enzyme activity consistently exhibited HSR's. These regions comprised 2-5% of the total length of the chromosome complement and were specifically localized, as demonstrated by G-banding. Analysis of chromosome replication patterns of the HSR in human neuroblastoma and in drug-resistant Chinese hamster cells by tritiated thymidine radioautography indicated that the long, abnormally staining region replicated relatively rapidly and synchronously and terminated replication before the midpoint of the S phase. The HSR thus appeared to represent a novel chromosome abnormality that may be present in cells with specialized functions. Drug-resistant Chinese hamster cells were characterized by overproduction of target enzyme, whereas human neuroblastoma cells had phenotypes of normal neuronal cells. Whether the HSR is transcriptionally active was not elucidated.


Physicochemical characterization of the male-specific RNA bacteriophage mu2: serological comparison with R17 fr, and Q beta. The physicochemical values and amino acid composition determined for bacteriophage mu2 suggest a close relationship with R17 and fr; significant differences are found with Qbeta; these results are supported by serological studies.


Purification of the alpha subunit of avian myeloblastosis virus DNA polymerase by polyuridylic acid-sepharose. The alpha subunit of the avian myeloblastosis virus DNA polymerase could be readily purified to near homogeneity using a polyuridylic acid-Sepharose column chromatography step.


Respiratory syncytial virus ts mutants and nuclear immunofluorescence. A replicated sector-plating procedure was used to isolate 35 induced temperature-sensitive (ts) mutants and one spontaneous ts mutant from a wild-type stock of respiratory syncytial (RS) virus cloned from recent clinical material. Seven of these mutants were ts for plaque formation at 37 degrees C as well as at the restrictive temperature of 39 degrees C. The wild-type strain did not differ markedly from standard laboratory strains of RS virus. It was dependent on exogenous arginine (84 mug/ml) for optimal growth, and was not significantly inhibited by mitomycin C (10 mug/ml). It was sensitive to actinomycin D (2.5 mug/ml) during the early part of the growth phase. A characteristic focal cytopathic effect was obtained in BS-C-1 cells. Staining of infected monolayers by an indirect immunofluorescence procedure revealed a profusion of filamentous processes extending from the plasma membrane, and a similar modification of the surface of infected cells could be visualized by scanning electron microscopy. Filament production was inhibited when certain ts mutants were incubated at 39 degrees C, confirming the virus-specific nature of the phenomenon. Thirty-four of the mutants were classified into three groups by immunofluorescence. Complementation was observed in mixed infection with a single mutant from each group. Nuclear, as well as cytoplasmic, immunofluorescence was detected in RS virus-infected cells using a high-titer bovine anti-bovine RS virus serum. Visualization of nuclear antigen was dependent on the inhibition of cytoplasmic fluorescence obtained when ts mutants in groups I and III were incubated at restrictive temperature.


Presence of murine leukemia virus envelope proteins gp70 and p15(E) in a common polyprotein of infected cells. The murine leukemia virus envelope proteins, p15(E) and gp70, exhibit a mode of processing distinct from that of virion core proteins according to three criteria. First, the incorporation of both p15(E) and gp70 into virions is more sensitive to the metabolic analogue 2-deoxy-D-glucose than the incorporation of core proteins. Second, the kinetics with which the newly synthesized envelope proteins appear in the released virions is delayed relative to the appearance of core proteins. Third, immunoprecipitation of large polypeptides from infected cells reveals the presence of gp70 and p15(E) in a common precursor distinct from the core polyprotein.


New temperate bacteriophage for Bacillus subtilis, rho 11. A new temperate bacteriophage, rho11, isolated by J. Hoch, has been characterized. This new phage is very similar to the temperate phage phi3T in size (380 nm), host range, homoimmunity, DNA buoyant density (1.694 g/ml), antigenicity, and molecular weight (around 6.0 X 10(7)) as determined in gels. Like phi3T, rho11 converts thymine auxotrophs to prototrophy at high frequency (250 out of 250 tested). Phage rho11 differs from phi3T in plaque morphology and in the endonuclease R-EcoRI digest pattern. Sixteen of the 20 rho11 DNA fragments have migration patterns corresponding to those of the 21 fragments of phi3T. The close similarities yet clear differences between these phages suggest that the two phages have a common ancestor.


Radioisotope investigation of continuous bladder irrigation after transurethral resection. Radioisotope studies using 131I serum albumin were performed on 20 patients to investigate the possibility of intravascular absorption of the irrigating solution during continuous bladder irrigation after transurethral resection of the prostate. In only 5 of 20 patients was a minimal absorption of 1 to 34 cc observed. On the basis of these studies the routine use of continuous bladder irrigation after transurethral resection can be recommended, provided techniques are sterile.


In vitro uptake of 3H testosterone and its conversion to dihydrotestosterone by prostatic carcinoma and other tissues. Needle biopsies of normal, benign hyperplastic, neoplastic and metastatic prostatic tissues were used to study the uptake of 3H testosterone by these tissues and their ability to convert testosterone to dihydrotestosterone. Histological quantification is important because stroma is active in both of these areas of biochemical activity. The 3H testosterone uptake by the tissues is relatively similar but benign prostatic hyperplasia and normal tissue consistently convert more testosterone to dihydrotestosterone than do neoplastic  tissues. The least active in this regard are pure biopsies of neoplastic cells obtained from nodal metastases, suggesting extensive loss or repression of 5-alpha-reductase activity. Further, this defect is present in neoplastic tissues even if the patient has had an orchiectomy and/or received hormonal therapy. It is not known whether testosterone may substitute for dihydrotestosterone in the neoplastic nucleus. Our studies indicate that animal models that yield data on suppresion of 5-alpha-reductase activity by certain agents may have limited relevance to the tissues of human prostatic carcinoma.


Herpes simplex virus type 2 and cancer of the prostate. A seroepidemiologic study was performed to determine if there was an association between antibodies to herpes simplex virus type 2 and cancer of the prostate, similar to that reported for herpes simplex virus type 2 and cervical carcinoma. No significant difference in herpes simplex virus type 2 antibodies was seen between patients with cancer of the prostate and those with benign prostatic hypertrophy. Further studies are needed to define the possible role of herpes simplex virus type 2 in the etiology of cancer of the prostate.


Combined electromyography and gas urethral pressure profilometry before and after transurethral resection of the prostate. Combined electromyographic and gas urethral pressure profilometry was done on 10 consecutive patients before and 3 months after transurethral resection of the prostate. A significant reduction was found postoperatively in the functional urethral length, whereas the maximum urethral closure pressure remained unchanged. Increase in urethral resistance in prostatic obstruction of the posterior urethra was related to the increase in the functional length of the posterior urethra rather than to mechanical occlusion of the urethral lumen. Periurethral striated muscle activity was recorded from the membranous urethra to the urethrovesical junction with the maximal activity located in the membranous urethra. Marked striated muscle activity also was found consistently at the bladder neck.


Pneumocystis carinii pneumonia. Diagnosis by examination of pulmonary secretions. To determine if examination of respiratory secretions is useful in diagnosing Pneumocystis carinii pneumonia, smear preparations of expectorated sputum, tracheal aspirates, and transtracheal aspirates stained by the Gomori methenamine silver nitrate method were examined. Pneumocysts were observed more frequently in material obtained by transtracheal aspiration than in secretions obtained by the other methods. Transtracheal aspiration yielded material containing pneumocysts in 8 (13%) of 60 patients; each had pulmonary infiltrates and clinical courses consistent with P carinii pneumonia. Of 330 smear preparations examined from expectorated sputum, three patients had pneumocysts in their sputum and one had organisms in both transtracheal aspiration and expectorated sputum; all three had pneumonia. This study provides evidence that transtracheal aspiration is a useful initial step in the approach to the diagnosis of P carinii pneumonia.


The audiovisual interview. A new tool in medical education. The audiovisual interview with a patient in the office of the student physician or physician is an essential undergraduate, graduate, and postgraduate educational management tool. Immediate feedback and insight are obtained as to how the patient and educator perceive the performance and service of the student or professional. Therapeutic failures may be recognized, and misconceptions and misreading of verbal and nonverbal communications can be corrected immediately. There is access to integrating psychosocial and biologic variables, with a better chance to extract more valid information for creative problem-solving and less of a chance for therapeutic failures. The student recognizes and appreciates the therapy and healing in the dialogue.


Quantitative chemical analyses and antigenic properties of peptidoglycans from Clostridium botulinum and other clostridia. The cell wall peptodoglycans were isolated from Clostridium botulinum and some other species of the genus Clostridium by hot formamide extraction and their quantitative chemical composition and antigenic properties were determined. The petidoglycan of C. botulinum type E was found to be a diaminopimelic acid (DAP)-containing type composed of glucosamine, muramic acid, glutamic acid, alanine and DAP in the molar ratio of 0.76:0.78:1.00:1.88:0.81. All other types of C. botulinum and Clostridium sporogenes also belonged to the same peptidoglycan type. The peptidoglycans of Clostridium bifermentans and Clostridium histoloyticum contained DAP but they differed from those of C. botulinum in the molar ratio of alanine to glutamic acid. The peptidoglycan of Clostridium perfringens was composed of glutamic acid, alanine, DAP and glycine in the molar ratio of 1.00:1.64:0.94:0.90. On the other hand, the peptidoglycan of Clostridium septicum was found to contain lysine instead of DAP and the molar ratio was 1.00:1.41:0.96 for glutamic acid, alanine and lysine. In spite of the difference in amino acid composition of peptidoglycans among the clostridia, the quantitative precipitin test demonstrated that antiserum against C. botulinum type E peptidoglycan cross-reacted with the peptidoglycans from other clostridia as well as various types of C. botulinum.


[Ventricular fibrillation and asystole precursors in myocardial infarct]. Ventricular fibrillation and asystole are a frequent cause of death in myocardial infarction. The data of continuous monitoring the heart in 134 patients with acute myocardial infarction and ventricular fibrillation and asystole. The immediate precursors of ventricular fibrillation were predominantly ventricular extrasystoles. A frequent precursor of ventricular fibrillation consists in paroxysmal ventricular tachycardia. In some patients the ventricular fibrillation was preceded by the block of the bundle of His, non-paroxysmal ventricular tathycardia, escaping contractions and some other arrhythmias. A factor providing for the development of ventricular fibrillation consists in the Q-T interval lengthening on ECG. Ventricular asystole is usually preceeded by atrioventricular block, Stage II-III, and the block of the bundle of His, as well as by ventricular tachycardia and extrasystole, in some cases--by sinus bradycardia and sinoauricular block (weakness of the sinus node). The examination of the rhythm and conductivity disorders preceeding the ventricular fibrillation is of great importance in view of the possibilities of prevention of "arrhythmic death".


Experimental induction of hepatocellular hyalin (Mallory bodies) in mice by griseofulvin treatment. 1. Light microscopic observation. Griseofulvin (GF) feeding of mice resulted in protoporphyria, liver cell damage, bile duct alterations, and finally hepatoma formation. In addition, hepatocellular hyalin developed, resembling in its morphology classic Mallory bodies (MB) as seen in alcoholic and nonalcoholic liver disorders in man. Liver cells containing MB often displayed features of severe cell damage and MB were finally released into the sinusoids and degraded by macrophages. The rapid disappearance of MB following GF discontinuation and the reappearance after resumption of GF feeding suggest an intimate relationship between metabolic alterations in the hepatocytes exerted by the drug and MB formation. This assumption is further supported by the fact that MB change their tinctoreal properties in chromotrope aniline blue-stained sections after GF discontinuation, possibly relfecting degeneration. Long term GF treatment apparently primed the liver for MB formation since the cells were able to respond almost instantly with MB to a GF challenge after a 1-month GF-free period.


Application of immunofluorescent staining on paraffin sections improved by trypsin digestion. The purpose of this study was to explore a method by which an improved immunofluorescent staining can be applied to formalin-fixed paraffin sections to demonstrate cellular or tissue deposits of immunoglobulins, complement and fibrin, and to demonstrate alpha-1-antitrypsin storage and hepatitis B antigens in liver, toxoplasma in heart, and carcinoembryonic antigens in colonic cancer. It was shown that immunohistochemical demonstration for the above mentioned antigens, but not for complement, was feasible. The paraffin sections were first treated with trypsin and the indirect staining method was used. The trypsin treatment was found to decrease the nonspecific background fluorescence through digestion of the tissue. It probably also unmasked the immunoreactive sites of viral antigens and alpha-1-antitrypsin. In general,  a 2-hour digestion was satisfactory for the types of tissues examined in this study, and an optimal period of digestion could be sought to obtain the best result for a specific antigen. This method may be a useful adjuvant to histopathologic study, in which a retrospective immunohistochemical examination may be desirable.


Plasma testosterone concentrations in alcoholics. Plasma testosterone concentrations were normal in 17 hospitalized alcoholics after a large dose of alcohol and in 16 Skid Row alcoholics. The findings fail to support the idea that the direct effects of alcohol on steroid metabolism cause gynecomastia and testicular atrophy.


A storefront clinic on the bowery.

A storefront clinic on the bowery. Analysis of the patient population of a small storefront clinic on the Bowery of New York City has revealed the emergence of a new category of Bowery residents consisting of young, generally White, schizophrenic men with little history of alcoholism.


Palliative push-through intubation for malignant obstruction of the gastroesophageal junction. Methods available for palliative intubation of the gastroesophageal junction for malignant obstruction are discussed. In a previous report from this unit, we noted that the push-through method with a Souttar tube is superior in many respect to the pull-through method with the Mousseau-Barbin tube in cases of esophageal carcinoma. However, a push-through method at the cardia, although highly desirable, had not yet been employed because of safety reasons. This paper describes a technique to overcome the dangers of push-through intubation at the gastroesophageal junction and reports its successful use in 16 patients.


Prevention and diagnosis of venous thrombosis in patients with hip fractures. A survey of current practice. 643 orthopaedic surgeons were sent a questionary asking how they attempted to prevent and diagnose deep venous thrombosis (D.V.T.) in patients with hip fractures. 411 (64%) replied. Of those who replied, 51% offered no prophylaxis, only 3% routinely used oral anticoagulation, and 85% relied on clinical signs in the diagnosis.


Warfarin sodium in prevention of deep venous thrombosis and pulmonary embolism in patients with fractured neck of femur. In a prospective controlled randomised trial, the prophylactic value of warfarin sodium (in doses aimed at maintaining a "Thrombotest" value of 10% and given from the day of admission until independent mobility had been achieved or for 3 mo, whichever was the sooner) was assessed in 160 elderly patients who had sustained a fracture of the femoral neck. Treatment significantly reduced the frequency of deep venous thrombosis (D.V.T.), whether indicated by the 125I-fibrinogen test during life or assessed by detailed post-mortem studies. Pulmonary embolism was eliminated in treated patients, but the difference in mortality between the treatment and control groups was not significant, indicating that causes of death other than pulmonary embolism are of major importance in these elderly patients. A case is made out for prophylactic anticoagulation on a selective basis.


80% of patients with intrinsic asthma are homozygous for HLA W6. Is intrinsic asthma a recessive disease? Of 26 patients with intrinsic asthma, 21 (81%) were homozygous for the histocompatibility antigen HLA-W6. Also, half the patients had complement defects, in particular low levels of C2. This is the first indication of a strong genetic component in intrinsic asthma, apart from that already known from family studies. These findings suggest that intrinsic asthma may be a recessive disease.


Separate autoantibodies to human pancreatic glucagon and somatostatin cells. Autoantibodies reacting with discrete populations of cells in normal human pancreatic islets were found by immunofluorescence in 17 out of 1279 sera. A double immunofluorescence technique, with antisera to pancreatic glucagon, insulin, somatostatin, and human pancreatic polypeptide was used to show that 13 of the sera contained anitbodies reacting specifically with glucagon cells, while the other 4 reacted with somatostatin cells. These antibodies were directed against intracellular components and not against the hormones themselves. Both types of antibody occurred independently of the islet-cell antibodies which have been described in diabetes mellitus. These findings suggest selective damage to individual cell types in the pancreatic islets and raise the possibility of corresponding hormone deficiency syndromes.


Active specific immunotherapy for ovarian cancer. Ten patients with advanced or recurrent ovarian cancer were treated with a combination of chemotherapy and active specific immunotherapy after tumour stasis had been induced. They were inoculated with irradiated allogeneic cryopreserved tumour cells and B.C.G. once monthly in addition to receiving conventional chemotherapy. The overall duration of "remission", median survival, and projected 24-month actuarial survival in the patients receiving immunotherapy were apparently better than in a retrospectively matched control group treated by chemotherapy alone.


Insulin, glucagon, aminoacid imbalance, and hepatic encephalopathy. Hepatic encephalopathy (H.E.) is associated with and perhaps caused by changes in plasma-aminoacid patterns--decreased branched-chain aminoacids (B.C.A.A.) and increased aromatic aminoacids (A.A.A.). The decreased B.C.A.A. may be in part secondary to hyperinsulinaemia, but the B.C.A.A. are catabolised by both fat and muscle. The increase in A.A.A. may reflect a "catabolic stimulus" reflected in hyperglucagonaemia, particularly in severe hepatic failure and H.E., and a decreased insulin/glucagon ratio. Endogenous protein, lean body-mass, or liver then releases large amounts of A.A. and the A.A.A. cannot be catabolised by the failing liver, and thus accumulate in the circulation. With decreased plasma-B.C.A.A., the molar ratio of B.C.A.A. and A.A.A. decreases allowing the toxic A.A.A. to penetrate the blood-brain barrier in increased amounts and encephalopathy develops. Appropriate therapy for H.E. must include reversal of the "catabolic state" by providing sufficient B.C.A.A. and calories to decrease the flux of A.A.A. from muscle and liver, and the restoration of the normal molar ratio of B.C.A.A. and A.A.A.


Pathogenesis and phenotypes of an X-linked recessive lymphoproliferative syndrome. A new X-linked recessive lymphoproliferative syndrome has variable phenotypes: fatal infectious mononucleosis (I.M.), agammaglobulinaemia after I.M., American Burkitt's lymphoma, histiocytic lymphoma, immunoblastic sarcoma of B cells, or plasmacytoma. An immunodeficiency to rubeola and the Epstein-Barr virus probably ensues from the mutant gene. The phenotypes (spectrum of B-cell disorders) have a common inheritance and the aetiology is similar.


Drug addiction in pregnancy.

Drug addiction in pregnancy. 32 pregnancies in 29 drug-addicted women were studied ouver eight years in one obstetric department working in close liaison with a drug dependency centre. Of the 24 pregnancies which came to term, only 10 were seen at the antenatal clinic before 22 weeks' gestation. 19 of the women were addicted to heroin or methadone or a mixture of both, 4 were taking soft drugs, and 1 was taking pethidine only. Labour commenced spontaneously in 17 pregnancies and was induced in 7. All labours lasted less than twenty hours. 23 infants survived. Those born to the mother taking pethidine and to 4 mothers who withdrew their drug of dependence four weeks before delivery showed no signs of narcotic withdrawal, but 13 out of 14 infants born to mothers taking heroin or methadone developed narcotic withdrawal syndrome. It is recommended that drug therapy during pregnancy in addicts should be supervised by a psychiatrist known to the patient and that oral methadone be substituted for heroin. Planned induction will ensure delivery in hospital, at the hospital which has supervised the pregnancy. Babies in danger of developing narcotic withdrawal syndrome should be observed in the special care baby unit for the first week of life.


Bone-marrow transplantation in severe aplastic anaemia. Twenty-one patients weth severe aplastic anaemia were evaluated at a single hospital between 1972 and 1975. Patients without histocompatible donors were treated conventionally with androgens, corticosteroids, and HLA-matched platelet and granulocyte transfusions. Bone-marrow transplantation was performed in patients with HLA-identical siblings. The two groups had comparable clinical and haematological prognostic indicators and received similar supportive therapy. All nine patients who were not transplanted died. Median survival in these patients was 82 days (range 21-545). Seven of the twelve (58%) transplant recipients were alive at 120 days--greater than 930 days (p less than 0.04). The one-year actuarial survival of the transplant group was 53%. This study shows that bone-marrow transplantation is a rational alternative to conventional therapy in selected patients with aplastic anaemia.


Cerebral ventricular size and cognitive impairment in chronic schizophrenia. By comparison with age-matched controls in employment, 17 institutionalised schizophrenic patients were shown by computerised axial tomography of the brain to have increased cerebral ventricular size. Within the group of schizophrenic patients increased ventricular size was highly significantly related to indices of cognitive impairment.


Double blind crossover trial of levamisole in recurrent aphthous ulceration. A double blind crossover trial of levamisole has been carried out in 47 patients with recurrent oral ulceration. Significant decreases in the number of ulcers and ulcer days were found after 2 months of intermittent administration of levamisole. About 64% of patients responded to the drug by a decrease in the number of ulcers of more than 50%, for two or more months. The remaining 36% of patients failed to respond to levamisole and 23% of these had an increased number of ulcers. The side-effects recorded in patients taking levamisole were comparable with those in patients on placebo, except for a flu-like syndrome in 1 patient and urticaria in another, necessitating withdrawal of the drug. The mechanism of action of levamisole in recurrent oral ulceration is not known, but it is suggested that levamisole may correct a deficiency of suppressor cells, or potentiate the cellular responses to crossreacting microbial agents.


Low renin hypertension. A distinct entity. In an attempt to resolve conflicting reports about the identity of a low-renin subgroup in essential hypertension, the distribution of plasma-renin activity (P.R.A.) has been examined in 82 hypertensive subjects before and after stimulation with bendrofluazide. The unstimulated basal P.R.A. showed no evidence of a separate subgroup of patients with low P.R.A. values although the distribution was slightly skewed with a tail to the right when compared with 83 normotensive subjects. In 38 of the patients post-stimulation P.R.A. observed in age and sex matched normotensive controls exposed to the same stimulus. However the percentage rise in P.R.A. in all 83 patients was less than half that of the controls. Thus the identification of a low-renin subgroup of hypertensive patients is critically determined by the standard of comparison employed: if the percentage rise is considered subnormal responsiveness is a feature of essential hypertension. If absolute post-stimulation values are used, there is a substantial group of patients with "low renin hypertension". The demarcation of such a group is, however, essentially arbitrary.


Cryoanalgesia. A new approach to pain relief. Cryotherapy has been clinically applied to relieve pain using a new cryosurgical probe to block peripheral nerve function to achieve analgesia. Sixty-four patients with intractable pain were treated with cryoanalgesia. Fifty-two obtained relief of pain for a median duration of 11 days and a range of up to 224 days.


Infant botulism. Identification of Clostridium botulinum and its toxins in faeces. Clostridium botulinum and its toxin were identified in the faeces of four infants, aged 6 to 13 weeks, who had symptoms consistent with botulism. Two cases had type-A toxin and two cases had type-B toxin present in their faeces. No toxin was detectable in sera C. botulinum and toxin could be recovered from faeces more than 8 weeks after admission to hospital. All four cases occurred within a 6-month period. The source of the toxin in these infants may have been in-vivo production from ingested organisms.


Prolactin response to electroconvulsive therapy. Prolactin response to electroconvulsive therapy (E.C.T.)was investigated in nine patients with endogenous depression. Four patients undergoing minor gynaecological surgery who had had the same type of intravenous anaesthesia as the E.C.T. group were studied as controls. 15 minutes after E.C.T. there was a 10 to 50 fold increase in serum-prolactin in eight of the patients. The effects of anaesthesia and surgery on serum-prolactin in the controls were negligible.


Pulsatile blood-flow in arterial grafts. The distensibility of arterial wall is an important factor in the haemodynamics of pulsatile blood-flow. Autogenous-vein grafts have a dynamic response to the arterial pressure pulse (compliance) which approaches that of normal arterial wall, whereas synthetic prostheses are generally incompliant, or become so shortly after implantation. Although synthetic grafts have little effect on steady-state flow, their lack of compliance greatly interferes with pulsatile flow and this may be an important factor in explaining their lack of success as replacements for medium and small sized arteries.


Diagnosis of Giardia lamblia infection as a cause of diarrhoea. Retrospective analysis of the records of 31 patients diagnosed as having Giardia lamblia infection in our hospital over a five-year period suggests that the condition is not considered often or early enough. Adult patients particularly "suffer" more, having to endure more investigations (mean of 16) than do symptomatic children (mean of 6) before a diagnosis is made. The length of time to reach the diagnosis from first referral further supports this view, being almost seven weeks in adults and three weeks in children--both groups having had symptoms for an average of seven months before referral.


Reactions to iophendylate in relation to multiple sclerosis. A retrospective survey was made of 57 consecutive patients referred for myelography by one neurological team. Reactions occurred in patients with multiple sclerosis significantly more often than in all other patients (P=0.01). This finding appears to support the belief that demyelination may be associated with more severe reactions to iophendylate myelography.


Activation of complement by the alternative pathway as a factor in the pathogenesis of periodontal disease. Dental plaque and a bacterium, Actinomyces viscosus, isolated from plaque that can reproduce periodontal disease in germ-free rats, are activators of complement by the alternative pathway. It is suggested that this process is involved in the pathogenesis of chronic inflammatory periodontal disease.


Hyperglycaemia and diabetes mellitus.

Hyperglycaemia and diabetes mellitus. Recommended criteria for the diagnosis of maturity-onset diabetes mellitus based on glucose tolerance tests vary considerably; none are derived from long-term observations of the further development of different degrees of glucose intolerance. Evidence from several epidemiological investigations suggests that the risk of specific diabetic complications becomes important only in people with capillary whole-blood sugar concentrations exceeding 200 mg/dl 2 hours after a 50 g oral glucose load, who have overnight fasting blood-sugar concentrations usually exceeding 110 mg/dl. Lesser degrees of glucose intolerance may, nevertheless, indicate an additional risk of atherosclerotic arterial disease.  Assessment of "borderline diabetics" should, therefore, include and evaluation of other known risk factors for arterial disease and any treatment programme should be determined in the light of these as well as by the degree of glycaemia.


Smoking and other risk factors for coronary heart-disease in British civil servants. A five-year follow-up of 18 403 male British civil servants between the age of 40 and 64, who had been the subject of an earlier clinical survey found 277 deaths from coronary heart-disease (C.H.D.). After adjusting for age, current cigarette smoking, systolic and diastolic blood-pressure, and blood-cholesterol were shown to be related to both the prevalence of one or more indices of cardiac ischaemia and to the risk of cardiac death. Neither blood-glucose two hours after a 50 g load nor weight/height showed any such simple linear association with mortality. Multivariate analysis confirmed that the main risk factors were independently related to cardiac morbidity and mortality. Irrespective of blood-pressure or plasma-cholesterol, current cigarette smokers thus had a higher risk of C.H.D. death than those not smoking cigarettes.


Immunological abnormalities in patients who had the oculomucocutaneous syndrome associated with practolol therapy. Patients with and without adverse reactions on practolol therapy showed altered immune responses. There was cutaneous anergy to Candida albicans and streptokinase/streptodornase antigens and depression of lymphocyte function in vitro. Anticomplementary activity and a wide range of autoantibodies were found in patients who had received practolol.


Adenovirus type 7; 1971-74.

Adenovirus type 7; 1971-74. The spread of adenovirus type 7 in England and Wales between 1971 and 1974 and the clinical features of infections with this virus were investigated in a retrospective study of virological reports and patients' clinical records. An epidemic in 1972-74 apparently stared in the North-East and spread to the South-West. Between March 1973 and the end of October 1974 the virus was recovered in 59 of 74 specimens from 42 patients. The mean age of the patients was 9 years, which suggests that a large pool of young susceptibles was important in the dissemination of the epidemic. Sore throats, cervical lymphadenopathy, conjunctivitis, and abdominal pain were common symptoms. Meningism was present in 12 patients; 2 cases had apparent neuropsychiatric sequelae.


Initial treatment of stage IIIA Hodgkin's disease. Comparison of radiotherapy with combined chemotherapy. British National Lymphoma Investigation. 117 patients with stage IIIA Hodgkin's disease were randomly allocated for treatment in a multicentre trial comparing the results of total nodal irradiation (T.N.I.) with those of combination chemotherapy. Staging procedures for most patients included laparotomy; a few patients whose staging did not include laparotomy were studied separately. Of the 81 patients staged by laparotomy, 40 out of 42 (95%) achieved complete remission (C.R.) after treatment by T.N.I. and 29 out of 39 (74%) achieved C.R. during treatment with mustine hydrochloride, vincristine ("Oncovin"), procarbazine, and prednisone (MOPP) (P=0.018). An analysis of the disease-free survival up to four years favoured the group of patients treated by T.N.I. (P less than 0.01) but differences in overall survival were not statistically significant. In the 36 patients with presumed IIIA disease whose staging did not include laparotomy no significant differences in the incidence of C.R. or rates of disease-free or overall survival were observed. It is concluded that T.N.I. is the optimum initial treatment for patients with IIIA disease whose staging includes laparotomy.


Effect of a diet of polyunsaturated fats on some platelet-function tests. The fat in the normal diet of 19 apparently well men was partly replaced by linoleic acid. This produced striking changes in many platelet-function tests, suggesting decreased platelet activation. Twenty controls maintaining their normal diet showed no change. It is concluded that normal people have a degree of platelet activation which can be decreased. This may be relevant to the benefits attributed to a diet containing polyunsaturated fats.


Circulating immune complexes in multiple sclerosis and other neurological diseases. Circulating immune complexes were detected in 49% of sera from patients with multiple sclerosis, 45% of monosymptomatic optic neuritis, 45% of Guillain-Barré syndrome, and 15% of normal sera studied. The frequency of immune complexes in multiple-sclerosis sera was not correlated with the clinical status of the patients. Results with serial blood-samples were variable.


[The antigenic relationship between Syringospora clausseni and the Salmonella C(1) group O antigen]. The antiserum against Salmonella (0 6, 7) antigen aggultinated Syringospora clausseni, and the serum against this fungus cross-agglutinated Salmonella (0 6, 7) antigen. Cross aglutination and absorption experiments showed that there was a common antigenic determinant between Syringospora clausseni and S. cholerae suis (6,7). This antigenic determinant may resemble the Minor antigen which is not used in usual sero-typing of Salmonella.


Antenatal diagnosis of neural tube defects. One hundred women with pregnancies at risk for the recurrence of neural tube defects have entered our monitoring programme of echography and alphafetoprotein estimation (AFP) on amniotic fluid and maternal serum during the second trimester. The results of these pregnancies, the application of the programme, sources of error, and the reliability of alphafetoprotein levels are discussed. Conclusions regarding the value of the tests and routine antenatal screening are made.


"Crab" care and cancer chemotherapy.

"Crab" care and cancer chemotherapy. The letters CRAB indicate that there are four broad uses of chemotherapy in treating solid tumours: (i) curative, which is always the aim but as yet can rarely be reliably achieved with chemotherapy alone; (ii) relieving chemotherapy for widespread or incurable disease; (iii) adjuvant care to prevent peripheral occult disease developing after standard surgery or radiotherapy; and (iv) basal chemotherapy, to reduce the size, viability and especially the peripheral extent of large, localized tumour masses in preparation for definitive treatment usually by radiotherapy and/or extirpative surgery.


Drugs in pregnancy and lactation.

Drugs in pregnancy and lactation. The hazards of exposing the human fetus to drugs have become increasingly apparent in the last 15 years, during which time drug usage has steadily increased. Even though a direct cause-and-effect relationship between certain commonly used drugs and fetal disorders or malformations has been difficult to establish, the principle of avoidance of all but essential medications in pregnancy and in the potentially pregnant has become increasingly important. This paper summarizes the factors determining fetal damage and lists the problems associated with some drugs frequently encountered in practice.


Inhibition of uridine-cytidine kinase by 5-azacytidine 5'-triphosphate. 5-Azacytidine 5'-triphosphate (5-aza-CTP) inhibited the phosphorylation of uridine, cytidine, and 5-azacytidine (5-aza-C) in a reaction catalyzed by uridine-cytidine kinase. The inhibition appeared to be competitive with respect to the adenosine 5'-triphosphate and noncompetitive with respect to nucleoside substrates. 5-aza-CTP was a potent inhibitor of 5-aza-C phosphorylation but a weak inhibitor of uridine and cytidine phosphorylation. These results suggest that the feedback inhibition of uridine-cytidine kinase by 5-aza-CTP may limit the amount of intracellular nucleotide analog formed in drug-treated cells.


A new hamster fibrosarcoma model for in vitro/in vivo evaluation of cancer chemotherapeutic agents. A hamster fetal cell clone has been developed for in vitro chemotherapeutic studies as well as in an in vivo fibrosarcoma model system. Highly reproducible quantitative in vitro chemotherapeutic data can be obtained with this cell line within 5 days, and as few as 10(2) cells produce rapidly growing fibrosarcomas when injected subcutaneously into adult hamsters. We found using these cells in vitro that 1-beta-D-arabinofuranosylcytosine (ara-C) can antagonize the effect of 5-azacytidine (aza-C) if given simultaneously or if aza-C treatment is preceded by a 2-hr exposure to ara-c. Using the same cell line as in vivo model for chemotherapy it was also shown that ara-C and cyclocytidine significantly inhibited tumor growth. This hamster cell line may be quite useful as an in vitro/in vivo model system for the study of cancer chemotherapeutic agents.


Combination chemotherapy in murine neuroblastoma. The C1300 murine neuroblastoma system has been studied to determine its relevance as a chemotherapy model to the human disease. Studies using combination therapy revealed that BCNU/cyclophosphamide combination therapy increased the median lifespan 300% in A/J mice bearing the C1300 tumor. Cyclophosphamide/imidazole carboxamide and adriamycin/imidazole carboxamide combinations were less active, increasing median lifespans 189% and 144%, respectively. Vincristine/bleomycin were inactive even when the schedule was adjusted to coincide with the time of maximum mitoses following vincristine injections. These results suggest the BCNU/cyclophosphamide combination chemotherapy may be effective in human disease.


Increased circulating levels of transcobalamin ii in gaucher's disease. The presence of several serum protein abnormalities in Gaucher's disease prompted a study of vitamin B12 binding proteins, in which 14 of 15 consecutive patients displayed increased circulating transcobalamin II unassociated with elevations of serum vitamin B12 or other vitamin B12 binders. Transcobalamin II levels were most significantly increased in nine patients with disease severe enough to require splenectomy (P less than 0.01), but were not correlated with liver size or levels of any other laboratory feature of Gaucher's disease studied. Splenectomy, per se, did not alter circulating transcobalamin II. Chracterization of the binder in Gaucher's disease revealed identity with normal serum transcobalamin II in acid inhibition of vitamin B12 binding, chromatographic behavior, immunologic specificity and functional integrity in vitamin B12 delivery. This observation suggests a relation between reticuloendothelial-cell activity and transcobalamin II metabolism. Elevated transcobalamin II levels may provide an additional means for diagnosis and assessment of Gaucher's disease.


Chemical characterisation of the Thy-1 glycoproteins from the membranes of rat thymocytes and brain. The Thy-1 antigens from both thymocytes and brain of rats are major membrane glycoproteins of about 25,000 molecular weight of which 30% is carbohydrate. The brain and thymus glycoproteins contain very similar amounts of each amino acid, but have strikingly different carbohydrate compositions. The antigenic determinants are likely to be in the protein part of the molecule.


Effects of coupled tumor specific antigens (CTSA) on the growth of transplanted tumors in C3 H/HEJ mice. The effects of coupled tumor specific antigens (CTSA) on the suppression of tumor growth in inbred mice were investigated. Seventy six week old C3H/HEJ female mice were used in the experiment. They were divided into seven groups; each group consisted of ten mice, and each group received a different treatment. The treatments for the different groups were: Human gamma globulin coupled with tumor specific antigens and emulsified in Freund's complete adjuvant (group I); Tumor specific antigens emulsified in Freund's complete adjuvant (group II); Freund's complete adjuvant (group III); Tumor specific antigens (group IV); Human gamma globulin (group V); Groups VI and VII were untreated. Animals in groups (I to V) were given two injections per week for two weeks prior to the transplantation of tumor tissue. They were subsequently given sixteen more injections during an eight week period. The sixth group was transplanted with tumor tissue and the seventh group was neither treated nor transplanted with tumor. The proliferation of the tumor tissue in the different animals was monitored by computing tumor volume at weekly intervals. The results showed that animals in group I developed a state of immune resistance against the transplanted tumor. At the conclusion of the experiment, the average tumor volume in this group was six times smaller than the average volume in the untreated group and twelve times smaller than the average volume in the group treated with Freund's complete adjuvant. Varying degrees of suppression were also noted in the other treated groups.


Adenoid cystic carcinoma of minor salivary gland. Histochemical and electron microscopic studies of cystlike space. Five cases of adenoid cystic carcinoma of minor salivary glands were studied. The mucoid material in the characteristic cystlike space of this neoplasm was distaseresistant periodic acid-Schiff (PAS)--positive, alcain blue-positive, toluidine blue-positive, and mucicarmine-positive. Verhoeff-Van Gieson's method and Weighert's method did not reveal elastic tissue in the cystlike spaces. Mallory's method revealed that a central core in cystlike spaces was similar in stainability to collagen. Wilder's method did not reveal reticular fibers in these spaces. Electron microscopy revealed three readily recognizable zones: a juxtacellular zone of a network of replicated basal lamina, and intermediate zone of stellate granules of mucoid material, and a central core of densely packed aperiodic filaments or collagen fibrils. The histogenesis of cystlike spaces and their realtionship with biologic behaviors of the neoplasm were discussed.


Hyaline bodies: some observations on their ultrastructure. The ultrastruct of hyaline bodies was examined. Their constant association with elements of squamous epithelium pointed to an epithelial component in their structure. Elements of red blood cells, blood vessels, and endothelium were not evi-ent in these hyaline bodies, thereby negating avascular origin. Due to ultrastrucural limitations, the exact composition of the structures could not be determined.


[Distribution study using 57Co-, 51Cr-, 111In- and 99mTc-bleomycin in mice with a solid Ehrlich carcinoma]. From the comparative studies of 57Co-, 51Cr-, 111In- and 99mTc-Bleomycin using 282 solid Ehrlich-carcinoma-bearing mice, 57Co was found to be the most suitable bleomycin preparation for tumorscintigraphy. The results obtained by 111In-Bleomycin of linear tumor cell absorption indicates a possible use of 111In-Bleomycin as an agent for objective histological differentiation also in cells previously treated with therapeutic agents.


[Frequency distribution of an index for free thyroxin in relation to age and thyroid status]. We compared an index for free thyroxine (FT4I) between groups of patients which were formed according to the results of radioiodine testing. An elevation of free thyroxine (as measured by the FT4I) which has been reported in elderly women by other authors could not be confirmed. Overlapping between euthyroidism and hyperthyroidism was not found as disturbing as reported elsewhere, a finding which can probably be explained by the different criteria for the categories "euthyroidism" and "hyperthyroidism". A group with depressed radioiodine uptake had an unexpected high percentage of elevated FT4I. These cases may be explained as toxic goitres. The incidence of hypothyroidism (as judged by FT4I) in this group is low compared with the incidence of obvious exogenous exposure to excessive iodide. Cases presenting with a normal radioiodide uptake together with absent suppression by thyroxine administration are more often connected with a normal FT4I and are therefore believed to be euthyroid; less frequently they are truly hyperthyroid (FT4I). In patients previously treated with radioiodine an elevated FT4I is found suprisingly often. A reevaluation of the radioiodine dosage and the course of the disease in these numerous patients seems to be indicated.


Deficiency in plasma protein synthesis caused by x-ray-incuded lethal albino alleles in mouse. Plasma protein synthesis was studied in mice bearing x-ray induced lethal mutations at the albino locus. Newborn albino mutants showed a decrease in each of the three principal plasma proteins, albumin, alpha-fetoprotein, and transferrin, when compared with colored littermate controls. Incorporation of [14C]leucine into plasma proteins of the newborn albinos 30 min after injection was only 1/5 that of the controls, but incorporation into total liver protein was only slightly diminished. Incorporation of [14C]leucine into an albumin fraction  obtained by immunoprecipitation from livers incubated in vitro in an amino acid mixture was also strongly diminished. Thus, the liver of 18-day-old albino fetuses incorporated into this fraction 1/3 and that of newborn albinos 1/8 as much as the controls, but in both cases the incorporation into total liver protein was only 25% less than in the respective controls. These results indicate that the rather severe structural abnormalities observed in the mutants in the endoplasmic reticulum and the Golgi apparatus are not associated with a general deficiency of hepatic protein synthesis. Instead the data from this and previous work show that the progressive deficiency from fetal life to birth involves certain specific proteins represented by several perinatally developing enzymes and by plasma proteins. It is suggested that the mutational effects observed in these mice are due to deletions involving regulatory rather than structural genes at or near the albino locus.


Anticomplementary nature of smaller DNA produced during synthesis of extensive DNA copies of poliovirus RNA. The reverse transcriptase (RNA-directed DNA nucleotidyltransferase) from avian myeloblastosis virus is able to make an extensive, possibly complete, complementary DNA copy of intact poliovirus RNA. In the presence of high concentrations of deoxyribonucleoside triphosphates, ribonucleoside triphosphates, or sodium pyrophosphate, this DNA is the only species produced. Without these additives, however, a second size class of DNA is also synthesized. This material has a sedimentation coefficient between roughly 4 and 10 S and is produced later in the reaction, largely after synthesis of the larger complementary DNA has ceased. The smaller DNA consists primarily of material anticomplementary to the RNA template and contains a faithful and uniform representation of the viral sequences. It most likely arises by transcription of the larger DNA species.


Stepwise biosynthesis in vitro of globin genes from globin mRNA by DNA polymerase of avian myeloblastosis virus. Two approaches have been explored for the synthesis of double-stranded DNA from single-stranded DNA template complementary to rabbit 9S globin mRNA (cDNA). (i) cDNA was elongated with dCMP or dTMP homopolymeric tracts using terminal deoxynucleotidyltransferase (EC 2.7.7.31; nucleosidetriphosphate:DNA deoxynucleotidylexotransferase). cDNA-dC, in the presence of an oligo(dG)10 primer, was an efficient template with either DNA polymerase of Escherichia coli (EC 2.7.7.7; deoxynucleosidetriphosphate:DNA deoxynucleotidyltransferase) or RNA-directed DNA polymerase of avian myeloblastosis virus. cDNA-dT [ with an oligo(dA)10 primer] functioned as template only with E. coli polymerase. (ii) cDNA, without homopolymeric tails, was also efficiently copied in the absence of oligonucleotide primer, by DNA polymerase of avian myeloblastosis virus or of E. coli. The product of the reaction consisted of long hairpin molecules which could be converted into DNA duplex (melting temperature, 93 degrees) by digestion with single-strand nuclease S1. The data indicate that a loop structure on the 3' end of cDNA allowed DNA synthesis to take place by a "self-priming" mechanism. Some of the double-stranded DNA synthesized corresponded to the entire sequence of the 9S mRNA template. The synthesis of full-length double-stranded DNA from mouse globin mRNA and immunoglobulin light chain mRNA is also discussed.


Human somatotropin: biological characterization of the recombinant molecule. The recombinant hormone obtained by non-covalent interaction of the NH2-terminal 134 amino acid fragment with the COOH-terminal 51 amino acid fragment of the reduced-carbamidomethylated human somatotropin molecule is found to exhibit nearly full biological activity of the native hormone, as evidenced by the stimulation of hepatic ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) in vivo and protein synthesis in mouse mammary gland in vitro. Radioimmunoassay data indicate that the recombinant behaves immunochemically in a manner almost identical to that of the native hormone.


A new class of genetically transmitted retravirus isolated from Mus cervicolor. The cocultivation of spleen cells from the Southeast Asian mouse, Mus cervicolor, with heterologous cell lines has permitted the isolation of a new retravirus (designated M432) that can be transmitted to tissue culture cells of the laboratory mouse, M. musculus. Cells infected with M432 contain cytoplasmic type A particles and budding forms with compact,spherical nucleoids; extracellular virions lack surface spikes and have a condensed, central core surrounded by an intermediate line. Like other retraviruses, M432 bands isopycnically in sucrose at 1.16-1.17 g/cm3 and contains a 70S RNA genome composed of 35S subunits and an RNA-dependent DNA polymerase (RNA-dependent DNA nucleotidyltransferase). The viral reverse transcriptase requires magnesium as a cofactor and transcribes the synthetic template:primer poly(rC)-oligo(dG) more efficiently than poly(rA)-oligo(dT). [3H]DNA transcripts of the viral RNA genome detect multiple copies of endogenous virogene sequences in the cellular DNA of normal M. cervicolor, and fewer copies in heterologous cells infected with M432. Partially related nucleic acid sequences are also detected in the DNA of M. caroli and M. musculus as well as in more distantly related species (rat and hamster), reflecting the evolutionary conservation of these gene sequences in rodents. Although the virus from M. cervicolor shares certain morphologic and biochemical properties with murine type B viruses, the new isolate is unrelated by nucleic acid hybridization criteria to the mouse mammary tumor virus, the bovine leukemia virus, the Mason-Pfizer monkey virus, or known murine type C viruses, including endogenous type C viruses isolated from M. cervicolor.


Characterization of heteropolymeric hexosaminidase A in human X mouse hybrid cells. Expression of heteropolymeric hexosaminidase A activity is reported in a human X mouse hybrid cell line that contains an X/15 translocation chromosome but lacks human chromosome 5 and has no detectable human hexosaminidase B activity. (Hexosaminidase is beta-N-acetylglucosaminidase; EC 3.2.1.30; 2-acetamido-2-deoxy-beta-D-glucoside acetamidodeoxyglucohydrolase.) That the "hexosaminidase A" enzyme of these cells contains the human hexosaminidase-alpha subunit and not the human hexosaminidase-beta subunit is indicated by the cells' reactions to specific antisera prepared against the alpha subunit and against the beta subunit. Our results indicate that the "hexosaminidase A" activity in this hybrid cell line is the expression of a hybrid molecule composed of human hexosaminidase-alpha subunit and a mouse hexosaminidase subunit. These results are consistent with the hypothesis that the human hexosaminidase A enzyme is formed from alpha and beta subunits coded for by genes on chromosomes 15 and 5, respectively.


Molecular determinants of immunogenicity: the immunon model of immune response. The immunological response in vivo to a series of size-fractionated linear polymers of acrylamide substituted with hapten has been measured in mice. A sharp threshold was observed in immunogenic response elicited by various polymer preparations. All polymers with less than 12 to 16 appropriately spaced hapten groups per molecule were nonimmunogenic, while those polymers with greater than this number were fully immunogenic. The results lead to the conclusion that the immunological response at its most elementary level is quantized, i.e., a minimum specific number of antigen receptors (approximately 12 to 16) must be connected together as a spatially continuous cluster, an immunon, before an immunogenic signal is delivered to the responding cell.


Palliation for carcinoma of the esophagus. From 1950 to 1973, 169 patients received irradiation for esophageal squamous cell carcinoma. The average survival time was 10 months, with 7% of the patients living 2 years or more. The median survival time was 7 months; palliation averaged 6 months. Most completing therapy (89%) achieved some palliation: 66% had significant relief of dysphagia for 2 months or longer. The anatomical location of the malignant obstruction did not influence therapeutic response; there was similar  response in cases of upper, middle, and lower esophageal lesions. Thirty patients with progressive obstruction underwent endoesophageal intubation with Celestin tube placement; this procedure provided symptomatic relief with minimal morbidity.


[Metachromasia, double refraction and dichroism caused by Toluidine Blue reaction (author's transl)]. The present paper is concerned with those optical phenomena which may be caused in histological structures by the toluidine blue reaction. They relate to absorption as well as refraction properties. The paper gives a detailed description of how the toluidine blue reaction is carried out on histological preparations. The analysis of absorption results leads, in connection with physicochemical considerations, to a new explanation of the cause of toluidine blue metachromasia. In this, the assumption is made that the conditions of attachment of protons to the hydrogen-bearing nitrogen of dye molecules are largely responsible for the occurrence of metachromasia, the way in which the attachment of the proton to this quaternary nitrogen is influenced being of no consequence in this particular connection. It may result from both a combination of homogeneous toluidine blue molecules into associates and a shift to the alkaline region of the pH value of the dye solution. However, the term metachromasia is used to describe only that shift of the absorption spectrum which is produced by associates. The thus produced metachromasia ("concentration metachromasia") involves the development of a so-call "gamma-band" (with an absorption peak of gamma = 546 nm), there being a causal rather than a fundamental difference between the latter band and the normal metachromatic mu-band (with an absorption peak of gamma = 540 nm). Whereas in the case of concentration metachromasia and for an aqueous solution there may be observed an association of dye molecules having a maximum intermolecular distances of less than 5 angström units, which is due to the large number of toluidine blue molecules per unit volume, mu-metachromasia is usually observed in connection with chromotropic structures. This association results in the lone-pair electrons of the hydrogen-bearing nitrogen atom being included in the intermolecular resonance system, which in turn results in the attachment of a proton to this nitrogen being weakened, which leads to the assumption of a red color. The difference to gamma-metachromasia lies in the fact that even by treatment with dilute solutions, in which the dye is present in a monomeric form, such a metachromasia may be produced on account of the sufficiently dense charge pattern of the chromotropic structure. This particular pattern tends to induce an association of dye molecules which in turn are associated, through hydrogen bridges, with the anionic groups. The orthochromatic toluidine blue reaction was found to be a possible method of detecting bridge-bond-active hydrogen in histological structures. The cause of the assumption of a blue color, which is observed in this connection, is a monomeric attachment of the dye. Additional factors leading to ortho-chromatism are also discussed...


Cumulation and elimination of horse-anti-dog lymphocyte and normal horse gammaglobulin in dogs. Two groups of dogs received daily intravenous doses of 20 mg/kg 131-I-labelled horse-anti-dog lymphocyte globulin or normal horse gammaglobulin respectively over a period of 11 days. Horse-anti-dog lymphocyte globulin showed a significantly higher eleimination rate than normal horse gammaglobulin. In contrary to the continuous increase in serum radioactivity during normal horse gammaglobulin treatment, there was a plateau after the 5th day in the horse-anti-dog lymphocyte globulin group. The xenogeneic protein concentration, measured with the single radial immunodiffusion technique, at the end of treatment was 165 +/- 8 mg/1 in the horse-anti-dog lymphocyte globulin, compared to 498 +/- 15 mg/1 in the normal horse gammaglobulin group. After treatment horse-anti-dog-lymphocyte globulin treated animals showed a significantly higher increase in active hemagglutination titer against horse erythrocytes with an average of 2(-8).


[Operative therapy for primary malignant bone tumors (author's transl)]. During the last 20 years, particularly in Europe, high dosage radiation therapy was primarily advocated and secondarily surgical amputation. Today, the earliest possible surgical elimination is considered to be the most sensible. This need not necessarily take the form of a mutilating procedure since, on the basis of American statistics, the results of resection procedures can be considered to be equally good. In each case, the diagnosis must be histologically clarified by biopsy before drastic surgery. In the context of a plan of therapy which is individually discussed among surgeons, radiation therapists and internists, additional tasks such as metastasectomy and stabilizing procedures in tumor-induced fractures fall to the surgeon. While it is still too early for a survey, we nevertheless hope that the positive aspects of combined therapy in our individual cases will increasingly benefit the total number of patients with malignant bone tumors - even if only in the form of a prolongation of life with less symptoms.


[Arthritis related to intestinal anastomoses]. Jejuno-colic and jejuno-ileal anastomoses may provoke arthritis. The recently recognized physiopathology is that of arthritis due to immune complexes related to pullulation of Escherichia coli and of Bacilus fragilis. These cases of arthritis, usually sensitive to therapy, have, in some stutborn cases, required the re-establishment of intestinal continuity, which in each case has made the joint phenomena disappear.


[Joint manifestations of Whipple's disease]. Of all the signs of Whipple's disease, the joint manifestations are among the most constant and the earliest to indicate the enteropathy, appearing long before the digestive and general signs. Essentially they consist of painful, peripheral joint manifestations: either simple arthralgia, or true arthritis differing in the degree of pain, the degree of the clinical signs accompanying the pain, the mode of evolution, and the number and the grouping of the joints affected, thus occurring in numerous clinical forms of which the two principal ones are subacute oligoarthritis with a tendency to migrate and chronic polyarthritis that gives rise to few definitive deformations. The radiographic appearance is usually normal. There is nothing specific about the laboratory aspects of the inflammatory syndrome. Synovial histology may in some cases clarify the diagnosis by demonstration of histiocytes with positive PAS granulations. The axial joint manifestations, which are always associated with the preceding ones, are infrequent and practically limited to unilateral or bilateral sacro-iliac lesions, with little or no clinical expression, that are discovered by standard radiology. Jejunal biopsy can be the key to early diagnosis. The pathogenesis remains obscure. The treatment is the same as for Whipple's disease, long-term antibiotic therapy.


Orcein positive hepatocellular material in long-standing biliary diseases. I. Histochemical characteristics. Orcein positive material, which accumulates in liver cells in long-standing biliary diseases, was studied histochemically in 5 patients with primary biliary cirrhosis. The material was highly basophilic after previous oxidation of tissue sections and could be demonstrated by orcein at pH 2, alcian blue at pH 0.2, and toluidine blue at pH 2.5. The comparative experiments suggested that sulphonic acid residues in orcein positive material after the oxidation were responsible for the staining reactions. In addition, the staining characteristics indicated the protein nature of the material. The staining reactions suggested that orcein positive material is associated with copper in liver cells and indicated the presence of a copper-protein complex. In contrast to orcein and alcian blue reactions, the oxidation of tissue sections abolished the positive histochemical reaction for copper. This was considered to indicate a dissociation of the copper-protein complex and an oxidation of the liberated sulphydryl groups to sulphonic acid residues, which are probably responsible for the basophilic staining reactions.


Orcein positive hepatocellular material in long-standing biliary diseases. II. Ultrastructural studies. An ultrastructural study of liver cells was performed on 4 patients with primary biliary cirrhosis (PBC) and on 3 patients with chronic active hepatitis (CAH). In liver cells of PBC patients large (ad 2-3 mu in diameter) particles were seen, which morphologically resembed autophagic vacuoles or large secondary lysosymes. The morphology, size, location, and quantity of these particles corresponded to the orcein positive material seen in light microscopy of adjacent sections in specimens from PBC patients. These large particles were not seen in liver  cells of CAH patients, which also lacked the orcein positive material in light microscopy. The author suggests that the observed particles indicate the activation of lysosomal compartment in liver cells in PBC, and that the orcein positive material (copper-protein complex accumulating in liver cells in chronic cholestasis) is taken into the phagolysosomal metabolism and processing in liver cells, and possibly resembles in this respect the intracellular metabolism of iron-compounds.


Restriction of human immune antibodies to heavy-chain variable subgroups. Human immune antibodies such as anti-Rh and anti-Kell antibodies were tested in hemagglutination and hemagglutination inhibition experiments for VH subgroup composition. A striking VH subgroup restriction was found in several of these groups of antibodies. In the majority of cases there was a restriction to one particular VH subgroup for a single antibody specificity in a given individual. In some cases there was also an overall restriction to one particular subgroup for antibodies with the same antibody specificity. This was particularly pronounced for anti-D antibodies, which was primarily restricted to VHII, and for the anti-Kell, which was particularly related to VHIII. Subgroup-specific antigens for all the main VH subgroups were blocked on combination of the antibody molecule with antigen. No relation was found between VH restriction and restriction to IgG subclass, or genetic markers or chi and lambda light-chain type.


Bence Jones proteins and light chains of immunoglobulins. XIV. Conformational dependency and molecular localization of the kappa (kappa) and lambda (lambda) antigenic determinants. The region on the light chain molecule responsible for expression of the kappa and lambda antigenic determinants was determined by comparative immunochemical analyses of intact Bence Jones proteins and naturally occurring or enzymatically derived fragments of Bence Jones proteins that lacked extensive portions of the V region or part of the C region. The reactivity of these fragments with numerous antisera having specificity for light-chain antigenic determinants indicated the essentiality of the intact light polypeptide chain for expression of the kappa and lambda antigenic determinants. The conformational dependency of the kappa and lambda antigenic determinants was also evidenced by denaturation-renaturation studies on kappa and lambda chains. The V domain, C domain, and interdomain 'switch' region contribute to the expression of kappa and lambda antigenicity and to certain isotypic and allotypic specificities.


Nephritic factor: its structure and function and its relationship to initiating factor of the alternative pathway. Nephritic factor (NF) has a molecular weight of 170,000 and is composed of two disulfide-linked 85,000-dalton chains. NF assembles the fluid phase C3 convertase from Factors B and D, C3, and magnesium by physically incorporating itself into the enzyme complex. NF exerts its stabilizing effect on the cell-bound C3/C5 convertase, EC3b,B, by physically associating itself with this complex. On decay of the cell-bound enzyme NF is released into the fluid phase and retains its binding and stabilizing potential. Its activity is resistant to diisopropylfluorophosphate treatment. Because NF causes agglutination of EC3b,B, it must be endowed with more than one binding site.


IgG on infants' B lymphocytes: enhanced binding of IgG by Ig M-bearing lymphoid cells in early childhood. IgM/IgD-bearing lymphocytes (B cells) from children in the first few weeks of life were found to also have surface IgG, unlike most normal adult B cells. The IgG was loosely bound to the lymphocyte surface and was partially or completely removed by incubation at 37 degrees C or by trypsinization. When F(ab')2 antisera were employed, very few infant B cells had surface IgG, although the IgM staining was similar to that obtained with the native antisera. IgM/IgD-positive cells bound IgG anti-Rh-coated (Ripley) erythrocytes, unlike most adult B lymphocytes. Capping experiments suggested that an Fc receptor on the cells could be redistributed by the anti-IgM-surface IgM complex. These data indicate that, during infancy, B-lymphocyte receptors for IgG are of altered affinity, frequency, or availability compared with adult B-lymphocyte Fc receptors and resemble the Fc receptors found on "third population" (Fc + Ig-) mononuclear cells and monocytes.


Studies of Ia antigens on murine peritoneal macrophages. Murine peritoneal cells, both induced and noninduced, were examined for Ia antigens by a variety of techniques. Complement-mediated cytotoxicity and indirect immunofluorescence, analyzed by both visual microscopy and the fluorescence-activated cell sorter, detected Ia antigens on the surface of an average of 8% to 15% of cells with the morphologic and functional characteristics of macrophages. Internal radioisotope labeling studies showed that these antigens were actually synthesized by the macrophages. The antigens were borne on molecules which consisted of two coponents with apparent molecular weights of roughly 33,000 and 25,000 daltons. At least some of these molecules existed as a two-chain structure of 58,000 daltons linked by disulfide bonds. Although macrophage Ia antigens appeared to be structurally similar to the Ia antigens found on spleen cells, the radioisotope labeling studies indicated that the quantity of labeled Ia-bearing molecules isolated from peritoneal macrophages was at most 1/15 that found for B lymphocytes. In addition, anti-Ia antisera failed to inhibit the binding of heat-aggregated immunoglobulin to the Fc receptor of macrophage populations, similar to the low levels of Ia antigens found in T-lymphocyte populations. These studies suggest that Ia antigens exist only a subpopulation of peritoneal macrophages. Alternatively, all cells in the population might bear small amounts of Ia antigens with only a fraction having sufficient numbers of molecules to be detected by the assay systems used.


Studies with B-cell allo- and hetero-antisera: parallel reactivity and special properties. The expression of B-cell antigens on various cell populations was studied through the use of human alloantisera and with heteroantisera raised to preparations of the alloantigen bearing molecules isolated from B-cell lines. The allo-and hetero-antisera competed with each other in blocking experiments and gave closely parallel results, reacting with normal and leukemic B lymphocytes, monocytes, E-rosette-negative acute lymphatic leukemias, all acute and certain chronic myelogenous leukemias, and a minor population of cells in fetal spleen and liver. These highly immunogenic surface components appeared to comprise the dominant B- cell specific plasma membrane determinants. Neither type of antiserum reacted with any but a minor population of normal or pokeweed-mitogen-transformed T cells, fetal thymic lymphocytes, E-rosette-positive acute lymphatic leukemias, or Sezary-cell leukemia. Through the use of these antisera evidence was obtained that Fc-receptor-bearing Ig-negative lymphocytes were divisible into two groups according to the presence or absence of the B-cell antigens. Both hetero- and allo-antisera blocked binding of immune complexes or antibody-coated ox erythrocytes to Fc receptors on B cells. F(ab')2 fragments of the heteroantibodies strongly inhibited antibody-dependent cell-mediated killing.


Subpopulations of human lymphoblastoid cell lines. Correlation with the expression of surface receptors and content of Epstein-Barr virus genome. Forty lymphoblast cell lines derived from normal subjects, patients with infectious mononucleosis, leukemia, and Burkitt's lymphoma have been studied for surface receptors including surface Ig, complement receptors by the EAC rosette and fluorescent (Raji cell) techniques, and Fc (aggregate) receptor by direct and indirect immunofluorescence. Because of the B-cell tropism of the Epstein-Barr virus (EBV), an effort was made to correlate the expresion of various surface properties of lymphoblastoid cell lines with the content of EBV viral DNA as determined by complementary RNA-DNA (cNRA-DNA) hybridization on membrane filters or by DNA-DNA renaturation kinetic analysis. The only correlation established was with the Fc receptor determined by direct immunofluorescence. No correlation of EBV genome equivalents per cell with complement receptor or surface Ig was noted, suggesting that the expression of these receptors is not influenced by EBV viral DNA content. Subgroups of lymphoblastoid cell lines were on the basis of variable expression of surface receptors, designated B1, B2, B3, B4, and T. The distribution of lymphoblastoid cell lines into these subgroups were in the ratio of 14:4:1:4:1. The B1, B2, and B4 cell lines (except Molt 4F) were found to contain EBV. The B3 subgroup, for wich cell line 698 was the sole example, expressed surface immunoglobulins but no other B-cell characteristics, and H.S.B., a T-cell line, lacked detectable EBV.


Studies on antibodies to histones by immunofluorescence. When mouse kidney tissue sections were extracted with 0.1 N hydrochloric acid, sera with antibodies to certain nuclear antigens no longer stained tissue nuclei by immunofluorescence. This effect was due to removal of histones and nuclear acidic proteins Sm and nuclear ribonucleoprotein by the acid. DNA remained in the nuclei of the acid-extracted tissue sections. When solutions of calf thymus histones were reacted with acid-extracted tissues, histones combined with nuclear DNA to form complexes of DNA-histone. These complexes contained antigenic determinants which reacted with sera containing antibodies to deoxyribonucleoprotein to give nuclear staining demonstrated by immunofluorescence. The reaction was immunologically specific in that sera with antibodies to Sm and nuclear ribonucleoprotein were not reactive with reconstituted DNA-histone in nuclei. Other basic proteins such as protamine, poly-L-lysine, and poly-L-arginine could not substitute for histones. The method is introduced as a specific and reproducible assay for study of antibodies to histones.