Hemodynamic improvement after oral hydralazine in left ventricular failure: a comparison with nitroprusside infusion in 16 patients. Hydralazine was administered in a single oral dose of 50 to 100 mg in 16 patients with left ventricular failure due to cardiomyopathy. It produced sustained effects for at least 4 h characterized by a significant increase in cardiac output, a reduction in arterial and pulmonary arterial pressure, and a slight rise in heart rate. When compared to nitroprusside infusion in these same patients, hydralazine produced a similar reduction in systemic vascular resistance but a slightly greater increase in cardiac index (0.74 versus 0.95 litres/min-m2), with a lesser fall in mean arterial pressure (7.8 versus 13.6 mm Hg, P less than 0.01), mean pulmonary arterial pressure (4.2 versus 11.3 mm Hg, P less than 0.001), and pulmonary wedge pressure (5.5 versus 9.9 mm Hg, P less than 0.001). Forearm venous tone decreased and venous compliance increased during nitroprusside infusion, but they were unchanged after hydralazine therapy. These data suggest that hydralazine may be a useful agent in the treatment of chronic left ventricular failure.


Pulmonary hypertension in the CREST syndrome variant of progressive systemic sclerosis (scleroderma). Severe pulmonary hypertension without pulmonary fibrosis occurred in 10 patients with the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia), reputedly a benign variant of progressive systemic sclerosis. Time from the initial symptom, Raynaud's phenomenon, to the recognition of pulmonary hypertension was as long as 40 years. Pulmonary hypertension and increased pulmonary vascular resistance was shown in all patients. Autopsy examination in three of six deaths attributable to pulmonary hypertension showed intimal proliferation with myxomatous change in the small- and medium-sized pulmonary arteries similar to changes in the digital arteries of patients with scleroderma and Raynaud's phenomenon, and interlobular renal arteries of those with "scleroderma kidney." It is concluded that the CREST syndrome is not entirely benign but may be complicated, after a long clinical course, by progressive pulmonary vascular obliteration, pulmonary hypertension, and death in the absence of significant pulmonary fibrosis.


Intravenous theophylline therapy: nomogram guidelines. We evolved a nomogram for guiding and standardizing intravenous theophylline therapy in hospitalized patients. It provides rapid calculation of a loading dose based on body weight and previous therapy and a maintenance infusion rate related to three categories of expected metabolic activity. The guidelines were prospectively used in the treatment of 72 patients, mainly in a respiratory care unit. The nomogram was successfully used to attain near-steady-state serum concentrations in the therapeutic range of 8 to 20 mg/litre in 72% of patients, with only two patients outside of the range of 5 to 25 mg/litre. These guidelines facilitate initial theophylline dosage in older patients with liver and cardiac disease and provide a rational basis for interpreting serum concentration measurements and adjustment of drug therapy.


Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Clinical and immunologic characteristics are reported in a series of 20 patients with allergic bronchopulmonary aspergillosis seen by physicians in one consulting service during a period of 9 years. Seventeen of these patients have been identified in the past 2 years, reflecting the increasing recognition of the entity. Fifteen of the 20 patients are believed to have proven diagnoses; the other five are strongly suspected. Asthma, pulmonary infiltrates, and eosinophilia are the usual presenting symptoms. Serum immunoglobulin E was markedly elevated in all patients, and serum immunoglobulin D was normal in four out of five patients sampled. Bronchograms were abnormal in all cases in which they could be done. Lymphocyte transformation may be present in some cases but is not a diagnostic feature. The average age at time of diagnosis was 25.5 years, and seven of the 15 proven patients were 20 or younger.


Release of neutrophil chemotactic activity during immediate hypersensitivity reactions in humans. Heat-stable, serum-derived chemotactic activity for neutrophils is shown in a human model of immunoglobulin E-mediated asthma. Twenty-six ragweed-sensitive subjects underwent bronchial provocation  challenge using ragweed and Mecholyl. Increased neutrophil chemotactic activity was found in serum tested from 5 to 30 min after a positive ragweed-inhalation challenge, but not after negative ragweed challenge. The appearance of neutrophil chemotactic activity did not reflect the effects of bronchospasm alone, because it was not found after bronchospastic responses to Mecholyl in the same subjects. There were no accompanying changes of serum complement activity, nor evidence of inhibition of the chemotactic activity by proir exposure to antisera to the third and fifth components of complement. Ultrafiltration of serum showed chemotactic activity contained in fractions of at least 50 000 daltons. This appears to be the first demonstration of neutrophil chemotactic activity liberated during experimentally induced immunoglobulin E-mediated asthma in humans.


Reversible hematologic sequelae of diabetes mellitus. Seven patients with diabetes mellitus were hospitalized and their blood sugar concentrations regulated as a result of fasting blood sugar, sugar around meals, urinary sugar, and hemoglobin AIC assays. Erythrocyte half-life as measured by 51 Cr increased in all patients from a mean of 27 days to 31 days, while hemoglobin AIC levels decreased from a mean of 10.1% to 5.6%. Leukocyte adherence increased in all patients from a mean of 28% to 51%. Most striking were the changes observed in platelet function in response to epinephrine. The length of the secondary lag phase of platelet aggregation, after a stimulus with final concentration of 70 muM of epinephrine, increased from a mean of 19 seconds to 65 seconds. Studies in additional patients confirmed an inverse correlation between hemoglobin AIC concentration and the secondary lag phase (r = 0.87, P less than 0.001). These studies found that certain secondary sequelas of diabetes can be corrected by strict carbohydrate control and confirmed that hemoglobin AIC assays provide a useful means of showing the degree of control of glucose metabolism in diabetic patients.


Pericardial tumor of fibrosis mimicking pericardial effusion by echocardiography. Echocardiograms of three patients with metastatic carcinoma or lymphoma showed a sonolucent space posterior to the left ventricular epicardium, as seen in pericardial effusion. However, at surgery or autopsy no pericardial fluid was found. Instead, the pericardium was infiltrated by neoplastic tissue or fibrosis. In view of this finding, we suggest caution in the interpretation of "positive" echocardiograms for pericardial effusion in patients with neoplastic disease, especially if pericardiocentesis is being considered.


Meglumine iodipamide (Cholografin) hepatotoxicity. Two cases of meglumine iodipamide (Cholografin) hepatotoxicity were confirmed by liver biopsy. The hepatic lesion was centrilobular in location and resolved within a short period of time. Nausea and vomiting commonly reported after intravenous cholangiography may be clinical manifestations of this entity.


Rabies: risk, management, prophylaxis, and immunization. The management of persons who may have been exposed to rabies infection is important. An interpretation of both the risk of infection and the effectiveness of treatment is presented and a postexposure antirabies treatment guide included. These recommendations were established by the Public Health Service Advisory Committee on Immunization Practices and incorporate many current concepts of the World Health Organization Expert Committee on Rabies.


A method for better physician-patient communication. Dismissal interviews were recorded between 48 patients and their physicians. Each patient took home a cassette containing this interview. About 3 months later, the patients received a questionnaire designed to assess the acceptability and usefulness of this method of communication. Most patients proved to have ready access to a cassette player. Their responses were highly favorable: 91% thought they were helped to understand the physician's discussion; 75% found it helpful to have their spouse or relatives listen to the tape; 62% preferred the recording to a letter; and 86% of the patients believed that the taped interview improved their health care. Many studies record the inadequacy of communication by physicians to their patients. This technique of recording dismissal interviews may make a contribution to improving such communication.


Preservation of cochlear function after extensive labyrinthine destruction. Four ears are presented with extensive destruction of the bony and membranous labyrinth with the loss of caloric function but with retention of hearing. Fourteen similar cases described previously in the literature are reviewed. Our cases are unique in that hearing was preserved after surgical removal of the disease in the inner ear itself. We are unaware of any previous well-documented reports showing such extensive destruction of the pars superior portion of the labyrinth with the preservation of hearing. Possible explanations and theoretical implications are discussed.


Laryngeal spasm: a neurophysiologic redefinition. Within the limits of standard neurophysiologic techniques, we have attempted to redefine laryngeal spasm as distinct from the glottic closure reflex. This distinction is based upon the observation that laryngeal spasm is solely mediated by the superior laryngeal nerve. Stimulation of other afferent nerves, capable of eliciting the glottic closure reflex, produces little adductor after-discharge activity that is characteristic of laryngeal spasm. In this regard, modification of output function from the adductor motoneuron aggregate by means of temporal and spatial summation of sensory input data has been described, and its characteristics further defined in response to varying ventilatory states and barbiturate levels.


Development of hearing loss in kanamycin treated chinchillas. Behaviorally determined auditory thresholds of chinchillas were monitored before, during and after daily administration of kanamycin sulfate (200 mg/kg per day). Drug treatment was terminated as soon as a shift in high-frequency thresholds was observed. In surviving animals, hearing loss spread toward lower frequencies and stabilized after eight to nine days. The stable hearing loss was limited, on the average, to frequencies above 3 kHz. The magnitude of the loss was constant across frequencies and averaged about 40 dB. Virtually complete outer hair cell loss was seen in the basal portion of the cochleae of all surviving animals.


Tracheobronchiomegaly: report of two cases with widely differing symptomatology. Two cases of tracheobronchiomegaly are reported to call attention to this disease. Physicians must be mindful of this entity as another cause of recurring pneumonia which may be treatable. Various proposed etiologies for this syndrome are reviewed. The findings in and interpretation of our cases and those in the literature suggest that tracheobronchiomegaly is a congenital anomaly differing from others of the tracheobronchial tree because of its spectacular radiological appearance. The two following cases typify different presentations of this syndrome. One is largely asymptomatic; the other demonstrates super-infection of stagnant secretions, making the patient functionally bronchiectacic with progressive suppurative pulmonary destruction. The authors believe that aggressive management designed to mobilize airway secretions is indicated. There is usually no place for surgery in this disease beyond establishing the diagnosis.


Electrocochleography and recruitment.

Electrocochleography and recruitment. Electrocochleography was performed in about 80 recruiting ears, including Ménière ears showing hearing loss due to asphyxia, noise trauma, or the use of ototoxic drugs. Criteria for recruitment detection on the basis of electrocochleography were investigated by means of the description of action potential waveforms, slopes of action potential input-output curves, and latency-intensity functions. The validity of two models for the mechanism of loudness recruitment is discussed in relation to data obtained from narrow-band response contributions to the compound action potential in response to tonebursts. A relationship was found between the shape of the AP input-output curve for toneburst stimulation and the shape of the response area, which favors the recruitment model recently proposed by Evans. This justifies use of the slope of the input-output curve as an indicator for the presence of loudness recruitment, and additional support is provided by the latency at near-threshold values. The AP waveform seems to have pure illustrative interest.


In vivo observation of tracheal microcirculation in dogs. Tracheal microcirculation was studied in six healthy anesthetized adult mongrel dogs. A transparent balloon was used to apply pressure to the tracheal mucosa during observation of the microcirculation. Pressures of microvascular occlusion were measured using an electrically callibrated silicone, envelope placed on the observation balloon. The different vessel sizes were measured and classified using the operating microscope. Capillary occlusion pressures ranged from 10 to 40 msurements of tracheal diameter were performed. Progressive local and generalized dilatation occurred. Capillary occlusion pressure was lower in the more dilated specimens. The lower than expected occlusion pressures are thought to be a result of the tracheal dilatation and may be related to the administration of drugs or other factors.


Anaerobic bacteria in otitis media.

Anaerobic bacteria in otitis media. Anaerobic bacteria, Peptostrepotococcus intermedius and Propionibacterium acnes, were found in mixed culture specimens from four to ten tested cases of chronic secretory otitis media. These anaerobic bacteria were in a mixed infection flora with aerobic bacteria most often Staphylococcus epidermidis and Cornybacterium sp. which do not fit any established species. The findings of anaerobic bacteria in otitis media is consistent with the sporadic report of the involvement of anaerobic bacteria in otitis media in the literature since 1898.


Goblet cell population in the pathological middle ear and eustachian tube of children and adults. On 64 temporal bones from slightly abnormal and pathological prematures and newborn infants, children, and adults, 35,000-40,000 counts of goblet cells were done in different parts of the Eustachian tube and middle ear. The goblet cells were present in all Eustachian tubes and middle ear areas. In ears previously exposed to infection the density was slightly increased in the tubal orifice and in most parts of the middle ear. In subacute and acute pathological actions, especially tubal occlusion, and chronic diseases, such as active chronic otitis and in secretory otitis media, the goblet-cell density is appreciably increased.


Stapedial reflex decay in retrocochlear and cochlear lesions. Review of procedures and methods for conducting SRD tests. The procedures for conducting and interpreting Stapedial Reflex Decay (SRD) are discussed. A modification of currently used procedures and interpretations in which testing is conducted at 750 and 1500 Hz as well as 500, 1000 and 2000 Hz is also discussed. Abnormal decay is defined as fatigue to half-life in less than 6.2 seconds. The SRD test patterns of 464 ears with cochlear lesions and 68 ears with retrocochlear lesions are presented and discussed. The findings are strongly supportive of SRD testing using the proposed procedures and interpretations.


Effect of click rate on the latency of auditory brain stem responses in humans. Auditory brain stem responses are the far-field reflections of electrical activity originating in the auditory pathway in its course from the cochlea to cortex that can be recorded from scalp electrodes using computer averaging techniques. There are seven components in the initial 10 msec following a click signal which have been shown to have an orderly change in latency as a function of signal intensity. The results of this study show that click repetition rate can also significantly affect the response latency measure. Responses were measured in six normal hearing subjects at click rates of 10, 30, 50 and 100/sec and af four intensity levels (30, 40, 50, and 60 dB sensation level). The mean latency shift of component V was approximately 0.5 msec when the responses at 10 and 100/sec were compared. This is equivalent to a 15-20 dB decrease in signal intensity at the 10/sec click rate. An analysis of the time of occurrence of this shift using brief click trains at 100/sec showed the shift in latency to be complete by the fifth click. The latency shift was similar at the four signal levels tested. The latency shift was similar at the four signal levels tested. The latency shift of component V appeared to be a monaural and therefore a potentially peripheral process. The results are interpreted as an objective measure of adaptation in the human auditory system with implications for the measurement in disorders of hearing.


Cochlear, brain stem, and cortical evoked responses in nonorganic hearing loss. After complete but inconclusive audiometric evaluation, 30 suspected cases of nonorganic hearing loss (NOHL) were referred to this laboratory for a complete battery of electric response audiometry tests (recording of cochlear, brain stem and cortical evoked responses). The chief advantages of these tests lie in their ability to more objectively confirm the presence of NOHL and to elicit the true threshold of the subject. Such tests along with psychiatric evaluation, indicate that NOHL can be subdivided into categories, examples of which are presented and discussed: malingering or conscious simulation of deafness for obvious personal gain, and psychogenic deafness in which an emotional problem (e.g., combat stress, anxiety) is unconsciously converted into a hearing problem in an escape mechanism. The basis of NOHL in some cases may be a mixture of both conscious components (malingering) and unconscious components (psychogenic). Several cases of NOHL are really nonorganic overlays or exaggeration on a small to moderate organic hearing loss. The psychogenic hearing loss seen in soldiers with combat neurosis may have originally developed as a psychogenic exaggeration of a temporary threshold shift induced by the noise of battle. Thus objective electrophysiological hearing tests and psychiatric evaluation have contributed to a better understanding of NOHL.


Limitations of parotid scans.

Limitations of parotid scans. In 1967, Gates and Work proposed techentium scanning as a diagnostic tool for salivary neoplasms. Since then, many publications have dealt with the results of scanning. The impression has been that it has certain diagnostic implications, especially in regard to the lesions which is radiopositive on the scan. A review of 29 salivary scans from the University of Iowa Hospitals was carried out, and the conclusion reached was that nuclear scanning using technetium gave little assurance of a specific histological entity in any individual case. Cases having both cold and hot nodules ran the gamut from benign and nonneoplastic to frankly malignant lesions. These cases are illustrated, and the conclusion is reached that salivary scanning at its present stage of development may only delay the proper diagnostic step of excisional (at least lateral lobectomy) biopsy for all nondiffuse parotid mass lesions.


Course of the peripheral gustatory nerves. The multiple variations of the course of the gustatory nerves still considered possible are discussed. Recent investigations lead to the conclusion that there is only one path for the gustatory fibers for each gustatory area: 1) from the anterior part of the tongue via the tympanic cord and facial nerve to the medulla oblongata; 2) for the posterior part of the tongue in the IX cranial nerve; and 3) from the soft palate via the greater superficial petrosal nerve to the facial nerve. The trigeminal nerve carries no gustatory fibers to the brain.


Microclip application in tympanoplasty.

Microclip application in tympanoplasty. A new technique for attaching a tympanoplastic graft to its recipient bed is presented. One millimeter stainless steel "microclips" are used to hold the tympanic graft securely in position. Results and experience of microclip application in 404 cases are discussed.


The problems of recurrent gastro-jejunal ulcer. Recurrent gastro-jejunal (stomal, anastomotic) ulcer after extensive Billroth II re-resection with or without vagotomy, is an uncommon but serious and difficult problem. Two illustrative cases are presented. Following a transthoracic vagotomy both patients remained symptom-free after 18 months and 3 years respectively. Transthoracic vagotomy performed as the sole procedure in selected cases of this type, offers definite advantages such as technical ease, low morbidity and mortality, and freedom from the sequelae of a minimal gastric remnant or a total gastrectomy.


Bronchial resection. Feasibility and surgical considerations in lung surgery. Four patients who had bronchial resection for benign and malignant bronchial lesions are reported. The aims were to salvage as much as possible of functioning lung tissue, especially in patients with benign lesions. In all but the patient with a pulmonary carcinoma, the long-term airway result was excellent. Bronchoplastic procedures are suitable and recommended for patients with benign, localised intrabronchial lesions.


Surgical treatment of cardiac myxoma. A case report. A patient with a left atrial myxoma operated on successfully three years ago is reported. The symptomatology and diagnosis of the tumour and surgical considerations are briefly discussed, and the necessity of a long follow-up period is stressed.


Clinical appearance and treatment of malignant melanoma of the skin. A report is presented on cases of malignant melanoma of the skin recorded in the Finnish Cancer Registry between 1963 and 1968. The material consisted of 693 cases where the diagnosis of melanoma was confirmed by reclassification of the histological specimens and/or by careful perusal of the hospital records. In females melanoma was most frequent on the lower extremities (43%). One half of the tumours of males were located on the trunk and two thirds of these where on the posterior side of the trunk. Most of the tumours were in stage I at the time of diagnosis (males 75%, females 80%). The mean duration of symptoms, was 4.0 months in males and 4.2 months in females. In stage I, the duration of symptoms was under four months in 40% of cases and in stage II in 37% of cases, whereas in stage III this figure was 68%. The most common symptoms were increase in size (46%) and bleeding from the tumour (11%). Only 28 patients were treated radically while "wide" excision was the most common surgical method (48%).


Survival rates of patients with malignant melanoma of the skin. This paper reports on cases of malignant melanoma of the skin diagnosed in Finland between 1963 and 1968. Sufficient data for estimating the survival was obtained in 691 cases. The ten-year relative survival rate for the entire series was 41% for males and 53% for females. This sex difference remained constant throughout the various divisions of the material. The ten-year relative survival rate of males with tumour in stage I was 52% and that of females 59%. The highest survival rate of stage I tumour in males was for the tumours of the lower extremities (77%) and in females for those in the head and neck (79%). The relative survival of patients with tumour of the trunk in stage I was lowest in both sexes (males 49%, females 45%). The ten-year relative survival rate of patients with a local recurrence was 33% in males and 27% in females. The relative ten-year survival rates of patients with superficial melanoma were 130% in males and 92% in females.


The profunda femoris artery in reconstructive vascular surgery. Thirty patients with 43 ischaemic limbs were treated by profundal revascularization. 10 patients had impending gangrene preoperatively; the limbs were saved in 8 cases, and four have not had postoperative claudication symptoms. None had postoperative rest pain. In 53% of the whole material the results were evaluated as excellent with no ischaemic symptoms, and in 30% as good with only slight claudication. Profundal revascularization is a valuable method of saving pregangrenous limbs in advanced arteriosclerosis and a worthwhile alternative to femoro-popliteal bypass in suitable cases.


Dumping following partial gastrectomy.

Dumping following partial gastrectomy. The incidence of dumping has varied from 1 to 75% in a number of reported series. The discrepancy probably depends mainly on different definitions of the dumping syndrome. In the present work, the clinical diagnostic index (CDI) first proposed by Sigstad in 1968, has been used in a follow-up study of 241 patients after gastric resection for ulcer disease. 86% of the patients were satisfied with the result of the operation. Dumping occurred daily in 14.1% and 19.5% had the symptoms occasionally. The differences in the frequency of dumping after BI and BII resection were not statistically significant, gastro-jejunal fixation (GJF) and the position of the anastomosis had no influence on the prognosis.


Short term prognosis in sciatica. A prospective study of factors influencing the results with special reference to myelography. 334 Types of follow-up data were collected in 158 patients with sciatica. The following information was obtained: (a) in L4-L5 herniations, Achilles tendon reflex disturbance was not explained by S1 root compression, as visualized at this level on myelography, (b) a water-soluble myelogram was also reliable for extreme lateral herniations and only those herniations dislocated into the intervertebral root canal remained undiagnosed, (c) a positive neurological or myelographic diagnosis of herniation did not mean a better short-term prognosis. Operative removal of a large herniated mass gave the best chance of good recovery. The main indication for myelography is a guide to the surgeon for the correct operative level.


Amniotic fluid and serum lactic dehydrogenase in intrauterine death of the foetus. Total lactic dehydrogenase (LDH) activity in amniotic fluid was determined in 17 cases of intrauterine death of the foetus. All values were above the normal range. In 7 cases with known duration of foetal death the values of LDH tended to increase with the interval between foetal death and amniotic fluid sampling. Serum LDH was significantly higher in cases of foetal death compared to normal pregnancies.


A clinical comparison of prostaglandin F2alpha and intra-amniotic saline for induction of midtrimester abortion. The relative safety and effectiveness of hypertonic saline and intra-amniotic prostaglandin F2alpha (PGF2alpha), when used under clinical rather than research conditions, were evaluated for 100 patients aborted with a 20% saline solution, and 100 patients aborted with PGF2alpha (40 mg initially and an additional 20 mg if abortion had not occurred in 24 hours). While the overall risk of morbidity was similar for the two procedures, rates of incomplete abortion were higher with prostaglandin (51.0%) than with hypertonic saline (35.0%). The prostaglandin procedure, however, was associated with a significantly shorter median time from instillation to abortion of the fetus (25.3 versus 34.5 hours).


The use of ultrasonic echo technique in the diagnosis of developmental anomalies of the uterus. In the course of the fusion of the Müllerian ducts various anomalies of the uterus may be observed depending on the length of the septum between them. These anomalies can be recognized by the "B-scan" ultrasonic echo technique. Anomalies in pregnancy and puerperium were diagnosed in five cases and all of them were confirmed by clinical examination. The ultrasonic echo technique was applied in cases where manual examination revealed a uterus differing in shape from normal, the patient had a breech presentation in her previous or present pregnancy; and the involution of the uterus was slow. All the patients were multiparas and had breech presentation in their previous pregnancies. In four of the present pregnancies breech presentation was established and in three cases pregnancy was terminated before the thirty-seventh week. The involution of the uterus in the puerperium was generally slow.


The distribution of subunit sizes of soluble proteins in human tissues. 1. The distribution of subunit sizes of soluble proteins in human tissues has been examined by the technique of gel filtration chromatography followed by SDS polyacrylamide gel electrophoresis. 2. Up to 101 different polypeptides were identified. These appear to represent primarily the substituent polypeptides of easily solubilized 'non-enzyme' proteins. 3. The subunit sizes ranged between 7000 and 270000 and the distribution was continuous unimodal and skewed. The mean size was estimated at 54 600+/-42 900. 4. The distribution of subunit sizes and the overall mean were found to be similar to those reported for easily solubilized human enzymes and other vertebrate proteins. These results suggest that the average structural gene coding such polypeptides consists of about 1400 base pairs.


Genetic variants of human erythrocyte glucose 6-phosphate dehydrogenase: new variants in West Africa characterized by column chromatography. Five electrophoretically slow-moving genetic variants of glucose 6-phosphate dehydrogenase are described: four are from Nigeria and one is from Togo. All variants have normal or moderately reduced activity, and they are not associated with adverse clinical or haematological manifestations. Three variants have been fully characterized and are different from all previously described ones. Two variants have been partially characterized and at least one of them is also probably new. The overall population incidence of sporadic variants of G6PD in the Nigerian population is 0-3%. In the course of this study a previously described ion-exchange chromatographic technique for the characterization of G6PD variants has been extensively evaluated. Data are given on ten different variants to demonstrate the high resolving power of this technique.


A method for analysing fertility of heterozygotes for autosomal recessive disorders, with special reference to cystic fibrosis, Tay-Sachs disease and phenylketonuria. Increased fertility of heterozygotes with respect to decreased foetal loss among offspring of heterozygotes has been proposed by several authors as a possible explanation for the high gene frequency of CF, TSD and PKU in certain populations. Studies comparing reproductive outcome of heterozygotes with reproductive performance in the general population or in special control groups have been done on several occasions. These studies, however, are known to be heavily biased, on the one side by the fact that ascertainment of heterozygotes through affected offspinrg will tend to underestimate the relative frequency of smaller families, and on the other side because of the inadequacy of census data for comparison and the biases inherent in selection of control families. Careful analysis of the biases involved provides suggestions for proper corrections. From this a method has been developed which offers a better approach to the study of heterozygote fertility in those autosomal recessive conditions which lack a test for direct heterozygote detection.


The identical-twin transfusion syndrome: a source of error in estimating IQ resemblance and heritability. Published studies show that among identical twins, lower birthweight is associated with lower adult intelligence. However, no such relation between birthweight and adult IQ exists among fraternal twins. A likely explanation for the association between birthweight and intelligence among identical twins is the identical twin transfusion syndrome which occurs only between some monochorionic identical twin pairs. The IQ scores from separated identical twins were reanalysed to explore the consequences of identical twin transfusion syndrome for IQ resemblance and heritability. Among 129 published cases of identical twin pairs reared apart, 76 pairs contained some birthweight information. The 76 pairs were separated into three classes: 23 pairs in which there was clear evidence of a substantial birthweight differences (indicating the probable existence of the identical twin transfusion syndrome), 27 pairs in which the information on birthweight was ambiguous (?), and 26 pairs in which there was clear evidence that the twins were similar in birthweight. The reanalyses showed: (1) birthweight differences are positively associated with IQ differences in the total sample of separated identical twins; (2) within the group of 23 twin pairs who showed large birthweight differences, there was a positive relation between birthweight differences and IQ differences; (3) when heritability of IQ is estimated for those twins who do not suffer large birthweight differences, the resemblance (and thus, h2/b) of the separated identical twins' IG is 0-95. Given that the average reliability of the individual IQ test is around 0-95, these data suggest that genetic factors and errors of measurement cause the individual differences in IQ among human beings. Because of the identical twin transfusion syndrome, previous studies of MZ twins have underestimated the effect of genetic factors on IQ. An analysis of the IQs for heavier and lighter birthweight twins suggests that the main effect of the identical twin transfusion syndrome is to lower the IQ of the lighter birthweight twin, rather than to raise the IQ of the more fortunate partner or to influence the IQ of both members. This reanalysis suggests that postnatal cultural and social environment produce little of the total phenotypic variation in IQ found in the normal population. In the future, investigators who use twin studies to estimated heritability must ascertain whether their identical twin pairs suffered from the identical twin transfusion syndrome. Accurate estimates of heritability can only be obtained using identical twins who do not suffer from placental circulation problems. Most likely, the identical twin transfusion syndrome produces anoxia and brain damage during early prenatal development in the smaller identical twin. The anoxia is caused by a lowering of the haemoglobin content of the smaller twin by 35% or more.


Placentation and zygosity of twins in Northern Nigeria. Details of placentation and zygosity are reported from a survey of 627 consecutive twin births at three hospitals in Northern Nigeria. Zygosity was determined by study of sex, red cell antigens (ABO, MNSs and Rh) and placental enzymes (PGM1, PGM2, PGM3 and Pep A). The proportion of DZ twins amongst the various ethnic groups in this part of Nigeria is intermediate between that found amongst Yorubas in Western Nigeria and populations in the U.S.A. and England.


The relationship between inbreeding, migration and population density in Norway. An investigation of the present levels of inbreeding and the proportion of non-migrants (residents in municipality of birth) in rural districts of Norway reveals a relationship between these two characteristics. There is a steady upward trend from 0.39% first- and second-cousin marriages in municipalities with less than 50% non-migrants to 4.3% such consanguineous matings in municipalities where 85% or more of the inhabitants are non-migrants. There is also a significant negative correlation (rs=-0.86, N=18) between inbreeding and population density per square km by county in Norway. In rural districts of Norway maximum inbreeding is observed in sparsley populated areas with maximum proportion of non-migrants, and the ratio of second- to first-cousin marriages ranges between 3.4 and 4.1. A similar high ratio (3.7) is also encountered in densely populated trading and industrial municipalities and in the smaller towns, whereas the semi-urban municipalities and the larger towns have the lowest inbreeding recorded and also a low ratio (1.9). The lowest proportion of non-migrants (39.3%) is recorded in the semi-urban municipalities.


Isolation by distance in human populations. Malécot's theory of isolation by distance under 'continuous' migration is shown to fit acceptably to various human populations. Although it provides a less complete and reliable prediction of population structure than migration matrices, it is applicable to a greater range of structures and data.


[Cellular and humoral response to tumor antigens in the hamster]. Studies on the histological of the lympoid organs and the evolution of the immune response were done during the growth of a tumour induced by SV40 transformed cells. The immune response was characterized by a high level of circulating antibodies and presence in the thymus and spleen of lymphoid cells containing IgG with antibody function.


[IgG subclasses in malignant melanoma].

[IgG subclasses in malignant melanoma]. The 397 sera from 185 melanoma patients have been studied and classified in three groups according to the stage of disease. Our findings revealed an alteration of the level of IgG4 subclass which is related to the dissemination of disease. The percentage of abnormalities (either increased or decreased levels of IgG4) was more frequent in stage II and III (55% and 53% respectively) than in stage I (19%), The higher frequencies of high titers of IgG4 were essentially detected in advanced disease. The biological significance of the increase of IgG4 in melanoma remains obscure. It may be related to the development of facilitating antibodies of IgG4 subclass.


[Host-tumour relationships and immediate hypersensitivity reactions]. When radiolabelled lymphoid cells and the extracellular dye Lissamine green were injected IV into C3H mice carrying non-necrotic methylcholanthrene-induced tumours, the tumour content of these agents was significantly lower than in other organs. The tumour content of these circulating blood components was significantly increased by the intratumoral (IT) induction of local passive anaphylactic reactions, and such reactions exerted an anti-tumour effect, and enhanced the therapeutic activity of IT BCG. No anti-tumour IgE antibody was detected in this model, but the tumour inhibited passive and active anaphylactic reactions in its host.


[Studies on tumour--associated immunoglobulins in human cancer]. Human sarcomas, carcinomas and brain tumours were assayed for the presence of immunoglobulins IgG. Among 16 tumours tested, 14 had detectable amount of IgG that could be released when incubated in culture conditions. Addition of iodoacetamide--a metabolic inhibitor--inhibited this " uncoating process ". The uncoated cells rebound IgG if incubated subsequently with any of the cancer sera tested. However, when the autologous serum was present during the uncoating incubation, subsequent rebinding at 4 degree C of IgG from the same or other cancer sera was significantly decreased compared to alquots pre-incubated in other sera.


[Nature of the MAF-producing cell].

[Nature of the MAF-producing cell]. Lymphocytes from allograft recipient mice, stimulated in vitro by the donor strain cells, release a mediator (the macrophage activating factor of MAF) which is able to render cytotoxic normal macrophages. This work investigates the origin and characteristics of the MAF-producing sensitized lymphocytes. The congenitally athymic Nude mice sensitive to anti-0-serum plus complement, resistent to treatment with corticosteroid hormones and dependent of the presence of the thymus in adult life.


[Abnormal specificities of immune alloantisera]. Sera from repeatedly immunized with allogenic lymphocytes contain IgG that can be fixed by syngenic tumour cells. When compared to the specific anti-H-2 immune response, the paradoxical tumour reactivity is often very high, suggesting an active immunization process. Selective absorptions have demonstrated that the majority of these "anomalous" IgG are directed against membrane components of tumour cells. The nature of the detected tumour-associated determinants is not well elucidated: they are not found on normal embryonnic or adult tissue, but are highly expressed by all in vitro murine malignant cell lines thus far tested, and to a lesser extent by the corresponding in vitro maintained tumours.


[Antitoxoplasmic immunity on congenitally athymic nude mice]. Susceptibility to toxoplasmic infection was found to be the same in Nude mice (nu/nu) as in controls. Vaccination with avirlent toxoplasma (Beverley strains) confered an incomplete immunity to Nude mice: in 20 to 40% of cases, mortality was delayed as compared to unvaccinated control. Cellular (activation of macrophages) and humoral (circulating antibodies) immune responses were partially present in Nude mice.


[Thermolability at 56 degrees C of mouse IgE antibodies]. The heat inactivation at 56 degrees C of mouse IgE antibodies, measured by their PCA activity, was studied in various experimental conditions. Mouse IgE antibodies are partially protected against heat inactivation when previously diluted in sodium chloride or in phosphate buffer media. The protection is better at a higher dilution and molarity (phosphate 1M) and at pH 7. Heat inactivation is increased by the presence of reducing, alkylating and denaturating agents. Heat lability depends upon the concentration of serum proteins in the medium and is increased in presence of immunoglobulins.


[Enhancing antibodies and supressive cells in maternal anti-fetal immune reaction]. Some of the mechanisms of tolerance to the foetal allograft have been studied in vivo, both at cellular and humoral level. It has been shown that immunoglobulins, mostly IgG1, can be detected and eluted from the placenta of allogeneic and syngeneic pregnancies in a wide variety of combination (CBA, C57Ks A/Jax, Balb C, DBA2). These immunoglobulins, in the case of allogeneic pregnancy, bind to paternal thymocytes exclusively, demonstrating antibody activity toward paternal antigens. They promote (although partly "non-specifically") direct allogeneic mast cell degranulation. In vivo, eluates only from a C57Ks female X A/Jax male placenta exclusively induce a significant enhancement of SA1 (A/Jax, h-2a strain) tumor graft in C57Ks (H-2d) recipients. Intraperitoneal transfer of 1.0 to 1.7 X 10(7) spleen cells from C57Ks two weeks pregnant from A/Jax male does also promotes SA1 growth and survival. T and B enriched population, obtained by the nylon wool techniques, display similar activity. Further experiments are in progress to discard T cell contamination in the B enriched population and to study eventual macrophage involvement. Thus, two agents of the facilitation reaction--suppressor cells and enhancing antibodies--have been demonstrated in vivo during pregnacy, protecting the foetus against hazards of the rejection reaction, which is also demonstrates by other in vivo techniques in our laboratory.


[Immunochemical and biological properties of goat immunoglobulin G]. Two subclasses of immunoglobulins G, the IgG1 and the IgG2, were isolated from goat serum and colostrum. The two subclasses are different in their physico-chemical and biological properties, but generally their properties resemble those of other immunoglobulins in bovidae.


[Purification and properties of thy1 antigens (author's transl)]. Thy1 antigens have been isolated from rat thymus and brain. The Thy1 molecules purified are membrane glycoproteins of molecular weight 25,000 containing 30% carbohydrate by weight. Brain and thymus glycoproteins have very similar amino-acid composition but different carbohydrate composition. All antigenic determinants associated with Thy1 are present on the purified molecules and are likely to be on the polypeptide backbone of the glycoprotein.


[Isolation and characterization of a retinal antigen inducing experimental autoimmune uveo-retinitis]. A soluble antigen was extracted from the retinas of different mammals and purified by isoelectric focusing in a sucrose density gradient-ampholine column (LKB, Sweden). The isoelectic point of the molecule is about 5.5, its molecular weight about 55,000 and its electrophoretic mobility with reference to albumin 0.7. The S antigen is revealed by one precipitin line in immunodiffusion and immunoelectrophoresis with guinea pig immune sera against bovine or guinea pig retinas, and shows an identity reaction with S antigen from other species. The antigen, inoculated with complete Freund's adjuvant into the guinea pig foot pad, induces experimental uveo-retinitis.


[Experimental autoimmune uveo-retinitis (EAU): cellular immunity and humoral antibodies in the induction of ocular lesions and tolerance to retinal antigens]. EAU is induced in guinea pigs by one inoculation into the foot-pad of a retinal extract in complete Freund's adjuvant. The evolution of the antibodies (complement fixation) is compared with the évolution of the disease (intensity evaluated by frequent ophthalmological examinations). The successful passive transfer of the disease by local injections of immune serum and the demonstration by immunofluorescence of immune complexes in the ocular tissues are arguments for the role of humoral antibodies in the induction of the disease. EAUmay be inhibited by repeated subcutaneous or intradermal injections of the antigen, either before or after the onset of the inflammation. These injections depress the delayed hypersensitivity and increase the titre of complement fixing and passive anaphylactic antibodies.


[Characteristics of intestinal immune response of rats infected with Nippostrongylus brasiliensis]. After infection of rats with Nippostrongylus brasiliensis the response was a synthesis of hemagglutinating antibodies in intestinal secretions, the activity of which is mainly due to IgA. When rats were infected with 83 larvae (which is the smallest immunizing dose), local antibodies were evidenced just after parasite localization had occurred in the gut, whereas serum antibodies were not detected before a challenge infection. Some of these local antibodies were directed against two types of worm antigen which can induce immunity: sevretory antigens and phosphorylcholine. These experiments a role for local antibodies in mechanism of worn expulsion.


[Antibody mediated adherence of rat peritoneal exudate cells to Trichinella spiralis larvae]. Washed peritoneal exudate cells from rats firmly adhere to Trichinella spiralis larvae in the presence of serum containing anti-Trichinella antibodies. This effect is observed when muscle larvae, cells and dilutions of antisera are incubated for 1 h at 37 degrees C.. No adherence takes place at 4 degrees. Whole serum or its gammaglobulin fraction are active and the effect is inhibited by the addition of Trichinella antigens. Complement is not essential since antiserum heated for 2 h at 56 degrees is active. Washed cells from infested animals do not adhere to the larvae in the absence of antiserum, but normal cells adhere to larvae previously incubated with antisera. It is suggested that the adherence phenomenon is due to the activation of cells by a complex of antigen and antibody formed on the surface of the larvae.


[Study of X antigen of Salmonella typhi responsible for the production of protective antibody towards chick embryo]. Laboratory animals are not sensitive to human S. typhi strain (O+ Vi+). But the chick embryo is very susceptible to infection by this strain. This property can be used to test protective activity of immuno sera. Several antigenic fractions have been prepared from Ty6S strain (0- Vi+) by washing methods. The " outer layer " of the bacteria is easily removed by NaCl 0,5 M. Injected in rabbits this preparation produces the synthesis of protective antibodies. The active antigen X is spun down with the Vi antigen. The relation of X antigen to Vi antigen is being studied.


[Induction of chemotaxis by soluble immune complexes]. These complexes, obtained either by adding antigen in excess to immune sera or by redissolving an immune precipitate with antigen, could in the presence of fresh serum stimulate PMN leucocytes to migrate. Complexes with a molecular composition Ab1Ag1 (ot C fixing) showed higher activity than complexes of larger size. The experiments suggest that they activate some sequence of the contact system of coagulation.


[Influence of levamisole on antibody production]. IgM and IgG anti-sheep red blood cells agglutinins were measured from dayy + 2 to day + 30 in SPF mice immunized with 108 SRC and treated with 2.5 or 25 mg LMS/dg. Untreated control mice produced high levels (1:8200) of IgM-antibodies from day + 4 to day + 20. Early, day + 4, IgG-agglutinins appeared together with IgM-antibodies in mice treated with 2.5 mg LMS/kg, whereas administration of 25 mg LMS/kg induced the synthesis of antibodies belonging only to the IgG class. Titres were significantly lower (1:512) in LMS-treated mice than in controls. The switch to IgG of antibody formation is another for the ability of LMS to stimulate T cell activities.


[Isolation and partial characterization of (PAF) platelet-activating-factor]. Platelet-activating-factor is a new mediator of anaphylaxis released in numerous mammalian species from basophils and mastocytes by antigens, anti-IgE antiserum, ionophore A 23187, C3a, C5a and neutrophil cationic protein. It is probably a lyso-1-phosphatidylcholine, as evidenced by structural studies isomg phospholipases. It may explain the involvement of platelets in immunopathology.


[Heterogeneity of the gastric intrinsic factor autoantibodies of types I and II]. Variable results were obtained in a study of the immunologic reaction of the intrinsic factor (IF)-autoantibodies (IFA) to the human, hog and rat IF antigens. Effectively, some IFA I were unable to block completely all the binding sites of B12 to IF. As to the IFA II, some did not show a total effectiveness in neutralizing the activity of IF in certain human gastric juices. In another study conducted on patients with pernicious anemia, the antibodies obtained from their sera reacted differently to the hog and rat IF; some reacted identically to homologous and heterologous IF others were less and even not effective on the heterologous IF. From these results it was suggested that, within the two main branches of IFA, there would be subdivided groups with selective effect on different antigenic sites of IF.


[Suppressive cells induced by cyclophosphamide in the spleen of C3H mice]. The spleen cell population of C3H/He mice injected with a single sublethal dose of cyclophosphamide (CY) was analysed. An initial atrophy was followed by a considerable hypertrophy and a progressive return to normal. During the phase of spleen atrophy, both B and T cell compartments were depleted. During regeneration, the percentage of Ig+ cells increased rapidly, and at the peak of splenomegaly, the percentage of Ig+ cells was high while no Thy1-2+ cells were detectable. The peculiar points of histology were disappearance of normal T and B compartments, substituted by a layer of lymphoid cells. During the phase of splenectomegaly, the in vitro reactivity of spleen cells to the mitogens PHA and LPS was drastically decreased. Furthermore, the spleen cell population from CY treated mice contained suppressor cells, capable of inhibiting the in vitro reactivity of normal lymphocytes to these mitogens and the multiplication of tumour cells in culture. These cells were adherent, Ig+, Thy1-2- cells. They developed in CY treated T deprived mice. After velocity sedimentation the suppressive activity was detected in the 6 mm/h fraction.


[PHA transformation of coelomocytes of Lubricus terrestris]. This transformation was studied at various concentrations of PHA and during different periods of incubation. The coelomocytes were separated into adhering and non-adhering cells. The adhering cells were separated into trypsin-sensitive and trypsin-resistant. Results have clearly shown (P less than or equal to 0.01) that the coelomocytes do transform to PHA. Only the trypsin-resistant adhering cells (5-10%) having a high phagocytic activity, were capable of inducing the transformation of  the non-adhering coelomocytes. None of these sub-populations of coelomocytes did transform alone. These results reinforce the existence in earthworms of a T-cell like function and perhaps receptors similar to those observed in higher vertebrates and confirm the cooperation of two cell types to achieve this activity.


[Autoimmunity and deficiency of cell-mediated immunity in primary myelofibrosis]. Untreated patients with primary myelofibrosis show (1) a high frequency of cutaneous anergy, (2) normal lymphocytosis with decreased level of E-rosette-forming cells in most patients, (3) normal lymphocyte reactivity to PHA and in MLR, and (4) a relative frequency of LE cells and anti-organ antibodies.


[The temporary immunodepression observed in trichinosis: is it related to acceptance of this parasite by its host?]. Swiss mice given 200 Trichinella larvae followed by a further 200 larvae 21 days later were found to be immune and did not show any immunodepression to sheep red blood cells (SRBC). When the challenge dose was given 56 days after the first infection, the pattern of infection was unaffected and an immunodepression to SRBC was observed. Therefore, the immunodepression in trichinellosis might be related to the migrating phase only.


[Genetic selection of mice for quantitative responsiveness of lymphocytes to phytohemagglutinin]. A two-way selection was performed in mice according to the quantitative response of small lymphocytes to the mitogenic activity of phytohaemagglutinin (PHA). The response of inguinal lymph node cells of each mouse to an optimal dose of PHA was measured by 3H-thymidine incorporation using a micro-plate method. Starting from four outbred mouse strains we mated on the one hand mice getting the best response and on the other hand mice getting the poorest response. A progressive separation of the two lines was observed. At the 7th generation a 3-fold difference was found between the two lines. A similar interline difference was observed when concanavalin A (ConA) was used as mitogen. The separation of the two lines was also evident when spleen cells or thymus cells were cultured with PHA or ConA.


[Considerations on the origin of the diversity of immunoglobulins (author's transl)]. In spite of the numerous theories proposed to explain the origin of the diversity of immunoglobulins, none can define satisfactorily the nature of the generator of diversity and its mode of action. Even the concept of the variable and constant portions of immunoglobulin chains is no longer valid which opens up the question about the hypothetical existence of the V and C genes. Moreover, phylogenetic considerations strongly suggest that there is a fundamental difference in the mechanism of amino acid substitution for the immunoglobulins and for homologous proteins undergoing normal divergent evolution. A conceptionally and functionally simple mechanism, based on a variable translation of the immunoglobulin mRNA, has been suggested as the generator of diversity (Rev. canad. Biol., 1969, 28, 179). The criteria of this mechanism are (1) the presence of inosine in the mRNA and (2) the existence of a series of overmethylated tRNAs for the selective recognition of inosine-containing codons. Although the experimental proof for this mechanism is still lacking, it cannot be fortuitous that the lack of adenosine deaminase is associated with immune deficiency and that an increased tRNA methylase activity exists in plasmocytomas.


[Non-specific polygenic regulation of antibody synthesis]. Four two-way genetic selections of outbred mice for the quantitative character "agglutinin production" to heterologous erythrocytes and flagellar or somatic antigens of Salmonella are briefly described. The principal genetic parameters regulating the quantitative antibody response are the following: 1) the character is polygenic; the number of independent loci is estimated between 7 and 16; 2) the heritability of the character (h2) is comprised between 0.17 and 0.21; 3) the maximal interline separation RT (4.8-7.8 log2) is reached after about 15 consecutive generations of selective breeding; (4) the rate of interline separation/generation RG is 0.32-0.48 log2. 5) The phenotypic variance V(P) of the foundation populations is due for 52%-63% to genetic factors V(G) and for 37%-48% to environmental factors V(E); 6) The effect of the selective breeding is essentially non-specific; it modifies the antibody responsiveness to many unrelated complex immunogens.


[Genetic analysis of the synthesis of IgE and hemagglutinating antibodies in high and low responder lines (HL and LL) of mice and their hybrids]. Immune responses depend upon the dose of antigen and the line of mice. Threshold doses of antigen are lower in HL, higher in LL and intermediate in hybrids. The responses obtained in F1, F2 and backcrosses demonstrate the genetic control of the interline difference. The correlation between IgE and hemagglutinating antibodies responses suggests a common genetic control for the synthesis of the two types of antibodies.


[Multiple expressions of mouse peritoneal cell immune potential]. Peritoneal cells (PC) from unstimulated mice are able to form a high number of rosettes (RFC) (20 to 50%) with sheep red blood cells (SRBC) or bromelin treated isologous mouse red blood cells (MRBC(b)). In culture, this population develops a high number of plaque forming cells (PFC) against SRBC and MRBC(b) with a maximum at day 3-4, while the number of RFC decreases in such a way that the total number of RFC + PFC remains constant. The significance of such results is discussed. Evidence is provided, by the use of radioactive labelling, that IgM antibodies and different sub-classes of IgG are synthesized in vitro by PC during culture.


[Isolation and characterization of mitogens from Nocardia]. Two methods have been devised to isolate mitogens from Nocardia cells. (1) Lysozyme treatment of delipidated cells followed by fractionation of  the soluble extract leads to a mitogen devoid of cell wall constituents. (2) Cell disruption followed by differential centrifugations shows that two mitogenic structures are present: the cell wall and fragments of the cytoplasmic membrane. The active component of the cell wall is the peptidoglycan wherefrom soluble mitogenic fractions have been obtained using bacteriolytic enzymes other than lysozyme. An intact glycan moiety seems necessary for mitogenic activity.


[Evolution of the immune response against Micrococcus lysodeikticus]. The immune response of rabbits immunized with Micrococcus lysodeikticus freeze-dried bacteria was studied by following the variation of the affinity and the heterogeneity of the antibodies during immunization. Partial or complete amino acid sequences were determined on the isolated light and heavy chains, and comparative studies were initiated in litter mates. No relationship between the affinity and the restriction in heterogeneity was observed. Sequences are indistinguishable from those reported for antibodies of other specificities.


[Suppression of reaginic antibodies].

[Suppression of reaginic antibodies]. The primary as well as an ongoing IgE response to the haptens--2,4-dinitrophenyl (DNP) and benzylpénicilloyl (BPO) determinants--were readily abrogated in an immunologically specific manner by the administration of conjugates consisting of the corresponding hapten coupled to the isologous, non-immunogenic murine gamma globulins (MgammaG), i. e., DNP8-MgammaG or BPO9-MgammaG. The epitope density of the DNPx-MgammaG and BPOx-MgammaG was shown to play a dominant role in determining whether or not these conjugates were tolerogenic. Using the adoptive transfer system in mice, it was demonstrated that this method of immunosuppression was not due to the formation of suppressor cells, but involved the elimination of hapten specific IgE-forming Bepsilon cells or the inactivation of these cells through the blockade of their antigen binding receptors. This method of suppression of anti-hapten IgE antibodies, by the use of conjugates of haptens with isologous gamma-globulins, proved also effective in rats and dogs.


The nature of the K cell and the role of antibody-dependent cell mediated cytotoxicity (ADCC) in the rejection of tumours. Antibody dependent lymphocytotoxicity has been characterized in cytolytic, cytostatic and microcytotoxicity assay. A " null " K cell was found in all assays and has been identified as a non phagocytic, non adherent, intermediate sized cell of lymphoid-like morphology with Mg++-independent C' receptors, lacking both T and B lymphocyte membrane antigens. In addition, recent reports suggest that a subpopulation of T cells is active in both cytolytic and microcytotoxicity assays, acting through an IgM mediating molecule. Cytolysis of tumours in a 51Cr-release assay has been demonstrated with both heterologous and allogenic antisera with varying sensitivity depending on certain membrane characteristics of different tumour lines. Cytolysis of tumours coated with syngeneic tumour specific antiserum was not demonstrated despite the presence of an equivalent amount of antibody on the tumour membrane. However, K-cell mediated cytostasis measured by the inhibition of incorporation of 125I-IUdR can be demonstrated with heterologous, allogeneic and syngeneic antisera.


[Comparative study of the effect of aeration conditions on the biosynthesis of oxytetracycline by an actinomyces rimosus culture and of lincomycin by an Actinomyces roesolus culture]. The effect of aeration conditions on growth of the oxytetracycline- and lincomycin-producing organisms and antibiotic biosynthesis was studied. It was shown that the lincomycin-producing organism respiration rate was much higher and required better aeration condition-than the oxytetracycline-producing organism. The highest respiration rate of the young myces lium was observed in the growth phase. During the period of the antibiotic biosynthesis the rate of oxygen consumption somewhat decreased though remained sufficiently high. Decreased productivity of the mycelium at the end of the process was accompanied by a drop in the respiration rate. The lack of oxgen lowered the mycelium productivity with respect to the antibiotic formation to a much much greater extent than the culture growth rate. The limiting of the antibiotic biosynthesis process by the lack of dissolved oxygen was accompanied by changes in the culture metabolism evident from production of organic acids: ketoacids and volatile acids by Act. rimosus and volatile and lactic acids by Act. roseolus.


[Impairment of immune response in parasitic infections]. Parasite escape mechanisms may depend upon factors intrinsic to parasites (host antigen uptake, antigenic variation) and upon partial failure of host's immune mechanisms. Impairment of immune response in parasitic infections, analysed and discussed from literature (138 references), is characterized by a high prevalence of autoantibodies and the common observation of immunosuppression in human parasitic infections as well as in experimental models. The high prevalence of autoantibodies accompanying increased levels of immunoglobulins contrasts with the low prevalence of autoimmune diseases in parasitic endemic areas. Evidence for cell mediated autoimmune process has rarely been reported. This might be related to an impairment of T-helper cell function and to the direct role, on B cells, of mitogens from parasite origin. Immunosuppression has been described in many human parasitic infections and in numerous experimental models. The defect in host's immune response is expressed by an impairment of both humoral and cell mediated immune responses to various heterologous antigens, and increased susceptibility to tumorigenesis, prolonged survival of skin allografts and an increased susceptibility to bacterial or viral infections. Various mechanisms of immunosuppression have been described, including failure of macrophage function or release of soluble immunosuppressive factors by parasites. The authors report some of their recent experiments in experimental schistosomiasis, which have allowed the characterization of such factors. Parasites appear in general to play a role in the regulation of the immune response that they have themselves evoked.


[Effect of cobalt on the growth of a Micromonospora purpurea var.  violacea 1935 culture and on the biosynthesis  of gentamincin]. The effect of cobalt on growth of Micromonospora purpurea var. violacea 1935 and biosynthess of gentamicin in complex soy-bean meal or "synthetic" gelatin medium was studied. In optimal concentrations cobalt increased the activity level of the culture fluid almost 6 times in both media having practically no effect on the amount of the mycelium formed. Addition of cobalt to the medium resulted in retardation of the organism growth and consumption of the nutrients. Stimulation of gentamicin biosynthesis by cobalt was inversely proportional to the time of the trace element addition. The cobalt effect depended on the aeration conditions, inorganic phosphorus level in the medium and physiological condition of the mycelium.


[Immunosuppressive factors released by Schistosoma mansoni]. Immunosuppressive factors were evidenced in cell-free supernatant of S. mansoni schistosomes culture and incubation products of the parasite. Both parasitic materials decreased tritiated thymidine and leucine uptake in normal spleen cells from CBA mouse and Fischer rats and in peripheral human blood lymphocytes stimulated either by non specific mitogens (PHA, ConA, or LPS) or by allogeneic cells. The suppressive factor(s) was (were) heat-resistant, dialyzable and of molecular weight 500-1,000. The inhibition of lymphocyte proliferation was not due to cytotoxic or cytostatic activity on lymphoid cells, nor did the parasitic reagents interfere with the binding of fluorescein-labelled ConA. The suppressive activity was also demonstrated in the serum from rats infected for 4 weeks by S. mansoni and in the dialyzable fraction of it. This suggests the release by the parasite in vitro as well as in vivo of inhibitory factor(s) decreasing lymphocyte proliferation and brings therefore a new light on the machanism of immune deficiency in parasitic infections.


[Further study of the patterns of penicillin active transport in the kidney tubules of rabbits in vitro and in vivo]. A number of inhibitors of benzylpenicillin active transport in surviving sections of the abbit kidney cortex has been found for the first time. The capacity for such transport was shown with respect to all natural and semisynthetic penicillins tested. The section accumulation method was recommended for the use in screening new penicillins with prolonged action. Absence of corelation between the value of the section/medium concentration gradient and the index of penicillin kidney clearance was registered. It was shown that the binding level of penicillins by blood serum proteins did not define the rate of their excretion with the urine in rabbits.


[Multiple sclerosis: a multi-specific immune deficiency disease]. New immunological data (Brit. med. J., 1976, 1, 183-186) lead us to a fundamental reconsideration of the immunopathological concept of multiple sclerosis (MS). The increased incidence of the infection rate during childhood, the low humoral and cell-mediated immune responses towards many bacterial and viral antigens and the presence of these specific immune deficiencies in a group of doubtful MS cases being at the first bout of the disease, led us to consider MS as a multi-specific immune deficiency disease, possibly having its origin in the genes controlling the immune response to these specific antigens. We now consider MS as being the end result of multi-specific immune deficiencies, which would explain the increased incidence of tonsillectomies, appendicectomies and repeated infections during childhood and the presence of numerous small inflammatory and pyrexic processes, often benign, but susceptible to cause in the target tissue--the central nervous tissue--the demyelinization process which could well be not specific at all. This new optic opens the way to the use of different immunotherapy regimens including transfer factor or whole lymphokines, and stimulation of the immune response with immunological adjuvants rather than immunosuppressive agents used during recent years (like steroids, ACTH) which have an antiinflammatory as well as an immunosuppressive function.


[Deacylating activity of sera as a cause for the ineffectiveness of the treatment of experimental plaque in white mice with benzylpenicillin]. It was shown that serum of albino mice infected with plague microbe cells inactivated benzylpenicillin. Such deacetylating activity reached its peak by the 3rd day and after that decreased reaching by the 5th--7th day the level registered in non-infected animal and being apparently of non-specific character. Ampicillin proved to be 2 times more resistant to the effect of serum acylase as compared to benzylpenicillin. It was supposed that the ability of serum of infected animals to inactivate benzylpenicillin by splitting off phenylace acid was the cause of ineffective treatment of experimental plague of albino mice with comparatively low doses of the drug.


[Contribution of immuno-hematology in understanding autoimmune phenomena]. Acquired hemolytic anemia (AHA) can be considered under four aspects: 1) The nature and specificity of involved autoantibodies correspond to weakly differentiated structures of high frequency but normal human blood group antigens. 2) The pathologic role of autoantibody can be experimentally demonstrated by parallel measures of the specific red cell survival. 3) In certain cases of AHA--secondary to infections (Mycoplasma pneumoniae, infectious mononucleosis) or drugs (methyl dopa), or related to tumours (dermoid ovarian cyste, ovary teratoma) or tissue damages (haemorragic rectocolitis)--the relation between a clinical precise circumstance and the production of autoantibody can actually be demonstrated. 4) In idiopathic AHA, in addition to various autoantibodies, an immunological disorder is observed, including the production of allo- and heteroantibodies and, in 50% of the cases, a global deficit in immunoglobulin. 5) On these bases, the nature of autoimmunity is discussed. If specific modifications can explain secondary AHA, they can hardly account for idiopathic AHA. Cellular non-specific anomalies should be considered.


[Responsible agents and mechanisms of direct allogeneic anaphylactic degranulation]. Because mast cells from inbred mice possess both H-2 Ag and Fe receptors they can be degranulated by anaphylactic allo-Ab (DAAD). Beside IgG1, IgE allo-Ab were shown to exist and to be able to achieve DAAD. So far, to be the target of DAAD, an Ag must be present on the mast cell membrane and presumably not linked to the Fe receptor. The mechanism of DAAD involves very likely a double interaction of the Ab (by its two reactive ends) with the mast cell membrane.


[Effect of a polysaccharide-contaning preparation from El Tor vibrions on the phagocytic activity of leukocytes and on the lysozyme titer]. The dynamics of changes in some indices of the natural immunity of mice treated with EL-Tor vibrio preparations in doses of 50 and 500 gemma/mouse was studied. The blood for analysis was taken from the mice 24 hours, 3, 7 and 10 days after the preparation administration. The results of the study showed that administration of the polysaccharide-containing preparations from El-Tor vibrios in doses of 50 and 500 gemma/mouse was accompanied by some shifts in the regulatory mechanisms: suppression of the serum lysozyme activity on the 1st and 3rd days and its stimulation on the 7th and 10th days. The percentage of phagocytosis and its completeness increased. The indices of phagocytosis and its completeness by the respective periods decreased.


[Biochemical changes in the kidney cells of dogs after the intravenous administration of deoxycholate sodium (the nephrotoxic action of amphotericin B)]. The effect of sodium desoxycholate on the plasmic membranes and chromatin of the dog kidney cells after its intravenous administration to the animals in a dose of 1.2 mg/kg equal to the content of sodium desoxycholate in the therapeutic preparation of amphotericin B once a day for 8 days was studied. It was shown that sodium desoxycholate did not induce any detactable shifts in the protein composition of the plasmic membranes. At the same time administration of sodium desoxycholate was accompanied by disorders in the fractions of the membrane-bound and free chromatin of the dog kidneys. It was found that sodium desoxycholate promoted binding of chromatin to the nuclear membrane, changed the chemical composition of the both fractions studied and damaged the spectrum of the histones  of free chromatin. An analogous character of the effect on the above subcellular structures of the kidney tissue was observed with the used of amphotericin B. However, the level of the effect of the antibiotic complex with sodium desoxycholate on the above structures was more significant than that of sodium desoxycholate used alone. The data obtained were indicative of sodium desoxycholate toxicity in vivo and promoted elucidatio  of the cause of amphotericin B toxic effect on microbial cells.


[Chronic granulomatous disease (CGD): in vitro enhancement of bactericidal activity of CGD phagocytes by rifampicin]. In a series of 29 experiments on CGD patients, we have studied the in vitro bactericidal capacity of normal and CGD phagocytes against penicillin, streptomycin and rifampicin sensitive Staphylococcus aureus. The bactericidal activity of phagogyte preparations was tested at different intervals during a 21 hour incubation. The CGD-phagocyte bactericidy peaks after 90 min when penicillin is used; in contrast, a significant enhancement of the bactericidal activity is noted with rifampicin and best noted after 21 hours of incubation. To elucidate the mode of action of this antibiotic, a rifampicin resistant S. aureus was used in a series of experiments; The results  point to a mixt type of action: antimicrobial and metabolic.


[Action of cycloheximide on RNA synthesis and the formation of structures in the Venezuelan equine encephalomelitis virus]. The studies showed that the effect of cycloheximide on reproduction of the virus of Venezuelan equine encephalitis (VEE) depended on the time of the antibiotic administration. When the antibiotic was added 3--5 hours after the inoculation (after formation of the virus RNA-polymerase), accumulation of virus RNA and 60--100 S virus structures was observed in the cells, while virus nucleotides and infection virus did not practically form. The 60--100 S structures included the cell proteins. They were resistant to EDTA and their swimming density in cesium chloride was 1.3--1.4 gm/cm3, it was characteristic of RNA of a non-ribosomic nature. According to these properties 60--100 S structures may be classified as belonging to the "hybrid" RNA analogous to the RNA complexes of VEE virus with the cell proteins. Probably addition of cycloheximide provided conditions in the infected cells for increase of the "hybrid", structural pool since the synthesis of the structural virus proteins was suppressed.


[Non-specific responses of C3H/He low responder mice to LPS and to TCA-extracted endotoxin]. In vitro and in vivo host reponses to lipopolysaccharide (LPS) and various immunostimulants were compared in C3h low-and highresponder mice, their F1, F2 and backcross hybrids. In contrast to the responsiveness of a congeneic high responder subline, LPS is unable to stimulate thymidine incorporation by splenocytes of the low-responder subline and to protect these mice against an unrelated bacterial infection, Moreover, although endotoxin extracted by trichloroacetic acid was mitogenic in these low-responder mice, it was still unable to increase their resistance against an infectious challenge; in addition, the LD50 of both endotoxin preparations was about 3,500 fold greater than in the high-responder mice. For this latter assay, mice were adrenaloctomized since it is well established that mouse's susceptibility to LPS is dramatically enhanced in the absence of glucocorticoids. Inheritance of susceptibility to lethal effect of endotoxin and of LPS-induced non-specific resistance to infection was also tested in both sublines, their hybrids and backcross progeny. The present findings are consistent with the hypothesis that these LPS host-responses may be determined by a single autosomal dominant gene.


[Impairment of humoral immunity in aging]. 1) Aging is associated with a hypergammaglobulinemia consistng of an increase in the serum IgG and IgA, plus a reduction in the IgM. This is associated with an increase of the B lymphocyte circulating pool, and an increase of the ratio IgG-B cells; 2) There is a reduction of the serum concentration of natural isoagglutinins. 3) The secondary IgG response against diphteria toxin (DT) is similar in 15 young and 15 old subjects. 4) There is a reduction of the IgE response against DT in old subjects.


[Pharmacokinetics of rifampicin in single and repeated administration to patients with inflammatory processes in the lungs of nontuberculotic etiology]. Rifampicin is a broad spectrum semisynthetic antibiotic of the group of rifampicins. It is active against both grampositive and gramnegative organisms and mycobacteria. The studies on the pharmacokinetics of rifampicin showed that the drug was well absorbed from the gastro-intestinal tract. After a single administration of rifampicin in a dose of 150 mg its maximum concentration in the blood was registered in an hour. This concentration was preserved at the therapeutic level for 5 hours. Practically no accumulation of rifampicin was observed in its use in a dose of 150 mg 4 times a day for 5 days. Perspectivity of rifampicin use in the treatment of patients with inflammatory processes in the lungs of non-tuberculosis etiology was shown.


[Role of C1 subcomponents in platelet aggregation induced by aggregated IgG]. Studies have been performed with platelets using C1 haemolytic assays and platelet aggregation induced by anti-C1q, anti-C1s and aggregated IgG in the presence of C1 subcomponents C1q, C1r and C1s. C1q was removed by EDTA or modified by collagenase from human platelets while after the same treatment C1s remained bound to the platelets. EDTA-treated platelets were no longer aggregated by aggregated IgG. The addition of C1q restored the reactivity of the platelets to aggregated IgG while the addition of C1s or C1s was without effect. Furthermore, the addition of C1r or C1s to C1q inhibited the action of C1q in platelet aggregation induced by IgG. The possible association between the different C1 subcomponents and human platelets is discussed.


Emergence of gentamicin-resistant Klebsiella in a general hospital. Gentamicin had been in use in a general hospital for over 7 years before any gentamicin-resistant Klebsiella were observed. In 1974 and 1975, nine different gentamicin-resistant serobiotypes of Klebsiella were isolated from 35 patients. The first strain to appear had R-factor-mediated gentamicin resistance, and it infected 19 patients during a period of almost 2 years, spreading largely by case-to-case infection in patients with urinary catheters. It appeared to lose the capacity to transfer its gentamicin resistance after it had infected five of the patients. We had previously isolated on the same ward a gentamicin-susceptible Klebsiella of identical type, and it was found to be capable of acquiring an R-factor for gentamicin resistance. All of the other types of gentamicin-resistant Klebsiella infected few patients and did not persist in the hospital; four of them had R-factor-mediated resistance to gentamicin and all four, as did the original strain, cotransferred kanamycin, neomycin, and tobramycin resistance. Every gentamicin-resistant Klebsiella was susceptible to amikacin and netilmicin.


Drug resistance and R plasmids in Salmonella typhi isolated in Korea. A total of 949 strains of Salmonella typhi isolated in Korea from 1968 to 1975 were tested for drug resistance and distribution of R plasmids. Resistance was mostly restricted to streptomycin (SM) and sulfisomidine (SA), singly or in combination, at a low degree. A small number of strains (1.5%) were resistant to four or more drugs: chloramphenicol (CM), tetracycline (TC), SM, SA, ampicillin (AP), and kanamycin (KM). No strain was resistant to nalidixic acid or to a 1:20 mixture of trimethoprim and sulfamethoxazole. Nor was there any strain singly resistant to CM, TC, AP, or KM. Transfer experiments of multiple-drug resistance to Escherichia coli ML1410 showed that all the strains resistant to four or more drugs carried R plasmids, whereas those weakly resistant to three or less drugs did not. The quadruply resistant strains carried one R plasmid determining CM, TC, SM, and SA resistance, and sextuply resistant ones carried two plasmids, one determining CM, TC, SM, and SA resistance and the other determining AP and KM resistance. One strain carrying a plasmid determining AP and KM resistance was also found. The transfer frequency of CM, TC, SM, and SA resistance was much higher than that of AP and KM resistance. The resistance of S. typhi was more efficiently transferred to E. coli at 25 degrees C than at 37 degrees C.


Pharmacokinetics of amikacin during hemodialysis and peritoneal dialysis. The pharmacokinetics of amikacin were examined in six bilaterally nephrectomized patients undergoing hemodialysis and in four patients with a minimal residual renal function undergoing peritoneal dialysis. The mean elimination half-life before the dialysis was 86.5 h in the anephric patients and 44.3 h in the patients with minimal residual kidney function. The results from the anephric patients suggest that some extrarenal elimination of amikacin may occur. The mean volume of distribution was about 25% of the total body weight. This is in accordance with values reported from subjects with normal renal function. During hemodialysis the half-life decreased to less than 10% (5.6 h) of the pretreatment value. The effectiveness of peritoneal dialysis was less as the half-life decreased to only about 30% (17.9 h) of the pretreatment value. During the dialyses a significant correlation between the half-life of amikacin and the decrease in blood urea and serum creatinine was demonstrated. The pharmacokinetic data were used to make dosage regimen recommendations for the treatment of patients undergoing intermittent hemodialysis or peritoneal dialysis.


Microdilution transfer plate technique for determining in vitro synergy of antimicrobial agents. A microdilution transfer plate technique for determining in vitro synergy of antimicrobial agents is described. Combinations of gentamicin-nalidixic acid against Proteus mirabilis and rifampin-amphotericin B against Candida albicans are used as examples to demonstrate the technique. Results correlate with published data obtained by conventional methods. The technique is effective for evaluating the in vitro effects of antimicrobial agent combinations against both bacteria and fungi. The technique enables one to produce a checkerboard gradient in a fast, convenient, and reproducible way; results are easily visualized.


Effects of purines and pyrimidines on the fungistatic activity of 5-fluorocytosine in Aspergillus species. The ability of some exogenously supplied purines, pyrimidines, and their nucleosides to antagonize the in vitro fungistatic activity of 5-fluorocytosine (5-FC) in Aspergillus species was examined. All compounds tested except thymidine were capable of altering the minimal inhibitory concentration of 5-FC for seven strains of aspergilli tested. In most instances, there was a reciprocal correlation between the ability of a compound to antagonize the fungistatic activity of 5-FC and the quantity of 5-FC taken up by cells in the presence of the compound over a 72-h period.


Prevention of 5-fluorouracil-caused growth inhibition in Sordaria fimicola. Growth (dry weight accumulation) of Sordaria fimicola in standing liquid culture (sucrose-nitrate-salts-vitamins) is inhibited by the presence of 5 muM 5-fluorouracil in the medium. This inhibition is completely prevented by uracil, deoxyuridine, and 5-bromouracil, partly prevented (40 to 90% of growth observed without 5-fluorouracil) by uridine, thymidine, and 5-bromodeoxyuridine, and slightly prevented by trifluorothymine, cytosine, cytidine, deoxycytidine, and 5-methylcytosine (all at 0.5 to 1 mM). Thymidine and thymine riboside were without any apparent effect. Growth is also inhibited by 0.2 mM 6-azauracil, and this inhibition was completely prevented by uracil and uridine, partly prevented by deoxyuridine, 5-bromouracil, cytidine, and 5-methylcytosine, and slightly prevented by thymine, thymidine, 5-bromodeoxyuridine, cytosine, and deoxycytidine. The data suggest that the observed inhibition of growth by 5-fluorouracil is due to inhibition of both ribonucleic acid and deoxyribonucleic acid synthesis. The data also allow inferences concerning pyrimidine interconversions in S. fimicola; i.e., thymine can be anabolized to thymidylic acid without first being demethylated, although demethylation appears to occur also.


Antimicrobial prophylaxis for catheter-associated bacteriuria. We evaluated short-term systemic antimicrobial prophylaxis for catheter-associated bacteriuria in women undergoing elective gynecological operations in a prospective, controlled, double-masked study. Nine of 100 placebo-treated patients acquired bacteriuria during catheterization compared with 3 of 96 of the drug-treated group. However, at the time of hospital discharge, clean-voided urine specimens were positive as frequently in the drug-treated group (8 of 82 patients cultured) as in the placebo group (8 of 75 patients cultured). No difference in febrile morbidity due to bacteriuria was noted between the prophylaxis and placebo groups. The incidence of catheter-associated bacteriuria may be reduced by antimicrobial prophylaxis. However, because the protective effect is transient and is associated with the selection of resistant organisms, prophylaxis is not indicated for patients at low risk for acquired bacteriuria and in whom the sequelae of catheter-associated infections are infrequent.


Bone marrow toxicity associated with 5-fluorocytosine therapy. Bone marrow toxicity occurred in 4 of 15 patients treated with 5-fluorocytosine (5-FC) for serious fungal infections. The development of marrow toxicity appeared to be related to serum 5-FC levels of 125 mug/ml or greater. In three patients, accumulation of toxic levels of 5-FC was related to diminished renal function. One patient with acute renal failure and prolonged high levels of 5-FC developed marrow aplasia and died of bacterial sepsis. Three patients experienced leukopenia, which was readily reversed when the dosage of 5-FC was decreased and the serum concentration was lowered. With careful monitoring of serum 5-FC concentration and renal function, the dose-related toxic effects of 5-FC on the marrow can be avoided.


Pharmacokinetics of cefamandole in patients with renal failure. The pharmacokinetics of cefamandole were studied in four patients with stable renal failure, two patients undergoing peritoneal dialysis, and four patients undergoing hemodialysis. Peak concentrations of cefamandole in serum were achieved 1 to 2 h after intramuscular injection in the patients with stable renal impairment, and the concentrations declined slowly, with half-life values of 12.3 to 18 h. Cefamandole was removed only very slowly by peritoneal dialysis. Hemodialysis was more efficient in removing cefamandole, with serum half-life values ranging from 3.8 to 7.9 h. The mean apparent volume of distribution of cefamandole in these 10 patients was 21.92 liters, or 31% of the body weight.


Changes in superhelical density of closed circular deoxyribonucleic acid by intercalation of anti-R-plasmid drugs and primaquine. The following compounds, which possess anti-R-plasmid activity (Hahn and Ciak, 1976) in decreasing order, were shown by viscometric titration to change systematically the superhelical density of closed circular PM2 deoxyribonucleic acid in the manner of intercalators: ethidium bromide, quinacrine, acridine orange, quinine, chlorpromazine, chloroquine, and methylene blue. The same effect was caused by the antimalarial drug primaquine, which has not been tested for antiplasmid activity.


In vitro activity of ticarcillin against anaerobic bacteria compared with that of carbenicillin and penicillin. A total of 334 clinical anaerobic isolates were tested in an anaerobic glove box by the agar dilution technique for susceptibility to clinically achievable levels of ticarcillin, carbenicillin, and penicillin. Thirty-two micrograms or less of penicillin per milliliter inhibited 91% of all strains, whereas 100 mug of carbenicillin and ticarcillin per ml inhibited 95 and 98%, respectively. A total of 82% (85 strains) of Bacteroides were inhibited by penicillin, and 93 and 96% were inhibited by carbenicillin and ticarcillin, respectively. Thirteen (24%) of 55 strains of Bacteroides fragilis tested were resistant to 32 mug of penicillin per ml, and 6 (11%) and 3 (5%) were resistant to 100 mug of carbenicillin and ticarcillin per ml, respectively. Within the therapeutic range, ticarcillin was the most effective of the three penicillins tested against B. fragilis subsp. fragilis.


Pharmacokinetics of cefamandole in patients with normal and impaired renal function. The pharmacokinetics of cefamandole, a new cephalosporin, were investigated in 23 patients with urinary tract infections and normal or varying degrees of impairment of renal function. A daily dose of 1.5 to 3.0 g administered intramuscularly was tolerated well and resulted in very high urine concentrations. The pharmacokinetics of the antibiotic were compared with isotopically labeled [(131)I]hippurate and [(125)I]iothalamate, which were used for determination of effective renal plasma flow and glomerular filtration rate, respectively. It was shown that cefamandole was excreted by glomerular filtration as well as by active tubular secretion. Probenecid inhibited the tubular secretion of cefamandole. The serum half-life of cefamandole in patients with normal renal function was approximately 1.5 h and increased in patients along with increasing impairment of renal function. Our studies indicate that a dosage regimen of 1 g of cefamandole every 8 h in patients with normal renal function results in urine concentrations sufficiently high for treatment of most common urinary tract infections. In patients with impaired renal function, the dosage interval should be increased or the dosage lowered according to the serum creatinine values.


Simple, direct broth-disk method for antibiotic susceptibility testing of Ureaplasma urealyticum. A simple, direct broth-disk test, utilizing urine sediment as the inoculum and impregnated paper disks as the source of antibiotic, was developed and used to test the susceptibility of 54 isolates of Ureaplasma urealyticum (T-strain mycoplasmas) to minocycline, doxycycline, demeclocycline, tetracycline, and erythromycin. The concentration of each antibiotic was calculated to approximate the attainable blood level. Resistance or susceptibility to each antibiotic was determined by growth, indicated by a color change of the medium in each tube, comparable to that of a control culture without antibiotic. Of the 54 T-mycoplasmas tested, 46 (85.2%) were inhibited by 1 mug of minocycline per ml, 45 (83.3%) were inhibited by 1 mug of doxycycline per ml, 38 (72.2%) were inhibited by 1 mug of demeclocycline per ml, 18 (33.3%) were inhibited by 1 mug of tetracycline per ml, and only 2 (3.7%) were inhibited by 3 mug of erythromycin per ml. Seven (13%) of the 54 T-mycoplasmas tested were resistant to all five antibiotics. There was good correlation between results obtained by this direct broth-disk method and minimal inhibitory concentrations obtained by the direct broth dilution method.


Evaluation of the performance parameters of a prediluted, quantitative antibiotic susceptibility test device. A multiwelled plastic strip containing prediluted antibiotics was tested. Antibiotics available at the time of testing included ampicillin, penicillin, methicillin, erythromycin, clindamycin, tetracycline, and minocycline. The effects of inoculum size, inoculum volume, temperature, and time of incubation were determined. A limited clinical evaluation using laboratory strains of selected bacteria proved this product to be a rapid, economical, and reliable method for the determination of the minimal inhibitory concentration of antibiotics.


Amphotericin B susceptibility testing of yeasts with a bactec radiometric system. The effect of amphotericin B on CO(2) production was studied using a Bactec 225. A radiometric procedure for yeast susceptibility testing that requires 3 h of incubation was developed. A total of 48 yeast isolates was tested in this system and the results were correlated to tube dilution studies. The drug concentration causing at least a 44% decrease in CO(2) production correlated to the tube dilution minimal inhibitory concentration in 85% of isolates tested and was within one tube dilution of the minimal inhibitory concentration in over 95% of yeasts tested.


Development of a chemically defined medium for the synthesis of actinomycin D by Streptomyces parvulus. A chemically defined medium, consisting of d-fructose, l-glutamic acid, l-histidine, K(2)HPO(4), MgSO(4).7H(2)O, ZnSO(4).7H(2)O, CaCl(2).2H(2)O, FeSO(4).7H(2)O, CoCl(2).6H(2)O, and deionized water, was developed for synthesis of high yields (500 to 600 mug/ml) of actinomycin D by Streptomyces parvulus. Under these nutritional conditions, growth and actinomycin formation did not follow a typical trophophase-idiophase pattern. The amino acids appeared to have a sparing action on the utilization of d-fructose which was slowly and incompletely metabolized during mycelium development and antibiotic production. A significant repression of actinomycin synthesis by S. parvulus was observed when d-glucose (0.01 to 0.25%) was added to the culture medium. The repression was not due to a decline in the pH of the medium during glucose catabolism.


Combined antiviral effects of interferon, adenine, arabinoside, hypoxanthine arabinoside, and adenine arabinoside-5'-monophosphate in human fibroblast cultures. Adenine arabinoside and human interferon are currently being evaluated in clinical trials against herpes- and poxvirus infections. Interferon production is also a normal antiviral response. It is therefore important to examine the combined actions of interferon and antiviral arabinosides for possible synergy or antagonism. We have examined the antiviral activities of human fibroblast interferon, adenine arabinoside, hypoxanthine arabinoside, and adenine arabinoside 5'-monophosphate individually, using plaque inhibition of vaccinia and herpes simplex type 2 viruses in human skin fibroblast cultures. By combining doses of interferon and arabinosides that, acting alone, give intermediate degrees of plaque inhibition, we were able to compare the combined antiviral activity with that calculated from the activity of each inhibitor alone, assuming that the activities are statistically independent. Our results show that the plaque-inhibitory activities of interferon and the arabinosides tested are statistically independent. The results also show that the arabinosides do not destabilize the antiviral state previously induced by interferon, and that interferon pretreatment does not interfere with subsequent arabinoside action in infected cells. We have also found that arabinosides do not affect the induction of interferon synthesis by either Newcastle disease virus or double-stranded ribonucleic acid, and are not themselves interferon inducers.


Lethal and mutagenic effects of 5-iodouracil on bacteriophage T4td8rII. Evidence was obtained which indicates that the lethal effect of 5-iodouracil (IUra) on bacteriophage T4 is not due to a mutagenic process. T4td8rII (thymine requiring, rapid lysis) double mutants were constructed. Reversion of T4td8rII to r(+) was measured. First, reversion by growth in the presence of the structural analogues chlorouracil (ClUra) and bromouracil (BrUra) did not correlate with their relative lethal effects (for mutagenesis: IUra </= ClUra </= BrUra; for lethality: ClUra < BrUra < IUra). Second, reversion frequencies of T4td8rII in infected cells increased linearly with time of growth in the presence of IUra, whereas the frequency of lethality was constant with time. Third, reversion frequencies increased markedly at low levels of IUra substitution, whereas lethal effects were apparent only with extensive IUra substitution. Fourth, the reversion frequency of the nonviable fraction of IUra-substituted T4td8rII (as examined by multiplicity reactivation) did not differ significantly from that of the viable IUra-substituted T4td8 fraction. If mutagenesis caused lethality, then the nonviable T4td8rII fraction should accumulate mutations and have a higher reversion frequency.


Cefadroxil, a new broad-spectrum cephalosporin. Cefadroxil is a new semisynthetic cephalosporin with a broad antibacterial spectrum and a high chemotherapeutic potential when administered orally. The inhibitory activity of this compound was similar to that of cephalexin and cephradine when tested against 602 clinical isolates on Mueller-Hinton medium. In the oral treatment of experimental infections of mice, cefadroxil was more effective than cephalexin against Streptococcus pyogenes, and comparably effective against Streptococcus pneumoniae, Staphylococcus aureus, and several gram-negative species. Administered orally to mice, at doses ranging from 25 to 100 mg/kg, cefadroxil attained peak concentrations in the blood similar to those of cephalexin. At a dose of 200 mg/kg, however, higher peak levels were noted with cefadroxil than with cephalexin. In regard to other properties which were investigated, the behavior of cefadroxil compared favorably to that of cephalexin.