The fetal trimethadione syndrome: report of an additional family and further delineation of this syndrome.

We describe a family in which seven pregnancies resulted in four infants who died and in three abortions. During these pregnancies the mother took trimethadione (Tridione), as well as other anticonvulsants. Two normal children were born after treatment with all medications were stopped. There have now been 53 reported pregnancies in which the fetuses were exposed to trimethadione or paramethadione; 48 (87%) resulted in fetal loss or a child born with congenital malformations. The most common defects include malformed ears, cleft palate, cardiac defects, urogenital malformations, and skeletal abnormalities. Delayed mental and physical development were also seen. These findings constitute a clinical entity termed the fetal trimethadione syndrome. The malformation rate is believed to be due to the teratogenic effects of trimethadione. Physicians need to be aware of the danger of trimethadione and related drugs during pregnancy and should withhold these medications during this period.


Quantitation of the enzymically deficient cross reacting material in GM1 gangliosidoses.

Normal quantities of GM1 beta-galactosidase cross reacting material (CRM) (0.31-0.47 microgram/mg protein) were detected by a sensitive radial immunodiffusion assay in skin fibroblasts from patients with GM1 gangliosidosis type 1 and adult variants, whereas elevated levels were found in GM1 gangliosidosis type 2 (0.41-0.72 microgram/mg protein). The specific activity of the immunologically CRM towards GM1 ganglioside of normal fibroblasts was about 500 times that of type 1, 100 times that of type 2, and 30 times that of the adult variants.


Drug product advertising and prescribing: a review of the evidence.

A review of the effect of advertising drug products in medical journals on the prescribing of drugs is presented. The scope of advertisiig, the content of advertising, the latent effects of advertising, the effects of advertising on prescribing, and the social costs and benefits of advertising are discussed. Advertising for antibiotic and psychotropic drug products is reviewed in some detail. It is concluded that there is inconclusive evidence that the pharmaceutical industry, through journal advertising, is persuading physicians to prescribe drugs too often or unwisely, or both. It is suggested that pharmacists study the information needs of health care practioners and provide good drug information services.


Interdisciplinary diabetic team in a community hospital.

An interdisciplinary diabetic team which provides inpatient and outpatient diabetic instructional services in a 200-bed community hospital is discussed. The team consists of a pharmacist, a dietitian, and a registered nurse, each of whom is assigned to a specific area of diabetic education. Instructional objectives include coordination of teaching efforts by hospital personnel, standardization of education, and development of evaluation procedures. Upon notification of a physician request for diabetic team services, a form which contains competency-based instructional objectives and patient referral questions is placed in the patient's chart. Diabetic instruction may then be initiated by ward personnel or a member of the diabetic team. Outpatient classes are offered for those who desire or require additional or indepth instruction.


Regulation of function of transplanted parathyroid glands in man.

The results of studies performed in nine patients who had undergone successful parathyroidectomy and gland transplantation are presented. Transplantation of parathyroid tissue to the forearm, performed for therapeutic reasons, provided a unique opportunity to sample parathyroid gland effluent and to assess secretory function in vivo. The relationship of calcium to immunoreactive parathyroid hormone (iPTH) release was studied during calcium and ethylenediamine tetraacetic acid (EDTA) infusions as well as dialysis against a low calcium bath (low calcium dialysis) in patients with chronic renal failure. Calcium infusions caused an abrupt decrease in hormone release down to a persistent base line within 30 minutes, whereas EDTA infusion caused a sharp increase which peaked between 30 to 60 minutes and returned towards base line despite continuation of the hypocalcemic stimulus. Low calcium dialysis caused an irregular release of hormone which appeared to deplete gland reserves during the period of the stimulus. Ready access to the venous effluent of the transplanted tissue makes this an excellent model for studying parathyroid physiology in man.


Genetic studies of free-ranging macaques of Cayo Santiago. I. Description of the population and some nonpolymorphic red cell enzymes.

Phenotypes of eight red cell enzymes at nine genetic loci were determined in the semi-free-ranging population of rhesus macaques; Macaca mulatta, that inhabit Cayo Santiago. The following enzymes were examined electrophoretically: adenosine deaminase, glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, indophenol oxidase, lactate dehydrogenase, malate dehydrogenase, phosphoglucomutase-1, phosphoglumutase-2, and purine nucleoside phosphorylase. Hemolysates from at least 372 animals were analyzed, and no variants of the enzymes were observed with the exception of malate dehydrogenase. Three animals displaying a variant form of malate dehydrogenase were found.


Correlation of tooth size and body size in living hominoid primates, with a note on relative brain size in Aegyptopithecus and Proconsul.

Second molar length and body weight are used to test the correlation between tooth size and body size in living Hominoidea. These variates are highly correlated (r= 0.942, p less than 0.001), indicating that tooth size can be used in dentally unspecialized fossil hominoids as one method of predicting the average body weight of species. Based on tooth size, the average body weight of Aegyptopithecus zeuxis is estimated to have been beteen 4.5 and 7.5 kg, which is corroborated by known cranial and postcranial elements. Using Radinsky's estimates of brain size, the encephalization quotient (EQ) for Aegyptopithecus was between 0.65 and 1.04. A similar analysis for Proconsul africanus yields a body weight between 16 and 34 kg, and an EQ between 1.19 and 1.96.


Regional variation in tooth size and pathology in fossil hominids.

Tooth size and dental pathology in fossil hominids were studied to test for regional differences in these parameters. The results showed little regional variation in tooth size for the Middle and Upper Pleistocene sites compared (except for Krapina) but considerable differences in the severity of attrition and dental pathology. These differences were considered indicative of regional differences in the functional load borne by the teeth, and in view of the similar technological status of the groups studied, were attributed to environmental differences in the diet. Since, in all regions, reduction in tooth size appeared to continue at the same rate for the periods investigated, no association can be established between presumed selective pressures related to differences in functional demands made on the dentition, and tooth reduction.


Clozapine plasma levels and convulsions.

Two patients receiving clozapine developed grand mal seizures. The plasma levels in one of the patients at the time of the seizure were approximately 100% higher than on 12 previous occasions. This finding led to the conclusion and the patient's admission that she had taken an overdose. Plasma levels in the other patient exceeded the range the authors had noted in previous studies. The authors emphasize the usefulness of plasma level monitoring in relation to safety, drug defaulting, and side effects.


[Nitrogen balances and clinical development in the case of post-operative infusion therapy with solution of essential and complete amino acids ].

Nitrogen balance was studied in eleven patients receiving parenteral nutrition after operation. None of nine patients showed evidence of azotaemia. In two patients suffering from renal insufficiency in a stage of compensated retention there was no deterioration of metabolism as an immediate consequence of operation. The use of essential amino acids did not reveal any advantage over the infusion of a complete amino acid solution of high value.


Evaluation of virginiamycin in feed for treatment and retreatment of swine dysentery.

Virginiamycin, fed at a concentration of 110 mg/kg of feed for 2 weeks followed by concentrations of either 27.5 or 55 mg/kg for 3 weeks, was effective in treatment and control of experimentally induced swine dysentery. However, diarrhea recurred 4 days after withdrawal of medicated feed. Subsequently, the frequency of diarrhea decreased in 3 of 4 groups retreated with virginiamycin (110 mg/kg of feed) for 5 days. Feeding of virginiamycin (110 mg/kg) for 1 week after onset of diarrhea was of little value because of the development of a more severe (augmented) form of the disease after withdrawal of medicated feed. Feeding of virginiamycin (55 mg/kg) at the time of exposure and continuing for 3 weeks (followed by intermittent retreatments of 55 mg/kg) aided in treatment and control of swine dysentery. With this regimen, a few swine developed diarrhea during initial medication, but all developed diarrhea after withdrawal fo medicated feed. Frequency of diarrhea was less after each retreatment. This was attributed to the development of immunity from the recurring diarrhea.


Chronic bile duct cannulation of rhesus macaques (Macaca mulatta) without causing biliary fistulas.

Two surgical procedures were used for establishing chronic bile duct cannulations in rhesus macaques (Macaca mulatta) while maintaining an intact enterohepatic circulation for use in metabolism studies. One procedure resulted in the formation of biliary fistulas in all of the animals, whereas the other procedure allowed successful maintenance of the macaques without fistulation for up to 8 months after surgery. The possible importance of pressure against bile outflow in the development of the fistulas was discussed.


Pulmonary functions in conscious and anesthetized rhesus macaques.

Techniques for measurements of selected pulmonary functions for a period of 6 hours in conscious and lightly anesthetized rhesus macaques are described. Among all variables measured, only higher PaCO2 (367 +/- 32 mm of Hg) occurred in macaques breathing O2 as compared with those breathing room air. Tidal volume, respiratory rate, minute volume, O2 consumption, and specific ventilation in conscious and anesthetized monkeys were not significantly different. Further, respiratory and metabolic values from lightly anesthetized macaques in the present study agree well with the reports of others. However, differences were the higher values for O2 consumption, tidal volume, respiratory rate, and minute volume obtained with the presently described techniques as compared with certain reported data.


Cardiovascular and hepatic responses of rhesus macaques to staphylococcal enterotoxin B.

Certain cardiovascular and hepatic functions were measured for a period of 6 to 14 hours in conscious, chaired, male rhesus macaques given (intravenously (IV) or orally) staphylococcal enterotoxin B (SEB). In macaques orally given SEB (1 mg/kg), there was little change in the cardiovascular variables. The half-life of injected indocyanine green was apparently prolonged in macaques given SEB as compared with that in the controls. However, in macaques given SEB (0.05 or 1.0 mg/kg) by IV injection, there were tachycardia, increase in arterial resistance, and decreases in blood pressure, cardiac output, stroke volume, cardiac work, mean cardiac power, and central blood volume. In addition, mean transit time from caudal vena cava to ascending aorta was prolonged and a simultaneous reduction of hepatic removal of indocyanine green occurred.


Lymphocyte subpopulations in spontaneous disease of rhesus macaques.

The immunologic status of rhesus macaques (Macaca mulatta) with naturally occurring disease was evaluated by determining the percentages of B and T lymphocytes and mitogen responsiveness of lymphocytes in peripheral blood and lymph nodes. The B lymphocytes were identified by the presence of cell surface immunoglobulin and receptors for complement. The T lymphocytes were identified by their ability to form spontaneous rosettes with sheep red blood cells. Rhesus macaques with idiopathic or primary amyloidosis had normal lymphocyte characteristics. Peripheral blood lymphocytes from rhesus macaques with atypical tuberculosis had decreased percentages of spontaneous rosette-forming cells and depressed responses to concanavalin A, and those with chronic diarrhea or chronic arthritis were also found to have abnormal peripheral blood lymphocyte characteristics. The percentage of B and T lymphocytes in normal lymph nodes was variable, making simultaneous histologic examination necessary for evaluation of diseased animals.


Sodium etidronate in the treatment of Paget's disease of bone. A study of long-term results.

Subjects (109) with symptomatic Paget's disease of bone were treated with 5, 10, or 20 mg of sodium etidronate (EHDP)/kg body weight - day for 6 to 24 months. Significant decreases in serum alkaline phosphatase and urinary hydroxyproline were noted after 6 months of therapy; no significant further improvement resulted after prolonged therapy. Some patients maintained biochemical remission after withdrawal of EHDP but others showed a relapse, related primarily to the pretreatment severity. Clinical improvement was noted in 61% of the patients. Similar findings were seen after a second course of EHDP. No side-effects were noted in patients treated with 5 mg of EHDP/kg body weight - day. In patients treated with 10 or 20 mg of EHDP/kg body weight - day, severe diarrhea, bone pain, and nontraumatic fractures were noted in 3, 13, and 12 patients respectively. Quantitative histomorphometry showed mineralization delay in patients receiving 10 or 20 mg of EHDP/kg body weight - day but not in those receiving 5 mg/kg body weight - day. Five milligrams of EHDP/kg body weight - day was effective and appears to be safer than the higher doses.


Hepatic toxicity associated with gold therapy.

Three patients with rheumatoid arthritis developed jaundice after initiation of chrysotherapy. Gold sodium thiomalate had been administered in dosages of 37.5, 60, and 110 mg in these patients before the onset of jaundice. Liver function studies indicated a cholestatic jaundice in all subjects. One patient underwent exploratory laparotomy because of progressive jaundice. Liver biopsy was done in two patients. In one patient significant bile stasis and thrombi were seen in the biliary tree. In another patient liver biopsy showed ballooning of hepatocytes with minimal cholestasis. All patients recovered spontaneously. Awareness of this rare complication may prevent unnecessary diagnostic and surgical procedures in patients with rheumatoid arthritis who may develop jaundice while receiving chrysotherapy.


Thyroidal and peripheral production of thyroid hormones. Review of recent findings and their clinical implications.

There are two biologically active thyroid hormones, thyroxine (T4) and triiodothyronine (T3). Most T3 is produced extrathyroidally, so that alterations in circulating thyroid hormone concentrations may occur as a result of both thyroidal and extrathyroidal abnormalities. Extrathyroidal T4 conversion to T3 is decreased in patients with different acute and chronic illnesses. When T4 conversion to T3 is impaired and serum T3 concentrations decline, serum concentrations of biologically inactive 3,3',5'-triiodothyronine (reverse T3) increase. In this review, we present current information on thyroidal and extrathyroidal T4 and T3 production in normal subjects and patients with various thyroid diseases and other illnesses, consider the physiologic significance of these changes, and discuss the value and interpretation of various iodothyronine measurements.


[Behavior of rumen ciliate populations cultured in sucrose and sucrose-urea media].

The behaviour of rumen ciliates in culture in vitro is studied according to the concentration of substrates and requirements of middle removal. The most favorable concentrations, for a best ciliate's survival is from 0.4 to 0.6 mg/ml of sucrose and 0.05 mg/ml of urea. We observe two periods in the culture: in the first, Entodinium grows essentially, in the second the population of holotrich ciliates increases. If survival is almost the same, the population is most important in culture with sucrose urea than with sucrose.


Cervical pharyngostomy.

The technique of cervical pharyngostomy is presented as a safe alternative procedure to the nasogastric tube for patients requiring prolonged periods of gastrointestinal decompression or tube feeding. The results in 21 cases are described. The complication rate is low and the use of cervical pharyngostomy is therefore justified in that it reduces patient discomfort and makes treatment more efficient.


[Description of Hepatocystis bainae n.sp., parasite of Hipposideros galeritus (Cantor), Microchiroptera, in Malaysia (author's transl)].

Hepatocystis bainae n. sp., parasite on the Microchiropteran bat, Hipposideros galeritus is described and differentiated from Hepatocystis rodhaini; it is characterized by the type of the microgametocytes ("diffuse"), the small size of the hepatic schizonts and the repartition of the colloide.


Emergence in a burn center of populations of bacteria resistant to gentamicin, tobramycin, and amikacin: evidence for the need for changes in zone diameter interpretative standards.

From July 1974 through June 1976, a number of isolates of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa from the Burn Center exhibited a shift to smaller zone diameters with gentamicin than did isolates from the general hospital population. Although many had zone diameters >/=13 mm and would have been considered susceptible by this breakpoint, they were found to have minimal inhibitory concentrations (MICs) of >/=8 mug of gentamicin per ml by agar dilution testing. Zone diameters and MICs of gentamicin, tobramycin, and amikacin were subsequently compared for 168 isolates from both the Burn Center and general hospital. The results revealed many isolates that fell into presently used gentamicin- and tobramycin-"susceptible" categories by disk diffusion tests but were resistant by MIC. The data indicated that criteria for gentamicin disk diffusion testing should include an intermediate or indeterminate category, and that the limits of the intermediate category for tobramycin and amikacin should be expanded.


Feasibility of screening for penicillinase-producing Neisseria gonorrhoeae from primary culture plates by using a rapid microacidometric test.

We have shown that it is possible to screen for penicillinase-producing Neisseria gonorrhoeae directly from primary culture plates. Experiments involving the cocultivation of four genera of beta-lactamase-positive (beta-lac(+)) bacteria and a beta-lactamase-negative (beta-lac(-)) N. gonorrhoeae on modified Thayer-Martin medium indicated that suppressed or inhibited beta-lac(+) bacteria did not give false-positive results when isolated beta-lac(-) colonies of gonococci were tested. Colonies were assayed for beta-lac production by an adaptation of a microacidometric method in which bacteria could be tested before or after the addition of oxidase reagent.


Methadone: antimicrobial activity and interaction with antibiotics.

We studied the effect of methadone, alone and in combination with antimicrobial agents, on two strains each of Staphylococcus aureus, Pseudomonas aeruginosa, and Serratia marcescens isolated from blood streams of parenteral drug abusers with bacterial endocarditis. Methadone has its own antibacterial effect, although at supraphysiological concentrations, and is even synergistic with antimicrobial agents against some organisms. Thus, methadone does not interfere with the antibacterial effects of antibiotics in vitro.


Anaerobic and aerobic hydrogen gas formation by the blue-green alga Anabaena cylindrica.

An investigation was made of certain factors involved in the formation of hydrogen gas, both in an anaerobic environment (argon) and in air, by the blue-green alga Anabaena cylindrica. The alga had not been previously adapted under hydrogen gas and hence the hydrogen evolution occurred entirely within the nitrogen-fixing heterocyst cells; organisms grown in a fixed nitrogen source, and which were therefore devoid of heterocysts, did not produce hydrogen under these conditions. Use of the inhibitor dichlorophenyl-dimethyl urea showed that hydrogen formation was directly dependent on photosystem I and only indirectly dependent on photosystem II, consistent with heterocysts being the site of hydrogen formation. The uncouplers carbonyl cyanide chlorophenyl hydrazone and dinitrophenol almost completely inhibited hydrogen formation, indicating that the process occurs almost entirely via the adenosine 5'-triphosphate-dependent nitrogenase. Salicylaldoxime also inhibited hydrogen formation, again illustrating the necessity of photophosphorylation. Whereas hydrogen formation could usually only be observed in anaerobic, dinitrogen-free environments, incubation in the presence of the dinitrogen-fixing inhibitor carbon monoxide plus the hydrogenase inhibitor acetylene resulted in significant formation of hydrogen even in air. Hydrogen formation was studied in batch cultures as a function of age of the cultures and also as a function of culture concentration, in both cases the cultures being harvested in logarithmic growth. Hydrogen evolution (and acetylene-reducing activity) exhibited a distinct maximum with respect to the age of the cultures. Finally, the levels of the protective enzyme, superoxide dismutase, were measured in heterocyst and vegetative cell fractions of the organism; the level was twice as high in heterocyst cells (2.3 units/mg of protein) as in vegetative cells (1.1 units/mg of protein). A simple procedure for isolating heterocyst cells is described.


Degradation of the plant flavonoid phellamurin by Aspergillus niger.

We have previously described the structure of phellamurin, a plant flavonoid, as 3,4',5,7-tetrahydroxy-8-isoprenylflavanone-7-O-glucoside (17). Degradation of phellamurin by Aspergillus niger using modified Czapek-Dox medium as well as phellamurin or one of its degradation products as a sole carbon source, is reported here. Eleven compounds are identified from phellamurin degradation products. A. niger apparently decomposes phellamurin by first removing glucose with beta-glucosidase; neophellamuretin is the first degradation product. Fission of the heterocyclic ring of (5''-hydroxyisopropyl-4'',5''-dihydrofurano)[2'',3''-h]3,4',5-trihydroxyflavanone, which is obtained from neophellamuretin through a few alterations of the side chain, is followed by cleavage of a C--C bond between C=O and carbon at alpha-position and conversion of (5''-hydroxyisopropyl-4'',5''-dihydrofurano)[2'',3''-d]-2',4,6',alpha-tetrahydroxychalcone to rho-hydroxymandelic acid (B-ring) and 2,4,6-trihydroxy-5-carboxyphenylacetic acid (A-ring). It is suggested that rho-hydroxymandelic acid is oxidized to rho-hydroxybenzoic acid. 2,4,6-Trihydroxy-5-carboxyphenylacetic acid is metabolized to phloroglucinol carboxylic acid, which subsequently is decarboxylated to phloroglucinol. These results provided new information on the isoprene unit metabolism of the side chain of phellamurin and firmly established the degradation pathway of phellamurin by A. niger.


(14C)acetate assimilation by a type I obligate methylotroph, Methylococcus capsulatus.

Methanol and formate oxidation supported the assimilation of [14C]acetate by cell suspensions of Methylococcus capsulatus; oxidation of other primary alcohols, except ethanol, did not. The extent of [1-14C]acetate assimilation supported by methanol oxidation was decreased in the presence of primary alcohols, except ethanol. Potassium cyanide (0.33 mM) completely inhibited the oxidation of formate and its stimulation of [1-14C]acetate assimilation. The amount of [1-14C]acetate assimilation supported by methanol oxidation was significantly inhibited by cyanide.


Nosocomial outbreak of Candida parapsilosis fungemia related to intravenous infusions.

Candida parapsilosis is rarely isolated from blood cultures. Our hospital surveillance detected an increased rate of isolation of C parapsilosis during a four month period. Fourteen postoperative patients receiving intravenous (IV) hyperalimentation and eight burn patients receiving IV albumin were involved. Hectic fever, the major clinical manifestation, was seen in 61% of cases. Therapy in the postoperative patients consisted merely of discontinuing IV catheters and hyperalimentation, while amphotericin B was needed in five of eight burn patients to control persistent fungemia. Epidemiologic analysis identified a source of the organism in the IV-additive preparation room where C parapsilosis was found contaminating a vacuum system. Organisms apparently refluxed into IV bottles when aliquots were removed to accommodate additives. Of 103 patients who received fluids prepared with the contaminated system, 21% became infected with C parapsilosis. Infection surveillance was instrumental in detection and control of the outbreak. Routine guideline should be established to insure the sterility of IV fluids containing additives.


Action of Nitroglycerin and amyl nitrite in labile and essential hypertension: hemodynamic differences.

Seventeen patients with labile hypertension received nitroglycerin and 18 received amyl nitrite. Twelve patients with established essential hypertension received nitroglycerin and 12 received amyl nitrite. Nitroglycerin reduced the systolic and mean arterial pressures and cardiac output in both groups, but had no effect on diastolic pressure and total peripheral resistance. Amyl nitrite decreased systolic, diastolic, and mean arterial pressures and peripheral vascular resistance and increased heart rate and cardiac output in labile hypertensives. In established hypertensive patients, amyl nitrite decreased systolic, diastolic, and mean arterial pressures and cardiac output, and had little effect on peripheral vascular resistance. Nitroglycerin reduced arterial pressure in labile and established hypertensives through venodilation and peripheral venous pooling. Amyl nitrite and effects similar to nitroglycerin in established hypertensives; in labile hypertensives it reduced arterial pressure through arterial dilation and a decrease in peripheral vascular resistance.


Lead, zinc, and erythrocyte delta-aminolevulinic acid dehydratase: relationships in lead toxicity.

A lead-intoxicated patient with extremely high blood lead levels and unexpectedly mild symptoms was studied prior to and following treatment with calcium disodium edetate (ethylenediaminetetraacetic acid) and then prior to and following oral administration of zinc sulfate. During chelation therapy, erythrocyte (delta)-aminolevulinic acid dehydratase (ALAD) activity decreased as blood lead levels fell. Urinary excretion of zinc increased and was more than 3.5 times greater than that of lead. The ratio of blood lead to serum zinc was greatest (1.47) when ALAD activity was lowest. Oral administration of zinc sulfate following chelation therapy resulted in a significant increase in mean ALAD activity. In vitro additions of zinc chloride to the patient's erythrocytes resulted in reactivation of ALAD activity. These studies suggest that zinc is an important element in the ALAD system in man. Zinc may play a protective role in lead toxicity, and zinc supplementation may be a useful adjunct to chelation therapy for lead toxicity.


Chronic, inhalation exposure of rats, rabbits, and monkeys to 1,2,4-trichlorobenzene.

Three groups composed of rats, rabbits, and monkeys were exposed for 26 weeks to 1,2,4-trichlorobenzene (-TCB), and one group of each species was used as a control group. The nominal exposure concentrations of 1,2,4-TCB were 25.0, 50.0, and 100.0 ppm. Pulmonary function and operant behavior tests in monkeys, ophthalmoscopic examinations in rabbits and monkeys, and measurement of body weights and hematologic and serum biochemical determinations in all species were conducted before and during the exposure period. At termination of 1, 3, and 6 months of exposure, microscopic examination of selected rat tissues was performed. Microscopic changes were seen in the parenchymal of livers and kidneys from all groups of rats exposed to 1,2,4-TCB when sacrificed after 4 and 13 weeks of exposure, but no exposure-related abnormalities or other effects were seen after 26 weeks of exposure in any species.


Influence of sulfide compounds on the metabolism of Methanobacterium strain AZ.

Various organic sulfides and inorganic sulfide were studied in respect to their effect on growth and methane production of Methanobacterium strain AZ. In mineral, sulfide-free medium, cysteine regulated the specific rate of methane production (optimum concentration = 5-10(-4) mole/1). A supplement of sulfide (10(-4) mole/1) caused an additional stimulation. Coenzyme M** or glutathione could be substituted for cysteine when sulfide was present. Growth was stimulated by CoM and glutathione to the same extent as with cysteine in sulfide-containing media. The concentration of sulfide in cysteine-containing media affected the excretion of amino acids.


Bacteriocins from Myxococcus fulvus (Myxobacterales).

Bacteriocin-like activities were found in several Myxococcus fulvus strains. One strain, Mx f16, exerted strong inhibitory effects on several myxobacterial strains. Synthesis of its bacteriocinic activity could not be induced by mitomycin. Electrophoresis and molecular sieve chromatography revealed at least three different bacteriocinic substances of low molecular weight.


Characterization and function of intracellular proteases in sporulating Bacillus cereus.

Intracellular proteases from sporulating Bacillus cereus have been purified by ammonium sulfate fractionation, heat treatment and DEAE cellulose column chromatography. After the last purification step, two protease activities, with an activity ratio of about thirty to one are resolved. Both proteases are resistant to o-phenanthroline but sensitive to phenyl methyl sulfonyl fluoride. Their separation by polyacrylamide gel electrophoresis and DEAE cellulose column chromatography, their difference in heat sensitivity and a mutation affecting only the major intracellular protease (IP1) suggest that the two are products of distinct genes. An IP1 mutant previously shown to produce coat defective spores (4) also turnsover protein with a reduced rate during late sporulation stages. Correlated with the slower turnover rate in this mutant is the more rapid disappearance of IP1. A partial revertant of this mutant has a protein turnover rate intermediate between that of the original mutant and wild type. These correlations imply that IP1 has an important role in protein turnover during sporulation.


[Fabry's disease. Carbamazepine therapy in acrodyniform syndrome].

A 19 year old male affected with Fabry's disease suffered from severe nervous manifestations. Despite very peculiar pains of the extremities, the diagnosis has been missed for a long time and was painted out at this age because of sharp reconstitution of the family history. Fabry's disease was confirmed by discovering typical corneal lesion, a low leucocyte (W.B.C.) alpha-galactosidase activity and foam cells in renal glomerular epithelium. The importance of an early diagnosis is obvious in this case: 10 Instead of degrading narcotic therapy, Carbamazepin brought forward normal social and school living. 20 Familial investigations show up that all the siblings were affected (three boys including the propositus)--several symptoms were found in the heterozygous conductor mother. Despite the rarety of Fabry's disease, the authors emphasize the easiness of diagnosis on simple clinical and biochemical grounds. The authors insist on the symptomatic and therapeutic action of Carbamazepin or Diphenytoin in order to prevent painfull symptoms which often appear during initial course of the disease.


[Chondrodystrophy in monozygous twins, secondary to cellular division disorder].

The case of two twins with micromelic dwarfism noticed at birth are reported. The studies performed on fibroblasts, lymphocytes and epiphyseal cartilage, suggest that a disturbance is involved in the cell division mechanisms.


[Endocrine sequela of radiation treatment of extracranial head and neck tumors].

A study of the thyroid and hypothalamo-pituitary functions was undertaken in 14 children having been irradiated for tumors of the neck and head. The following anomalies were found: S.T.H. deficiency: 8 cases, A.C.T.H. deficiency: 2 cases, T.S.H. deficiency: 4 cases, primary thyroid insufficiency: 4 cases. Growth was severely impaired since the height of 10 out of 14 patients was less than or equal to 2 S.D. These results emphasize the frequency of endocrine lesions related to radiotherapy, as the lesions were essentially extracranial. They also show a repercussion on growth, which worsen the long-term prognosis of these diseases.


[Neutron therapy in the GDR. VIII. The calculation of dose distributions (author's transl)].

The calculation of dose distribution for each patient is a basis for the neutron therapy. A computerprogram was developed for it basing on the matrix-method. We find out several field matrix for each field size. The dose calculation goes by addition of the matrix values on the certain points inside the patient's cross-section. A correction of the dose distribution in consequence of the oblique beam is possible. Dose distributions for several irradiation techniques are discussed.


[Immune reactions in breast cancer patients (author's transl)].

Immunological reactivity was studied in 76 breast cancer patients taking into consideration the extent of disease and mode of treatment. The following tests were used: delayed hypersensitivity skin reaction after application of tissue antigens from mammary cancer and embryonal tissues prepared by Westphal's method (Silber's modification), tuberculin and 2,4-dinitrochlorbenzene (DCNB). Humoral immune reactivity was evaluated with a mikroprecipitation test using antigens from fetal, tumorous and spleen cells. Tests were performed before and after treatment. The results confirm that positive skin reactions are found mostly in stage I and II. In advanced stages depression of all immune reactions was seen. Some changes of immune reactivity depend on the mode of treatment. Immune competence was not depressed by surgical treatment and the most distinct immune depression was provoked by cytostatic chemotherapy. Our observations suggest that the cytostatics Thiophosphamid, Cyclophosphamid and Fluorouracil are immundepressants.


[Estimates of trace elements requirements of children receiving total parenteral nutrition].

Ten children on total parenteral nutrition were studied. Plasma copper, zinc, manganese and selenium levels were determined by neutron activation and gamma spectrometry, every 10 days. With a copper intake of 20 microgram/kg/24 h, the average level 120 microgram% (94-144) was normal (N: 118 microgram +/- 11%). With a manganese intake of 40 microgram/kg/24 h, the level increased to 2.6 microgram% (1.3-4.5) (N: 1.1 microgram +/- 0.2%). With a zinc intake of 30 microgram/kg/24 h, the level decreased to 45.9 microgram % (20-63) (N: 83 microgram +/- 28%); with an intake of 50 microgram/kg/24 h the level remained under normal. With a selenium intake of 1 microgram/kg/24 h, the level decreased to 10.6 ng/ml (3.6-21.6) (N: 38.2 ng/ml +/- 11.9), but was normalized with an intake of 3 microgram/kg/24 h. From these results, with all reserves that estimation implies, the authors suggest that the disorders due to deficit or excess of trace elements could be avoided by daily intakes per kg of body weight: copper 20 microgram, zinc 100 microgram, manganese 10 microgram and selenium 3 microgram, with supplementation of iron, iodine and fluoride.


[Genetic control of hexosaminidases].

The authors present the results they obtained which interspecific cell hybrids. The hexosaminidases A, B and C, seem to be under the control of the two genes alpha and beta, B and CS constituing homopolymers (beta beta)n and (alpha alpha)n, A being a heteropolymer (alpha beta)n. The isozyme CF, particularly abundant in fetal tissues and found also in Tay-Sachs by some authors is, in all probability, under independent genetic control.


Influence of modifications of physicochemical and biological properties of haptoglobin. VII. Immunochemical reactivity of haptoglobin with modified tyrosine residues.

Tyrosine residues in human haptoglobin (Hp) type 2-1 were modified by treatment with various amounts of N-acetylimidazole, iodine or tetranitromethane. Rabbit antisera directed against native Hp, Ac-Hp, 1-Hp and NO2-Hp in cross-reactions by immunoprecipitation showed serologic identify of native Hp and most of the modified derivatives, with the exception of derivatives modified by means of a high excess of N-acetylimidazole, which showed partial identity with remaining preparations, irrespective of the antiserum used. The results indicate that tyrosine residues play no essential role in the immunochemical reactivity of haptoglobin.


Gold nephropathy: tissue analysis by X-ray fluorescent spectroscopy.

Three patients developed proteinuria following gold therapy for rheumatoid arthritis. The clinical syndrome was a self-limiting proteinuria with normal renal function. By light and electron microscopic appearances the renal lesion was an epimembranous deposit form of membranous glomerulopathy. Immunofluorescent study showed granular deposits of IgG and C3 complement along glomerular basement membranes. By X-ray fluorescent spectroscopic examination, gold was seen to be present within the proximal convoluted tubular cells but was not identified in the glomerular subepithelial deposits. These findings are consistent with an immune-complex form of glomerulopathy in which gold is neither the antigen nor a hapten in the glomerular deposits, and they suggest the hypothesis that antibodies to tubular epithelial antigens induced by gold therapy may be a causative factor in the renal disease associated with gold therapy in rheumatoid arthritis.


Cromolyn effects on vernal keratoconjunctivitis in children.

A double-masked, coded trial was undertaken to evaluate the effect of the topical administration of 2% cromolyn sodium eye drops on vernal keratoconjunctivitis in 14 children. One eye of each patient was treated for one year with cromoly, the other eye with placebo. Cromolyn reduced the characteristic vernal keratitis, vernal corneal ulcers and plaques, and limbal edema and infiltrates but did not affect the number or size of the giant papillae. The drug's long-term topical use did not have any adverse side effects.


Ultrastructural study of cell cultures infected with swinepox and orf viruses.

Monolayer cells of a porcine kidney cell line were infected with the PP-1 strain of swinepox virus, while secondary or third subcultured monolayer cells of African green monkey kidney were inoculated with the Iwate BT-9 strain of orf virus. Those infected cells were fixed when CPE became remarkable in the monolayers and examined by electron microscope. In the cytoplasm of cells infected with both viruses, various immature forms of viral particles in different developmental stages were observed. Micells were detected very close to the opening of immature particles. Mature particles asssociated with a double membrane were frequently observed. From those observations it was suggested that the developmental sequence of both viruses is essentially the same as that of vaccinia (Dales, 1973). Besides various virus forms as well as factories, the following ultrastructural changes were noted in swinepox infected cells, i.e. 1) intranuclear inclusions which consist of very fine filaments, 2) fibrillar structures with cross striations located in the nuclear inclusions, and 3) similar striated fibrillar structures in or just adjacent to virus factories (B type inclusions) in the cytoplasm. Those observations made with in vitro cells are in good accordance with the descriptions by previous investigators on in vivo materials. Accordingly those ultrastructural changes characterize the swinepox infection.


alpha1-Antitrypsin polymorphism in Malaysian Macaca irus.

alpha1-Antitrypsin types were determined in 200 individual specimens of Malaysian Macaca irus. We found the pattern B in 76 samples, BC in 116, and C in 8. Assuming that these patterns are determined by codominant alleles at one locus, this distribution constitutes a significant (P less than 0.001) deviation from Hardy-Weinberg equilibrium, because of an excess of BC and low prevalence of C. We found no clear evidence for the presence of alpha1-antitrypsin deficiency comparable to the situation in man.


Genetic control of quantitative variation in carbonic anhydrase isozymes of mammals. I. The concentration within single erythrocytes of the mouse.

The levels of the carbonic anhydrase isozymes (CA and CA II) in single erythrocytes of DBA/2J mice were assayed by measuring the specific immunofluorescence of CA I and CA II with a microspectrofluorometric technique. Measurements of 100 randomly selected cells showed a range (in relative fluorescence units) of 21-52 (mean 31.3 +/- 7.5) for CA I and 30-80 (mean 45.6 +/- 10.7) for CA II. The CA II/CA I ratio of the means obtained by the single-cell fluorescence assay was similar to the ratios obtained for the two isozymes from hemolysates of DBA/2J mice using an immunodiffusion assay. The influence of cell age on the variation in carbonic anhydrase levels was determined by separating red cells into several fractions by a gravity sedimentation procedure. The younger cells showed higher levels of CA I and CA II than the older cells; however, the extensive overlap in the variability between the cells from the different fractions indicated that although cell age was contributing to the overall heterogeneity, its influence was not pronounced.


Human Pb, human post-Pb, and nonhuman primate Pb proteins: immunological and biochemical relationships.

The isolation and characterization of a protein from human parotid saliva termed the "post-Pb protein" is described. By several criteria, this protein is closely related to the human Pb proteins. When reacted against antisera to human Pb protein in double diffusion, the post-Pb protein is found to be related to the Pb proteins by lines of identity. However, when the partial N-terminal amino acid sequences of the post-Pb protein and Pb proteins are compare, the sequences are not identical. Because of the similarity in size of the Pb and post-Pb proteins and because of the observed sequence differences, any product-precursor relationship between the Pb and post-Pb proteins is unlikely. The post-Pb protein probably is the product of a genetic locus different from the Pb locus. Two additional species of nonhuman primates (Papio papio and P. sphinx) have been found to have Pb proteins electrophoretically similar to these found in the rhesus monkey and differing from those in the human. The isolated Pb proteins of the rhesus monkey have been found to have close biochemical and immunological relationships to the human Pb proteins.


Isolation and genetic characterization of alcohol dehydrogenase thermostability variants occurring in natural populations of Drosophila melanogaster.

Drosophila melanogaster collected from natural populations were examined fo thermostability variants within electrophoretic mobility classes of two enzymes. In alcohol dehydrogenases, two discrete forms of the "slow" allozyme and three discrete forms of the "fast" allozyme were revealed by postelectrophoretic treatments ranging from 15 sec at 40 C to 40 sec at 43 C. All variants have been mapped to within 0.7 unit of the Adh locus. Results of a geographic survey indicate that two alleles giving rise to fast-moderate and slow-moderate allozymes are common everywhere; other variants have a collective frequency ranging from 0% to 7%. In a test of the possibility that the rare Adh alleles could be generated by intragenic recombination between the two common alleles, electrophoresis and heat treatment of progeny recombinant for flanking markers of Adh revealed no new allozymes. Among 27 stocks containing slow alpha-glycerophosphate dehydrogenase allozymes and 109 fast stocks, heat treatments revealed no additional variation.


Methylated nucleotide sequences in HeLa-cell ribosomal ribonucleic acid. Correlation between the results from 'fingerprinting' hydrolysates obtained by digestion with T1 ribonuclease and with T1 plus pancreatic ribonuclease.

The methylated nucleotide sequences in HeLa-cell rRNA were previously characterized after enzymic digestion of the rRNA by T1 ribonuclease alone or by combined T1 plus pancreatic ribonucleases. For any methylated product occurring in a T1-ribonuclease digest there must be one or more corresponding products in a combined T1-plus-pancreatic-ribonuclease digest. Here we correlate fully the inter-relationship between the methylated products occurring in the two digestion systems. The analysis has led to the resolution of some previous uncertainties and has permitted an almost complete qualitative and quantitative description of the methylated components in HeLa-cell rRNA. The data are compared with those reported by other authors for HeLa-cell rRNA.


The subunit and polypeptide-chain structure of rabbit secretory immunoglobulin A. Isolation of a proteolytic fragment suitable for sequence studies on the variable region of alpha-chain.

A method was developed for the preparation of a proteolytic fragment of rabbit secretory immunoglobulin A (sIgA) which contains the variable region of the alpha-chain; this fragment is suitable for primary-sequence studies. The serologically defined subclasses of sIgA are shown to correlate partially with the nature of the binding of a constituent chain of sIgA, called secretory piece. Data are also presented on the relative resistance of sIgA to enzymic and reductive cleavage, compared with immunoglobulin G.


Sequence studies on the heavy chain of rabbit immunoglobulin A of different alpha-locus allotypes.

The amino acid sequence was determined of part of the variable region of heavy chain from rabbit immunoglobulin A of allotypes a1 and a3. Two corrections of the primary sequence of Aa1 gamma-chains are reported; most of the structural correlates of the alpha-locus allotypes are confirmed. The amino acid sequence of the N-terminal 20 residues of alpha-negative molecules was also determined and found to be homologous to the human VhIII subgroup. These molecules are present in a much higher proportion in the alpha-chain pool than in the gamma-chain.


A humoral cytotoxic substance produced by a human killer cell line.

The production of a cytotoxic factor synthesized by human haemic killer cells growing in vitro is described. The factor can be found extra- and intra-cellularly. It is released from the cells by an apocrine form of secretion, illustrated by light and electron micrographs. The culture fluid from 14C-labelled killer cells reveals numerous radioactive bands following SDS-gel electrophoresis. The killing factor is precipitated by 30 to 60% saturation of ammonium sulphate. Cultures of human rhabdomyosarcoma and osteosarcoma cells are more susceptible to the killer cells than normal human dermal or lung fibroblasts. During contact or killer with target cells a higher level of cytotoxic activity can be detected in the culture fluid. The cell-killing activity is completely inactivated by 30 min at 60 degrees C, but it is not absorbed by target cells during 1 h of incubation. The cytotoxic factor is unlikely to be an interferon since it did not prevent the replication of a wide range of viruses and only a low level of interferon could be detected in the culture medium. The introduction of Strep. faecalis into cultures of killer cells caused their transformation into immunoblast-like cells, indicating their lymphoid origin. The cells did not phagocytose the microorganism. When the humoral factor was injected into fibro-sarcoma-bearing mice approximately 50% survived, whereas all control animals died.


Analysis of treatment of childhood leukaemia. V. Advantage of reduced chemotherapy during and immediately after cranial irradiation.

This paper compares anti-leukaemic efficiency with toxicity to the patient of chemotherapy during and immediately after central nervous system irradiation. The drug regimen consisted of daily mercaptopurine (MP) and weekly methotrexate (MTX) at the maximum tolerated dose. Of 140 patients with acute lymphoblastic leukaemia allocated to receive this drug regimen during and after cranial irradiation, 8 died in complete remission within 6 months of the end of irradiation. Details of the nature of these deaths are given. This result led the Working Party to modify the chemotherapy scheduled for this stage in treatment. The modified chemotherapy consisted of MP at reduced dosage before and during cranial irradiation and omission of MP and MTX for 3 weeks after irradiation, during which time daily prednisolone with 2 doses of vincristine were substituted. Following that, the treatment reverted to the original schedule of daily MP and weekly MTX at maximum tolerated dose. Of 109 patients allocated to this modified regimen only one died in remission within 24 weeks after cranial irradiation. Analysis of the anti-leukaemic effect of the modified regimen showed that up to 600 days it was at least as effective as the original more intensive regimen. We conclude that there is a definite advantage in keeping chemotherapy to a minimum during and immediately following cranial prophylactic irradiation.


IgG4 autoantibodies against erythrocytes, without increased haemolysis: a case report.

A patient is described who, notwithstanding a strongly positive direct antiglobulin test with anti-IgG serum, apparently did not suffer from haemolytic anaemia. The survival of the patient's red cells, measured with 51Cr, was only slightly decreased. In vitro, the sensitized cells of the patient showed only a minimal tendency to adhere to monocytes. The patient's spleen functioned normally, since 51Cr-labelled donor erythrocytes, either sensitized with IgG-anti-D or damaged by heating, were eliminated rapidly from the circulation and sequestered in the spleen. These apparently contradictory findings could be explained by the fact that the patient's red cells were sensitized with autoantibodies, mainly belonging to the IgG4 subclass. Only weak IgG1 and IgG3 autoantibodies were detectable. Since previously the patient had suffered from a severe haemolytic anaemia, it is postulated that a switch has occurred from 'active' to 'inactive' IgG autoantibodies, perhaps induced by prednisone therapy.


Lead poisoning in a group of demolition workers.

The incidence of lead poisoning in industry has fallen dramatically since the beginning of the twentieth century. This reduction has been partly attributable to increased awareness, improved ventilation and hygiene facilities, and technical changes which have allowed other substances to replace lead, but improved medical surveillance of workers exposed to lead in certain defined industries has also been important. Not all industries where lead exposure can occur are at present covered by specific regulations dealing with lead, however. We report the diagnosis and treatment of eleven oxyacetylene metal burners involved in the demolition of a railway station, who rapidly developed frank lead poisoning. The most suitable measurements to employ in evaluating such a population are considered. The selection, based on blood lead and haemoglobin measurements, of those who should receive further treatment is discussed. Symptoms were found to be more nearly related to indices of effect or toxicity of lead than to indices of exposure or absorption. The effects of chelation therapy upon symptoms, blood lead, haemoglobin and urinary porphyrins are recorded. The need for careful follow-up is illustrated.


Amniotic fluid insulin and glucagon in normal pregnancy and pregnancy complicated by rhesus isoimmunization.

Immunoreactive insulin (IRI) and immunoreactive glucagon (IRG) were determined in the amniotic fluid from 28 rhesus isoimmunized pregnancies with moderately affected fetuses and from 15 normal pregnancies; in umbilical arterial plasma from nine newborn infants with rhesus haemolytic disease of moderate degree and from 19 normal infants; in plasma from their respective mothers at delivery; and in the urine of 13 normal infants at birth. Levels of IRI and IRG in amniotic fluid from rhesus cases were not different from those of normal pregnancies. IRG was detected in the first voided neonatal urine.


Intravenous infusion of a dextrin, Caloreen, in human subjects: metabolic studies.

1. Caloreen, a glucose-polymer dextrin infused into human volunteers, although producing a clear increase in total plasma carbohydrate did not produce a satisfactory increase in plasma glucose levels or serum insulin levels. 2. Urinary losses were high and although small fragments of the dextrin (suggesting metabolic breakdown of the dextrin) were demonstrated in the urine, no suppression of plasma free fatty acid, glucagon or immediate increase in the respiratory quotient were noted, suggesting that the metabolism is too slow to make it useful for parenteral nutrition in its present form. 3. A dextrin with fewer branch-links might be more suitable.


The B-vitamin content of baboon (Papio cynocephalus) milk.

1. The B-vitamins in milk from baboons (Papio cynocephalus) at various stages of lactation were measured microbiologically. 2. Mature milk contained, on average (microgram/ml): thiamin 0.18 riboflavin 0.74, nicotinic acid 3.2, folate 0.03, vitamin B6 0.70 vitamin B12 0.002, pantothenic acid 2.63, biotin 0.0065. 3. Colostrum contained much less vitamin B6 and pantothenic acid than mature milk; otherwise, there were only slight changes in composition as lactation progressed. Neither these changes, nor the absolute values, resembled those for human or cow's milk. 4. The average daily secretion of B-vitamins in milk represented less than 10% of the mother's dietary intake; that of folate was less than 0.5% of the mother's dietary intake. 5. Baboon milk was calculated to provide infants with approximately the following quantities of B-vitamins (/d): thiamin 0.06 mg, riboflavin 0.25 mg, nicotinic acid 1.1 mg, folate 10 microgram, vitamin B6 0.25 mg, vitamin B12 0.7 microgram, pantothenic acid 0.9 mg, biotin 2.2 microgram.


Interaction of the unique competitive inhibitor imidazole with human carbonic anhydrase B.

Imidazole was previously found to be unique among the inhibitors of human carbonic anhydrase B (HCAB) in that it binds competitively with the CO2 substrate (Khalifah, R. G. (1971), J. Biol. Chem. 246, 2561). We report here an aromatic ultraviolet difference spectral study of its interaction with HCAB and compare it with a variety of other inhibitors. Imidazole is found to be unique in that: (1) it generates a different spectrum upon binding that is also much supressed in intensity; (2) its affinity for HCAB is maximal at high pH, being abolished upon its protonation and being independent of active-site ionizations. Imidazole differs from CO2 in that it binds competitively with the anionic inhibitor iodide. The unique properties of imidazole binding are consistent with the recently determined crystal structure of its complex with HCAB showing it to bind as a weak and distant fifth ligand of the essential zinc atom, rather than displacing the solvent molecule in the fourth ligand position (Kannan, K.K., Petef,  M., Fridborg, K., Cid-Dresdner, H., and Lövgren, S. (1977), FEBS Lett 73, 115).


Cytochrome P-450 for 11beta- and 18-hydroxylase activities of bovine adrenocortical mitochondria: one enzyme or two?

The 11beta- and 18-hydroxylase activities of a highly purified cytochrome P-450 from bovine adrenocortical mitochondria have been examined in detail with a view to determining whether the two activities are shown by a single protein or by two distinct proteins. The purified enzyme shows a single N-terminal residue (glutamic acid) and its amino acid composition is reported. Both enzyme activities decay considerably during storage at 4 degrees C for 11 days and the rates of decay are similar for the two activities. Metyrapone inhibits both activities competitively (Ki = 1.50 and 1.43 micrometer for 11beta- and 18-hydroxylase, respectively). Carbon monoxide inhibits both activities and the ratio CO:O2 for 50% inhibition is similar for the two activities (K = 1.69 and 1.53). A variety of nonspecific inhibitors produce approximately the same inhibition of both activities. Finally, antiserum produced by rabbits to the purified enzyme on double diffusion in agarose gels gives a single band with the purified enzyme. Increasing concentrations of antiserum added to the assay system produce increasing and proportionate inhibition of both activities. The evidence strongly supports earlier suggestions that the two hydroxylase activities occur in a single protein.


Interconversion of conformational isomers of light chains in the Mcg immunoglobulins.

Previous crystallographic studies in this laboratory demonstrated that immunoglobulin light chains with the same amino acid sequence can have at least two and probably three or more conformations, depending on whether the second member of an interacting pair is a light or heavy chain. If a heavy chain is not available in the assembly medium, a second light chain plays the structural role of the heavy chain in the formation of a dimer. In the present work, the lambda-type light chains were dissociated from the heavy chains of a serum IgG1 immunoglobulin from the patient Mcg and reassembled noncovalently into a dimer. The reassembly process was completed by allowing the penultimate half-cystine residues to form an interchain disulfide bond. The covalently linked dimer was compared with the Mcg urinary Bence-Jones dimer, for which an atomic model has been fitted to a 2.3-A electron density map. The assembled dimer and the native Bence-Jones protein were indistinguishable in their chromatographic and electrophoretic properties, as well as in their activity in the binding of bis(dinitrophenyl)lysine. These results indicate that the light chains can be converted into the two types of Bence-Jones conformational isomers. The procedure was also reversed: the two Bence-Jones isomers were dissociated and reassembled as the single type of isomer associating with each of two heavy chains in the IgG1 protein. The change in activity occurring when a light chain associates with a heavy chain instead of a second light chain is illustrated by the fact that the Mcg IgG1 immunoglobulin does not bind dis(dinitrophenyl)lysine in measurable amounts.


The light-harvesting chlorophylla  a/b.protein complex of the green alga Acetabularia mediterranea. Isolation and characterization of two subunits.

In the green alga Acetabularia mediterranea a light-harvesting chlorophyll a/b.protein complex of 67 000 daltons has been found which contains two polypeptide chains of 21 500 and 23 000 daltons. These two polypeptides were isolated on a preparative scale and were further characterized by several different methods. Both polypeptides proved to be very similar. While their amino acid and sugar compositions as well as their immunochemical properties were almost identical the tryptic peptides and the cyanogen bromide fragments of the two polypeptides revealed minor but significant differences. The 67 000-dalton chlorophyll a/b.protein complex and its two polypeptide components were compared to the light-harvesting chlorophyll a/b.protein of higher plants.


Enzyme alteration in skeletal muscle of mice with muscular dystrophy.

1. Developmental enzyme alterations were investigated in skeletal muscle of the hereditary progressive muscular dystrophy (PMD) mice of C57BL/6J strain. 2. Enzymes examined were classified into three groups according to changes of activities in dystrophy muscle during ageing. Activities of creatine kinase (EC 2.7.3.2), pyruvate kinase (EC 2.7.1.40), glycogen phosphorylase (EC 2.4.1.1), and fructose-biphosphate aldolase (EC 4.1.2.13), each of which had the respective muscle specific isoenzyme of extremely high activity in normal adult skeletal muscle, decreased rapidly in dystrophy muscle from the early stage of the disease with ageing. Activities of glycogen synthase (EC 2.4.1.11) and hexokinase (EC 2.7.1.1) were higher in dystrophy muscle in the early stage but decreased gradually to lower levels than those in the control with ageing. Activities of glucose-6-phosphate dehydrogenase (EC 1.1.1.49) were always much higher in dystrophy muscle than in the control, with no relation to ageing. 3. Isoenzymes of creatine kinase, pyruvate kinase and phosphorylase in dystrophy muscle were mainly the muscle types, indicating that muscle differentiation was not blocked profoundly even in dystrophy muscle. In limited cases, especially in the early stage of the disease, very weak activities of the non-muscle fetal type isoenzymes of creatine kinase and phosphorylase were detected, apparently associated with partial muscle regeneration in dystrophy muscle.


[Primary photosynthetic reactions in isolated chloroplasts fixed by glutaric aldehyde].

The primary photosynthetic reactions in isolated pea chloroplasts with the structures fixed by increasing concentrations of glutaric aldehyde were studied. It was shown that under chloroplast fixation by 5--25 mM of glutaric aldehyde, a significant inhibition of processes responsible for energy transformation in biological membranes was observed. The highest sensitivity was observed for the phosphorylation reactions, photo-induced changes in absorption at 520 nm, photo-induced quenching of atebrin fluorescence and slow component of delayed light emission. The photo-induced proton uptake was found to be less sensitive to fixation by glutaric aldehyde. It was also shown that on chloroplast fixation the extent of the steady-state P700 oxidation and the lifetime of the photosystem I and II chlorophyll fluorescence are both increased, a fact is indicating of loss in the effectiveness of light energy transfer from the antenna molecules to the reaction centres. Presumably the conformational changes play an essential role at the initial steps of light energy transformation.


[Light-induced oxygen uptake by chromatophores and subchromatophore pigment-protein complexes of Rhodospirillum rubrum].

Chromatophores of R. rubrum incubated with electron donors, e. g. reduced diaminodurene, TMPD, phenazine methosulphate, cytochrome c or ferrocyanide, are able to catalyze O2 uptake upon illumination. This process is inhibited by o-phenanthroline as well as upon extraction of quinones from chromatophores, but not by antimycin A, rotenone or CN-. The O2 uptake sensitive to the action of o-phenanthroline is also observed in the illuminated subchromatophore P870 reaction center complexes and reaction center  plus light-harvesting antenna complexes incubated with electron donors, quinones and detergents. The data obtained are in agreement with a suggestion that the photooxidase activity of chromatophores and subchromatophore pigment-protein complexes is due to the interaction of photoreduced ubiquinone with O2.


[Isoenzyme composition and some properties of pea lipoxygenase].

The isoenzyme composition and some properties of lipoxygenase isolated from the seeds and 10-day old sprouts of pea plant were studied. The enzyme activity assay, using gel- and ion-exchange chromatography, disc-electrophoresis in polyacrylamide gel, etc. revealed that the plant contains two lipoxygenase systems of unsaturated long-chain fatty acids oxidation. The existence of four lipoxygenase isoenzymes whose combination determines the type of lipoxygenase-catalyzed reactions of linoleic acid oxidation, has been confirmed.


[Thrombocyte adenase of healthy monkeys and monkeys with different degrees of hemoblastosis].

Sensitive radioactive method was used to study the activity of blood platelet adenase in healthy monkeys and in monkeys with hemoblastosis of different severity. A considerable increase of the specific activity of the enzyme in hemoblastosis with an expressed clinical picture and a reduction of the enzymatic activity at the stage of remission and in mild form of the disease was demonstrated. No adenase was revealed in the platelets of healthy monkeys.


[Role of mitochondrial membrane lipid hydrolysis in their swelling induced by thyroxine].

The thyroxin-induced mitochondrial swelling was accompanied by an accumulation in organellas of free fatty acids which level was restored after the mitochondria contraction in the ATP presence. EGTA induced mitochondrial contractions as well, but with no free fatty acids utilization. Apparently, the thyroxin-induced mitochondrial swelling is the result of the membrane phospholipase activation and of the increase in the membrane cationic permeability due to the hydrolysis of membrane phospholipids.


[Formation of nerve fibers between organotypic explants of the hippocampus and mammillary bodies of newborn mice].

Nervous fiber bundles formed between the explants during the organotypic cocultivation of the hippocampus and mamillary nuclei of the newborn mouse. Some of the fibers within these bundles were the continuation of axons localized in the alveus of the Ammon's horn. It is suggested that under conditions of cultivation the hippocampal pyramidal neurons deprived of the afferent leads-in from other brain structures are capable of forming the projection efferent connections typical of the intact hippocampus neurons.


Antithrombin Pittsburgh: an alpha1-antitrypsin variant causing hemorrhagic disease.

A 10-year-old boy had a severe lifelong hemorrhagic disorder that had necessitated more than 50 hospitalizations. Laboratory examination showed prolonged bleeding, clotting, partial thromboplastin, prothrombin, and thrombin times. These findings were due to a potent inhibitor of the thrombin-fibrinogen reaction. This inhibitor was similar to heparin in that it acted immediately and did not interfere with the coagulant activities of certain venoms. It differed from heparin in not being adsorbed to barium citrate or neutralized by protamine sulfate. The inhibitory effect was found in the alpha1-globulin fraction. It was identified immunologically and functionally as a double-banded alpha1-antitrypsin of a previously unreported phenotype. The inhibitory effects were depressed by trypsin and heterologous anti-alpha1-antitrypsin.


An unusual case of a plasma cell neoplasm with an IgG3lambda myeloma and a gamma3 heavy chain disease protein.

A unique case of gamma3 heavy chain disease with two related serum proteins is reported. One molecule appears to be an IgG3lambda myeloma protein. The second molecule is a dimer of a shortened gamma3 heavy chain that has an unblocked amino terminus and lacks the VH and CH1 domains. Its probable origin as a synthetic product is discussed. The clinical and pathologic features of this patient resemble those of other patients with gamma heavy chain disease more than those of patients with multiple myeloma. It seems likely that the heavy chain disease protein is the result of a mutational event in the malignant clone originally producing the myeloma protein.


Behavioural and pharmacokinetic studies in the monkey (Macaca mulatta) with diazepam, nordiazepam and related 1,4-benzodiazepines.

1. Behavioural activity (delayed differentiation and spatial delayed alternation) and pharmacokinetics of diazepam and its metabolites, N-desmethyldiazepam (nordiazepam), 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-desmethyldiazepam (oxazepam), and of dipotassium clorazepate (clorazepate), were studied in the monkey (Macaca mulatta). Diazepam and its metabolites (1.8 and 3.0 mg/kg) and clorazepate (2.6 and 4.3 mg/kg) were given by intraperitoneal injection. 2. Hydroxylation of diazepam (temazepam and oxazepam) led to a loss of, or a considerable reduction in, behavioural activity, whereas activity was preserved, though modified, by demethylation (nordiazepam). It was not possible to establish change in behaviour at specific time intervals after clorazepate, but combined performance data revealed an effect. 3. The maximum mean plasma concentrations of diazepam, temazepam, oxazepam and clorazepate were observed at 0.5 h, and the maximum mean plasma concentration of nordiazepam was observed at 1 hour. Plasma concentrations of nordiazepam were the highest and decreased monoexponentially. Plasma concenqrations of the other drugs declined rapidly at first but more slowly later, and these data were analysed as biexponential models. In the analysis for metabolites, nordiazepam reached measurable levels after the injection of diazepam and clorazepate. 4. It is suggested that differences in the effects of closely related benzodiazepines may not be due solely to their plasma pharmacokinetic properties, but may arise from differences in their intrinsic activity.


Trying to bridge some neuropsychological gaps between monkey and man.

It is puzzling that some anatomical systems in the brains of monkeys and men appear to function quite differently although there is no established basis for this either in their fine-grained anatomical organizations or in the inherent behavioural capacities of the two species. It is suggested that in some instances the discrepancies may arise because inappropriate tests have been used with the animals, and examples are given of positive evidence for cross-modal perception and a possible experimental basis for hemispheric specialization in the monkey. In other instances, they may derive from inadequate or inappropriate methods of testing human subjects, and attention is focused on two major examples: memory disorders associated with medial temporal lobe lesions and blindness associated with occipital lesions in man. In both examples it has been generally concluded that the human deficits are far more severe and even qualitatively different from those studied in the monkey. Evidence suggests that the discrepancies may be resolved if human subjects are tested not by means of 'commentary' questions (e.g 'do you see this? or 'do you recognize this?') but by methods that depend upon forced-choice or identification procedures that are more closely related to those used with animal subjects. It is argued that the study of dissociations between a capacity and its acknowledgement by a human subject may suggest a type of brain organization that is consistent both with the engineering approach that Craik would have fostered and also with one that places older and newer brain structures in the single evolutionary framework.


Total hepatic ischaemia in the Rhesus monkey.

During operations for major hepatic trauma it may be necessary temporarily to deprive the liver of its blood supply by occlusion of the hepatic artery and portal vein. The maximum 'safe period' of total hepatic ischaemia in man is unknown. In the monkey the ischaemic liver 'leaks' potassium, and levels of this element in the hepatic veins rise during ischaemia reaching a peak immediately after blood supply to the liver is restored. However, critical systemic levels of potassium are never reached and severe biochemical disturbance does not occur until 2 h following revascularization in animals having experienced ischaemic periods of longer than 20 min.


Leakage from T tube tracts as determined by contrast radiology.

The continuity of the T tube tract on removal of the drain was studied by fluoroscopic examination in 51 patients. Leakage was found in 25 cases (abdominal cavity 7, wound drain 6, local cavity 11, combined abdominal and wound drain leakage 1). No correlation was found between the incidence of pyrexia or pain and the presence of leakage. These complications, noted in 10 patients, are probably explained by bacterial contamination of the bile in combination with the trauma caused by extraction of the tube.


Noxythiolln-resistant organisms in a district general hospital.

Twelve strains of Pseudomonas aeruginosa, three strains of Klebsiella aerogenes, and two strains of Escherichia coli were found to be resistant to noxythiolin. Some of the pseudomonads were isolated from patients in the same ward, not all of whom were on noxythiolin treatment. The strains from these patients were indistinguishable from each other on phage typing, which suggested cross-contamination. No Gram-positive organism was found to be resistant to noxythiolin. Noxythiolin should not be used before a disc diffusion sensitivity test has been performed to determine whether the organisms are sensitive to it. This is particularly important when pseudomonads are the offending organisms.


Nutritional requirements and penicillin susceptibilities of gonococci from pharyngeal and anogenital sites.

Neisseria gonorrhoeae was isolated from 5.9% of oropharyngeal specimens obtained from patients attending a clinic for sexually transmitted diseases. Oropharyngeal isolates from 69 patients and anogenital isolated from 97 other patients attending the same clinic were compared. Many of the gonococci could be differentiated by the compounds required for growth in chemically defined media or by differences in the minimum inhibitory concentration (MIC) of penicillin G. Strains with requirements for either proline (Pro-) or arginine (Arg-) or for none of the compounds that are used for differentiation (zero phenotype) were more common in the oropharynx (91.3% of patients) than in anogenital sites (73.2% of patients). On the other hand, gonococci with multiple requirements that include arginine, hypoxanthine, and uracil (AHU strains) were present in oropharyngeal specimens from only three patients (4.4%), but were isolated from anogenital specimens from 18 patients (18.6%). A high susceptibility to penicillin characterised the AHU strains from all sites, as others have reported. The penicillin MIC ranged from 0.003-0.72 microgram/ml for strains with Pro-, Arg-, and zero phenotypes. However, a penicillin MIC greater than or equal to 0.42 microgram/ml was found for 17.6% of oropharyngeal isolates of these types, but for only 4.1% of Pro-, Arg-, and zero isolates from anogenital sites. None of these moderately resistant strains produced beta-lactamase. Our findings indicate that gonococci differ in their ability to colonise the oropharynx successfully.


Sensitivity pattern of Neisseria gonorrhoeae to penicillin and screening for beta-lactamase production in Ibadan, Nigeria.

The few reports from Africa on sensitivity determinations of Neisseria gonorrhoeae suggest that there is an increasing resistance in the strains, as has been found in other parts of the world. In the current study, the penicillin sensitivities and β-lactamase production of 80 consecutive strains of N. gonorrhoeae isolated from cases of acute urethritis in African men in Ibadan were studied. Of these strains, 17·5% had a penicillin minimum inhibitory concentration (MIC) of 0·038 μg/ml or less and were considered as being `fully sensitive'. However, 82·5% had an MIC of 0·075 μg penicillin/ml or more, and were considered as having `diminished sensitivity' to penicillin. It was thought that this high incidence of relatively insensitive strains was owing to the sequential selection of these strains because of the easy availability and abuse of antimicrobial agents by the general population. Furthermore, 13 strains (16·25%) demonstrated high level resistance with MIC values of over 0·6 μg penicillin per ml and it is probable that many of the strains will demonstrate multiresistance to the commonly misused antimicrobial agents. Consequently, treatment of patients harbouring these strains may present problems because of financial constraints of the health services in purchasing the appropriate antibiotics. Despite the high level resistance of the strains in an environment of intensive penicillin and ampicillin use, none of the strains studied showed any evidence of β-lactamase production. Nevertheless, continuous surveillance of β-lactamase production by the gonococcus is recommended in the larger medical centres in developing countries.


Diagnosis of rectal gonorrhoea by blind anorectal swabs compared with direct vision swabs taken via a proctoscope.

Eight hundred and twenty-three examinations were carried out on 662 homosexual patients. At each examination a blind anorectal swab and a rectal swab taken via a proctoscope were inoculated on to a culture plate. From a total of 100 gonococcal infections of the rectum 96 gave positive results from blind anorectal swabs and 99 from swabs taken via a proctoscope. Blind anorectal swabs proved to be a reliable method in the diagnosis of rectal gonorrhoea.


Comparative investigation of the relationship between cerebral indices and learning abilities.

Indices of cerebral development were computed for 23 different species in order to assess their capacity to accurately reflect differences in learning ability. The resulting correlations between index values and performance on a variety of tasks strongly suggest that this approach may offer the best type of continuum for the comparative study of learning. It was further suggested that if the index proposed by Jerison were expanded to reflect possible neuronal connections, a more powerful measure might be obtained.


Clinical, biochemical, and physiological features distinguishing myoclonus responsive to 5-hydroxytryptophan, tryptophan with a monoamine oxidase inhibitor, and clonazepam.

Fifteen patients with a variety of myoclonic syndromes were studied clinically, pharmacologically, and physiologically. CSF tryptophan, 5HIAA, and HVA were also measured. Of these patients, 8 were improved to varying degrees by therapy with 5HTP, tryptophan in combination with MAOI (but not tryptophan alone), and clonazepam. This group included 6 cases of post-anoxic myoclonus, one case of post-traumatic myoclonus and one undiagnosed case of non-progressive focal myoclonus and epilepsy. In this group low levels of CSF 5HIAA were found compared to non-responsive cases and controls. Two cases of dysynergia cerebellaris myoclonica, 2 cases of undiagnosed aetiology, 2 cases of essential myoclonus, and one case of palatal myoclonus failed to respond to drug therapy. However, even amongst the responsive group the improvement varied. The most dramatic responses were seen in those patients in whom physiological study suggested that myoclonus was mediated by brain-stem structures. Less dramatic responses were seen in patients in whom the myoclonus appeared to originate from cortical structures. The neurochemical basis of myoclonus responding to 5HT precursors and clonazepam is discussed. It is suggested that such myoclonus arises from a relative hypoactivity of the 5HT neuronal system which results in a release of abnormal responses to sensory stimuli which characterize this type of myoclonus.


Osmotic opening of the blood-brain barrier in the rhesus monkey without measurable brain edema.

The blood-brain barrier in the rhesus monkey was opened to intravascular Evans blue-albumin, without causing brain edema or altering brain electrolytes, by perfusing 2.5 molal recrystallized D,L-lactamide into the internal carotid artery for 20--30 sec. Gross neurological and behavioral sequelae were absent in 7 of 8 animals with barrier opening, and 2 days after perfusion no statistically significant changes were observed in sodium, potassium or water contents of perfused as compared to unperfused gray and white matters of brains of the 7 normal animals. Brain endema may not have developed because parenchymal albumin was excreted or metabolized by 2 days. It is suggested also that closure of the barrier after several hours prevents salt from accompanying plasma fluid into the brain. Entry of fluid without salt would reduce, before measurable edema developed, any transcapillary osmotic gradient established by prior entry of plasma albumin.


Connections of latero-dorsal nucleus of the thalamus. II. Experimental study in Papio papio.

Modifications of the latero-dorsal (L.D.) nucleus of the thalamus have been observed earlier in man in relation to limbic lesion of various etiologies. Our proposal was to determine the role of L.D. in memory disturbances. We attempted to study the connections of L.D. in Papio papio baboon after surgical lesion using silver impregnations as well as traditional techniques. We found three afferent pathways: from the fornix, the posterior cingulate and the parietal cortex (area 7). The most important is the afferent system from the fornix, it terminates in the antero-dorso-medial part of L.D.; the other two afferent pathways have a postero-lateral projection in L.D. The three efferent systems to parietal cortex, cingulate and fornix were not delineated in this study. It was concluded that the antero-dorso-medial portion of L.D. is connected to the limbic system and the ventro-postero-lateral portion integrated into a large parieto-cingulo-parahippocampal circuit to which it is joined by direct and indirect projections with several relays. These connections have important implications, perhaps, in our understanding of memory disturbances.


Quantitation of myelin carbonic anhydrase-development and subfractionation of rat brain myelin and comparison with myelin from other species.

A number of related studies have been performed to characterize further the carbonic anhydrase activity of myelin. Recent assertions that carbonic anhydrase activity is intrinsic to the myelin sheath were subjected to the additional test of isolation of rat brain myelin in the presence of purified carbonic anhydrase. This procedure did not increase the carbonic anhydrase activity in myelin above the endogenous level, indicating that this enzyme does not stick to myelin membranes. A developmental study of rat brain carbonic anhydrase showed that the enzyme activity increased in whole brain homogenates and in myelin, with the greatest increments in enzyme activity occurring before the animals were 60 days old. When myelin from adult rat brains was fractionated on a density gradient, carbonic anhydrase activity was relatively enriched in the heavy subfraction but was present in all three layers. This finding suggested that the activity in myelin preparations was not due to contamination with a carbonic anhydrase-rich membrane fragment. Carbonic anhydrase in myelin was not confined to the rat. Beef brain homogenates and myelin had low activities of the enzyme, but myelin from rabbit, cat, monkey and mouse had carbonic anhydrase activities comparable to that of the rat, accounting for 6.3--13.6% of the respective homogenate activities.


Bone sarcomas: etiology and immunology.

The etiology of skeletal sarcomas is found in induced by viruses in man (as they are in exogenous agents (irradiation, oncornavirus) acting in a peculiar setting of host factors. Patients with skeletal sarcomas react immunologically to autologous and allogeneic sarcoma cells, but reactors can be found among the healthy persons with or without exposure to patients with sarcomas. Various modalities of immunotherapy are available to increase the patient's immune reactivities in general or to sarcoma cells in particular, but immunotherapy of skeletal sarcomas has not yet brought about clear-cut and substantial benefits in addition to or beyond the results of conventional treatment.


Danazol therapy in hormone-sensitive mammary carcinoma.

The effect of Danazol, a synthetic gonadotropin inhibitor, on two groups of Sprague-Dawley rats with dimethylbenze (a) anthracine (DMBA) induced mammary carcinoma was studied. Twenty-four (83%) of 29 control animals developed mammary tumors. Forty-four rats in one treatment group received Danazol after tumor reached 0.5 cm in diameter. Twenty-nine (66%) demonstrated tumor regression (p less than 0.005) and in 16 (36%) tumor disappeared (p less than 0.005). In a second treatment group (given Danazol daily after administration of DMBA), only seven of 50 rats (14%) developed palpable mammary carcinoma (p less than 0.0005). Danazol therapy resulted in regression of established mammary carcinoma in rats, and produced a striking inhibition of carcinogenesis in those animals treated from the time DMBA was administered. Danazol is clinically safe; studies using it in the treatment of breast cancer in women who are candidates for hormonal ablative therapy seem warranted.


The treatment of mycosis fungoides: adjuvant topical mechlorethamine after electron beam therapy.

The feasibility of employing adjuvant topical mechlorethamine after electron beam therapy in the treatment of patients with mycosis fungoides is demonstrated. Patients treated with a planned adjuvant topical mechlorethamine schedule had a median disease-free interval of 25 months compared to 17 months for the group treated with electron beam therapy alone. Projected relapse-free survivals are slightly better in the adjuvant group--37% versus 29%. Patients receiving adjuvant topical mechlorethamine after the electron beam were observed to have a low incidence of contact allergy to the medication. The topical medication can be continued if a contact allergy develops by using a planned desensitization program. We currently treat all mycosis fungoides patients with electron beam therapy, randomizing half to receive adjuvant topical mechlorethamine.


Preliminary clinical results of combined 433 Megahertz microwave therapy and radiation therapy on patients with advanced cancer.

Seventy patients with far-advanced histologically proven malignancies were treated with a combination of microwave irradiation (433.92 MHz) and ionizing radiation. Of the twenty-one patients who completed the planned course of treatments and are eligible for a minimum of nine-month follow-up, 90% experienced complete relief of symptoms and 10% received partial relief of symptoms. Complete regression of all localized tumor occurred in sixteen of the twenty patients (80%), and nine of the complete responders remain free of disease from nine to fourteen months. It was the opinion of the clinicians involved in this study that the heat administered by the microwave unit potentiated the effects of ionizing radiation over those which would have been seen if radiation were used alone. In view of the fact that all patients in this study had cancers which were previously considered to be refractory to further medical treatment, the marked relief of symptoms and tumor response to combined therapy were encouraging. This preliminary study confirms the impression that the effects of radiation are enhanced by heat and forms the basis for a randomized series involving far-advanced but previously untreated head and neck and gynecological malignancies.


Results of integrated management of supraglottic carcinoma.

Between January 1957 and June 1974, 173 patients with carcinoma of the supraglottic larynx were treated by an integrated approach at the University of California in San Francisco. The policy was to use radiotherapy or surgery alone for Stage I and II disease, radiotherapy combined with either supraglottic laryngectomy or total laryngectomy for resectable Stage III and IV disease, and radiotherapy alone for advanced unresectable disease. Control of the disease in the primary site was achieved in 92% of T1a, 88% of T1b, 80% of T2, 79% of T3 and 56% of T4 lesions. Of the 36 patients with late Stage I and resectable Stages III and IV disease treated by combined preoperative radiotherapy and supraglottic or total laryngectomy, the primary lesion was controlled in 33 (92%). Recurrent disease in the primary site after radiotherapy alone, when detected early, was usually controlled by subsequent surgery, whereas recurrent disease after surgery was not controlled by radiotherapy. Preservation of a functioning vocal apparatus was achieved in 44% of the patients whose primary lesion was controlled. Control of cervical lymph node metastasis was achieved in 71% of N1, 38% of N2, and 25% of N3 disease. No disease recurred in the radically dissected neck which received preoperative radiotherapy. Radiotherapy also reduced the incidence of subsequent neck disease in patients without cervical lymph node metastasis initially from 23% to 14%.


Are pelvic irradiation and routine staging laparotomy necessary in clinically staged IA and IIA Hodgkin's disease?

Thirty-nine patients with clinically staged IA and IIA Hodgkin's disease were treated with mantle plus paraaortic/splenic irradiation between 1968 and 1975. All patients had supradiaphragmatic presentations, and none had staging laparotomies. With a follow-up time of 1 to 9 years, mean 4.3 years, the overall relapse-free survival is 92% (100% for stage IA and 89% for stage IIA). The absolute relapse-free 5-year survival is 91% There were no pelvic recurrences. These data show that routine staging laparotomy and pelvic irradiation are not indicated for clinically staged IA and IIA Hodgkin's disease with supradiaphragmatic presentation. The criteria for staging laparotomy in early-stage Hodgkin's disease are discussed.


Treatment results of retinoblastoma at Indiana University Hospitals.

This paper summarizes a review of all cases (70) of retinoblastoma seen at Indiana University Hospitals over the past 25 years (from 1952 to 1977) to determine the results of treatment and causes of failure. All cases from July, 1967, to the present were managed by the same group of physicians, thus following a consistent philosophy of treatment for those patients. Thirty-two patients treated during this latter period have survived a minimun of two years and are alive. Visual acuity of 20/20 has been preserved in all 16 patients with unilateral disease and a range of 20/50 to 20/20 in 12 of the 16 patients with bilateral disease. Because of the highly specialized diagnostic and therapeutic techniques and equipment required for optimal treatment results, it is recommended that patients with retinoblastomas be referred to treatment centers specializing in the management of this disease.


Carcinomas of the paranasal sinuses: a study of sixty-six cases.

The therapy records of 66 patients with carcinomas of the paranasal sinuses were reviewed; primary carcinomas occurred in the maxillary sinus in 50 patients, the ethmoid sinus in 11 patients, the sphenoid sinus in 4 patients and the frontal sinus in 1 patient. The tumors of the maxillary sinus were staged retrospectively according to the American Joint Committee staging system recommended in 1976; 1 of 2 patients with T1, 5 of 11 patients with T2, 10 of 34 patients with T3 and 1 of 3 patients with T4 lesions showed no evidence of disease (NED) at 3 years. Combined high dose irradiation (6,000 rads in 6 weeks) followed by radical surgery in 4 to 6 weeks was well tolerated; this approach is recommended for the treatment of T1, T2, and selected T3-4 maxillary sinus lesions. Only 2 of 11 patients with ethmoid sinus lesions survived at 3 years.


Anaplastic seminoma.

Eight patients with the diagnosis of anaplastic seminoma of the testicle were treated during the megavoltage era from January 1959 to January 1976. Two patients with Stage I disease and one patient with Stage IV disease have died from their malignancy. By contrast, 57 patients with typical seminoma were treated during the same interval and with the same treatment methods. However, only two patients with typical seminoma have died. One of these patients had Stage II disease and one had Stage IV disease. There were no deaths among patients with Stage I typical seminoma. These results suggest that anaplastic seminoma has a poorer prognosis than typical seminoma even when the diseases are compared stage for stage. Implications for therapy are discussed.


Distribution and metabolism of vincristine in mice, rats, dogs, and monkeys.

An extraction procedure that allows measurement of [3H]vincristine and its metabolites in biologic fluids and tissues has been developed and used to determine the distribution and metabolism of vincristine in mice, rats, dogs, and monkeys. Very little tritium exchange occurred during the experiments. In mice and rats injected ip with [3H]vincristine, the peak serum levels of drug were reached at 15 minutes. For both mice and rats, the concentration of vincristine metabolites rose in the serum for 30 minutes, then remained high through 3 hours. For dogs and monkeys given an iv dose of [3H]vincristine, the initial serum levels fell rapidly, with half-lives for the first phase of 6 and 10 minutes respectively. The half-life for both of the second phases was 190 minutes. For both species, the serum level of metabolites fell for 2 hours, then remained relatively constant. These results were not appreciably altered when the animals were injected simultaneously with prednisone. Compared to serum levels in mice, rats, dogs, and monkeys, there was a marked accumulation of [3H]vincristine in all tissues examined, except the brain. The pancreas, spleen, kidneys, lungs, and liver of dogs and monkeys contained the largest amounts. The tissue distribution was not greatly different in dogs and monkeys injected simultaneously with prednisone. Urinary excretion of intact vincristine and its metabolites was observed for all four species. Both vincristine and its metabolites appeared in the bile of dogs and monkeys.


Distribution and metabolism of prednisone in mice, dogs, and monkeys.

A chromatographic procedure that allows measurement of [3H]prednisone and [3H]prednisolone in biologic fluids and tissues was developed and used to determine some of the biochemical properties of prednisone and its distribution and metabolism in mice, dogs, and monkeys. When prednisone was added to mouse serum in vitro at a concentration of 50 microgram/ml, approximately half of the drug became bound to serum proteins. Homogenates of mouse liver metabolized prednisone to prednisolone. Following ip or oral doses of prednisone to mice, serum levels of prednisone, prednisolone, and other metabolites were maximum at 15 minutes. 20-Dihydroprednisolone was identified as a metabolite in several biologic samples. For dogs and monkeys given in iv dose of prednisone, disappearance from the serum was biphasic with apparent half-lives of 15 and 82 minutes and 33 and 78 minutes respectively. The serum levels of prednisone and prednisolone in mice, dogs, and monkeys were not increased beyond expected levels by simultaneous administration of iv doses of vincristine. The prednisone content of the kidneys, liver, intestine, and bile of a monkey killed 30 minutes after an iv dose was higher than that in serum. Oral doses of prednisone were absorbed erratically by dogs and monkeys. Only small amounts of prednisone and prednisolone were excreted in the urine of dogs and monkeys given an iv or oral dose.


Evaluation of radiotherapay for localized inflammatory skin and perianal lesions in adult leukemia: A porspectively randomized double blind study.

Thirty-five episodes of localized infection among 20 patients with acute leukemia and granulocytopenia (less than 1000 cells/microliter) were treated with intensive supportive care including systemic antibiotics. In a double blind randomization, 17 of the episodes also received 400 rads of megavoltage irradiation to the site of the lesion given as a single dose and repeated 7 days later. No significant differences were observed in response rates between the irradiated and nonirradiated lesions. Overall, 65% of the irradiated infections and 44% of the nonirradiated lesions responded completely, a difference which is not significant. The median number of days required to achieve maximum clinical response was similar whether or not irradiation was given (10 versus 12 days). Management of such localized infections should include early diagnosis with prompt institution of intensive supportive care including appropriate systemic antibiotics, but low-dose irradiation cannot be recommended as part of the routine management of these lesions.


Immunohistochemical localization of somatostatin in the human hypothalamus.

In order to identify clearly the nervous structures containing somatostatin in the human hypothalamus, an immunohistochemical localization of this neurohormone was performed at light-microscopic level. Using a antiserum specific to somatostatin and the unlabeled antibody peroxidase-antiperoxidase technique, we have found somatostatin in neurons with cell bodies in an area in the anterior hypothalamus corresponding to the infundibular nucleus. Somatostatin-containing fibers were also detected in the neurovascular zone of the pituitary stalk, suggesting that somatostatin is released in that region to reach the capillaries in the pituitary portal plexus. A large bundle of somatostatin fibers extending from the anterior part of the paraventricular nucleus up to the posterior portion of the mammillary bodies has also been detected. The role of these fibers still remains to be clarified.


Histochemistry of the juxtaglomerular apparatus in the toad Bufo bufo. The glucose-6-phosphate dehydrogenase activity of the macula densa.

An investigation regarding the question of whether there exists a macula densa as part of the juxtaglomerular apparatus in the kidney of amphibians has been carried out. With the aid of a histochemical reaction for glucose-6-phosphate dehydrogenase activity, the presence of a macula densa zone as a specialized part of the distal tubule in the toad Bufo bufo was demonstrated. The functional significance of the high glucose-6-phosphate dehydrogenase activity in the macula densa cells is discussed.