Association of crescentic glomerulonephritis with membranous glomerulonephropathy: a report of three cases.

Association of membranous glomerulonephropathy with crescentic glomerulonephritis is apparently extremely rare. We report three patients who had this combination. One patient had biopsy-proven membranous glomerulonephropathy thirteen months prior to sudden and rapid decline in renal function necessitating hemodialysis. A repeat renal biopsy showed a superimposed crescentic nephritis and antiglomerular (GBM) antibodies were demonstrable in the serum. A second patient had proteinuria of unknown duration and then developed renal failure. Renal biopsy showed crescentic nephritis with a fine granular glomerular immunofluorescence for IgG typical of membranous glomerulonephropathy. Anti-GBM antibodies were present in this patient's serum. The third patient presented with acute renal failure of moderate severity. A renal biopsy revealed crescentic nephritis, granular deposits of immunoglobulins, and epimembranous electron-dense deposits typical of membranous glomerulonephropathy. Although his creatinine clearance improved spontaneously, nephrotic syndrome has persisted and a repeat renal biopsy showed a progression of the membranous glomerulonephropathy with the disappearance of the crescentic lesions. The reason for this peculiar association of membranous glomerulonephropathy and crescentic glomerulonephritis is unclear. It is possible that deposition of immune-complexes along glomerular basement membrane may render the glomerulus more susceptible to additional injury from a variety of other agents. Alternatively, depostis formed in one disease could initiate release of normal or altered basement membrane material and lead to formation of anti-GBM antibodies and subsequent development.


Lupus nephritis: correlation between light, electron microscopic and immunofluorescent findings and renal function.

Percutaneous renal biopsies from 56 patients with systemic lupus erythematosus were studied to determine the relationship between renal function and the light microscopic, electron microscopic and immunofluorescent antibody findings. The glomerular lesions were classified into 5 major groups: diffuse membranoproliferative glomerulonephritis (34%), diffuse proliferative glomerulonephritis (26.8%), membranous nephropathy (12.5%), minimal lesion ('nil') and minimal lesion with increased mesangial matrix and/or cells (21.4%) and focal and segmental glomerulonephritis (5.3%). Minimal lesions and focal and segmental glomerulonephritis were invariably associated with normal renal function. Patients with moderate to severe renal involvement and the nephrotic syndrome had predominantly diffuse membranoproliferative and diffuse proliferative glomerulonephritis. Membranous nephropathy was associated with moderate renal involvement and the nephrotic syndrome in 50% of cases. Patients with pure mesangial electron dense deposits had normal renal function or mild renal involvement when the deposits were heavy. Moderate and heavy subepithelial, and intramembranous/subepithelial deposits were associated with moderate to severe renal involvement and the nephrotic syndrome. Renal involvement was most severe with heavy subendothelial deposits. Cytoplasmic tubuloreticular structures measuring approximately 18 to 20 nm in diameter and 80 to 100 nm in length were found in 93% of all biopsies, but bore no relationship to the renal function of the patients. Anti-Hu-IgG fluorescent deposits were found in all the renal biopsies; in 81.3% these were associated with less heavily stained deposits of immunoglobulin IgA, IgD and IgM. Early complement components Clq and C4 were utilized in the complement pathway of activation. Pure mesangial fluorescent deposits were associated with normal renal function or mild proteinuria. Diffuse granular and lumpy deposits along the capillary loops were usually associated with moderate to severe renal involvement and the nephrotic syndrome. In the present series of cases, there was a good correlation between renal function of patients with systemic lupus erythematosus and the glomerular lesions as determined by light, electron microscopic and immunofluorescent microscopic findings.


A roentgenographic evaluation of frozen allografts versus autografts in anterior cervical spine fusions.

Serial roengenograms of 53 patients who had 76 cervical interspaces grafted with frozen, bone marrrow-free cadaver bone were compared to those obtained from 45 patients who received 63 iliac crest autografts for anterior cervical spine fusion. The roentgenograms were evaluated on the basis of achieving union, delayed union, non-union, and the presence of graft collapse and extrusion. No significant difference was noted in the union rate, with allografts (94%) or with autografts (97%). In 21 patients a higher rate of graft collapse was noted with allografts as compared to autografts in multilevel fusions. In these patients, allograft rejection or the biomechanical properties of the allograft may have contributed to a difference in the rate of graft collapse with cadaver bone. No difference in collapse rate was noted between allografts and autografts in 32 patients with single level fusions. Insertion of frozen bone allografts into intervertebral spaces of the cervical spine has not produced adverse reactions.


Cranial venous system and the posterior fossa in spina bifida aperta.

A study of the cerebral venous system in children with S.B.A. was undertaken, and this report concerns the gross structure of this structure of this system in the posterior fossa. Noteworthy is the closeness of the torcular to the foramen magnum. The lateral sinuses ran near to the foramen magnum to the sigmoid sinuses. The dura of the posterior fossa consisted of a plexiform structure in which no clear distinction could be made between various sinus systems normally present in the dural layers of the posterior fossa, thus constituting an occipital plexus. The walls of the sinuses were weak and were vulnerable to mechanical pressure. The foramen magnum of the skulls of children with S.B.A. was larger than in normal children. The distance of the torcular to the ventral margin of the foramen magnum was smaller in S.B.A. This distance remained unchanged at least until nine months of age in normal children as well as in children with S.B.A., although there was an increase in size of the foramen magnum in both with advancing age.


The case of the saltimbanque Prosper Lecomte. A contribution to the study of the history of progressive muscular atrophy (Aran-Duchenne) and amyotrophic lateral sclerosis (Charcot).

The historical value of the case history of Prosper Lecomte, a French circus owner who died in 1853, is brought again to attention. He appears to be the first patient in the historical literature by whom the diagnosis amyotrophic lateral sclerosis can be established with sufficient certainty.


The incidence of spina bifida occulta in idiopathic scoliosis.

A review of the roentgenograms of the spine of 100 patients with idiopathic scoliosis and 371 parents and siblings used as controls, showed an incidence of spina bifida occulta of 34 per cent and 41 per cent in their siblings. There was no increase in the incidence of spina bifida occulta in the patients with idiopathic scoliosis as compared with the control group. A review of the parents of these patients showed an incidence of spina bifida occulta of the lumbosacral area of 9 per cent in the mothers, and 13 per cent in the fathers, thus showing a decrease in the incidence of spina bifida occulta in the adult as compared with the teenager. The studies in the adult confirm the finding in the teenagers. There is no increased incidence of spina bifida occulta in idiopathic scoliosis.


The classic: Tendon transplants in orthopedic practice by A Codvilla.

Alessandro Codavilla (1861-1912), Director of the famous Rizzoli Institute of Bologna, was one of the leading figures in orthopedic surgery at the turn of the century. The surgical transplantation of tendons and muscles was being widely practiced in most of the leading centers at that time with very variable success. Codavilla is credited by many of his contemporaries including Bielsalski, Mayer and Steindler for his classic and fundamental studies in the physiological aspects of tendon transfer. Published in 1899, this article generally established the physiologic concepts of modern tendon transplantation surgery.


Absorption of vitamin A in patients with cystic fibrosis. Absorption is best with emulsified vitamin A alcohol.

Vitamin A absorption tests using vitamin A palmitate and alcohol separately in oil and oil-water emulsions were done on 43 patients with cystic fibrosis. Patients were given 7,000 units of vitamin A per kilogram of body weight with a fatty breakfast. Pancreatic enzymes were not given with the test meal and were withheld for five hours from start of test. Blood was drawn before administration of the vitamin and at three and five hours after administration. Serum vitamin A levels were estimated using the Carr-Price technique. The percentages of patients with normal vitamin A absorption were 85 with vitamin A alcohol in oil-water emulsion, 61 with vitamin A alcohol dissolved in oil, 64 with vitamin A palmitate in oil-water emulsion, and 19 with vitamin A palmitate in oil. The number of stools per day is an inverse indicator of retention time in the intestine. Absorption of fat soluble vitamins is always abnormal when a patient has four or more stools a day. The observations that cystic fibrosis patients with abnormal liver biopsies have poor absorption of vitamin A were not statistically significant. The question of the effect of cirrhosis in cystic fibrosis on vitamin A absorption remains unresolved.


Impaired resistance to infection.

An outline of the well defined disorders of impaired host defense has been presented. At this time the molecular biology and physiology of the immunity systems are poorly understood. Parameters of fetal function and development to maturity are almost totally unknown. In fact, it is the discovery of the clinical abnormalities which has occasioned the study and understanding of normal function. We have, however, arrived at a point where recognition of aberrations from normal is becoming facile and early detection, supportive and even corrective therapy are possible. To the author's knowledge not one instance of prenatal diagnosis of one of these disorders has been reported. This goal should soon be attained.


Inherited hypothyroidism.

Familial hypothyroidism results from both thyroidal and extrathyroidal dysfunction. Specific intrathyroidal abnormalities in thyroid hormone synthesis causing goitrous hypothyroidism are iodide trap defect, organification defect, "coupling" defect, iodoprotein defect, and dehalogenase defect. The diagnostic studies for each are outlined utilizing radioiodine(131I) studies. Other causes of cretinism include failure of the thyroid gland to respond to TSH and lack of pituitary TSH (or hypothalamic TRH). The syndrome of peripheral resistance to thyroid hormone is discussed. The diagnosis of inherited hypothyrodism rests on an adequate family history and measurement of both T4 and TSH levels which can be determined in cord blood or peripheral blood from the infant. The importance of early treatment of hypothyroidism in the neonatal period to prevent brain damage is emphasized. The rec:nt discovery of the importance of reverse T3 (RT3) in fetal thyroid metabolism is described, and the possibility of amniocentesis as an aid in prenatal diagnosis is considered. The place of intrauterine administration of thyroid hormone to the fetus at risk from hypothyroidism is uncertain at this time and requires carefully controlled studies and long-term follow-up.


Effects of marihuana-dextroamphetamine combination.

Under a double blind, randomized, complete block design, subjects were given either placebo and 10 mg/70 kg dextroamphetamine sulfate (A) orally followed 1 1/2 hr later by a marihuana cigarette (M) prepared to deliver 50 mug/kg delta-9-tetrahydrocannabinol (THC). Statistical analyses suggested that heart rate and blood pressure increased in an additive manner when both drugs were given. Electrocardiogram changes, when present, were nonspecific in character and appeared to be associated with marihuana. In a second study, psychomotor performance was evaluated by a similar design using doses of 10 mg/70 kg of A and M prepared to deliver 25 mug/kg THC. Impairment was related to smoking of M, and no difference could be distinguished between M alone and M-A combination. Subjective evaluation, as measured by the modified Cornell Medical Index (CMI) demonstrated only additive effects for the combination.


Intramuscular butorphanol and meperidine in postoperative pain.

Butorphanol, 1, 2, and 4 mg/70 kg, and meperidine, 40 and 80 mg/70 kg, were compared for analgesic activity and side effects in 104 hospitalized postoperative patients. Butorphanol proved to be 30 to 40 times as potent as meperidine on a weight basis. Both medications provided maximum pain relief approximately 1 hr after administration. The most common side effect in all groups was drowsiness.


Behavioral effects of organophosphate in man.

Increasingly widespread application of organophosphate pesticies has underscored the importance of studying their effects on human behavior. Clinical reports and laboratory investigations have generally supported the assumption that neurobehavioral manifestations of organophosphate toxicity are attributable to accumulation of acetylcholine at central and peripheral synapses as a result of cholinesterase inhibition. Despite methodologic shortcomings in many of the published studies, investigators generally agree on the presence of several behavioral sequelae of organophosphate poisoning: (a) impaired vigilance and reduced concentration, (b) slowing of information processing and psychomotor speed, (c) memory deficit, (d) linguistic disturbance, (e) depression, and (f) anxiety and irritability. The few studies of asymptomatic workers at risk for repeated exposure to organophosphate pesticides have produced only equivocal findings concerning the presence of less severe or latent forms of these behavioral abnormalities.


Clinical study of an amine fluoride gel and acidulated phosphate fluoride gel.

This study compared caries inhibition in children by an amine fluoride and an acidulated phosphate fluoride when administered in a topically applied gel. In addition, the effects of applying amine fluoride daily and weekly were compared. Four hundred and sixty-eight children, ages 6 to 13, were randomly assigned to one of five treatment groups and received a total of five, 5-minute treatments. The treatment and interval between each of the five treatments were as follows:(A)acidulated phosphate fluoride daily, (B) amine fluoride daily, (C) amine fluoride weekly, (D) placebo daily, and (E) placebo weekly. When the children were examined for total Decayed, Missing, and Filled Surfaces (DMFS) increments 2 years later, no significant differences were observed. However, when the data were examined for effects of DMFS for specific tooth surface, significant restriction (61%) of occlusal increment was shown in the group which was treated with amine fluoride daily for 5 consecutive days as compared with the control group.


SCANCANS--an interactive scanning cell analysis system.

This paper describes a computerized, general-purpose, interactive, scanning cell-analysis system developed at the Department of Clinical Cytology of the University Hospital in Uppsala. The system uses a Leitz MPV II scanning photometer, a PDP-8 computer with 24 k of core memory and a Tektronix 4010 graphic display terminal. A command interpreter and overlay structure which makes it simple to add new capabilities to the system is described. Some examples of command strings and the kind of operations the system can perform are included. Finally, the experience gained from using the system and some plans for future extensions are discussed.


Effect of feline panleukopenia virus infection on development of humoral and cellular immunity.

Cats were infected with feline panleukopenia virus (FPLV) at various ages pre- and post-parturition. All fetuses infected at 35 days of gestation from one queen and a single fetus infected at 45 days of gestation from a second queen had a significant delay in time of skin allograft rejection. Older fetuses and newborn kittens infected with FPLV did not show this delay in rejection time. Adult cats infected with FPLV demonstrated a significant decrease in lymphocyte responsiveness to two T cell mitogens, phytohemagglutinin and Concanavalin A, however there was no significant decrease in lymphocyte response to pokeweed mitogen, a T cell and B cell mitogen. Primary and secondary antibody responses to rabbit red blood cells (RRBC) were not affected by FPLV infection. The results suggest that FPLV has its primary immunosuppressive effect on T cell activity. This effect does not appear to be as severe as that observed for feline leukemia virus of kittens nor as for canine distemper virus in dogs.


Laboratory tests of renal function.

There are several tests available to evaluate renal function. Because the kidney has such complex and varied functions, no one test can adequately measure them. A rough measure of renal function can be obtained by examining the constituents of the urine. More specific aspects of tubular and glomerular function require more complex tests. Proper interpretation of these tests, however, requires knowledge of the patient's status and clinical course.


Control of epithelial development.

Interactions between epidermal and dermal cells of integumental systems exert finely regulated controls over epithelial development. Experimental reconstruction of skin tissues, in vitro and in vivo, from selected populations of dissociated embryonic chick and mouse cells provides a unique opportunity for analyzing the morphogenetic information intrinsic to individual cells. Dermal cells are shown not only to induce and specify particular epithelial structures; they also exercise the power to suppress potential developmental programs. Epidermal cells not only recognize and respond to dermal directives; they are also critical agents in the communication of cues for histogenetic patterning to both neighboring epithelial cells and subadjacent dermal elements. The role of the cell surface as a site for developmental control is discussed in the context of current evidence.


Controversies in current immunization policy and practices: one physician's viewpoint.

Immunization offers the best available method preventing diseases which exact huge tolls in terms of comfort, life and economic stability of humans. However, immunization is a mixed blessing because of unavoidable risks to recipients of almost any biologic product. Only by careful attention to the balance of risks between an immunization procedure and its corresponding disease will we achieve a rational, sound and appropriate policy and practice. This report details the author's analysis and opinion concerning some current controversies in immunization policy and practice. The reader is cautioned that the report represents one viewpoint; others report differing or even contradictory interpretations of the data presented, leading to different or even opposing views. The purpose of this report will be ably served if the reader considers the data himself (herself) and reaches an independent, informed opinion.


Beclomethasone dipropionate aerosol in the treatment of steroid-dependent asthma. A 12-week double-blind study comparing beclomethasone dipropionate and a vehicle aerosol.

In a randomized double-blind 12-week trial of steroid-dependent patients with chronic asthma, ten (59 percent) out of 17 patients receiving beclomethasone dipropionate aerosol in a total daily dose of 400mug were able to discontinue systemic corticosteroid therapy successfully, compared to two (13 percent) out of 15 patients in the placebo group (P=0.002). At the end of the trial, the average 8 am plasma cortisol level in the group receiving beclomethasone was more than twice the pretherapy value, whereas the level in the placebo group showed no significant change. There was no significant difference between the beclomethasone group and the placebo group in the overall incidence of side effects related to the aerosol and the effects of systemic corticosteroid withdrawal. Oral candidiasis was not found in any patient receiving beclomethasone dipropionate aerosol. Allergic nasal symptoms were disabling in many patients when the oral dosage of corticosteroids was tapered.


"Special article" in honor of the bicentennial year 1776-1976.

During this bicentennial year it is worthwhile to review the history of children who have suffered from mental illness during the course of America's movement from a small colony to a major "superpower." The lesson to be found in the history of these children suggests that perphaps our major priorities were not the mental health of children. Hopefully America's next bicentennial celebration will reveal a more enlightened attitude and concern for emotionally disturbed children.


Self states and performances of preadolescent boys carrying out leadership roles inconsistent with their social status.

A sample of 221 Boy Scouts was formed into (usually) 4-man teams which competed in 3 games of skill. 1 member of each team was randomly designated as its captain, with powers to administer and reward. All subjects took modified Thematic Apperception Tests (TATs) and adjective checklists. Captains who were already leaders in their troops responded with decreased élan. Captains who were not leaders responded with decreased élan and, in some cases, with feeling of withdrawal from relating to others and ineffectiveness as captains. The effects were unrelated to the actual success of their teams.


Minor physical anomalies and problem behavior in elementary school children.

The present study replicated and extended earlier findings on the relationship between minor physical anomalies and several classes of problem behavior in an unselected group of elementary school children. Teachers and peers were the judges of problem behavior. The problem checklist and a teacher ranking of hyperactivity were related to the incidence of minor physical anomalies for boys. A negative peer factor was also consistently related to the incidence of minor physical anomalies for both boys and girls. The behavior of high-anomaly girls was not easily characterized in terms of any one type of problem behavior. Sex differences and their implications are discussed.


Neurotic depression an empirical guide to two specific drug treatments.

A frequent problem confronting the physician - which of two possible treatments to select - is discussed, utilizing a group of neurotically depressed patients with anxiety. In these patients, treated with a phenothiazine (thioridazine) or a benzodiazepine (diazepam), the average severity of crucial symptoms such as depressed mood and ideas of suicide decreased by over 50% and did so during the initial four weeks of treatment, comprising the span of this double-blind study. The severity of many other related related symptoms decreased by almost one-half during that period. The results revealed a moderate but fairly consistent advantage for thioridazine for most symptoms. Details of differential effectiveness, as well as features and problems in the treatment of neurotic depression by the practitioner, are described below.


[Sisomicin versus gentamicin. A comparison of antibacterial and pharmacokinetic properties (author's transl)].

In a comparison of the antibacterial in-vitro activity of sisomicin, gentamicin, and tobramycine, sisomicin showed a higher activity against E. coli, indole-positive Proteus spp. and organisms of the Klebsiella-Enterobacter-Serratia group, whereas tobramycine was superior against Pseudomonas spp. However, the differences in activity between sisomicin and gentamicin were only within one step of dilution which is hardly sufficient to guarantee a basic superiority of one or the other preparation for clinical purposes. In 12 healthy probands serum levels and renal elimination of sisomicin and gentamicin after a single intramuscular injection of 1 mg/kg body weight were investigated in a randomised change-over trial. With corresponding serum levels, almost identical elimination half-lives of 109 and 111 minutes, and recovery values of 84 and 88.4%, respectively, there were no significant differences in the pharmacokinetics of sisomicin and gentamicin. Thus in the antibacterial treatment of gentamicin-sensitive gram-negative organisms sisomicin presents an equally good alternative. With organisms only moderately sensitive or resistant to gentamicin, sisomicin, tobramycine and amikacin should be additionally tested.


[Pharmacokinetics and clinical experience with amikacin. A new aminoglycoside antibiotic].

The pharmacokinetic data of amikacin were determined after a 1 hr constant infusion with a dosage of 7.5 mg/kg body weight in 12 healthy test subjects. Microbiological bioassay was performed by the agar diffusion test. After the infusion, the mean amikacin serum concentration was 37.5 mug/ml and, 8 hours later, decreased to an average of 1.3 mug/ml. The biological half-life amounted to a mean of 114.2 min, the area below the concentration-time-curve was calculated to an average of 140.4 hr - mug/ml. The renal clearance of amikacin was determined during a 4 hr constant infusion in 3 test individuals; the average clearance was 84.3 ml/min - 1.73 m2. 38 patients with severe bronchopulmonary, urinary and peritoneal infections were treated with an average daily dose of 10-15 mg of amikacin per kg body weight during a mean period of 10 days. 32 patients showed clinical improvement, 17 of them with complete elimination of the pathogenic bacteria.


[Evaluation of diagnostic parameters in chronic recurrent urinary tract infection in children. III. Pyuria, hematuria, and proteinuria (author's transl)].

Pyuria, proteinuria and haematuria have been shown to be unreliable parameters for the diagnosis of bacteriuria in 171 children with 455 recurrences of chronic urinary tract infection. Bacteriuria caused haematuria in 5%, proteinuria in 18% and even pyuria in only 47% of all instances. Pyuria has been also found in 11% of sterile urines. The incidence of pyuria increases with the age of the children and depends on the type of the organisms, but the latter was true mainly in children with obstructive lesions of the urinary tract. Children with repeated proteinuria during follow-up tend to have a higher incidence of pathologic findings on the i.v.-pyelogram.


Anorectic drugs: use in general practice.

The treatment of obesity is one of the major measures available today in the field of preventive medicine. In particular, the coronary epidemic of Western civilisation would be halted, and most cases of maturity-onset diabetes prevented, if obesity were to be treated effectively. Anorectic drugs act mainly on the satiety centre in the hypothalamus to produce anorexia. They also have various metabolic effects involving fat and carbohydrate metabolism, but many of these may be secondary to loss of weight. Most of the drugs are related directly or indirectly to amphetamine and in addition act by increasing general physical activity. Anorectic drugs tend to lose their effect after some months, and part of this reduction in effect may be due to chemical alterations produced by the drugs in the brain. All the drugs, with the exception of fenfluramine, have a stimulant effect on the central nervous system in some individuals, resulting in restlessness and nervousness, irritability and insomnia. Fenfluramine commonly produces drowsiness in normal doses, but has stimulant effects with overdosage. Dexamphetamine, phenmetrazine and benzphetamine all tend to cause euphoria and the risk of addiction is therefore considerable. Euphoria occasionally occurs with diethylpropion, phentermine and chlorphentermine, but to a much lesser extent. Side-effects also occur due to sympathetic stimulation and gastro-intestinal irritation. These side-effects may cause some individuals to stop taking the drug, but are never serious or dangerous. Drug interactions may occur with monoamine oxidase inhibitors and to a clinically unimportant extent, with antihypertensive drugs. The anorectic drugs have a very definite part to play in the treatment of obesity, mainly for those individuals who have altered their eating habits but have come to a plateau of weight which they find difficult to get below. The drugs are best given in a long-acting form and can safely be continued as long as weight loss persists, provided that the clinician exercises careful supervision. Dexamphetamine, phenmetrazine and benzphetamine should rarely be used because of the danger of addiction, and chlorphentermine is potentially hazardous for long-term use. Diethylpropion emerges as the drug of first choice, as fenfluramine has a tendency to cause depression and has a higher incidence of side-effects. Fenfluramine is mainly useful for people who are especially tense and for obese maturity-onset diabetics who have been unable to lose weight with the biguanides. Mazindol and phentermine appear to be useful as alternative drugs.


Drug-induced anaemias.

Many drugs have been reported to have caused anaemia. The most serious form involves marrow aplasia, but the way in which this is produced is not understood. A number of drugs lead to megaloblastic anaemia and where this is caused by interference with dihydrofolate reductase the explanation is obvious. However, some substances, notably anticonvulsants, cause megaloblastic anaemia by some other mechanism. A number of drugs cause intestinal bleeding with anaemia as a result. Sideroblastic anaemia is a relatively rare condition, sometimes caused by drugs, particularly those used in the treatment of tuberculosis. Leukaemia very occasionally supervenes in patients with drug-induced aplastic anaemia.


Urinary infections: which antibacterial drug and regimen?

Urinary tract infection (UTI) is a common problem in clinical practice. The proper criteria for the diagnosis and treatment of individual and recurrent episodes of UTI are described. The success of antibacterial therapy is dependent upon the urinary concentration of the drug and not its plasma or lymphatic concentration.


Which antirheumatic drug?

Successful therapy in a chronic rheumatic disease means choosing the right drug for the right patient with the right condition at the right time. In the treatment of gout three different types of treatment are given: for the acute episode, suppression and long-term therapy. Misuse of long-term therapy for acute gout will often aggravate the condition. As regards rheumatoid arthritis, in the absence of a known aetiology, treatment is essentially empirical and palliative; the use of milder well-tolerated anti-inflammatory agents for the less severe cases, more effective and more toxic agents for the more severe cases, and slow acting long-term agents for those not responding to previous measures is discussed. Night pain and morning stiffness has its own therapy. The place of corticosteroids throughout the whole field of rheumatology is evaluated. In the treatment of systemic lupus erythematosus corticosteroids still hold first place, but the cytotoxic (immunosuppressive) agents also play a part, though an arguable one.


Pharmacodynamic and pharmacokinetic drug interactions with coumarin anticoagulants.

Many drugs alter the anticoagulant effect of oral coumarins. It is essential that physicians be aware of interactions leading to increased or decreased anticoagulation or to erratic control. Interacting drugs can be classified as influencing the pharmacodynamics (pharmacological actions) or the pharmacokinetics (absorption, biotransformation, binding to plasma proteins, excretion) of oral coumarin anticoagulants. Significant pharmacodynamic interactions include those with vitamin K, salicylates, oestrogens, anabolic steroids, phenylbutazone and other anticoagulants. Significant pharmacokinetic interactions include those with cholestyramine, barbiturates, phenylbutazone, rifampicin and chloramphenicol. When prescribing coumarins, the physician should be fully aware of a patient's other drug therapy and the patient should be cautioned against adding new drugs without consultation. If changes in drug therapy are necessary, close monitoring of prothrombin time after the change is essential.


[Studies on the difference between habitual intercuspidation and redrograde contact position].

In a study of a different subject, the difference between habitual intercuspidation and retral contact position was determined in 21 fully dentulous patients. Registration of the retral position of the mandible was performed by interocclusal wax records and the graphic method. In none of the probands, habitual intercuspidation and retral contact position coincided. In contrast to other authors, we found that siginificant differences between the two methods of registration are an explanation for the differences found betweeen the two positions of the mandible in the sagittal direction.


[The prosthetic care of the mandible after absolute raising of the alveolar crest by means of visor-osteotomy].

An operative method for raising the alveolar ridge of the mandible is described. In connection with vestibuloplasty and lowering of the floor of the mouth, it provides a significantly improved base for dentures without involving the risks of free bone transplantation. In prosthetic treatment the temporarily disturbed sensitivity should be borne in mind. Follow-ups repeated after short intervals are necessary. Data on long-term experience is not yet available.


[Whole-skin transplantation in periodontal surgery].

Open vestibuloplasty in combination with mucogingival surgery has the disadvantage of a high tendency to relapse. The introduction of the gingival graft on to the open periosteum was a considerable improvement. The use of compound flaps taken from the hairless retroauricular region also showed good post-operative results. In addition to good healing and little tendency to shrink, there is the advantage of an ample supply of tissue.


Effect of anomers of D-glucose on alloxan inhibition of insulin release in isolated perifused pancreatic islets.

The in vitro inhibition of insulin released by alloxan (20 mg/100 ml) in collagenase isolated rat islets is preferentially prevented by alpha D-glucose at a concentration of 1.0 mg/ml, while at a higher anomer concentration (1.5 mg/ml) both alpha and beta D-glucose provide equal protection. The ability of alpha D-glucose compared with beta D-glucose to stimulate insulin release, in vitro, showed a similar dose-related response, as observed in the alloxan protective studies. Although, both alpha and beta D-glucose compete with mutorated D-glucose for transport into islet cells, neither anomer produced a significantly different degree of inhibition in the transport process. The shared alpha stereospecificity for D-glucose in protection against alloxan and in stimulating insulin secretion in these in vitro studies, suggest a common site of interaction which may involve the beta-cell membrane.


Effect of thyroid status on spontaneous and induced surges of luteinizing hormone.

This study was designed to describe the effects of thyroid status on the preovulatory surge of LH and to determine the site(s) at which these effects are exerted. The treatment of normal 4-day cycling rats with a hyperthyroid dose of thyroxine (T4, 20 mug/100 g BW/day) for 8 days resulted in surges of LH on proestrus which were depressed to 25% of control levels. In ovariectomized (OV) or ovariectomized-thyroidectomized (OV-Tx) rats maintained on a physiological regimen of T4 (2 mug/100 gBW/day), the amount of estrogen required to induce an LH surge was far greater than that required in OV-TX rats receiving no T4 replacement. These data suggest that T4 attenuates preovulatory surges of LH by acting at the hypothalamic-pituitary axis. However, the pituitary might be eliminated as a site of action since hyerthyroid proestrous rats responded to a challenge of LH-releasing hormone (500 ng) by secreting a quantity of LH equivalent to that in euthyroid animals. Similarly, there was no difference in the quantity of LH released by hyperthyroid and euthyroid proestrous rats in response to electrochemical stimulation (100 muA, 60 sec) of the medial preoptic area of the hypothalamus. On the other hand, hyperthyroid rats secreted significantly less LH in response to stimulation of the arcuate nucleus-median eminence area (ARN-ME) than did controls. Thus, T4, apparently modifies LH release by depressing the response of the ARN.


Control of prolactin and growth hormone secretion in mice by obesity.

Prolactin (PRL) and growth hormone (GH) secretions in mice rendered obese by the administration of gold thioglucose (GTG) are abnormal. The objective of the present experiments was to determine whether the effects were related to the drug or to the resultant obesity. Perphenazine-induced PRL release in normal mice and in GTG-injected non-obese mice was compared to that of GTG-injected obese mice after the initial development of obesity, after body weight reduction by diet control and after the resumption of obesity by ad lib. feeding. The GTG-injected mice which did not become obese had greater (50%) than normal levels of serum PRL following perphenazine stimulation in 2 of 3 experiments. This suggested that the injection of GTG directly affected the control mechanism for PRL secretion, but that the abnormal PRL secretion was probably not the cause of obesity that develops after GTG treatment. Perphenazine-induced PRL levels in mice rendered obese with GTG were much greater (2-3 times higher than normal). However, the unusually high levels of PRL were totally abolished when the body weights of these mice were brought down to normal by dietary restriction. Conversely, when obesity was permitted to recur by giving the mice free access to food, PRL levels reverted back to the original obese pattern. The concentrations of GH were usually lower than normal in GTG-obese mice, and these levels were also more often associated with the development of obesity than with the injection of GTG. The data show a marked influence of obesity on the control of PRL and GH secretions in the mouse.


Inhibition of calcium uptake by somatostatin in isolated rat islets of Langerhans.

Somatostatin (1 mug/ml) inhibited glucose (16.7 mM)-stimulated 45Ca uptake by isolated rat islets incubated in media containing no added calcium or calcium at a low concentration (0.2mM). Epinephrine (50 mug/ml) and mannoheptulose (20mM) also inhibited 45Ca uptake by islets incubated in the  presence of calcium (0.2mM). Addition of glucose (16.7 mM) caused a small but significant increase in insulin release from islets incubated in media containing no added calcium. In the presence of a low concentration of calcium (0.2 mM), glucose caused a much greater increase in insulin secretion which was inhibited by addition of somatostatin, epinephrine or mannoheptulose.


The effect of ovarian steroid feedback upon radioimmunoreactive luteinizing hormone releasing hormone in the hypothalamus.

A radioimmunoassay (RIA) method for luteinizing hormone (LH) releasing hormone (RH) utilizing rabbit antiserum against synthetic (Glu1)-LH-RH coupled with human serum albumin at the N-terminus, is described. This assay system for LH-RH also cross-reacted with several LH-RH analogues or fragments, but not with pituitary trophic hormones. The assay was performed on the hypothalamic extracts of adult ovariectomized rats and female immature rats which had been treated with estradiol. The FSH and LH levels in the pituitary gland and serum of the same animals were determined by RIA. The radioimmunoreactive LH-RH content of the stalk median eminence markedly increased seven days after ovariectomy. The serum levels and the pituitary contents of FSH and LH of the same rats were also significantly augmented. In immature rats, the hypothalamic content of LH-RH, as measured by RIA, was significantly increased one hour after the injection of estradiol. The FSH and LH levels in the pituitary showed a significant rise after 7 hours.


Comparative observation of the pancreatic A and B cells by the enzyme antibody method: light microscopic findings in dog and mouse tissue.

A and B cells of pancreatic islets of the dog and mouse were stained by the enzyme-antibody method. A cells, in general, were small in number, particularly in the mouse, and distributed at the peripheral zone of the islet. Furthermore, A cells were located very close to the intrainsular capillary. On the other hand, B cells occupied dominantly the islet and mainly existed in its central area, especially in the mouse and not adjacent to the intrainsular capillary. A positively reacting cell with anti-insulin antibody was also found in the uncinate process of the dog pancreas, while there was no positively reacting cell with anti-glucagon antibody. This fact, as there were only two kinds of islet cells, B cell and the third cell of the islet (named D cell) in the uncinate process, showed that the D cell had neither glucagon nor glucagon-like immunoreactivity.


Influence of abnormal postural and sensory conditions on human sensorimotor localization.

A wide range of experiments exposing subjects to unusual postural, sensory, and gravitational conditions have been discussed. In general, regardless of the nature of the experimental intervention, changes in sensory localization and sensorimotor coordination resulted. After prolonged exposure to the abnormal stimulus situation, sensory localization as well as sensorimotor coordination showed evidence of compensation, with performance returning toward normal. Our characterization and understanding of these experimental situations has only begun. Similar principles appear, however, to underlie many of these studies. Changes in interpreted posture induced by angular and linear acceleration are accompanied by changes in visual and auditory localization of comparable size. Rearrangement of the visual array by prism spectacles causes errors in sensorimotor coordination that are later eliminated by postural adjustments. Thus, in general, exposure to visual orientation, results in errors insensory localization; exposure to these abnormal states leads to compensatory alterations in postural and sensory mechanisms by a systematic modification of their interrelationship.


Some observations on the effectiveness of anabolic agents in increasing the growth rate of poultry.

This paper will discuss data obtained on the growth promoting effects of metabolically active agents for avian species generally used for food production. The compounds to be considered are those with estrogenic, androgenic, or thyroid hormone activity. Estrogens have been studied most extensively with poultry. At physiologically active levels, estrogens markedly stimulate food intake and at times, weight gain. There is a marked increase in fattening in chickens fed estrogenic compounds and generally a decrease in nitrogen retention. There seems to be a particular stimulation of lipogenesis of estrogenic compounds to the extent that protein synthesis is depressed. Generally high levels of estrogenic compounds are required for metabolic effects. Estrogens have marked effects on circulating nutrient levels and also decrease the choline requirement of growing chicks. Thyroid active substances have been extensively studied. Iodinated casein has been shown to stimulate early growth especially in growing ducks. Efficiency of feed utilization is depressed by feeding iodinated casein and body fat content is reduced. Feathering may be improved by thyroid hormone and in species where feathers are economically imported, it is sometimes advantageous to use these compounds. Methyltestosterone has been shown to be growth stimulating for female chickens and turkeys but relatively ineffective for males. In general, androgens seem to be somewhat less effective in stimulating growth rate and nitrogen retention in domestic birds compared to effects observed in mammals. The role of growth hormone as an anabolic agent in birds is somewhat obscure. Mammalian growth hormone preparations seem ineffective in poultry. The anabolic agents that will be considered in this paper are the hormone active substances with estrogenic, androgenic, or thyroid activity. These will be considered primarily as they affect growth and carcass composition of various species of poultry and not in their normal physiological roles. When considering the role of these compounds in production of human food through their effects on animals, the effects on growth rate, feed efficiency, and carcass composition are primary traits of concern and many other interesting aspects of the physiological effects of these compounds cannot be considered. The paper will not be an exhaustive review of the literature but will attempt to document the effects of these agents on the productive characteristics of poultry.


Physiological data including evaluation of immuno-response in relation to anabolic effects on veal calves.

In a series of experiments with a total of 1480 veal calves, different aspects of treating calves with anabolic steroids were examined. The anabolics used were 17beta-estradiol (E), trenbolone acetate (T), progesterone (P), testosterone (Te), C+T, E+P, E+Te and zeranole (Z). The N-retention was estimated by examining the urea: creatinine ratio in single urine specimens during the course of two feeding trials. Increased gain due to the treatment with E (20 mg implanted/calf) + P (200 mg) and Te (200 mg), respectively, E + T (140 mg) or Z (36 mg) was during the whole experimental period. The extra gain, due to anabolics seems to contain even more protein. This conclusion may be supported by the crude protein content of meat samples. The antibody production of a total of 311 male and female calves was investigated after the application of the following steroids: E (20 mg), T (200 mg), T (200 mg), E + T, P (200 mg), Te (200 mg), E + P, E + Te, and Z. Eleven days after the implantation of the steroids the animals were immunized with alumprecipitated human serumalbumin. Antibody-titres were determined by the Antigen-Binding-Capacity Test on day 14 following immunization. In nearly all groups the antibody-titres of female calves exceeded those of male calves on the average by 75%. The immune response of all experimental groups did not differ significantly from that of the corresponding control groups. However, the results indicate that both E + T and its single components E and T exert an immunodepressive effect in male calves. While the humoral antibody formation in the calf appears not to be influenced by anabolic steroids, it cannot be decided presently whether these substances effect cell-mediated immune reactions and/or unspecific mechanisms of resistance. When estradiol (20, 200, and 500 mg) and trenbolone acetate (140, 1400, 3500 mg) alone and in combination were implanted in female calves, blood glucose, GOT, GPT, alkaline phosphatase, LDH, cholesterine and bilirubine; Hb, PVC, quick value; urine density and pH were not affected by treatment. Some criteria of the mineral metabolism (Ca- and P-levels in serum and bone) was not altered by treatment. Trenbolone (1 400 and 3 500 mg), especially with estradiol, caused a decrease of the serum Mg-level and of the Mg-deposition in the bone. It is discussed that Trenbolone affects the dig-metabolism of calves. Some morphological findings are worth mentioning. The weight of uterus was not affected by the different doses of E or T, but a combination E + T led to a surprising weight increase. The proliferation of uterine glandular cells was responsible for the increased uterine size. The lumen of uterus was partially filled with a watery liquid. The reduction of the ovarian weight was accompanied by a diminution of follicular size for all treated calves, most evident for E (200, 500 mg) + T (1400, 3500 mg). A decrease in the number of follicles was also found for these two groups. T (3500 mg) caused an abnormal size of the clitoris and led to a reduction of the size of thymus.


Endogenous anabolic agents in farm animals.

This presentation is limited to the three groups of steroid sex hormones which alone or in combination have been shown to be anabolic when used in farm animals. It seems essential for realistic evaluation of public health aspects of use of these hormones that the discussions include naturally occurring levels of the hormones. The following topics will be dealt with for each group of hormones: 1. Types and sources; 2. Production rates; 3. Plasma levels; 4. Tissue concentrations; 5. Metabolism and excretion. Gestagens. Progesterone and 20-dihydroprogesterones are mainly produced in ovaries and placenta. Production rates are estimated to 10 and 14 mg/24 hrs in pregnant goats and sheep, respectively. Plasma levels during the luteal phase are of the order of 2--10 ng/ml, during pregnancy somewhat higher. Muscular tissue from calves contain 0.25 mg/g. In dairy cows progesterone is excreted with the milk which contains up to 30 ng/ml; butterfat up to 300 mg/g. In ruminants progesterone is metabolized mainly to androgens excreted with faeces. In pigs large parts are metabolized to pregnanediols excreted with urine. Androgens. Testosterone is mainly secreted by testes. Boar testes also produce large amounts of dehydroepiandrosterone and its sulphate. Production rates have been estimated to be 10 mg and 40--50 mg/24 hrs. in boars and bulls respectively. Plasma levels in bulls and rams are generally 2--10 ng/ml, in boars 2--25 ng/ml. Adipose tissue levels up to 22 ng/g are reported for bulls. In ruminants epitestosterone seems to be a major metabolite excreted mainly with faeces. In boars, urinary 11-deoxy-17-ketosteroids are major metabolites of testicular dehydroepiandrosterone. Castration shows elimination to be rapid. Estrogens. 17beta-Estradiol and estrone are produced in ovaries and placenta and, in large amounts, in boar and stallion testes. Production rates in late pregnancy are estimated to 10 mg oestrone/24 hrs. in goats, 2 mg estrone and up to 28 mg 17beta-estradiol/24 hrs. in sheep. In cows much higher values are found. Boars and stallions produce huge amounts daily. Plasma levels in non-pregnant animals are at the pg/ml level. In late pregnancy levels of 2--4 thousand pg/ml are encountered in sows and cows, in sheep and goats lower levels. Calf muscular tissue contains up to 410 and 610 pg/g of estrone and 17beta-estradiol respectively. In muscle from pregnant heifers corresponding values were 120 and 860 pg/g in the 4th month and 2100 and 370 pg/g in the 9th month of pregnancy. Ruminants in large measure metabolize 17 beta-estradiol and estrone to 17alpha-estradiol which possesses low estrogenic activity. In pigs estrone dominates in blood and urine. Major routes of elimination arre with faeces in ruminants, with urine in pigs and horses. Elimination rates are high. Results obtained during the last few years clearly show that all three groups of steroid sex hormones occur in considerable concentrations in plasma and tissue...


Metabolic fate of anabolic agents in treated animals and residue levels in their meat.

Anabolic agents applied in animal production can be classified as sex hormones, as far as one aspect of their biological activity is concerned. In respect to their chemical nature the agents can be divided into three sub-groups: (a) steroids natural to the body (endogenous steroids); (b) steroids foreign to the body; (c) other compounds foreign to the body. After exogenous application (oral or parenteral) metabolism of compounds in group (a), e.g. 17beta-estradiol or testosterone, follows the pathways for the identical endogenous hormones; i.e. enzymatic transformation of the biologically active molecule into less active compounds. Excretion seems to occur predominantly via the feces, followed by the excretion via the urine. Steroids foreign to the body (group [b]) may be simple esters of endogenous steroids (estradiol benzoate, testosterone propionate) or compounds with basically modified steroidal structures, like trenbolone acetate (estra-4, 9, 11-trien-17beta-OH-3one-Ac). After enzymatic cleavage of an ester in the animal, metabolism of natural steroids again follows the endogenous pathways. Other steroids are mainly excreted without changes of the original steroid structure. It has been demonstrated, that compounds applied as esters have a delayed elimination. Anabolic agents of nonsteroidal structure, (group [c]) like stilbene derivatives and zeranol (6-[6, 10-dihydroxy-undecyl] beta-resorcylicacid-mu-lactone) are not, or only to a minor percentage, catabolized in the body. It can be generalized so far, that the fraction of the hormone eliminated in the urine, is in the conjugated from, while the fraction appearing in the feces is in the free form. This is due to enterohepatic circulation, which occurs with both, the intact or catabolized compound. The elimination rate of anabolic agents not only depends on the absorption after oral or parenteral application, which is strongly related to the type of formula---or cleavage of possible esters, but also on the metabolic clearance rate, which is a function of several factors, for example binding to plasma proteins or tissue structures. Differences in the elimination rate between compounds could be attributed to these phenomena. Tissue residue formation not only depends on the elimination rate, but also on other factors like mode of application, formula and withdrawal time. The possibility for their detection is related to the method applied. In cases of adequate treatments of the animals, and with the exception of the implantation site (see below), positive hormone values in tissues (qualitative and quantitative) could only be obtained, when radioimmunoassay techniques with a sensitivity in the low nanogram range were applied...


Methods for controlling the application of anabolics in farm animals.

In the use of anabolic agents, the most pronounced effect on growth is caused by estrogens. For this reason primarily attention will be given to the methods of detection of estrogen administration to fattening animals. The detection methods can mainly be divided in histological, biological, chemical, and immunological determinations and these will be briefly discussed in the light of the present situation in many countries, where the use of anabolic agents is prohibited. From the point of view of control, this prohibition is much easier to handle than a situation in which the application of some specified products is permitted. The possibilities and limitations of control, when certain anabolic agents are permitted for use, will be discussed and evaluated. The conclusion is drawn that in this latter case a sufficient control is very difficult if at all possible considering the methods of control available at the time.


An overview of protein synthesis, degradation and the regulation of protein content in skeletal muscle.

In this review paper various aspects of protein synthesis and breakdown in skeletal muscle will be surveyed as an introduction to the more specialized topics concerned with anabolic agents and the production of muscle protein. The quantitatively important role of skeletal muscle in total protein and amino acid metabolism will be evaluated by considering the size, composition (RNA and protein) and metabolic activity of this tissue in mammalian organism. This will provide an initial basis for understanding how internal and external environmental factors may affect the rate of growth and final size of the muscle mass in the intact organism. The steps in protein synthesis, involving aminoacid activation, initiation, peptide chain elongation and termination will be described, with particular reference to the synthesis of protein in fibers of skeletal muscle. This account will include a review of the specificity of myofibrillar protein synthesis and the relationships between the biochemical aspects of protein synthesis and the structural organization of the muscle cell. The role of messenger RNA, tRNA and soluble protein factors in the regulation of muscle protein synthesis in the growing animal will be reviewed, together with a short account of the ways in which hormones may modulate the rate of protein synthesis in muscle cells. However, the available data do not lead to definite conclusions concerning the rate limiting step(s) in muscle protein synthesis or the quantitative significance of factors which affect them. The mechanisms and regulation of protein degradation and the role of degradation in the regulation of muscle protein content will also be discussed.


Epidemiological studies related to the use of hormonal agents in animal production.

The principal types of hormonal agents used in the production of meat for human consumption are estrogens, progestagens, and androgens. Only the last class is truly anabolic. Each type of compound named above has fairly characteristic toxic effects after prolonged intake. In this review, an attempt will be made to relate available information from experience with the administration of these three types of hormones to humans to the question whether sufficient amounts of these chemicals can remain in meat cut from carcasses of animals administered hormones during finishing to have deletarious effects on human ingesters. Present indications are that administration of stilbestrol to pregnant women may result in a somewhat increased incidence of cervical and vaginal cancers in their daughters; such administration appears to have no effect on the incidence of cancers in sons and only slight, if any, effect on that in the mothers. Other estrogens seem to have no specific effects on the incidence of cancer. Progestagens also are not known to induce any specific lesions. Although many androgens are known to produce edema, fever, and jaundice, they have not been found to cause specific lesions to any significant extent. With reference to stilbestrol, the doses given to the  mothers of affected children have ranged between 5 and 125 mg/day. Because muscle, liver, and kidney from steers treated with stilbestrol in the usual way (s. c. implantation of a pellet at the base of an ear) have been found to contain less than 0.5 ppb of stilbestrol one month after implantation of the pellet, it is obvious that, to approach even the lowest clinically used dose of stilbestrol, a person would have to eat daily a quantity of such animal products that would be impossible to ingest. The findings that a mean of 26.4% of an oral dose of stilbestrol is excreted within 24 hours and that 99.5% is excreted within a week indicate that cumulation of this chemical within the body from the low level of intake provided by meats is not likely to reach a significant level. This would be so even though the animal product contained more than the 0.5 ppb mentioned above.


Pharmacological and endocrinological studies on anabolic agents.

When used in connection with animal production the term "anabolic agents" covers a wide range. Ther steroidal male and female sex hormones are included in this list, as are the nonsteroidal estrogens. For the clinician and for the endocrinologist, anabolics are only steroids chemically related to testosterone and 19-nortestosterone. Estrogens, though possessing anabolic properties, too, do not belong to this class. This paper will deal with anabolic agents in in the stricter sense of which mainly trenbolone acetate combined with hexestrol has been recommended for bull and heifer fattening. To consider possible consumer injury from ingestion of meat from anabolic agent treated animals, it is necessary to know the pharmacological properties of the agents, the doses producing certain effects or might produce, and the levels of residues in the meat. Trenbolone acetate will be compared with the following anabolic agents: methenolone acetate, methandrostenolone, nandrone, androstanazole, and 19-nortestosterone. The activity spectrum of trenbolone acetate is similar to that of 19-nortestosterone or those anabolics that are derived from 19-nortestosterone. The compound has about three times stronger androgenic effect than testosterone propionate. Its index of dissociation between anabolic/androgenic activity is 2--3. This index is 3--10 for the other anabolic agents. As regards the virilizing potency, trenbolone acetate is also on the top of the list. It seems that androgenicity and degree of virilization run paralle. The antigonadotropic activity (inhibition of ovulation and testicular growth) of trenbolone acetate exceeds that of testosterone propionate by the factor 3. The compound is not estrogenic and seemingly not or only weakly progestationally active. In principle, the androgenic activity (symptoms of virilization) as well as the antigonadotropic effect (disturbances of the menstrual cycle in women, inhibition of spermiogenesis in men) of trenbolone acetate might be noted. This risk, however, can be excluded by mere calculation. In rats, 0.1 mg/kg trenbolone acetate have an antigonadotropic effect. This corresponds to a daily dose of 5--7 mg in humans. By the same extrapolation, a daily human dose of 100 mg can be calculated for androgenic activity. Such factors of conversion are, of course, not precise because rats are much less sensitive to androgens and anabolics than humans. Thus, testosterone propionate is active only in daily doses of 10--20 mg. If in humans trenbolone acetate also has three times the activity of testosterone propionate, effects in man had to be counted with not less than a daily intake of 3--5 mg trenbolone acetate. The dose which is recommended for livestock fattening is 300 mg. IT can, therefore, be excluded almost with certainty that the meat would contain such large amounts of hormone residues.


Role of growth hormone in improving animal production.

Pituitary growth hormone (GH) has considerable potential as an anabolic agent in animal production. For example, pigs treated with GH will grow faster (i.e. deposit protein), require less feed per unit of body weight gain, and will have less carcass fat than untreated animals. Lactating cows will produce more milk with less feed. It is likely, though not completely established, that young cattle will also respond to GH treatments. Most of the information on the mode of action of GH has been obtained with laboratory rather than farm animals. The hormone affects almost all aspects of metabolism although the specific mechanism for these effects is still not understood. Stimulation of protein accretion is reflected by increased nitrogen retention and incorporation of radioactive amino-acids into tissue proteins. An increased rate of protein synthesis is thought to be a result of enhanced ability of ribosomes to translate messenger RNA. GH increases polyamine synthesis by increased ornithine decarboxylase activity; RNA synthesis by increasing RNA polymerase and DNA synthesis by increased DNA polymerase. Cell division is stimulated in several tissues (e.g. muscle and lymphoid tissue). In vivo GH lowers the respiratory quotient indicating an increased oxidation of fatty acids. The numbers of fat cells do not change but the fat cells are reduced in size. The stimulating effects of GH on skeletal tissue, and perhaps other tissues as well, is mediated by the formation of at least three peptides called somatomedins. GH is a protein with a molecular weight of about 22,000 and contains 191 amino-acid residues. The amino-acid sequence varies with the species. GH isolated from one species is not always effective in a different species. Use of GH isolated from pituitaries does not appear to be economically feasible. A chemical synthesis for human GH has been accomplished. However, biological activity equivalent to the native hormone has not been unequivocally established. Synthesis of bovine or porcine GH is feasible but will be expensive. A partial sequence of GH with 39 amino-acid residues has some biological activity. Synthesis of this shorter peptide would be considerably less expensive. Since proteins generally are not active orally, an economic procedure for prolonged parenteral administration would have to be devised. Althernative approaches would be the stimulation of endogeneous production of GH with hypothalmic GH releasing factor. This factor has not been identified but is probably a small peptide. Agents such as arginine, DOPA, and prostaglandins, which are known to stimulate GH release under some conditions, could also be considered. Another approach would be the implantation of sparganum from the spirometra family (a flatworm). This treatment is known to mimic GH effects in the rat. Implantation of a GH producing tumour could also be considered. Clearly these latter suggestions are quite speculative and would present some obvious problems...


General aspects of the effectiveness of anabolic agents in increasing protein production in farm animals, in particular in bull calves.

The role of farm animals as converters of feed protein into protein edible for humans has often been criticized for the lack of efficiency of this process. In a series of 192 N-balance studies with veal calves it was found, however, that these animals convert at an early age even more than 70 percent of the feed protein into body protein. The deterioration of the N-conversion, so undesirable from a point of view of food production, is found when the animals grow older. With increasing age the conversion ratio went down to approximately 40-50 percent in our studies. This could only be explained by assuming a poorer efficiency of the intermediate metabolic processes with increasing age. For an increase of the production of edible protein from the available feed sources in the world, it is obviously of great importance to maintain the favourable conversion ratio of young farm animals for the longest possible time. The object of this paper is to consider whether and to what extent a positive effect on the efficiency of the protein formation can be exerted by the application of anabolic agents using the veal calf as a model. In the category of artificial estrogens we found DES to be effective in this respect. In the category of natural hormones testosterone and progesterone did not exert anabolic effects. The implantation of 17beta-estradiol improved the conversion of feed protein into body protein to approximately the same extent as DES. A combination of estradiol with testosterone tended to be more effective than estradiol alone. The more recently isolated agents zeranol and trenbolone did not lead to significant improvements in N-retention. A combination of trenbolone with estradiol improved N-retention better than any of the other treatments. The quantitative importance of the phenomena discussed for protein production is illustrated as follows. With the most effective treatment studied, the percentage of feed protein converted into body protein was increased during an experimental period of 38 days, from 39 percent in the control group to 58 percent in the treated group. There is no doubt that a further intensification of the research in this field is recommendable in order to create and study active agents combinining a high degree of efficacy with the absence of undesirable side effects for man and animals.


The anabolic effect of estrogens on nitrogen metabolism of growing and finishing cattle and sheep.

Estrogenic compounds are effective in stimulating live weight gains and improving feed efficiency of growing and finishing ruminants. With the proper use of diethylstilbestrol or estradiol, weight gain and feed efficiency are improved approximately 15 and 12 percent, respectively. The administration of estrogenic substances to finishing cattle or sheep results in heavier carcasses containing more protein and moisture and less fat. Estrogens do not appreciably affect rumen fermentation or digestibility of the diet but improve the utilization of the absorbed nutrients. Evidence to support the concept that the increased weight gained with estrogen treatment is the result of anabolic reactions includes a decrease in plasma urea, decrease in plasma levels of most of the essential amino-acids, decreased excretion of urea and total nitrogen in the urine and increased retention of nitrogen, phosphorus and calcium. There is no change in body water space or tubular reabsorption of urea in sheep treated with diethylstilbestrol to account for some of these observations. More direct evidence that estrogens exert their major influence on nitrogen metabolism in the body and more specifically on protein synthesis comes from an experiment where cattle fed diethylstilbestrol deposited 33 percent more protein and  18 percent less fat in body weight gain as compared with control animals. The use of the hormone resulted in a significant improvement in the efficiency of utilizing dietary protein for body gain and a slight decrease in the efficiency of converting dietary energy to body gain. Enlargement of the pituitary, thyroid and adrenal glands and higher plasma levels of growth hormone, insulin and glucose have been found in experiments designed to study the effect of estrogens on the endocrine system of ruminants. These studies, along with the observation that an intact pituitary gland is necessary for estrogens to increase nitrogen retention in sheep, support the theory that estrogens are anabolic in ruminants because of increased secretion of growth hormone by the anterior pituitary. If follows that the increased secretion of growth  hormone results in increased blood glucose which then stimulates secretion of insulin. Both growth hormone and insulin would be stimulatory to protein synthesis. This theory of the mode of action is further supported by the findings that injections of growth hormone closely resemble the effects of diethylstilbestrol on nitrogen retention and blood metabolites in sheep.


The effectiveness of anabolic agents in increasing rate of growth in farm animals; report on experiments in cattle.

In many countries anabolic agents are successfully used to increase the rate of growth of cattle. In the past widespread use was made of cheap synthetic estrogens such as diethylstilbestrol and hexestrol. However, new legislation in certain countries has restricted the use of synthetic estrogens. This has resulted in an intensive search by industry for alternative agents. On the one hand natural steroid hormones like estradiol, testosterone and progesterone were studied, while on the other hand products like an active compound of the resorcyclic acid lactones and the synthetic anabolic steroid trenbolone acetate were developed. Administration of anabolic agents to cattle is done in three ways. (1) The agent may be fed orally by incorporation into the concentrate feed or as a simple additive top dressing. If the agent is metabolised in the rumen, oral administration may still be possible by using coated materials which avoid rumen metabolism with subsequent absorption of the steroid from the small intestine. (2) The agent may be administered as a slow release implant, e.g. trenbolone acetate or various combined preparations of an androgen and estrogen. (3) Administration by repeated injection. This latter method is often impractical. Anabolic agents are normally administered to beef cattle or culled dairy cows during the last few months of the finishing period. Maximum weight gain performance in different types of cattle requires selection of the correct anabolic agent. Increased performance in female cattle is better when an androgenic steroid is administered. However, in intact males (bulls) best performance is only obtained when an estrogen, alone or in combination with an androgen, is administered. Castrate animals (steers) do best if a smaller amount of estrogen is combined with an androgen and administered, however there is evidence that androgen alone is as effective. In summary therefore, an additional response in growth of cattle may require the presence of an estrogen, as endogenous estrogen in the female and the exogenous form in the male. Only when this condition is met will administration of androgenic anabolic steroids result in maximum benefit, often improving the effect of estrogen given on its own. Anabolic agents have some beneficial effect on appetite. They may not affect the digestive processes of the alimentary system. They have a positive effect on nitrogen retention. The liver almost certainly has a central role in the regulation of nitrogen retention. Recent experiments suggest that urea entry rates in ruminants may be lowered, thus making available more nitrogen for protein synthesis. Muscle protein synthesis is altered with changes in carcass conformation. There are some changes in fat redistribution. How all these processes are integrated is not yet known. The possibility that anabolic agents establish a new hormonal status which is favourable to growth will be discussed...


Comparison of methods to calculate cardiac output using the CO2 rebreathing method.

A comparison was made of methods used to calculate cardiac output by the indirect (CO2) Fick procedure (equilibrium method). Alternative methods for calculation of arterial PCO2, mixed venous PCO2, and conversion of gas tension to content were tested. Cardiac output values determined with a "corrected" equilibrium PCO2, to approximate mixed venous PCO2, were observed to be closest to cardiac output values determined on similar populations by the dye dilution method. Arterial PCO2 was best estimated from the Bohr equation using a dead space in exercise from prediction equations in the literature applicable to the populations under study. CO2 dissociation curves used to derive the veno-arterial CO2 content difference, were shown to differ considerably. For the present, the curve by McHardy [25], as modified by Jones (personal communication), and similar to the standard Comroe curve [5], was chosen.


Influence of side-chain structure of aliphatic amino acids on binding to isoleucyl-tRNA synthetase from Escherichia coli MRE 600.

The binding of 10 isomeric alpha-amino-heptanoic acids, of two isomeric alpha-amino-octanoic acids, of isoleucinol and valinol, and of various alpha-hydroxy acids to isoleucyl-tRNA synthetase from Escherichia coli MRE 600 has been investigated by an ultracentrifuge method. It was found that the enzyme requires a primary amino group together with a not-too-small side chain as prerequisites for ligand recognition. Though the enzyme is absolutely specific for the L isomers, it is fairly tolerant against replacement of the carboxyl group of the natural substrate by more or less hydrophobic substituents. These findings can be explained in terms of Ogston's three-point-attachment model, if it is additionally assumed that there is no further space available in the binding region normally occupied by the alpha-hydrogen atom to accept other substituents which are as bulky as the carboxyl moiety. Similarly, the architecture of the binding region of the aliphatic side chain is discussed. Our measurements show that the free energy of binding strongly depends on the size and the structure of the remainder of the molecule. None of the isoleucine analogues employed is bound as tightly as the natural substrate itself, but there is a clear preference for side chains branched at the beta-carbon atom. The functioning of the side-chain recognition site is best understood by imaging a two-finger glove, of which one finger is tailored to a methyl and the other to an ethyl group. Both these fingers, together with the binding region for the glycine moiety and a steric barrier against a fourth substituent bulkier than hydrogen, are responsible for a high steric specificity towards the one side chain over its Cbeta epimer.


Preparation and specificity of endonuclease IV induced by bacteriophage T4.

Bacteriophage-T4-induced endonuclease IV suitable for DNA sequence analysis has been prepared by a modified and easily reproducible method. The specificity of T4-induced endonuclease IV has been investigated in order to verify whether this enzyme exhibits a single nucleotide recognition or a short sequence recognition. The 5'-terminal dinucleotides and 3'-terminal nucleotides of oligonucleotides released by T4-induced endonuclease IV from three single-stranded DNAs (from bacteriophages  phiX174, fd, M 13) have been analysed. In different DNAs, 74-82% of the 5'-terminal dinucleotides end in 5'-deoxycytidylic acid; small but significant levels of several dinucleotides ending in 5'-deoxyadenylic acid, 5'-thymidylic acid and 5'-deoxyguanylic acid are also found. As far as 3'-terminal nucleotides are concerned all nucleotides are present with a large predominance of thymidylic acid. It is concluded that T4-induced endonuclease IV recognizes short nucleotide sequences like all other DNases investigated so far. The spectrum of such sequences is, however, very narrow.


Cooperative effects of initiation factors and fMet-tRNA in the formation of the 40-S initiation complex.

In this paper the mode of action of IF-1 in 40-S initiation complex formation was studied with MS2 RNA as messenger. Using initiation factors IF-2 and IF-3 labeled in vitro it appeared that IF-1 did not influence the binding of these factors in the absence of fMet-tRNA. However, in the presence of fMet-tRNA it was found that the enhancement of the fMet-tRNA binding by IF-1 was accompanied with an equimolar increase in binding of IF-2. Moreover, it appeared that also in absence of IF-1, fMet-tRNA binding is coupled with an equimolar enhancement of the IF-2 binding, which suggests the existence of a preribosomal complex between IF-2 and fMet-tRNA. The apparent Km values for both the binding of fMet-tRNA and IF-2 to 30-S subunits were determined and appeared to be equal, which makes a functioning of such a preribosomal complex in protein initiation very likely. The participation of GTP in this complex will be discussed. Functions of IF-1 in dissociation and recycling of IF-2, described by others, and the stimulation on the 30-S subunit level might well be explained as pleiotropic effects of one basic action of IF-1, i.e. a conformational change of 30-S subunits.


Determination of the amino-acid sequence of the ribosomal protein S8 of Escherichia coli.

The primary structure of protein S8 from the 30-S ribosomal subunit of Escherichia coli was determined mainly by automatic Edman degradation using a modified Beckman protein sequenator and the solid-phase sequentor of Laursen. The complete sequence, containing 109 amino acids, was derived by analysing peptides from tryptic, chymotryptic, thermolysin, staphylococcal protease and cyanogen bromide digestion of the protein. The amino acid composition was found to be (aspartic acid)6, (asparagine)3, (threonine)5, (serine)5, (glutamic acid )7, (glutamine)6, (proline)5, (glycine)6, (alanine)11, (valine)9, (methionine)4, (isoleucine)7, (leucine)9, (tyrosine)3, (phenylalanine)3, (lysine)11, (arginine)8, (cysteine)1. S8 is a basic protein and binds to the 16-S RNA; knowledge of its sequence is necessary for a detailed study of its interaction with the ribosomal RNA.


A protein factor enhancing activation of inactive 30-S ribosomal subunits of Escherichia coli.

A protein factor partially purified from the S-100 fraction (supernatant from 100 000 x g spin) of Escherichia coli stimulates the conversion of 30-S ribosomal subunits from an inactive to an active form. The subunits are normally inactivated at low concentrations of Mg2+ and reactivated when heated under appropriate ionic conditions. The factor, which differs from the known soluble factors required for protein biosynthesis as well as from proteins of the 30-S subunit, enhances activation under conditions which by themselves allow for only a low level of activity to reappear. Fully active ribosomes and the assay reactions are not affected by the factor, indicating that its effect must be restricted to the activation process. The factor is likely to function by facilitating a conformational transition in the ribosome, and might act in vivo in a similar manner.


Valyl-tRNA, isoleucyl-tRNA and tyrosyl-tRNA synthetase from baker's yeast. Substrate specificity with regard to ATP analogs and mechanism of the aminoacylation reaction.

Nineteen analogs of ATP have been tested in the aminoacylation of valyl-tRNA, isoleucyl tRNA and tyrosyl-tRNA synthetases from baker's yeast. Four compounds are substrates for valyl tRNA and two for isoleucyl-tRNA synthetase, but there is no modified substrate for the tyrosyl tRNA synthetase. There is one inhibitor for valyl-tRNA synthetase, eight compounds inhibit isoleucyl-tRNA synthetase and two compounds inhibit tyrosyl-tRNA synthetase. Their Km and Ki and V values have been determined. The substrate specificity shows that positions 2, 6, 7, 8, 9, 2', and 3' of ATP are important for catalytic action of these aminoacyl-tRNA synthetases.


1. Membrane vesicles of Escherichia coli K-12 CS7, a strain gentically derepressed for glutamate permease, maintain low aspartate transport activity, like that of prep.

1. Membrane vesicles of Escherichia coli K-12 CS7, a strain gentically derepressed for glutamate permease, maintain low aspartate transport activity, like that of preparations of the wild-type parent. Growth of the parent CS101 on aspartate as the source of carnon or nitrogen results in derepression of both asparatate and glytamate transport. Growth of strain CS7 on aspartate derepresses aspartate transport to the same extent as in strains CS101, but only slightly increases the derepressed level of glutamate transport activity. 2. The affinity of the membrane transport system for glutamate is enhanced by sodium, while that for asparate is not. 3. Although the affinities for glutamate (23 muM) and aspartate (12 muM) are similar, aspartate does not inhibit glutamate transport, while glutamate competitively inhibits aspartate transport. 4. Aspartate transport, but not glutamate transport, is competitively inhibited by C4 dicarboxylic acids, whereas 2-oxoglutarate competitively inhibits glutamate transport, but not aspartate transport. 5. Competitive inhibition of L-aspartate transport by L-glutamate and by the 5-methyl ester of L-glutamate is abolished in the presence of 2-oxoglutarate. However, 2-oxoglutarate does not affect the competitive inhibition of L-aspartate transport by D-aspartate and by DL-threo-3-hydroxyaspartate. The relationship between the two dicarboxylic amino acid transport systems and the spatial characteristics of the aspartate carrier are discussed in the light of these findings.


The role of the anaesthesiologist in the intra- and post-operative management of kidney transplant patients.

Based on experiences with 256 kidney transplant operations in 239 patients over a period of ten years (18.6. 1965 to 15.4. 1975) the role of the anaesthesiologist as it had developed in our institution has been described. Some problems with regard to the anaesthetic management of living donors were discussed. The care of patients who, due to their deteriorating cerebral function, are potential donors was also described. An outline of the own anaesthetic management of the recipient has been given and alternative methods were mentioned. Some special points were specifically stressed like the choice of relaxants, fluid replacement, blood transfusion, diuretic treatment starting already intraoperatively. Good intensive care of the potential donor is of great importance for the function of the transplanted organ. Very important is also the postoperative treatment of the recipient, which in our institution is performed in a teamwork between anaesthesiologist, surgeon and nephrologist. Finally, the functional results of our series are briefly demonstrated.


Hyperbaric oxygenation for severe head injuries. Preliminary results of a controlled study.

60 patients were included in a prospective study to evaluate the effectiveness of hyperbaric oxygenation (OHP) as a treatment of head injury coma. They were assigned to nine subgroups according to age, level of consciousness and eventual neurosurgical procedure, and then selected randomly for OHP or standard therapy. OHP was administered in one or several series of daily exposure at 2.5 ATA. However, the OHP therapy protocol was to be interrupted in 11 cases developing pulmonary, hyperoxic, or infectious complications. Overall mortality and mean duration of coma in survivors were not different in both groups, indicating that OHP was either ineffective or too intermittently applicated. Analysis of results in subgroups revealed that, in one subgroup (18 patients), the rate of recovered consciousness at 1 month was significantly higher when OHP was used. These patients were under 30 and had a brain stem contusion without supratentorial mass lesion. The view is defended that, besides its toxic action on the normal nervous tissue, OHP can counteract edema and ischemia in the zones of brain injuries.


Prolongation of skin graft survival by sodium-copper-chlorophyllin. Inhibition of the first- and second-set phenomenon.

Sodium-copper-chlorophyllin which has a strong anticomplementary and membrane-stabilizing effect also has, by these mechanisms, a strong immunosuppressive competence. In HAN-rotation-breeded Wistar rats there is a time- and dose-dependent prolongation of skin allograft survival by this drug. The first-set and the second-set phenomena are inhibited.


Azathioprine hepatotoxicity, direct complication or secondary effect in rat liver transplantation.

The risk of azathioprine-induced hepatocellular damage was investigated using the auxiliary liver transplantation model in rats. This model permits to study the effect of the drug on both graft and the recipient's liver vascularized in different ways. Neither histopathological changes were observed, nor could any deaths be directly attributed to toxic effects of the drug on hepatocytes. Morphological lesions were absent in treated and untreated, subtotally hepatectomized rats with normal bile flow. However, lesions did become manifest after reimplantation (grafts) and/or ligation of the common bile duct (hosts). We concluded that in rats azathioprine is toxic for hepatocytes only when the normal bile flow is impeded, independent of the way of the liver vascularization.


Competitive proliferation in the hematopoietic tissues of irradiated hybrid mice engrafted with parental bone marrow and spleen.

The kinetics of growth and differentiation of hematopoietic stem cells differ markedly according to their origin. A study of the ability of CFU from bone marrow (BM) or spleen to repopulate hemopoietic organs has been carried out in lethally irradiated mice restored with BM cells admixed with spleen cells bearing different chromosomal markers. Hemopoietic cells originating from AKR (40 acrocentrics) and AKR/T1ALD (36 acrocentrics + 2 metacentrics) mice were engrafted into lethally irradiated (AKR X AKR/T1ALD)F1 or (C3H X AKR/T1ALD)F1 hybrid recipients. Within 10 days, the BM-derived elements outnumbered the spleen-derived population in BM and spleen. This held even when the number of injected spleen-CFU was twice that of BM-CFU. This difference of growth rate subsided within 20 days. The first cells to reappear in the thymus bore the recipient karyotype (endoregeneration); they were later replaced by BM-derived elements but spleen-derived cells were never present in thymus in the case of competitive engraftment. In contrast, the lymph node cells bore the BM karyotype as well as the spleen karyotype. Injecting the spleen cells 3 days prior to the BM cells partially counterbalanced the over-growth of the BM-derived elements in the BM and spleen but did not affect the thymic repopulation which remained strictly derived from BM-CFU. When mice were injected only with BM-CFU or only with spleen-CFU, BM-derived cells were found in the thymus as early as 10-12 days after engraftment whereas the spleen-derived cells did not appear in the thymus until days 18-20.


The effect of thymectomy on the competitive potential of C57BL/6 bone marrow graft.

When a mixture of bone marrow cells derived from mice of the CBA-T6T6 and C57BL/6 strains and Lewis rats is injected into lethally irradiated (C57BL/6 X CBA-T6T6)F1 hybrid recipients, a process of cell interaction takes place, which in less than 2 weeks leads to the complete and permanent take over in hematopoietic and lymphoid organs by the C57BL/6 cell population. This is shown by the chromosome marker technique (T6) analysis. Adult thymectomy of F1 hybrid hosts prior to irradiation and bone marrow transplantation does not alter the competitive potential of the C57BL/6 donor cell population. However, neonatal thymectomy of the prospective C57BL/6 donors significantly impairs their "superiority" as donor cells, and CBA-T6T6 dividing cells persist at all times in all tissues analyzed. The results lend support to the concept of thymus-dependent precursor cells residing in "prethymic" hematopoietic tissue.


Effect of hemic cells on hybrid resistance.

Injection of various parental strain hemic cells reduces the ability of the F1 hybrid to resist growth of grafted hemopoietic tissue from the same parent strain. Such an effect can be exerted by cells from lymph nodes, spleen, bone marrow, or thymus, the peritoneal macrophages, and the peripheral blood leukocytes. Embryonic and adult liver cells or blood erythrocytes do not inhibit hybrid resistance. It is assumed that hemic cells inhibit hybrid resistance through an effect on the hemopoietic microenvironment. The mechanism of this effect cannot be considered the result of a graft-versus-host reaction since lymphoid cells which are "immune" or "tolerant" to the hybrid antigens possess inhibitory activity similar to that of intact lymphoid cells. The hybrid resistance inhibitory cells maintain the inability of "parent-in-F1 hybrid" type chimeras to express hybrid resistance for at least 2 months.


Experience with second marrow transplants.

This report summarizes the experience with 25 patients who received a second marrow transplant. The marrow donor for the first transplant was an identical twin in four cases and a sibling matched at the major histocompatibility complex in 21 instances. The donor for the second transplant was the same as the first except for three patients whose second donor was another matched sibling. Nine patients with aplastic anemia rejected their first graft. Four of these patients were prepared for the second graft with a regimen of procarbazine and antithymocyte globulin (ATG) followed by cyclophosphamide or total body irradiation and were successfully regrafted. One rejected the second graft, two died of septicemia and one is alive and well 10 months after the second graft. Twelve patients with hematologic malignancy had a recurrence of disease after the first transplant. Despite preparation for the second graft with a variety of intensive chemotherapeutic regimens, the five patients who did not succumb to infection showed an early recurrence of disease. Four patients with hematologic malignancy had a failure of the first graft for unknown reasons, possibly related to the administration of ATG or methotrexate. One patient prepared for the second graft with procarbazine and ATG showed evidence of engraftment but died of infection. Two out of three patients given no additional preparation were successfully grafted. One died of recurrent central nervous system leukemia after 18 months and one is alive and well 26 months after the second graft.


Weak neuronal accumulation of octopamine in dopaminergic neurons of the rabbit retina.

Dopaminergic retinal neurons become weakly radioactive after the injection of tritiated octopamine into the vitreous, but no other neurons do so. This indicates the absence of any effective mechanism for the accumulation of octopamine in rabbit retina.


Localization of peroxidase activity in Trypanosoma cruzi microbodies.

Electron microscopic observation of Trypanosoma cruzi epimastigotes reveals the presence of microbody-like structures (microperoxisomes) in which 3,3'-diaminobenzidine (DAB) is peroxidized to electron-opaque material. The role of peroxidase in DAB peroxidation is supported by the enzyme demonstration in disrupted epimastigotes and the microbody-containing cell fractions.


Theories of enzyme specificity and their application to proteases and aminoacyl-transfer RNA synthetases.

The question of enzyme specificity which is a corollary of the phenomenon of biological recognition is reviewed. The following theories are outlined briefly: non-productive binding, induced fit, transition state binding, the general strain theory and the kinetic proofreading hypothesis. Data on proteolytic enzymes and aminoacyl-tRNA synthetases are discussed in the light of predictions made by the various theories. The specificity of inhibitor and substrate binding to chymotrypsin and subtilisins is revealed at the sub-molecular level as an example of binding specificity. Kinetic specificity is experimentally distinguished from binding specificity. Conformational adaptability of enzyme and substrate, which is crucial in some theories, is documented by data on aminoacyl-tRNA synthetases. Expected and observed specificity of tRNA charging is discussed with regard to a theoretical limit of specificity. Additional means seem necessary beside those contained in the isolated enzyme-substrate system to account for the high specificity of most synthetases. In conclusion, we have arrived at quite good explanations for moderate specificity such as is displayed by many proteases, but there are still ample difficulties in the understanding of highly specific enzyme reactions.


Localization of wheat germ agglutinin receptor sites on yeast cells by scanning electron microscopy.

WGA receptor sites on the surface of Saccharomyces cerevisiae cells pretreated with an alpha-mannanase were localized by gold granules labelled with WGA. The receptor sites were found on the bud scars, the mother cell-bud junction (chitin) and the bud, but not on the mother cell.


Possible significance of adverse reactions to glutamate in humans.

Of those exposed to Chinese restaurant food, our studies indicate that 25% report adverse reactions (Chinese restaurant syndrome (CRS)), presumably to the mono-sodium glutamate (MSG) content. The possible significance of the symptoms is discussed in the light of the known neuroexcitatory activity of MSG. It is suggested that CRS may result from a "benign" inborn "error" of metabolism that is deserving of further study, particularly in individuals with certain other metabolic abnormalities or who are on certain types of drug therapy.


Dependence of translation on 5'-terminal methylation of mRNA.

Many eukaryotic cell and viral mRNAs contain 5'-terminal m7G(5')ppp(5')N. Methylation is important for the in vitro translation of vesicular stomatitis virus and reovirus mRNAs. Unmethylated viral mRNAs are methylated by cell-free extrascts of wheat germ and L cells to form 5'-terminal structures of the type, m7GpppN and m7GpppNm, respectively. Rabbit globin mRNA also contains 5'-terminal 7-methylguanosine (m7G). Removal of the m7G by beta-elimination decreases translation. The efficient binding of mRNA to ribosomes is dependent on the presence of 5'-terminal m7G.


Genetic defects of iron transport.

Five genetic traits in man and laboratory animals have major effects on iron transport. The heterogeneous condition, hemochromatosis, in some families appears to segregate as a Mendelian trait, and is associated with defective control of intestinal iron absorption. In the very rare human autosomal recessive trait, atransferrinemia, there is an almost total lack of transferrin and gross maldistribution of iron through the body. In mice, sex-linked anemia (an X-linked recessive trait) causes iron deficiency through defective iron absorption, at the "exit" step; a similar defect probably exists in placental iron transfer. In microcytic anemia of mice, an autosomal recessive trait, iron absorption is also impaired because of a defect of iron entry into cells, which is probably generalized. Belgrade rat anemia, less understood at present, also may involve a major disorder of iron metabolism. Study of these mutations has provided new knowledge of iron metabolism and its genetic control Their phenotypic interaction with nutritional factors, especially the form and quantity of iron in the diet, may provide new insights for the study of nutrition.


Cellularity of adipose tissue in meat animals.

Present information indicates that for meat animals adipocyte number is achieved most rapidly in the perirenal depot and least rapidly in the interfascicular of intramuscular depot. Adipocyte volume appears to be largest in the perirenal depot and smallest in the interfascicular and intermuscular depots. The best estimates available suggest that adipocyte hyperplasia is completed by 14 months of age in bovine animals and 5 months of age in porcine animals. However, because of certain technique limitations and the presence of many small adipocytes in very obese animals, these estimates must be considered very tentative. Studies in ovine and porcine animals indicate that early under-nutrition is not effective in reducing the number of subcutaneous and perirenal adipocytes later in life. However, the number of interfascicular adipocytes may be reduced. Several studies have demonstrated that the interfascicular adipocytes are very late developing and that adipocyte number is very important to the total quantity of intramuscular lipid.


Theoretical model of ruminant adipose tissue metabolism in relation to the whole animal.

Based on theoretical considerations and experimental data, estimates of contributions of adipose tissue to energy expenditures in a lactating cow and a growing steer were developed. The estimates indicate that adipose energy expenditures range between 5 and 10% of total animal heat production dependent on productive function and diet. These energy expenditures can be partitioned among maintenance (3%), lipogenesis (1-5%) and lipolysis and triglyceride resynthesis (less thatn 1.0%). Specific sites at which acute and chronic effectors can act to produce changes in adipose function, and changes in adipose function produced by diet and during pregnancy, lactation and aging were discussed with emphasis being placed on the need for additional, definitive studies of specific interactions among pregnancy, diet, age, lactation and growth in producing ruminants.