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This paper examines the origins and the importance of pathological identification by the parent of the child who was maltreated or is at risk of maltreatment. The understanding of these identifications suggests methods of effective preventive action without recourse to the undesirable practice of removing the child from the home, other than in exceptional circumstances. Brief case history vignettes illustrate the clinical application of this approach.

Evidence suggests that physical results may be the least important criterion of successful management of maltreated children. Emotional, social, intellectual and personality development results should receive equal attention. The maltreated child may himself be a potential child-batterer and separation from his parents may not alter this prognosis. Professional ignorance, denial and collusion are all barriers to successful management, as are inadequate treatment facilities and a cumbersome legal system whose inappropriate priorities may readily produce tragedy.

The Dalkon shield was withdrawn from the market in the United States of America last year because of the reports of 11 maternal deaths and 209 cases of septic midtrimester abortions associated with the device in situ. Four cases of late midtrimester septic abortions resulting in neonatal deaths are presented. In one of these, the mother developed septicaemic shock and almost died. The true pregnancy rate with the Dalkon shield is much higher than was initially claimed, particularly if it is inserted in the puerperium. Surveys on the outcome of the pregnancy indicate that 50% end in spontaneous abortion and one in 20 pregnancies are ectopic. A high percentage of the abortions are septic. The Dalkon shield, therefore, has no advantages over other intrauterine contraceptive devices and it remains to be seen whether the recent modification of the device has overcome the disadvantages of the earlier version. If pregnancy is diagnosed with the device in situ, it should be removed if the string is visible. If pregnancy continues with the shield in place, the patient should be observed closely. Should septic abortion occur, active management is indicated and early evacuation of the uterus is recommended.

A survey of tow truck services operating in a defined area of the south-east suburbs of Melbourne was undertaken to determine their potential for delivering emergency medical care at the scene of crashes. Most towing firms have an association with a panel-beating shop, and operate within a limited area of one to three miles radius. The rapid response of tow trucks to crash scenes is due to their well-developed intelligence network of "spotters" and the short distances the trucks travel. Very little first aid is provided by the drivers, although one-fifth had some first aid training at some time. In about one-half of the calls to crashes a damaged vehicle is still at the scene, in about 20% an ambulance is called, and in about 5% a hospital admission occurs. Direct observation of 22 crashes suggests that on average, tow trucks arrive at a crash scene five minutes before the ambulance, and fifteen minutes before the police. There is a good case for making first aid training a preerequisite for issue of a tow truck operator's license.

The development of a centre for the investigation of genetic aspects of still birth, neonatal deaths and mental deficiency is described. It is suitably located in a maternity hospital and provides counselling early enough to prevent the brith of a subsequent affected infant in high-risk groups. A variety of laboratory and other facilities are in close proximity. This has the advantage of allowing procedures, such as amniocentesis and ultrasound examination for prenatal diagnosis, to be arranged in consultation with hospital staff members. The aetiology of the first 120 cases seen, their reason for referral, recurrence risk, and "decision made", are reported in detail elsewhere. The mode of operation with regard to source of case, appointments, staff and records is outlined fully in this paper. The conclusion to be reached is that, within two years of its inception, the genetic investigation centre is already providing a useful community service.

Afternood lying and standing blood pressure, pulse rate and plasma pindolol levels were measured twice, a month apart, in 16 cases in which hypertension was well controlled either by pindolol alone or by pindolol plus a diuretic. During the month preceding each observation, the daily dose of pindolol was given in either two or three divided doses. Plasma pindolol levels could be measured in only seven cases. In these, 4 p.m. plasma pindolol levels were significantly lower on the twice-daily dosage regimen. Mean afternoon lying and standing blood pressure and lying pulse rate values were slightly but not significantly higher on the twice-daily regimen. Mean standing pulse rates were significantly higher on the twice-daily regimen. It appears that, for the control of hypertension, pindolol can be given in a twice daily regimen in most cases.

Cell suspension cultures from parsley (Petroselinum hortense Hoffm.) were labelled in vivo with [2-3H] adenosine. The RNA isolated from the ribosomal pellet was fractionated on an oligo(dT)-cellulose column. Approximately 1.5% of the RNA, representing about 15% of the total radioactivity, was retained at high salt concentrations and eluted at low ionic strength. As determined by two independent methods, this fraction contained poly(A) segments with an average length of about 80 nucleotides. It was active as template in a cell-free system from wheat germ, directing the synthesis of peptides ranging in molecular weight from about 4000-40000 daltons.

A ribonucleoprotein was released from carefully purified rat liver mitochondrial polyribosomes after dissociation with 1 M potassium chloridepuromycin. This ribonucleoprotein was characterized by a sedimentation coefficient ranging from 10-14 S and buoyant density of 1.48 g cm(-3) in cesium chloride equilibrium centrifugation differing in these parameters from the subunits of mitochondrial ribosomes. Poly(A)-containing RNA constituted more than 30% of the total RNA content in this non-ribosomal ribonucleoprotein.

The release of subretinal fluid is only required in certain complicated types of retinal detachment and should be avoided when possible. An important consideration in releasing subretinal fluid is the timing of this step in relation to the application of diathermy or cryotherapy as the primary treatment modality. Drainage should precede application of cryotherapy but follow the use of diathermy. The most satisfactory site for drainage is either immediately above or below the medial or lateral long ciliary nerve, just posterior to the equator of the globe. A technique for drainage of subretinal fluid has been developed and evaluated. An 'L'-shaped scleral flap is dissected to produce a relatively staphylomatous zone and the choroid is perforated near its center.

When the incision of the choroid is performed with the aid of the microscope, release of subretinal fluid becomes an absolutely controlled microsurgical procedure. In a consecutive series of 100 eyes, operated with perforation and buckling, an anatomic reattachment rate of 83% was obtained. There have been 4 complications directly related to the release of subretinal fluid, 2 of which healed with good anatomical and functional result after additional treatment.

Drainage os subretinal fluid is generally regarded as being unnecessary when local buckling procedures are carried out, particularly when the buckle is placed radially, unless the patient has chronic glaucoma or the choroidal vessels are markedly sclerosed.However, there are many cases of retinal detachment where the eye is otherwise normal and where radial procedure is the detachment operation of choice in which a limited and controlled release of subretinal fluid will help considerably in the localisation, treatment by cryotherapy and final positioning of the tear on the buckle. This paper describes the technique employed and the advantages which may be gained by using this method in cases of deep bullous detachment of the retina. The results which have been obtained in cases in which this method has been used during the last 3 years are described.

Intraocular BSS and air used in combination with buckling procedures and exoplants have been helpful as aids in the release of subretinal fluid. BSS can be injected into the anterior chamber or through the pars plana and the buckling area. Air should only be injected through the pars plana. The advantages are discussed. Careful technique is generally exempt of complications.

The purpose of this investigation was to establish whether the hazards of drainage of subretinal fluid could be reduced. The technique employed utilizes a three-pronged circular grid with a central aperture, 1 mm in diameter. This rigid grid engages the sclera perpendicularly and can be satisfactorily controlled with one hand. Traction with this device elevates the scleral wall to a variable degree depending upon the rigidity of the sclera and the intraocular tension. This scleral elevation allows the point of penetration of the subretinal space to be further removed from the plane of the detached retina than normally would be achieved by conventional techniques. The data presented illustrates the advantages of this approach in terms of reducing the risk of retinal penetration, inadvertent vitreous release, and failure to penetrate the subretinal space in the drainage maneuver. It is suggested that this technique adds an additional safety feature to this problem area of retinal detachment surgery.

In a group of 250 cases operated upon for retinal detachment, drainage of the subretinal fluid was carried out in 96%. Since in 54 cases, i.e. 22%, a large quantity of subretinal fluid was evacuated, saline solution was injected into the vitreous. The following complications due to drainage were noted: intraocular haemorrhages (16%), incarceration of the retina (1%) and temporary iridocyclitis (2%). None of these complications prevented reattachment. In 54 cases in which injection of saline solution into the vitreous was carried out, we have noted: temporary occlusion of the central retinal artery (5 cases), temporary cloudiness in the vitreous body (2 cases) and traumatic cataract (1 case). The injection of saline solution into the vitreous was well tolerated. Although the complications due to drainage are rather numerous (intraocular infection and haemorrhages, incarceration of retina, secondary retinal hole, glial proliferation in the vitreous, dehiscence at the place of drainage), these complications rarely occur if the drainage is carried out in a proper manner. Despite the fact that drainage and injection of saline solution into the vitreous do not cause more severe complications, however, we consider that the method of avoiding drainage and internal tamponage, whenever it is possible, represents a fully justified trend.

In a study of 194 reoperation in which one third of the cases were managed without drainage of SRF, it was found that a number of failures occurred after non-drainage. Analysis of these failures shows that more than half could have been avoided if the choice of operation had been correct. It is felt that with careful attention to the criteria which was used to decide on the choice of surgical technique, the results obtained by the non-drainage method should be as good in the more complicated case as they have already been shown to be in the primary case. Because the drainage of SRF carries with it a high risk of surgical complications and these complications frequently result in the development of MPR, management of the reoperation should be carried out without drainage of SRF whenever possible.

An encircling constriction procedure has been added to the localized indentation operation. The inclusion of a cerclage does not in itself require drainage of subretinal fluid. Experiments were done in an animal model to determine the amount of constriction that would be tolerated by the eye without provoking a significant incidence of anterior segment ischemia or scleral erosion. From these experiments it was projected that the human eye might withstand a reduction in band length between 10 and 20% of its circumference without important morbidity. 119 patients were operated upon over six years with a cerclage constricted within these limits. Anterior segment ischemia occurred twice, scleral erosion not at all.

A double-edged cutting blade oscillates between a clockwise and a counter-clockwise high speed rotation without completing a full revolution. This imparts a great mechanicaldvantage and safety to the instrument's cutting efficiency. The cutter may also be used with a continuous high speed clockwise rotation. Multiple interchangeable probe tips are used that are of either double- or triple-walled construction. A fiber-optic light pipe surrounds the probe tip used for deep vitrectomy in conjunction with an irrigated fundus lens. A film will illustrate the use of the roto-extractor in two diabetic patients with old unabsorbed vitreous hemorrhage and membranes. In the first case, a pars plana incision was used for vitrectomy in conjunction with a cataract extraction. In the second case, the para plana vitrectomy was combined with an optical iridectomy necessitated by the presence of an updrawn pupil following previous cataract extraction complicated by vitreous loss. To date, 12 roto-extractors have been distributed to 12 various teaching institutions throughout the United States.

The prognosis in complicated retinal detachments has improved with advances in vitreous surgery. Different types of vitreous membranes require different instrumentation and different surgical techniques. This presentation describes the indications, instrumentation and surgical techniques for the management of various types of vitreous membranes. An exhibit on vitreous surgery illustrates various instrumentation.

Severe, seemingly permanent intraocular hemorrhages caused by ocular trauma, Eales' disease and retinal vein thrombosis, lead to late formation of a dense retrolental membrane, vitreous liquefaction and intumescent cataract with faulty light perception. In the absence of ultrasound, the diagnosis was made possible only after removal of the cataract. Lens extraction and excision of the vitreal membrane led to surprisingly good recovery of vision. Three cases are presented and the pathological study of a posthemorrhagic membrane.

Patients with sickle cell anemia in many cases develop proliferative retinopathy which frequently progresses to retinal hole formation and retinal detachment. These patients do very poorly with scleral buckling procedures. This is probably due to sickling of the red blood cells during surgery, which may interfere with the circulation to the structures of the anterior segment of the eye. We have previously reported avoiding this problem in three cases by performing a modified scleral buckling procedure in the hyperbaric oxygen chamber. This paper reports additional cases successfully treated with this technique. Blood studies performed during surgery in the hyperbaric chamber are reported and the technique is further described.

It has been reported in the literature, and is the clinical impression of many ophthalmologists, that the use of miotic drugs and especially Phospholine Iodide increases the incidence of retinal detachment. A review of 1,000 cases of retinal detachment is reported with a breakdown of the percentage of patients who previously had glaucoma and the various drugs with which they had been treated prior to the development of their retinal detachments. The incidence of bilateral cases is also studied and conclusions are drawn as to whether or not there is any increased incidence of retinal detachment or in the bilaterality in patients who are on miotic medications.

1. The retinal periphery was explored with binocular indirect ophthalmoscopy and scleral depression in members of the families of patients with detachment due to retinal disinsertions and 30 pedigrees have been thus obtained. 2. A genetic causation of this disease is postulated, based in the concentration of cases in some of the sibships studied (33% of the sibships with 2 or more siblings); furthermore, the disease was demonstrated in two identical twins and was absent in two fraternal twins. 3. The sex incidence was similar and the vast majority of affected individuals had normal parents, suggesting an autosomal recessive mode of inheritance for at least some of the cases.

Nine patients with congenital retinoschisis were examined. Two patients showed only the stellate c cystoid macular schisis without peripheral changes. Most of the affected eyes demonstrated a vision between 6/15 and 6/21. Fluorescein angiography did not reveal any macular abnormalities, even though changes were ophthalmoscopically visible. Patients in their twenties developed nonspecific macular degeneration, but did not have acceleration of visual deterioration.

Lattice degeneration has certain invariable histologic features but presents clinically in a variety of similar and dissimilar forms. Photographic documentation and statistical data on the evolution of round atrophic holes and of white lines are represented which tend to support the view that all of these clinical forms actuallysent one basic disease process.

A pathogenic analysis of full-thickness tears of the peripheral retina and their incidence in autopsy eyes is presented. Tears were classified according to their location (ora or postora, quadrant and zone), type of traction (zonuloretinal or vitreoretinal), morphological features (flap or operculum), presence or absence of posterior vitreous detachment, and their association with other ocular lesions. Tears were present in 2% of eyes. They were postoral in 92%, uniformly distributed in the quadrants, in the equatorial zone in 95%, related to vitreoretinal traction in 94%, of the flap type in 64%, accompanied by posterior vitreous detachment in 79% and were significantly more prevalent in eyes with lattice degeneration (17%). A simple classification of postoral tears is recommended which incorporates these pathogenic principles and includes three types according to their topographical relationship to the vitreous base: intrabasal--caused by avulsion of zonular traction tufts; juxtabasal--related to traction of the posteriorly detached vitreous on irregularities in posterior border of vitreous base; extrabasal--resulting from avulsion of cystic retinal tufts.

Peripheral cystoid degeneration is the result of malnutrition of the retinal tissue, already observed in postnatal development. The morphological substrate for a disturbance in the function of the blood-retinal barrier at the ora is the presence of a perivascular space around the capillaries.

To determine the risks of reoperation and clinical recurrence in Crohn's disease involving the colon, we analyzed by both crude and actuarial (life-table) methods follow-up data from 160 patients hospitalized with Crohn's colitis or ileocolitis from 1964 through 1973. A total of 100 patients (63 per cent) underwent major operation; of these, 58 required reoperation. By the 15th year after initial operation, there was a cumulative reoperation rate of 89 and an overall clinical recurrence rate of 94 per cent. Crude data implied that the reoperation rate diminished with each succeeding operative procedure, from 58 per cent after the first operation to 47 per cent after the fourth. By contrast, actuarial analysis revealed that at the three-year follow-up point, the cumulative chance of reoperation increased from 37 per cent after the first surgical procedure to 60 per cent after the fourth. The inexorable tendency of Crohn's ileocolitis to require repeated operations is demonstrable by actuarial methods.

The sudden arrival of 1600 Vietnamese orphans in San Francisco required the rapid development of a co-ordinated disaster plan, including the overnight establishment of a 1000-bed pediatric field hospital. The plan required rapid identification and involvement of lay and governmental resources, acute medical triage and provision of ongoing medical care and basic nurturing services and eventual discharge to adoptive families. Because one third of the orphans were under six months of age, conventional nursery resources were insufficient, and a "warehouse" model was implemented. This process required development of a specialized transportation and communication system, the services of 800 physicians, 1400 nurses, and 3200 volunteers and 162 back-up acute hospital beds. Disaster planning in most sizable American cities has focused on the problems of adults. Because of the unusual problem presented by infants and small children, we recommend that cities carefully evaluate their disaster planning with special reference to the needs of children.

To evaluate viral hepatitis as a hazard in general dentistry, we surveyed participants in an annual health-screening program at the 1972 American Dental Association session. Of 1245 practitioners, 0.9 per cent were positive for hepatitis B surface antigen, and 12.7 per cent were antibody positive. Of those who had had clinical hepatitis while studying or practicing dentistry, 43 per cent were seropositive. The frequency of evidence for prior infection with hepatitis B virus increased uniformly with increasing years of professional experience. The proportion of seropositive dentists did not vary with geographic region of the United States, or size of community. Only 10.5 per cent recognized illicit self-injection among patients, and their infection rate was not increased. These data indicate an increased frequency of infection with hepatitis B virus among general dentists, and are compatible with relatively uniform endemicity of subtype/ad strans of that agent in the general population for several decades.

Thyroid hormone and thyrotropin concentrations in amniotic fluid were studied by radioimmunoassays during pregnancy. The mean thyroxine concentration was 398 ng per 100 ml at 15 to 19 and 440 ng per 100 ml at 36 to 42 weeks. Although 3,3',5-tri-iodothyronine was undetectable (less than 25 ng per 100 ml), 3,3',5'-tri-iodothyronine levels were very high (range, 132 to 605 ng per 100 ml) at 15 to 30 weeks, but decreased substantially (range, 54 to 130 ng per 100 ml) thereafter. Thyrotropin was undetectable. The mean thyroxine and 3,3',5-tri-iodothyronine levels in amniotic fluid were much lower and the mean 3,3'5'-tri-iodothyronine much higher than the corresponding values in maternal serum at both 15 to 19 and 36 to 42 weeks of pregnancy. Measuring thyroid hormones in amniotic fluid, especially 3,3',5'-tri-iodothyronine, may aid in the diagnosis of fetal thyroid dysfunction and in identification of pregnancies of less than 30 weeks' gestation.

In exploring the immunologic causes of chronic neutropenia, we identified a persistent neutrophil-specific antibody with NA2 specificity in the blood of a nontransfused two-year-old girl with severe neutropenia. No such antibody was detected in the maternal blood. The antibody was first studied and identified when the patient was 11 months old, but she had had clinical manifestations since the age of one month. After a trial of steroid therapy, a marked but temporary reduction in the antibody titer occurred, accompanied by the rise of the neutrophils to normal level. Neutropenia reoccurred, however, when the antibody titer began to rise, despite continuation of steroid therapy. This transient response allowed the patient's neutrophils to become available and identified as NA2-positive. Although the cause of this disorder remains obscure, the data presented indicate that the anti-NA2 autoantibody is responsible for the neutropenia observed.

The onset of neurologic symptoms in a child who had markedly elevated blood phenylalanine levels during the first two weeks of life and who was promptly treated with a low phenylalanine diet, with excellent control of serum phenylalanine levels, suggested that this child had an unusual form of phenylketonuria. In assays of the components of the phenylalanine hydroxylating system (open liver biopsy at 14 months), the activity of phenylalanine hydroxylase was 20 per cent of the average normal adult value. By contrast, no dihydropteridine reductase activity was detected in the patient's liver, brain or cultured skin fibroblasts. Since dihydropteridine reductase is also essential for the biosynthesis of dopamine, norepinephrine, and serotonin, disturbed neurotransmitter function may be responsible for the patient's neurologic deterioration. On the basis of these results, assay of reductase in cultured skin fibroblasts may be advisable in the initial diagnosis of phenylketonuria.

Demographic risk factors in sisters and daughters of 150 patients with breast cancer were compared to those of controls. Plasma hormone levels in 36 teen-age daughters of patients and 31 controls were also studied to ascertain whether an "abnormal" hormone pattern underlies these risk factors. The patients' sisters had, on the average, menarche four months earlier and first full-term pregnancy 12 months later than the controls. The patients' daughters did not show these differences -- apparently owing to low fertility in the patients with early menarche. The patients' daughters had higher 22d-day estradiol-plus-estrone levels than controls (24.4 vs. 19.1 ng per 100 ml, P less than 0.05). Sixth-day prolactin was also elevated (19.0 vs. 14.2 ng per 100 ml, P less than 0.05). About half the patients' daughters could clearly be distinguished from the controls' daughters by means of the sixth-day information on both estrogens and prolactin. Hypersecretion of these hormones may be important factors in breast cancer.

To determine the characteristics of the radiographic resolution of bacteremic Streptococcus pneumoniae pneumonia we examined serial chest roentgenograms in 72 patients. Consolidation disappeared in all patients by eight to 10 weeks; volume loss (9 per cent), plural disease (9 per cent), and stranding (19 per cent) often persisted beyond eight weeks. Resolution occurred earlier in patients less than 50 years old (P less than 0.05) and in the absence of alcoholism and underlying airways disease regardless of age (P less than 0.05). Delayed clearing occurred when these complicating factors were present in patients over 50. Lung cancer was not responsible for delayed resolution of pneumonia. We conclude that an appropriate interval for serial radiographic examinations after therapy for pneumococcal pneumonia is six weeks.

A 7-A resolution map of the purple membrane has been obtained by electron microscopy of tilted, unstained specimens. The protein in the membrane contains seven, closely packed, alpha-helical segments which extend roughly perpendicular to the plane of the membrane for most of its width. Lipid bilayer regions fill the spaces between the protein molecules.

The protection of critical ecosystems appears to be a sounder management strategy than the protection of critical species. Environmental quality-control systems designed to protect ecosystems are described. These quality-control systems will make it possible to optimize the ability of ecosystems to assimilate and transform wastes and protect them from degradation.

By means of the gel filtration technique, the effect of nine benzodiazepine derivatives on the binding of L-tryptophan to human serum albumin was investigated. Using equimolar tryptophan and benzodiazepine concentrations, all benzodiazepines with binding constants higher than 10(4) (M(-1), displace L-tryptophan from its binding site to a high degree. The mechanism of the displacement was characterized as a competition for a common binding site. Some of the benzodiazepines displace L-tryptophan to a greater extent than salicylic acid. The benzostereospecific binding to human serum albumin. This study shows that there is only one binding site on the human serum albumin molecule, which binds tryptophan and the benzodiazepines in a highly stereospecific manner. Therefore it is concluded that the benzodiazepines and L-tryptophan must have similarities in their molecular structure, so that both can bind to the common binding site in such specific manner. These considerations are discussed in regard to the known influence of benzodiazepine derivatives on the L-tryptophan metabolism in brain. A direct involvement of the reported displacement in the pharmacological actions of the drugs seems not to be relevant because of their small therapeutical plasma levels.

14C-u-glucose and 32P-phosphate were given intravenously to pregnant rats, treated and untreated with hydroxyurea (HU). The incorporation of radioactivity into a variety of cell components of the embryo was measured. With this double-labelling technique it is possible to survey the effects of embryotoxic drugs on various pathways in mammalian embryos in vivo. Onset, extent and duration of the metabolic changes were measured after application of "non-teratogenic" and teratogenic doses of hydroxyurea (HU). 3 hrs after application of hydroxyurea only DNA synthesis is affected, whereas after 5 hrs RNA synthesis is also inhibited.

The action of adenosine on renal blood flow and kidney function in dogs was studied with bolus injections and infusion of adenosine into the renal artery. Simultaneous infusions of theophylline, 1-5 x 10(-6) mol/min into the renal artery which did not affect renal function by itself inhibited the adenosine induced vasoconstriction. From the bolus injection studies a dose response curve (DRC) was constructed. Theophylline shifted the DRC to the right in a parallel manner. pA2-pA10 was 0.98 indicating that theophylline inhibition of the adenosine effects may be interpreted as a competitive antagonism. Infusions of adenosine (0.3-1.1 mumol/min) caused a reduction of urine volume, sodium excretion and glomerular filtration rate (GFR). The decrease of GFR after adenosine infusion by 31.4% could be diminished by theophylline. It is suggested that adenosine action is based mainly on a constriction of the vasa afferentia in the outer zone of the cortex.

1. The effects of various concentrations of lanthanum (La3+) on the force of contraction and on action potentials was investigated in isolated papillary muscles of the guinea-pig. 2. The force of contraction was initially reduced by La3+. During long exposure to high concentrations (i.e. 50, 100 and 500 muM) the contraction amplitude was increased again and a rise in resting tension was observed. These late changes in force of contraction also occurred after short exposure to 500 muM La3+ (2 min) when La3+ had been removed from the medium. 3. The action potentials were shortened at 20% of repolarization (plateau level) during La3+ exposure, whereas at 90% of repolarization a transient prolongation was observed. The resting potentials were reduced only at high concentrations and long duration of exposure. 4. 500 muM La3+ reduced the force of contraction to the control value obtained before addition of ouabain (5x10(-7)M). The ouabain-induced shortening in action potential duration at the plateau level was not reversed by the same concentration of La3+. 5. It is concluded that the action of La3+ on cardiac muscle cannot be explained by a simple displacement of superficially bound calcium. The characteristic effects observed at high concentrations reduce the value of La3+ as a pharmacological tool used in the study of calcium turnover.

In experiments on isolated, electrically driven (240/min) rat hearts, perfused via the aorta at a constant flow (3.8 ml/min), the pharmacologically effective concentration range, the myocardial uptake and the subcellular distribution of three cardiac glycosides (digitoxin, digoxin, ouabain) were determined. The following results were obtained: 1. The effective range varied depending on the cardiac glycoside tested: With digoxin and ouabain very similar results were found- the positive inotropic concentration ranges being within 8x10(-6)M and 6x10(-5)M, the maximum positive inotropic effects attainable being about 100% and the concentration for half maximum effects (ED-50) being 2.4x10(-5)M and 2.3x10(-5)M, respectively. With digitoxin the inotropic concentration range was found to be within 3.6x10(-6)M and 2.4x10(-5)M with a maximum inotropic effect attainable of about 50% only and an ED-50 of 9.5x10(-6)M. The analysis of the time course of the inotropic action revealed extremely short half times for all cardiac glycosides studied (between 48 and 54 sec). 2. The myocardial uptake correlated with the physicochemical behaviour of the three cardiac glycosides studied and was found-depending on the perfusion time (5 to 60 min)-to be in the range of 23 and 36 (ouabain), 66 and 98 (digoxin) and 169 and 264 (digitoxin) nmoles/g wet weight. The respective computed half times for these uptake processes were 2.5 min (digoxin, ouabain) and 3.4 min )digitoxin). 3. Regarding the subcellular distribution an accumulation exceeding an "unspecific" binding (non-perfused hearts) was found mainly in the nuclear-membrane fraction. On the basis of these results (very short half times of either the pharmacological action and the cardiac uptake) the site of action of cardiac glycosides in the rat heart is supposed to be located at the surface membrane of the heart muscle cells. Furthermore, the above results are discussed with respect to those obtained in digitalis-sensitive species.

1. Isolated rabbit hearts were perfused with a modified Tyrode solution containing noradrenaline in concentrations increasing stepwise from 5.9 nM to 5.9 muM at 5 min intervals. This dose regime was applied twice before and once 20 min after starting perfusion with one of 9 tricyclic drugs. Ventricular rate and right atrial and ventricular tensions were recorded using the transverse method. 2. Infusions of noradrenaline evoked ventricular arrhythmias in hearts perfused with amitriptyline 4.8 muM, chlorpromazine 5.0 muM, desipramine 5.0 muM, dibenzepine 34.7 muM, doxepin 4.7 muM, imipramine 4.7 muM, noxiptiline 9.1 muM and opipramole 9.2 muM. The incidence of arrhythmias increased with the concentration of noradrenaline applied and the dose of tricyclic drug administered. Whenever arrhythmias had started they continued as long as noradrenaline was infused. Noradrenaline failed to produce arrhythmias in hearts not exposed to drugs and after iprindole 4.7 muM or cocaine 2.9-18 muM. 3. Propranolol 0.1 muM inhibited the incidence of arrhythmias after doxepin 4.7 muM plus noradrenaline 5.9-190 nM. 4. Neuronal uptake of exogenous noradrenaline in the rabbit heart was inhibited by the tricyclic drugs in the following order of declining p potency: doxepin, noxiptiline, amitriptyline, desipramine, chlorpromazine, imipramine, dibenzepine, opipramole and iprindole. 5. Among tricyclic drugs the potency to inhibit amine uptake is related to the incidence of arrhythmias evoked by a submaximal concentration of noradrenaline. It appears, however, that these two parameters are not causally linked. 6. The isolated rabbit heart perfused with noradrenaline might be used as a model for testing the arrhythmogenic actions of tricyclic drugs and the treatment of such arrhythmias.

In three species chronic treatment with the anorectic drug chlorphentermine causes a profound alteration of the phospholipid/lipid metabolism in the organism, resulting in an increase of the fractions of phospholipids and lipids, e.g. in lungs, livers and adrenals. The results are interpreted as drug-induced generalized phospholipidosis, which is caused by amphiphilic drugs, like chlorphentermine and others. Its extent depends on several factors, like content, pattern and turnover rate of phospholipids in different organs, and on the species.

The isolation of macromolecules that bind drugs and neurohumoral mediators at receptor sites will require analytical methods adequate to detect these substances in homogenates and crude mixtures. Although the binding of isotopically labeled agonists has been useful in a few instances, equilibrium binding studies of radioactive, lipophilic antagonists promises to be more useful with beta-adrenergic receptors. Alkylation by radioactive reagents that seek out specific receptors or specific functional groups on protein have been used in attempts to label other receptors. Conformationally directed labeling of receptor and receptor-related proteins by the latter group of alkylating agents has been used with receptors for cardiac glycosides and may be applicable to other systems.

The uptake of bretylium-(N-3H-methyl) iodide in the rat heart atrium in vitro was examined. The uptake was linear for at least 1 hr and was strongly inhibited by (+)-amphetamine, (-)-noradrenaline, desipramine, cocaine, DSP 4 [N-(2-bromobenzyl)-N-(2-chloroethyl)ethylamine hydrochloride], guanethidine and ouabain. The amphetamine sensitive part of the uptake was almost completely abolished by pre-treatment of the rats with 6-hydroxydopamine and was dependent on the presence of sodium ions. Reserpine had no effect. (+)-Amphetamine but not desipramine caused an increase of the efflux of bretylium from the tissue. The apparent Km value of the active bretylium uptake was 3 x 10(-6) M, which was 10 times higher than that of the uptake of (-)-noradrenaline in the rat heart atrium (Km = 3 x 10(-7) M). The inhibition constants (Ki) for bretylium in inhibiting the noradrenaline uptake and for (-)-noradrenaline in inhibiting the bretylium uptake were 7 x 10(-6) M and 4 x 10(-7) M, respectively. The results obtained support the hypothesis that bretylium is taken up by the same mechanism as that carrying noradrenaline into the nerve terminals but is not bound in the noradrenaline storage vesicles.

In the isolated electrically driven guinea-pig atrium the influence of D 600 and nifedipine on the action of noradrenaline was investigated. 1. The calcium-antagonists caused a dose-dependent negative inotropic effect. 10(-7) M of D 600 or nifedipine inhibited the contractile amplitude by 75 and 55%, respectively. 2. In spite of the pronounced negative inotropic effect evoked by the two calcium-antagonists, the maximal response to noradrenaline was not changed. The sensitivity of the myocardium to noradrenaline was only slightly diminished i.e. by a factor of 4.6 and 3 as calculated from the pD2-values. 3. The functional antagonism between noradrenaline and calcium-antagonists, therefore, offers the possibility to overcome cardiac side-effects of calcium-antagonists.

Pulmonary edema and plasma kininogen consumption caused by intravenously administered adrenaline, were inhibited in rats pretreated with acetylsalicylic acid, but not in rats pretreated with indomethacin or sodium salicylate. The possibility of a connection between this edema and mast cell-linked activation of kallikrein by adrenaline is discussed, as well as the possible role of acetylsalicylic acid acting as an acetylating inhibitor of these processes.

Simultaneous determinations of the striatal contents in acetylcholine (ACh), choline acetyl-transferase (ChAc) and acetyl-cholinesterase (AChE) were made in neonate rats from day 4 to day 16 after birth. While, during this period, ChAc and AChE increased 14 and 5-fold, respectively, the change of ACh levels was smaller and more gradual. ACh levels were unaltered following the injection of thioproperazine (5 mg/kg) until day 8, then within 6 days the cholinergic neurones developed a full sensitivity to this drug. The sensitivity to haloperidol (4 mg/kg), pimozide (4 mg/kg) and to the dopamine receptor stimulating drug apomorphine (10 mg/kg) appeared along with that to thioproperazine. These data confirm and extend previous reports that rat striatal cholinergic neurones are immature at birth; they suggest, in addition, that the development of dopamine receptors occurs prior to the appearance of functional cholinergic synapses or concomitant with this event.

On everted jejunal segments of mice the transfer and tissue uptake of 3H-digitoxin, over a concentration range from 2 times 10(-10)--1 times 10(-4)M, was investigated from the mucosal ("m") to the serosal ("s") side as well as in the opposite direction. 1. The time course of the absorption of 3H-digitoxin and some other compounds investigated (glucose, urea, p-aminohippurate) gave evidence of functional integrity throughout the 75 min-periods of the experiments. 2. When 3H-digitoxin was applied to the mucosal side the permeability coefficient showed a dose-dependent increase but returned to lower values at higher concentrations. When 3H-digitoxin was administered to the serosal side the permeability coefficient showed a dose-dependent decrease at high concentrations. The ratio of both coefficients "m" leads to "s"/"s" leads to "m" increased dose-dependently from 0.4--2.6. 3. The uptake of 3H-digitoxin--applied on the serosal side--into the tissue was independent of dose. However, having administered 3H-digitoxin on the mucosal side the tissue accumulation was 2--5 fold higher and the tissue/medium (T/M) ratio increased within the concentration range from 3.0-9.0 4. Under DNP (1 mM) the asymmetry and dose dependence of the permeability and tissue uptake up 3H-digitoxin observed in controls were almost abolished. Therefore it is likely that the transfer of 3H-digitoxin in the intact intestine involves a mechanism more complex than simple diffusion. The existence of more than a two compartment system and/or the contribution of an active transport mechanism is suggested.

After i.v. injection in the rat, d-tubocurarine is taken up and concentrated by the liver. A method is developed for the visualisation of d-tubocurarine inside the liver cell by electron microscopy. Glutaraldehyde fixed liver blocks were immersed in an ammonium molybdate solution; d-tubocurarine was precipitated at sites of high concentration by molybdate, to form an insoluble d-tubocurarine-molybdate complex. This precipitate was found predominantly at the surface of lysosome-like particles, but also inside these organelles. In subcellular fractionation experiments, d-tubocurarine was found with a high relative specific "activity" in the lysosomal fraction, lending support to a lysosomal localisation of d-tubocurarine.

1. The activities of some cholinergic compounds were investigated on the terminal ileum of the guinea-pig and their muscarinic potencies were found to be in the following order: acetylcholine (ACh) greater than diazoacetylcholine (DACh) greater than iodoacetylcholine (IACh) greater than azidoacetylcholine (AACh). 2. Protection experiments with atropine showed a decreased affinity of the four cholinergic compounds for the muscarinic receptor, demonstrating a direct interaction of the drugs and the receptor. 3. The maximal contractions (intrinsic activity) caused by DACh were greater than those casued by ACh, IACh and AACh. 4. Incubation of the ileum with ACh was followed by a reversible loss of its ability to contract (desensitization). The time course of recovery was similiar to that after incubation with AACh. 5. IACh caused a partial (50%), irreversible paralysis of the muscle. 6. The furaziridines seem to react partially irreversibly (30%), whereas paranitrophenyldiazonium fluoborate (p-NDP) caused a complete, irreversible blockade of the muscarinic receptor.

In vitro incubation of adrenaline with acetaldehyde resulted in the formation of an amorphous product (MA 3) which gave origin to two spots on chromatography plates. Preparative TLC allowed us to separate the corresponding substances, MA 4 and MA 5. Gas chromatography-mass spectrometry, ultraviolet and infrared spectra of MA 4 agree with the structure corresponding to 1,2-dimethyl-4,6,7-trihydroxy-1,2,3,4-tetrahydroisoquinoline. MA 5 is very unstable and was not further characterized. Pharmacological experiments were carried out with MA 3 and MA 4 (and in some cases, MA 5) on isolated saphenous vein strips and isolated guinea-pig atria; responses of the nictitating membrane, blood pressure and hind-limb perfusion pressure were obtained in the anaesthetized dog. There were only quantitative differences between the effects of MA 3, MA 4 and MA 5 (where tested). Therefore, these effects are described as effects of TIQs (tetrahydroisoquinolines). TIQs contracted isolated saphenous vein strips, behaving as total agonists; the dose-response curves were displaced to the right by phentolamine and to the left by cocaine (potentiation factor: 2.7 +/- 0.1). In the dog, contractions of the nictitating membrane, rises of blood pressure and of the perfusion pressure (after i.a. injection) were observed. On isolated guinea-pig atria, weak beta adrenergic receptor activation was found. With higher concentrations, beta receptor blockade was observed, for both cardiac and vascular smooth muscle receptors. The effects of TIQs were short-lasting, showing that a rapid inactivation occured both in vitro and in vivo; neuronal uptake appears to play an important role in inactivation, since cocaine was able to block about 70% of the inactivation capacity of isolated vein strips. The effects of nerve stimulation on the vein strips or on the nictitating membrane were reduced by TIQs; however, this did not affect responses to noradrenaline and enhanced those to tyramine or DMPP. Simultaneously with reduction of the effects of electrical stimulation, blockade of inactivation of endogenous and exogenous noradrenaline was induced by TIQs. Marked depletion of noradrenaline levels in the heart, hypothalamus and aorta of the guinea pig was caused by MA 3 (1-3 mg/kg). It is concluded that the condensation products of adrenaline with acetaldehyde are not devoid of pharmacological activity, are taken up by adrenergic nerve terminals and may act as false transmitters. The similarity of effects of TIQs and acetaldehyde suggests that formation of TIQs may occur in vivo, after acetaldehyde (or ethanol) administration, both in the adrenal gland and in sympathetic nerve terminals. These TIQ alkaloids could play an important role in alcoholic intoxication and in the ethanol withdrawal syndrome.

1. The isolated canine right atrium perfused through the sinus node artery at a constant pressure of 100 mm Hg with blood led from a support dog was suspended in a bath filed with blood and kept at constant temperature. This preparation maintained its constant tension development and rate over 5 hrs in all 5 control experiments. 2. A relatively small amount of acetylcholine (ACh) induced a negative inotropic effect at 0.01 mug and a negative chronotropic effect at 0.1 mug. 3. A relatively large dose of ACh induced a biphasic inotropic response, i.e., initially a negative inotropic response and secondarily a long-lasting positive tropic response. These positive chronotropic and inotropic responses were abolished by propranolol, hexamethonium or tetrodotoxin. 6. In the papillary muscle and atrial muscle preparations isolated from one canine heart, ACh caused negative and positive inotropic effect in both paced papillary and atrial muscle preparations. In contrast to the results obtained with atria, the positive inotropic response of the papillary muscle preparation was completely blocked by treatment with propranolol or tetrodotoxin. 7. From these results, it is suggested that in the canine atrium muscarinic mechanisms predominate over nicotinic ones. This may well be due to the known inhibition of nicotinic responses by stimulation of muscarinic receptors.

Effects of 6-hydroxydopamine (6-OH-DA) injected into the lateral brain ventricle on the carotid sinus baroreceptor reflex were studied in rabbits anesthetized with alpha-chloralose and urethane. As short term effects, injection of 500 mug/kg of 6-OH-DA caused a fall in blood pressure and heart rate, enhanced the depressor and bradycardia responses to electrical stimulation of the carotid sinus nerve (CSN), and inhibited the pressor response to carotid occlusion. These effects reached the maximum with 2 hrs and disappeared by the 4th hr. Intraventricular injection of noradrenaline (NA) could mimic most of these effects. At 4.5 hrs after injection of 6-OH-DA, NA content of the brain was definitely reduced: 21% of control in the hypothalamus and 14% in the pons-medulla. Rabbits treated with 6-OH-DA under penthobarbital anesthesia 24 hrs before showed a slight fall in resting blood pressure and almost normal baroreceptor function. Intraventricular application of phentolamine abolished the responses to CSN stimulation in 6-OH-DA pretreated as well as normal animals. These results suggest that the acute effects of 6-OH-DA are based on the increased release of NA from the affected nerve terminals and that noradrenergic neurons are involved in the central pathway of baroreceptor reflex. Moreover, the relfex may be functionally maintained by a small portion of brain NA content, even when noradrenergic neurons are greatly affected by 6-OH-DA.

1. Scorpion toxin II is potent in inducing contracture and spontaneous contractions of the chick biventer cervicis muscle. In addition, this toxin induces membrane depolarization and blockade of neuromuscular transmission in this muscle preparation. The purpose of the present study is to explore the possible mechanism of actions of toxin II. 2. The muscle contracture induced by toxin II is moderately accelerated by Ca2+-free Krebs solution, delayed by high Ca2+ (10 mM), high Mg2+ (10 mM) and low Na+ (60mM) Krebs solution. Moreover, this action is inhibited slightly by d-tubocurarine and completely by either procaine or tetrodotoxin, but unaffected by beta-bungarotoxin. All these findings suggest that toxin II induces contracture mainly by increasing the Na+ permeability of the muscle membrane. 3. Spontaneous contractions induced by toxin II are abolished by Ca2+-free Krebs solution, inhibited partially by either d-tubocurarine or beta-bungarotoxin and completely by tetrodotoxin or procaine. These results suggest that toxin II induces spontaneous contractions partially by releasing acetylcholine from nerve endings and partially by increasing the Na+ permeability of the muscle membrane.

The effects of glucose concentrations in the perfusion medium ranging from 5 to 15 mM and thiopental, on cerebral energy metabolism were studied using the isolated perfused rat brain. After a perfusion time of 30 min brain levels of the following substrates and metabolites were determined: P-creatine, ATP, ADP, AMP, glycogen, glucose, glucose-6P, fructose-6-P, pyruvate, lactate, alpha-ketoglutarate, glutamate, ammonia. In control experiments increasing the glucose concentration in the perfusion medium produced an increase of intracellular brain glucose concentration only, revealing a linear relationship between glucose content in brain and blood. Neither high-energy phosphates nor glycolytic intermediates were markedly affected by the changes in blood glucose. With an anesthetic dose of thiopental (0.15 mM) in the perfusion medium identical metabolic alterations occured in all experiments: P-creatine and glucose were significantly increased whereas ADP, AMP, lactate and pyruvate were diminished. Also with thiopental brain glucose was linearly related with the glucose concentration in the perfusion medium. The calculated regression line was apparently parallel with that from control experiments; that means thipental always caused an elevation of brain glucose by the same amount of 0.9 mumoles/g--irrespective of the initial cerebral glucose content. The results yield further evidence that glucose transport is not the rate-limiting step in glycolysis. The action of thiopetal on glycolytic pathway is discussed.

The effects of papaverine and of the organic calcium-antagonistic agents D 600 and nifedipine on the contraction induced by noradrenaline and calcium were studied on the isolated aorta and mesenteric artery. The affinities of both agonists, given as pD2-values, were significantly higher on the aorta than on the mesenteric artery. Under our experimental conditions D 600, nifedipine and papaverine were found to act as antagonists against calcium and noradrenaline in a non-competitive fashion. In either vessel, the calcium-antagonistic activity of D 600 and nifedipine was about 1000-fold greater than that of papaverine, whereas their antagonistic activity against noradrenaline was bout 1000-times weaker, i.e. D 600 as well as nifedipine were about equipotent with papaverine. The comparison between the calcium- and the noradrenaline-antagonistic activity offers the possiblity to evaluate the specifcity of calcium antagonistic agents.

Transplacental effect of benzo(a)pyrene was studied in organ cultures of embryonic lung tissue explanted from mouse donors injected by the carcinogen. Hyperplastic alteration of epithelium, followed by adenomatous changes were seen in embryonic lung tissue cultures from donor mice injected by benzo(a)pyrene. No alteration was seen in control cultures in which the mice were injected by a non-carcinogenic hydrocarbon (pyrene). Besides the blastomogenic action, a growth-promoting effect of the benzo(a)pyrene was observed in the particular organ cultures of the embryonic lung tissue.

Ultracytochemical visualization of specific carbohydrate receptors by means of lectins can provide valuable topological information about the functional status of cell surfaces in normal and transformed cells. In addition to the concanavalin A (Con A) rection and precoupling of lectin--peroxidase (PO) a new method is suggested using precoupling of the marker enzyme (PO) with an appropriated glycoprotein (glycopeptide) containing a lectin-specific carbohydrate. Furthermore, quantitative estimations of Con A reaction by means of automatic umage analysis are performed on peritoneal macrophages which point out a cluster formation, but give no hints for a loss of glycocalyx during the preparation process contrary to tumor cells.

Differences in cytostatic sensitivity between subcutaneously transplanted Lewis lung carcinomas and metastases from them were studied in vitro. Sensitivity to vinblastine sulphate and melphalan was determined as the reduction of the incorporation of H3-thymidine into drug-treated cells compared with control cells. The main result of the present study is that tumor cells obtained from pulmonary metastases are more sensitive to cytostatic drugs in vitro than are the cells obtained from the corresponding subtaneous tumors. When cells from pulmonary metastases are transplanted subcutaneously, the sensitivity of the resulting tumor closely resembles that of other subcutaneous tumors. However, when the tumor cells have been passed through many cycles where the pulmonary metastases from subcutaneous tumors were re-transplanted subcutaneously and then allowed to metastasize again, a selection of tumor cells has apparently occurred: they have become more sensitive even when grown subcutaneously. Different explanations of this phenomenon are discussed.

The effect of the combined treatment with leukeran, degranol and prednisolone on the lymphoid tissue and marrow hamopoiesis in rats is studied. The simultaneous administration of these drugs is shown to cause a more effective inhibition of the lymphoid tissue and a less suppression of the marrow, as compared with their separate administration.

The study of the possibilities of new DNA synthesis by the Sternberg-Reed cells of Hodgkin disease was done with tritated thymidine and autoradiography. The results showed that after incubation pulses of 30 and 60 minutes cells with lobulated nucleus, binucleated and trinucleated cells, identifiable to the diagnostic Sternberg-Reed cells, had possibilities of new DNA synthesis. This points to a more dynamic interpretation of this cell that was considered without chances of cnromosome replication.

The amino acid composition of melanosomes from human and Harding-Passey mouse melanomas and from pigmented tissues of cattle eyes isolated according to BOLT was studied. The 18 current amino acids and moreover dopa were found in all the hydrolysates studied. By means of apolar/polar amino acid ratio suggested by HATCH the possible properties of melanosomal protein(s) were infered. The higher level of cysteine and lysine in mouse melanosomes as compared with tyrosinase supports the theory of special matrix protein in melanosomes. Lysine seems to have a role in regulation of the quantity of synthesized melanin.

In a group of 30 patients with neoplastic processes, 13 were found to have a significantly increased serum alkaline phosphatase activity. This finding correlated with the results of investigation with 85Sr in 7 patients, but owing to a concomitant hepatal symptomatology, it proved of differential diagnostic value in only one of them. On the other hand, the activity of bone isoenzyme of alkaline phosphatase was significantly altered in 15 patients. In 14 of them the increase in bone isoenzyme activity corresponded to an X-ray and a radionuclear finding of a tumor process in the bones. This activity was within the normal range of values in only one patient with a positive result of the 85Sr investigation. An agreement between the results of determination of bone isoenzyme activity of alkaline phosphatase and those of radionuclear investigations was found in 27 patients. In addition, a correlation was established between the increased activity of bone isoenzyme and that of intestinal isoenzyme of alkaline phosphatase. Enzyme investigation can be suitably utilized, alongside radionuclear examination, for early detection of a bone process.

1. A method of evaluating in vitro phagocytic activity of leukocytes, using inert latex particles has been described. 2. 363 investigations have been carried out according to the method in clinically healthy donors, in patients with and without malignant disorders. The subjects have been divide into groups according to nature of the disease (operable and inoperable tumors, non-malignant, acute anc chronic disorders). 3. A statistical evaluation of the results revealed that the phagocytic capacity of leukocytes is significantly activated in the presence of a pathological process in the organism and this to a considerably higher degree in tumorous disorders than in non-malignant affections. The degree of activation of the phagocytic capacity of leukocytes can be measured by this method and the latter can be used in every haematological laboratory.

MOPP chemotherapy program was employed in 20 children with advanced Hodgkin disease (stages III and IV). Complete remissions were achieved in 13 patients (65%)within an average duration rate of 17.1 months varying from 2 to 40 months. If thses only one patient developed recurrency and died 10 months after the onset of treatment. The remaining 12 children are alive and well; an average survival rate since the onset of MOPP chemotherapy being 20 months. The patients with partial remission died from further progression of the disease within the period from 2 to 15 months. The study showed that histological type and mode of previous treatment had an influence on the results of chemotherapy used. The complications of MOPP chemotherapy were insignificant and easily controlled.

Addition of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (bht) to benz(a)pyrene (BP) exposed cell cultures results in slight reduction of transformation. The benz(a)pyrene hydroxylation is reduced when antioxidants are added to the incubation mixture.

The cytostatic activity of 2-thio-4-hydrazinouracil (THU) on some transplantable tumors has been studied. A strong effect of this compound (between 60% and 100% suppression) has been found in the case of Myeloma P-8 (MOPC-21) and Sarcoma 180 (Crocker). A less pronounced effect has been observed on Yoshida sarcoma, while the development of Jensen sarcoma is not influenced.

Nuclear DNA content was measured in 3 normal, 9 hyperplastic and 16 neoplastic rat thyroid glands. Thyroid hyperplasia and tumor growth were induced after treatment of the animals with X-rays and methylthiouracil. In the control animals only diploid thyroid epithelial cells were observed. At the stages of diffuse and nodular thyroid hyperplasia, the total DNA content per nucleus indicated for a diploid chromosome number and only a few cells were hyperdiploid. In the thyroid adenomas and carcinomas a scattering of the diploid region and an increase in the number of hyperdiploid cells was found. Among the various types of thyroid tumors neither difference in the number of hyperdiploid cells, nor typical pattern of distribution of these cells in the histogram was found. The increased number of hyperdiploid cells in the hyperplastic and neoplastic thyroids suggest an increase in the proportion of the cells entering the cell cycle and does not indicate for appearance of a neoplastic stemline.

Treatment failures were analysed in 43 head and neck cancer patients treated with a dynamic dose-fractionation in combination with breathing oxygen at ambient pressure. Infiltrative T3-4 lesions with necrosis showed poorer results than exophytic and necrosis-free infiltrative lesions. Possible differences in the oxygenation of the different types of lesion were considered to explain the results.

The authors have analysed 43 patients with thyroid carcinoma who had been treated at the surgery department of the Oncological Institute between 1960 and 1970. The patients are distributed in four groups according to the histologic tumor structure. Considering the specific properties of each particular group, the occurrence of metastases, treatment, survival and prognosis are being discussed. An outline is given on the characteristics of the various forms of thyroid carcinoma from the histological but mainly clinical aspects. The development of regional and distant metastases, surgical treatment, postoperative irradiation or application of radioiodine and hormonal tumor dependence are presented in the paper. The best results were obtained in the papillary and the follicular form, the prognosis in the latter being dependent on the degree of vascular invasion. The solid carcinoma of thyroid shows considerable differences in survival of patients depending on regional metastases and histologic grade. The anaplastic carcinoma has the worst prognosis where survival is expressed in months, exceptions are rare.

Two patients with vertebrobasilar ischemia are described in whom angiography demonstrated obstruction of one vertebral artery at the C1-2 level on rotation of the head. The possible anatomical explanation and physiological significance of this finding are discussed.

A case of venous angioma involving the frontal lobe is presented with surgical and histological confirmation. Only two other angiographically diagnosed cases have been reported previously in the literature. This case tends to support the entity of cerebral venous angioma as a distinct, though rare, type of cerebral vascular malformation.

The effects of changes in systemic blood pressure upon external carotid branches of the baboon have been measured by cerebral angiography. They have been shown to have an autoregulatory type of response down to a blood pressure of about 60 mmHg, below which they constrict.

Superselective arteriography and superselective embolisation is the future of a part of neuroradiology. After the first realisation in the territory of the external carotid artery, it was logical to extend it to the territory of the internal carotid artery. The technic of the balloon-catheter of Serbinenko is described and problems of embolisation in the internal carotid artery are discussed.

A critical evaluation revealed no distinct clinical complex of symptoms related to the radiological picture of chronic adhesive arachnoiditis in the lower lumbar sac in 72 patients. In all cases the arachnoiditis was diagnosed by myelography with water soluble contrast media and, in 16 cases, verified by operation and microscopy. The assumed cause of arachnoiditis was, in more than half of the cases, the combination of myelography and operation in close relation, and, in ten cases, a previous operation.

A comparison of the results obtained by 99m Tc-DTPA, 99m Tc-PP and 67Ga-citrate scanning in ten meningioma patients is reported. The association of conventional brain scanning, bone scanning and "tumor-positive" scanning makes it possible to identify the primary tumor, its real extent, the perifocal damage and the contiguous bone damage.

Three cases of painful ophthalmoplegia have been described in which symptoms suggesting a tumor of the orbit justified neuroradiological assessment. Phlebography in each case revealed stenosis of the superior ophthalmic vein in its third portion, and non-opicification of the cavernous sinus. Hirtz incidences revealed contralateral cavernous sinus opacification and venous drainage through the coronary sinus. These neuradiological findings helped to differentiate this syndrome from other affections which have similar signs and symptoms.

In the past twenty years, the vacuum extractor has gained wide use in Europe with an associated decrease in perinatal mortality. There, its use is considered by many to be much safet than a forceps delivery. Certain complications are associated with its use, but in general these are minor and transitory. On analysis, most of the serious complications reported in the literature are considered to be due to other associated factors, or to misuse of the vacuum extractor. Experience with the vacuum extractor in the United States has been minimal, and most authors feel that there are few indications for its use. Perhaps it is time that obstetricians in the United States take a more careful look at the European experience, and give the vacuum extractor a fair trial.

In this review the mechanisms whereby amniotic fluid serves to protect the fetus from microbial disease have considered. It appears from the data reviewed that the principal mode of antibacterial action of amniotic fluid is bacteriostasis. Thus, the host is able to cope with a small number of organisms introduced into the amniotic cavity; however when the amniotic fluid is grossly contaminated the host resistance capacity of the amniotic fluid may be overwhelmed. This may be understood best by the quantitative description of disease theroized by Theobald Smith (94). Smith suggested that disease was a function of the number of organisms with which a host is initially infected multiplied by the virulence of the organism. The effects of the number and virulence of the organism in producing disease is lessened by the host's resistance capacity. This concept of disease is summarized by the equation: Disease equals (number) (virulence)/resistance. Although these parameters do not possess numeric values, it is possible to see at least conceptually their interplay with respect to intrauterine infection. For example, the number of organisms reaching the amniotic fluid may be increased by various modes, namely maternal viremia or bacteremia; premature rupture of the fetal membranes, antenatal vaginal examination and possibly intrauterine fetal monitoring. While these circumstances may result in increased rate of infection, some reports conversely indicate that minimal bacterial contamination in the amniotic fluid is not an extraordinary occurrence and may not result in any maternal or fetal complication (73,74). The intrinsic host resistance capacity of the amniotic fluid likewise represents an important part of the Smith equation for disease. We have found that amniotic fluids may vary in antibacterial efficacy from almost no inhibitory activity to profound bactericidal activity (90). Obviously, the likelihood of the production of disease by an equivalent inoculum of a particular organism would be quite different depending upon the intrinsic inhibitory capacity of the amniotic fluid. The measurement of the inhibitory capacity of amniotic fluid holds some promise for enabling a physician to determine which patients may be at special risk of intrauterine infection.

Prostaglandin F2alpha (PGF2alpha) was injected intraamniotically in 122 patients between 14 and 20 weeks' gestation in the dosage schedule recommended by the drug manufacturer to induce abortion. Significantly more multiparous (47.5%) than primagravida patients (21.5%) aborted within 16 hours, but the mean duration between PGF2alpha injection and abortion was not significantly different. Complications occurred in 52 (42.6%) patients and included: fall in hematocrit of more than 5 percentage points, failure to abort within 48 hours after injection, infection requiring antibiotic therapy, cervical laceration or fistula, and uterine rupture. The atypical dilatation and effacement of the cervix occurring with PGF2alpha-induced contractions may possibly lead to cervical incompetence with later pregnancies. Although the efficacy of PGF2alpha as an abortifacient is confirmed, the large complication rate with the procedure cannot be ignored.

The purpose of this investigation was to determine whether the oxytocin challenge test (OCT) could serve as the primary method for managing pregnancies characterized by possible placental insufficiency. One hundred and five patients underwent 225 oxytocin challenge tests; no perinatal deaths occurred. Eight tests were positive, 21 suspicious, and 196 negative. Because of data obtained in a preliminary study, all 8 fetuses with positive tests were delivered by cesarean section. Four of the 8 had repetitive suspicious tests prior to a positive test, suggesting that utero-placental function may deteriorate gradually. Urinary excretion of estriol did not decrease significantly in any patient, suggesting that the OCT is a more sensitive indicator of placental function than excretion of estriol. Except for patients with preeclampsia who were induced for maternal indications, all pregnancies with a negative OCT were allowed to terminate spontaneously. Five of the 97 fetuses with negative tests developed late-onset deceleration patterns during labor. This indicates that a negative OCT will not necessarily predict fetal tolerance to labor, contrary to assertions made by some other investigators. It is concluded that the OCT can serve as the primary method for assessing the fetal status in pregnancies characterized by placental insufficiency.

The maternal febrile morbidity for 793 patients undergoing cesarean section was analyzed. The influence of length of labor, duration of ruptured membranes, and fetal heart rate monitoring was studied in both clinic and private patients. Morbidity among private patients was found to be consistently higher in monitored patients with comparable lengths of labor and durations of membrane rupture. The number of vaginal examinations, duration of monitoring, or number of fetal scalp electrode applications did not effect morbidity outcome.

Total maternal plasma cortisol levels were measured by a radioassay method in 9 patients who were in spontaneous labor and 10 patients who were electively induced at term with oxytocin. Determinations were made at onset of labor and repeated at full cervical dilatation. Total maternal plasma cortisol levels were also measured in 7 patients undergoing elective cesarean section without labor, determinations being made just prior to the procedure and at the time of uterine incision. Computerized analysis showed the mean initial cortisol level (+/- SE) in the spontaneous labor group (15.4 +/- 1.6 mug/100 ml) to be significantly less than the mean initial level of the group electively delivered by oxytocin induction (37.2 +/- 6 mug/100 ml), with P less than 0.01. The former value was also found to be significantly less than that of the group electively delivered by cesarean section (32.1 +/- 9.3 mug/100 ml), with P less than 0.05. A significant rise was noted at full cervical dilatation in the spontaneous labor group (P less than 0.05), whereas no change occurred in the two elective groups. No significant correlation was found between the maternal cortisol levels on the one hand and the cord cortisol levels. These findings indicate that a) maternal participation is unlikely in bringing about a surge of fetal plasma cortisol which is thought to precede spontaneous labor, b) elective termination of term pregnancy by oxytocin induction or cesarean section may be initially more stress-provoking to the mother than spontaneous labor, and c) maternal stress as measured by plasma cortisol level is not reflected in the fetus.

Radioimmunoassayable plasma oxytocin (OT) has been measured in maternal and fetal blood. Simultaneous samples were obtained in maternal forearm venous blood and in umbilical venous and arterial blood in 29 patients at term delivery. In addition, maternal forearm venous blood samples were also obtained 10 minutes prior to delivery. Mean OT level in maternal plasma at delivery was 82 +/- 12 muU/ml, and at 10 minutes prior to delivery the mean OT level was 90 +/- 11 muU/ml. The umbilical arterial plasma OT showed 95 +/- 12 muU/ml and the umbilical vein plasma OT was 60 +/- 10 muU/ml. Oxytocin levels higher in maternal blood than in fetal blood were found with the following incidence: In 51% of samples there was more OT in maternal venous blood than in umbilical arterial blood, and in 84% of samples there was more OT in maternal blood than umbilical vein blood. During the postpartum period, the mean maternal plasma OT was 66 +/- 8 muU/ml for the first day, and 50 +/- 9 muU/ml and 54 +/- 9 muU/ml for the second and third days, respectively. This study indicates that both the fetus and the mother are active producers of oxytocin.

Abdominal surgery (unrelated to delivery) during pregnancy is not common. Review of a recent 17-year experience at our institution revealed 112 surgical procedures among 25,189 deliveries--an incidence of 0.44% (1 case for every 225 deliveries). Progestational agents have been used prophylactically in such procedures, but few studies have adequately assessed the effectiveness of these drugs to prevent onset of premature labor. The present study involved 35 gravid patients who had been treated with various doses of hydroxyprogesterone caproate before and after operations unrelated to delivery. These 35 patients were matched with 35 gravid control patients who had undergone similar operations but who had not received progestational compounds. Analysis revealed no significant difference in the abortion rate between these two groups.

During the 17 years 1955 through 1971, 20 gravid patients underwent cholecystectomy. This represented 1 case for every 1259 deliveries (0.079% of 25,189 deliveries). The primary indication for surgery was repeated attacks of gallbladder colic. Generally, surgery was performed between the 10th and the 20th week of gestation. There was one spontaneous abortion; this occurred at 10 weeks of gestation, 42 days after surgery.

Previous investigators have demonstrated that 2.5 mg fo progesterone, administered intramuscularly to rabbits on the day of ovulation and the 2 preceding days (Days -2, -1, and 0) significantly and consistently accelerates ovum transport. In contrast, when given on the day of ovulation and the 2 following days (Days 0, +1, and +2), progesterone does not accelerate ovum transport. The experiments reported were designed to define more precisely the temporal relationships critical to progesterone-induced acceleration of tubal ovum transport. Our observations suggest 3 important conclusions: 1) Progesterone, when given at least 1 day, and not more than 2 days, prior to ovulation does induce accelerated ovum transport. 2) The progesterone responsive mechanism is dose dependent. 3) The acceleration is partially antagonized if progesterone treatment is begun 3 days prior to ovulation.

In a continuing oral contraceptive study of d-norgestrel, the 1,0-mg dose--the dose previously found to give the best cycle control--was administered cyclically on a "21-7 day" schedule to 284 women during 2650 cycles. None of the women conceived, and cycle control, though often altered, was generally acceptable. Side effects were minimal, and laboratory determinations performed prior to and during the administration of this agent revealed no clinically significant changes.

Plasma gonadotropin levels throughout the regular menstrual cycle in 10 Japanese women were measured daily using radioimmunoassay. At the peak of ovulation, mean FSH levels were 17.6 +/- 7.9 mlU/ml and mean LH levels were 75.2 +/- 26.0 mlU/ml. At midcycle, the mean gonadotropin levels were significantly lower in Japanese women than in Nigerian women who, as reported by Nylander (1973), had a high frequency of twinning. It is, therefore, suggested that the low frequency of dizygotic twinning in Japanese women might be related to their low output of gonadotropin.

Twelve women with congenital adrenal hyperplasia are reported. Initial diagnoses were made at ages ranging from 12 to 32, with epiphyseal fusion complete in all patients. During 6 to 10 years of corticosteroid therapy there occurred substantial reduction of hypertrichosis, disappearance of temporal recession, and decrease in eroticism. In 11 patients menstrual bleeding occurred within 4 months. Urinary excretion of total gonadotropins remained unchanged; total estrogens decreased slightly. By the end of followup, 7 patients with a mean age of 17 years had regular menses, 6 were ovulating, and 1 had a pregnancy. The other 5 patients, who continued to have irregular, anovulatory menstrual cycles, had a mean age of 28 years. The findings suggest that when excessive androgenization continues for a considerable period of time after puberty (as judged by bone age) noncyclic functioning of the gonadotropic mechanism is rendered irreversible.

Six cases of congenital vaginal atresia are described. Three of these patients had cryptomenorrhea while the other 3 had severe coital difficulties. Despite the fact that normal coitus was impossible in these 3 women, 2 of them achieved successful pregnancies and had to be delivered by emergency cesarean section followed by resection of the occluding membranes. The third patient (with dyspareunia) resorted to paraurethral coitus for more than 2 years before seeking advice. The management of vaginal atresia proved difficult because of the recurrence of stenosis at the site of the excised membrane. This was particularly marked in the young adolescent females not exposed to regular coitus. An operative method that could minimize this complication is discussed.

Cellular samples obtained by vaginal scrapings from 204 women exposed to diethylstilbestrol (DES) in utero were evaluated and compared with samples collected from a like number of controls. Several different sampling methods were evaluated. Vaginal scrapings contained columnar cells existing alone or in combination with squamous metaplastic cells and less frequently were characterized only by metaplastic cells. None of the control samples contained columnar cells and only 1 of 200 control samples contained metaplastic cells. The cellular findings in the offspring of women exposed to DES in utero varied in relation to age. Cellular abnormalities were demonstrated in 90.4% of women having scrapings of visible lesions and in 88.1% of women studied by 4-quadrant vaginal scrapings in the absence of clinical disease. Of 58 women with histopathologically proven adenosis, 57 (98.3%) had similar cellular abnormalities. Abnormalities were demonstrated in squamous epithelial cells of the vagina in 8 (3.9%) of the women exposed to DES in utero, and in 5 of these women there were similar changes in the uterine cervix. Only 2 (0.9%) of the women had cellular changes suggesting dysplasia of the vagina.

Over the past 10 years, it has been well established that Crohn's disease may involve any segment of the gastrointestinal tract from the mouth to the anus and may also cause destructive extraintestinal lesions. Extensive cutaneous ulceration has recently been recognized as one of the rare extraintestinal complications. A case of chronic vulvar ulceration due to Crohn's disease is reported. The clinical manifestations and management of such a lesion are discussed.

A retrospective study has been carried out on 25 patients treated at the University of Michigan Medical Center for carcinoma in situ of the vagina. Intraepithelial carcinoma of the vagina occurred as a primary entity, following treatment for preinvasive and invasive carcinoma of the cervix, and following hysterectomy for benign disease of the uterus. These patients were treated with either radium implantation or some form of surgery. Five patients had recurrences. These 5 were all subsequently retreated and are alive and without evidence of further recurrent neoplasm. This series of carcinoma in situ of the vagina is compared to other reported series. Emphasis is directed toward the need for continued use of Papanicolaou smear cytology tests in posthysterectomy patients, regardless of the reason for hysterectomy.

A case hydatidiform mole with coexistent living fetus is presented and the steps by which the diagnosis was reached are given prominence. The diagnosis in utero of an intact hydatidiform mole with associated fetus is extremely difficult, and the author thinks that the most useful diagnostic means for this rare situation is amniography.

The effects of tumor cells implanted into the brain of animals on survival rates and gross and microscopic brain changes have been ascertained. Walker carcinosarcoma 256 cell suspensions were injected at several brain sites in rats and leukemia L1210 and P388 and Ehrlich ascites tumor cells, intracerebrally into BDF1 mice. Such neoplasms provided for rapid and rather predictable growth increments. The survival rates were dependent on the number of cells introduced, those receiving the higher counts succumbing first. The brains of the animals revealed fairly discrete space-occupying lesions and neurological symptoms became apparent only hours before death due to intracranial pressure.

Fourteen long-term human malignant melanoma cell lines established from biopsy specimens, malignant effusions and the peripheral blood are reported. Methods of culture, heterologous transplantation studies and characterization of these cell lines are presented. Several of these cell lines have retained the ability to produce pigment over a period of years, permitting bioassays at a subcellular level. Studies of cell lines grown with and without tyrosine and some of the theoretical uses of human melanoma cell lines are presented.

The physician caring for the patient with rheumatoid arthritis should not look upon surgery as a last resort to be turned to when all else has failed and the situation is desperate. Surgical intervention may be important at any stage in the disease. Wrist fusion to obliterate pain and to restore a strong grip is advantageous whenever pain and instability compromise the function of that extremity. The knee with good painless flexion and extension cannot help but insure the patient's ability to get up and down from a chair. There are many goals that may be achieved through surgical intervention, and each of these should be considered and reviewed every time the physician sees the patient. Consider the benefits of prevention of disease progression, the stopping of bone resorption, the relief of pain, the restoration of motion, strength, and stability, and the preservation or restoration of the patient's confidence and determination to remain an independent member of society.

Reconstructive hand surgery is an established, proved, and effective method to correct deformities and increase function in rheumatoid patients. As more experience has been gathered, the indications for both arthrodesis and arthroplasty have been better established, and a better approach to reconstructive hand surgery has developed. In this discussion we have evaluated in detail the surgical treatment indicated for wrist, metacarpophalangeal joint, and thumb deformities. The treatment of swan-neck deformities and boutonniere deformities is discussed in other sections in this volume.