Effect of glucocorticoids on WBC counts in splenectomized renal transplant recipients. Change in peripheral blood WBC and differential cell count in response to oral glucocorticoids (steroids) was examined in 36 stable renal transplant patients receiving their usual steroid dose on a daily or alternate-day steroid schedule. Three hours following steroid therapy mean WBC count had increased significantly. Mean change in WBC count was +2,400 cells/cu mm with individual values ranging from -600 to +8,000/cu mm. No differences were observed between patients receiving daily or alternate-day regimens. Changes in WBC count were due almost entirely to an increase in segmented granulocytes and a decrease in lymphocytes. there was no correlation between dose of steroid and WBC responses. However, when retested, a given patient's WBC response to a given dose of steroid was reproducible. Differences between patients, with respect to WBC response to steroids, could not be explained by differences in azathioprine dose and was not related to initial WBC count hematocrit value, age, duration of transplant, or levels of serum creatinine, BUM, or serum phosphorus. Because of the clinical importance of the WBC count in the renal transplant recipient and the potential for large and unpredictable changes in WBC count in response to steroids, WBC and differential cell count should be obtained before the morning steroid dose.


Indirect immunofluorescense reaction in cysticercosis. The indirect immunofluorescence reaction (IIR) was used to investigate cysticercosis in the serum of 604 subjects; control group I, with 100 subjects gave the following results: 2 per cent positive, 3 per cent weak positive and 95 per cent negative. Group II had 35 cases of cysticercosis, showing 94.28 per cent positive, 5.71 per cent weak positive and 0 per cent negative. In group III, with 100 patients, other diseases were studied showing 5 per cent positive, 7 per cent weak positive and 88 per cent negative. Group IV, with 364 cases with possible cysticercosis, showed 48.90 per cent positive, 10.98 per cent weak positive and 40.10 per cent negative. In group V, five cases of Taenia saginata parasitosis were studied showing a weak positive reading.


Growth of host dependent Bdellovibrio in host cell free system. A particulate, subcellular fraction of Escherichia coli was shown to promote the growth of host dependent (H-D) Bdellovibrio in the absence of host cells. The growth promoting activity was enhanced by both cations and trypisn, and destroyed by pronase. During the axenic growth unipolar spheres appear in the elongating Bdellovibrio forms. Thymidine monophosphate was more readily incorporated than thymidine into the Bdellovibrio DNA during growth in the host free system.


Indomethacin in the treatment of primary dysmenorrhoea. The efficacy of indomethacin, a prostaglandin synthetase inhibitor, in severe dysmenorrhoea was established in a double-blind crossover study using aspirin and placebo as the control drugs. Forty-seven female undergraduates were treated twice with each of the three substances during six consecutive menstrual cycles. Good or moderate relief was achieved in 71% of the cycles treated with indomethacin, in 40% of those treated with aspirin and in 21% of those treated with the placebo. Dizziness and drowsiness were cited by 14 patients (30%) as side-effects of indomethacin, none of these patients discontinued the therapy because all obtained good or moderate relief from dysmenorrhoea. Indomethacin proved to be a valuable agent, and significantly better than aspirin in the treatment of dysmenorrhoea. It allowed many dysmenorrhoeic women to carry out their normal activities and work during the menstrual period.


Relationship of mastodynia with its endocrine environment and treatment in a double blind trial with lynestrenol. Serum analysis carried out about 7 days before menstruation in 33 patients with mastodynia and 20 controls confirmed that progesterone is frequently decreased and prolactinaemia increased in the patients with mastodynia compared with controls of the same age. In a double blind trial, administration of Lynestrenol to 47 patients with mastodynia (each of whom was given 10 mg per day from the 10th to the 24th day of the cycle) resulted in a significant improvement of this condition in 80% of the treated cases. The therapeutic failures may be explained by anomalies in the secretion of prolactin, and may possibly be linked to individual sensitivity factors.


Malakoplakia in ulcerative colitis.

Malakoplakia in ulcerative colitis. Classic malakoplakia was found in the colon of a patient with a 30-year history of proven ulcerative colitis. She had undergone total proctocolectomy after failure of medical treatment to control her illness. Immunoperoxidase studies showed immunoglobulins and muramidase within the malakoplakic histiocytes, and electron microscopy showed bacteria resembling Escherichia coli in the same cells. Immunologic studies on the patient showed an unusually high E coli antibody titer (1:512) in her serum and reduced numbers of circulating T-lymphocytes with reduced cytotoxic activity. This case shows the paradoxical rarity of malakoplakia in ulcerative colitis and reaffirms the presence of an immunologic defect that may be pathogenetically significant.


Disseminated petriellidosis (allescheriosis). Disseminated infection by Petriellidium (Allescheria) boydii occurred in an immunosuppressed renal allograft recipient. A probable airborne pulmonary infection underwent hematogenous spread to the brain, thyroid, and heart. The organism develops septate, branching hyphae in tissue and may be misdiagnosed as Aspergillus. The basic pathologic lesions are necrosis with a predominantly polymorphonuclear leukocytic reaction and abscess formation, and a mild granulomatous response with macrophages and multinucleated giant cells. A particular tropism for blood vessels was observed. The vascular organs, brain, and thyroid have been involved in all three disseminated cases reported thus far.


Right renal vein extension in cadaver kidney transplantation. Right renal vein extension by transverse closure of the transected inferior vena cava solves the problem of the short right renal vein in cadaver kidney transplantation.


Asymptomatic eyebrow mass. A rare presenting sign of malignant non-Hodgkin's lymphoma. A 60-year-old woman had a solitary mass in her left eyebrow that was first thought to be a dermoid cyst and following excision and histological examination was found to be a localized, malignant, non-Hodgkin's lymphoma of the mixed lymphocytic and histiocytic type. Subsequent lymphangiography after excisional biopsy of the left eyebrow mass demonstrated extensive para-aortic and inguinal lymph node involvement.


Wound excision to fascia in burn patients. All charts of burn patients admitted to the US Army Institute of Surgical Research over a four-year period were reviewed to determine the efficacy of excision of the burn wound to fascia as a therapeutic modality. Of 1,013 burn patients, 72 underwent this procedure. The patients who had excisions had a mean total burn size of 52% of body surface area (BSA) and a mean third-degree burn of 33%. We correlated survival with burn size, associated injuries, day of excision, wound coverage, and sepsis. Survival in the group who had excisions (57%) did not differ substantially from that of the other patients (38%) when broken down by burn size. Careful selection of patients for this procedure and criteria for selection are stressed.


[Comparative studies of the response of normolipemic and dyslipemic aged subjects to 2 forms of delayed-action nicotinic acid polyesters. Pentaerythrotol tetranicotinate and inositol hexanicotinate. Results of a controlled cross-over trial]. A cross-over trial was run to compare the effects of two delayed-action nicotinic acid polyesters (pentaerythritol-tetranticotinate, PETN, and inositol-hexanicotinate, MIEN) in 59 aged normo- and dyslipaemic subjects. PETN tended to normalise the lipid picture in much the same way as nicotin acid, without a drastic effect on circulating lipids and lipoproteins. MIEN, on the other hand, had only a slight effect on total blood lipids, and appeared to be ineffective or negative with respect to the other lipid parameters. PETN proved capable of releasing active concentrations of nicotinic acid in vivo for a period of time that was sufficient to correct hyperlipaemia in age subjects. The side-effects were slight, infrequent and quickly reversible.


[beta-cell pancreatic hyperplasia. Considerations on a clinical case]. Differential haematological and instrumental examinations (OGTT, protracted fasting, i.v. tolbutamide, blood insulin, pancreatic scintiscanning, oesophagogastroduodenoscopy, panoramic abdominal arteriography, and selective arteriography of the coeliac trunk), preceded subtotal pancreasectomy in a severe case of hypoglycaemia attributable to organic hyperinsulinism. Epstein's method was used to extract insulin from the pancreatic tissue for radioimmunological assay.


Chronic upper extremity arterial insufficiency. Etiology, manifestations, and operative management. Forty-eight arterial reconstructions were performed for chronic upper extremity ischemia in 43 patients, aged 31 to 81 years. Diagnostic arterial catheterization was the most frequent cause of symptomatic occlusion, followed by proximal arteriosclerotic lesions and noniatrogenic trauma. Doppler ultrasound evaluation provided important diagnostic and prognostic data that complemented information derived from arteriography. Indications for operation included disabling claudication (39 cases) or digital gangrene (four cases). Restoration of normal extremity function can be anticipated except in instances where poor forearm runoff exists. Autogenous saphenous and basilic interposition vein grafts have proved excellent for axillary-brachial revascularizations. Axillary-axillary bypass procedures for innominate-subclavian artery occlusions appear hemodynamically sound and technically simple. Follow-up, averaging 48 months, extended to 144 months. Late vein graft failure or progressive distal occlusive disease was not encountered.


Use of synthetic absorbable sutures for abdominal and chest wound closure. Experience with 650 consecutive cases. The advent of synthetic collagen suture (polyglycolic acid and polyglacin 910) has provided a new dimension in surgical suturing. However, surgeons in general have not yet taken full advantage of the potential that this new material offers. Associated evisceration and wound dehiscence rates as well as the incidence rate of wound infection were assessed since these represent standards by which the suture material can be evaluated. In an entire series of 650 cases, there has been one case of wound dehiscence with evisceration. The incidence of infection has been less than 1%, which is comparable to previous experience with interrupted, nonabsorbable sutures. The time required for closure using the new material has been approximately one third of that associated with the use of conventional interrupted closure sutures. This implies a substantial cost reduction for the patient. As a result of this experience, the synthetic absorbable sutures seem to represent the material of choice for routine abdominal or chest wound closure.


Mechanisms of bacterial mutagenesis and properties of mutagenesis tester strains. Bacterial tester strains are available which can detect base pair substitution, frameshift and deletion mutations. I consider possible mechanisms for these types of event. I describe the four main types of DNA repair process operating in Escherichia coli and Salmonella typhimurium and how they may influence mutation: Means of modifying repair processes to increase the sensitivity of tester strains are discussed. The properties of some current strains are briefly described. I comment adversely on forward mutation systems and discuss aspects of the strategy and methodology of mutagenicity testing with bacteria.


Pituitary adenomas and dyspituitarism.

Pituitary adenomas and dyspituitarism. Recent studies of the structure and function of pituitary adenomas reveal that the majority are functional and that the commonest type is a prolactin secreting adenoma. Studies of hypothalamic-pituitary function provide evidence to suggest that the adenoma develops following prolonged hypothalamic stimulation of the pituitary gland, and that the clinical dyspituitarism is due to the hypothalamic-pituitary dysfunction and not to pituitary destruction by the adenoma. Pituitary adenomas may be classified into those due to a basic neuroendocrine dysfunction (prolactin secreting, acromegaly, Cushing's disease) and those arising secondary to end-organ failure (TSH and FSH secreting). The former group have APUD characteristics and may form part of a pluriglandular syndrome of apudomas. The persistence of a basic neuroendocrine dysfunction following the surgical removal of an adenoma explains the frequent recurrence of symptoms in patients and indicates a need for continued surveillance and long-term therapy.


The application of clinical trials to solid tumour management: an introduction. This paper discusses the relevance of clinical trials to the management of solid tumours. It introduces the types of clinical trials, the requirements for patient assessment, and an overall strategy for importance of statistical and ethical considerations is discussed. There is an invitation for practising surgeons to participate in trials relevant to their speciality. The necessay framework and requirements for a clinical protocol are discussed separately in the following paper.


Bilateral renal artery aneurysms: in-situ and extracorporeal repair. Renal artery aneurysms are uncommon, but when they do occur they are frequently associated with hypertension which may be amenable to surgery. Complex arterial abnormalities which formerly would have been treated by nephrectomy may now be reconstructed with preservation of the kidney. This is illustrated by a patient with renovascular hypertension and bilateral renal artery aneurysms, in whom arteriography and renal vein renin ratios were used as a guide to surgery performed in two stages. An in-situ repair was performed on one side. On the other side, where the aneurysm involved the three main branches of the renal artery, an extracorporeal repair was performed using continuous cold perfusion, substitution of the pathological segment with the patient's internal iliac artery, and autotransplantation to the iliac fossa. Both kidneys were retained and the hypertension was cured.


Occupational hazards of missile operations with special regard to the hydrazine propellants. The second generation of ballistic missiles and boosters, characterized by increased range and quick reaction capability, required the development of new high-energy storage propellants. This exploration led to the introduction of hydrazine (Hz), monomethylhydrazine (MMH), and 1,1-dimethylhydrazine (UDMH) into the USAF inventory. These compounds are all storable, noncryogenic, high-energy fuels which may be used alone or in combination as mixed amine fuels. Early toxicology experiments were to produce data on acute and subacute effects of the propellants in order to set standards for test and operational procedures to protect propellant handlers. The early work indicated that, despite similar chemical characteristics, there were marked differences between the compounds in terms of toxicological mechanisms. Since the propellant systems have been used for some 15 years, recent emphasis on toxicology has been centered on the more chronic effects and on an increasing body of evidence from animal experiments that the compounds may possess oncogenic potential as well as chronic systemic effects. This paper addresses itself to data leading up to current occupational standards.


Explosive decompression of subjects up to a 20,000-m altitude using a two-pressure flying suit. The RSAF two-pressure flying suit system to protect the pilot at high altitude has been tested from different medical safety aspects. To secure adequate alveolar oxygen pressure, the suit admits up to 70 mm Hg (9.3 kPa) positive pressure breathing by counter-pressure against the thorax and by a 3.2 times higher pressure in the anti-G suit. After 1 h of oxygen breathing, subjects were exposed to explosive decompression from an altitude of 9,000 m to 17,500 or 20,000 m in 0.5 s in a hypobaric chamber. No symptoms of decompression sickness or of alveolar rupture with gas embolism to the central nervous system were seen. Pulmonary X-rays after the test did not reveal any signs of lung rupture with extrapulmonary gas leakage. With the precordial Doppler ultrasound technique, intracardial gas bubbles (silent bubbles) could be detected only in one subject after explosive decompression to a 20,000-m altitude in the 10 experiments.


An early behavioral description of a person with Turner's syndrome. A person with Turner's syndrome was described by Dr. Charles Pears in the Philosophical Transactions of the Royal Society, London, in 1805. The description included behavioral traits of mild temperament, absence of heterosexual interests, and concern about social stigmatization. These traits are the object of current behavior genetic studies of persons with Turner's syndrome.


Studies on sex-organ development. Changes in chromatin structure during spermatogenesis in maturing rooster testis as demonstrated by the initiation pattern of ribonucleic acid synthesis in vitro. To probe the structural change in the genome of the differentiating germ cell of the maturing rooster testis, the chromatin from nuclei at various stages of differentiation were transcribed with prokaryotic RNA polymerase from Escherichia coli or with eukaryotic RNA polymerase II from wheat germ. The transcription was performed under conditions of blockage of RNA chain reinitiation in vitro with rifampicin or rifampicin AF/013. With the E. coli enzyme, the changes in (1) the titration curve for the enzyme-chromatin interaction, (2) the number of initiation sites, (3) the rate of elongation of RNA chains, and (4) the kinetics of the formation of stable initiation complexes revealed the unmasking of DNA in elongated spermatids and the masking of DNA in spermatozoa. In both cases the stability of the DNA duplex in the initiation region for RNA synthesis greatly increased. In contrast with the E. coli enzyme, the wheat-germ RNA polymerase II was relatively inefficient at transcribing chromatin of elongated spermatids. Such behaviour can be predicted if unmasked double-stranded DNA is present in elongated spermatids.


[Measurement of cerebral blood flow with hydrogen clearance method: technique and a comparative study with the venous out flow method (author's transl)]. Local cerebral blood flow was measured with hydrogen clearance method in fifteen dogs and compared to direct measurement obtained by Michenfelder's venous out flow method. The sagittal sinus was exposed by a midline frontooccipital incision and extensive craniectomy. A tappered catheter was passed in to the superior sagittal. sinus. For measuring hydrogen clearance, platinum wire electrodes with a red tip of 0.5 mm in length and 0.3 mm in diameter were introduced into the parietal and occipital cortex. About ten percent hydrogen gas was given directly into the endotracheal tube for three to five minutes and the obtained clearance curves were transferred to semilog graph papers. Total cerebral blood flow was caliculated by bicompartmental analysis and compared to the two minutes initial slop index. The results are as follows. 1) A linear regression analysis of flows caliculated from the initial slope and bicompartmental analysis shows a high correlation coefficient. 2) There is a high correlation between flows caliculated from electrodes used at the same experiments. 3) Cerebral blood flow from the initial slope measured by hydrogen clearance method shows a high correlation wit flows caliculated from Michenfelder's venous out flow method.


Membrane fluidity, capping of cell-surface antigens and immune response in mouse leukaemia cells. Transplantation of primary GRSL cells in the ascitic form led to a decrease in membrane microviscosity as measured by the fluorescence polarization technique. The transplanted GRSL ascitic cells showed a markedly lower ability to form caps with respect to both virus-related (MLr, GIX) and normal (H-2.7(G), H-2.8(K) and TL1.2) cell-surface antigens and their appropriate antisera in the indirect membrane immunofluorescence tests, than did primary GRSL cells, transplanted GRSL cells growing in solid form, and thymocytes, which all exhibited significantly higher membrane microviscosities. Transplantation of primary GRSL cells into syngeneic mice pre-irradiated with 400 rad did not lead to a fall in membrane microviscosity. It is suggested that the host immune response in intact mice leads to a selective survival of ascitic tumour cells with low membrane microviscosity.


A model of salmonella enteritis: the behaviour of Salmonella enteritidis in chick intestine studies by light and electron microscopy. Salmonella enteritidis was injected into isolated "loops" of duodenum, midgut and ileocaeca in anaesthetized 1-day-old chicks. Using light microscopy with conventional staining and fluorescent antibody techniques, the organism were observed in increasing numbers in the epithelium and lamina propria of each region between 2 and 12 h after inoculation. The potential ability of the salmonellas to enter the mucosa at any level of the intestine was thus demonstrated. The penetration of caecal epithelium by the organisms was studied by electron-microscopy. Uptake of salmonellas was associated with evaginations which formed at the luminal surface of the epithelium. In the epithelial cells, the bacteria were enclosed within membrane-bound vacuoles and appeared undamaged by intracellular passage. Surface evaginations almost completely replaced the brush border in regions where large numbers of the organisms were involved. Occasional salmonellas were found in the lamina propria both free and intracellularly. Results of culture and light microscopy following oral and intracloacal inoculation are also presented.


Observations on the in vivo reaction of antinuclear antibodies with epidermal cells. In evaluating the normal skin of five patients with mixed connective tissue disease, four patients were noted to have both basement membrane zone and speckled epidermal nuclear immunofluorescence. The positive epidermal nuclear reaction was found to be associated with IgG, and no evidence of complement involvement was seen. In vitro testing demonstrated that normal control skin incubated with high-titred antisera to nuclear ribonucleoprotein reporduced the findings observed in direct staining, but incubation with high-titred antisera to other nuclear antigens such as Sm and single-stranded deoxyribonucleic acid did not cause positive epidermal nuclear staining. The association of antibodies to ribonucleoprotein and speckled epidermal nuclear immunofluorescence is discussed. Also considered is the possibility of other factors affecting nuclear membrane permeability.


Mycophenolic acid in psoriasis.

Mycophenolic acid in psoriasis. Mycophenolic acid (MPA) is a fermentation product of a penicillium mould which has shown antitumour acitivity in certain animal models. It blocks nucleic acid synthesis by interfering with the interconversions of inosine monophosphate (IMP), xanthine monophosphate (XMP) and guanine monophosphate (GMP) thereby inhibiting growth and/or replication of tumour cells. In vivo activity depends on the presence of a beta-glucuronidase which is abundant in the cell wall of epithelial tissues. Encouraged by results obtained in earlier clinical trials, we have studied 28 patients with psoriasis, 21 in double-blind fashion. A comparison of disease severity in patients before and after receiving MPA versus patients receiving placebo clearly showed the superiority of drug over placebo. The mean severity score of patients receiving MPA as an initial course of therapy improved by 56% versus 9% in patients receiving placebo. Patients receiving MPA after an initial course of placebo therapy showed improvement in their mean severity score averaging 86%. Those patients receiving placebo after an initial course of MPA showed worsening of their mean severity score averaging 70%. Overall, about 75% of MPA treated patients have shown good to excellent responses, and toxicity appears low. Evidence suggests that MPA may be very useful in treating severe psoriasis.


Calcium-induced damage of haemoglobin SS and normal erythrocytes. An ionophore specific for divalent cations has been used to load normal erythrocytes and erythrocytes from patients with sickle cell anaemia (Hb SS disease), with small amounts of calcium. Such calcium accumulation leads to decreased cellular water, potassium, adenosine triphosphate (ATP), and osmotic fragility, all characteristics of irreversibly sickled cells (ISCs). In addition, calcium loading of Hb SS, but not normal, erythrocytes causes a marked decrease of haemoglobin oxygen affinity; another, and specific, hallmark of ISCs. Ionophore-induced accumulation of calcium by deoxygenated Hb SS erythrocytes also leads to temporary retention of sickled shape following reoxygenation, despite the absence of detectable intracellular haemoglobin S fibres. All these effects require calcium in the incubation medium and support the idea that increased intracellular calcium is important in the formation of ISCs in patients with Hb SS disease.


Lack of effect of prednisone administration on bleeding time and platelet function of normal subjects. The effect of 80 mg prednisone given orally for 2 d on normal and post-aspirin bleeding times and platelet function has been studied in a randomized, multiple cross-over, double-blind controlled trial in 12 normal volunteers. Mean template bleeding times were 6.6 min (placebo/placebo), 5.9 min (prednisone/placebo), 10.0 min (placebo/aspirin) and 8.7 min (prednisone/aspirin). The shortening after prednisone administration was not statistically significant. Prednisone had no effect on platelet glass bead retention nor on platelet aggregation by collagen, adrenalin and adenosine diphosphate. Thus conventional clinical doses of prednisone did not impair platelet function and did not enhance primary haemostatis in normal subjects as measured by the bleeding time.


A new system of microsurgery for human and experimental corneal graftin. I. The contact lens corneal cutter, stereotaxic eye holder, donor disc chuck, and frame. A new microsurgical system is presented for human and experimental corneal grafting. The system is based on novel methods of corneal cutting and holding which simplify collection procedures and minimise operator manipulation during transplantation.


A new system of microsurgery for human and experimental corneal grafting. II. Clinical and experimental applications. After preliminary testing with pig, dog, rabbit, monkey, cat, and human cadaver eyes the CLCC system has been used for penetrating and lamellar keratoplasty in human subjects. Clinical experience covers a broad range of corneal pathology. Detailed operative instructions and observations are given. In the experimental situation the CLCC is being used to achieve deep lamellar corneal dissection for a continuing study of non-penetrating keratoplasty.


Mastering the donor eye: a new device for obtaining donor corneal discs. In recognition of the many inexactitudes involved in cutting donor corneal discs, a new instrument is here described which should help to eliminate many of then, and its mode of use is outlined. For a long time instruments available to assist the corneal surgeon in his management of donor material have been inadequate. Many devices are awkward to use, or give rise to donor discs of an unreliable or uneven edge profile. In an attempt to overcome these difficulties we have designed, produced and tested a new instrument which we feel represents an advance. Because different surgeons use fresh or stored material, and because some prefer to trephine from the epithelial surface while others opt to punch from the endothelium, we have endeavoured to meet all these requirements.


The binding of lipopolysaccharide from Escherichia coli to mammalian cell membranes and its effect on liposomes. The kinetics of the absorption of 32P- or 14C-labelled lipopolysaccharide from Escherichia coli NCTC 8623, serotype 0 125, chemotype XII, to erythrocytes, leukocytes, peritoneal macrophages and peritoneal lymphocytes was examined. Under variable conditions maximal levels of binding were found due to saturation of receptor sites on the cell membrane or steric hindrance by bound lipopolysaccharide. During adsorption slight leakage of haemoglobin was found but complete lysis of erythrocytes was ruled out after noting the effect of lipopolysaccharide on artificial lipid bilayers. The affinit of lipopolysaccharide to cell membranes revealed a consistent pattern of cyclic fluctuation between adsorption and desorption. A model was proposed to explain this cyclic fluctuation in binding based on membrane reorganization. It was significant that the cycle of lipopolysaccharide adsorption-desorption proceeded to completion even if the process was interrupted. The indication was that, once triggered, membrane reorganization occurred independently without influence from the test environment.


Preferential release of new outer membrane fragments by exponentially growing Escherichia coli. We have examined whether the outer membrane fragments released by normally growing Escherichia coli contain relatively old or new outer membrane. Double-label experiments show that after incorporation of radioactive leucine into E. coli protein, there is a preferential release of outer membrane material which contains a high percentage of newly labeled protein. This implies that outer membrane fragments are preferentially released from those regions where newly synthesized proteins are inserted into the outer membrane. We estimate that these insertion regions cover no more than 13% of the total outer membrane, and that newly inserted proteins diffuse in the plane of the outer membrane with a diffusion constant less than or equal to 5.10(-13) cm2/s.


The effect of osmotic shock on the accessibility of the murein layer of exponentially growing Escherichia coli to lysozyme. The restricted access of lysozyme to the murein layer of exponential phase Escherichia coli is enhanced considerably by osmotic shock. When cells suspended in Tris/EDTA/sucrose are diluted 11-fold in water or 10 mM EDTA in the presence of lysozyme, their susceptibility to lysozyme increases by a factor of 50--100, for both Escherichia coli JC411 and W3110, grown to the early exponential phase in unsuppleneted or supplemented minimal media, and in Brain Heart Infusion. Since an 11-fold dilution causes lysis of lysozyme spheroplasts, the effects of  a 2-fold dilution have also been investigated. A 2-fold dilution of cell suspended in TrisEDTA/sucrose still increases their susceptibility to lysozyme by a factor of 10--50, but the resulting spheroplasts remain intact. EDTA is necessary to permit lysozyme access to the murein layer during the dilution, which is ineffective in the presence of 5 mM MgCl2. These results are discussed in terms of the formation of lysozyme spheroplasts from young Escherichia coli.


Phosphate transport in membrane vesicles from Escherichia coli. Escherichia coli strain AN710 possesses only the PIT system for phosphate transport. Membrane vesicles from this strain, which contain phosphate internally, perform exchange and active transport of phosphate. The energy for active transport is supplied by the respiratory chain with ascorbate phenazine methosulphate as electron donor. To a lesser extent also the oxidation of D-lactate energizes phosphate transport; the oxidation of succinate is only marginally effective. Phosphate transport is driven by the proton-motive force and in particular by the pH gradient across the membrane. This view is supported by the observation that phosphate transport is stimulated by valinomycin, inhibited by nigericin and abolished by the uncoupler carbonyl cyanide m-chlorophenylhydrazone. Neither inhibitor affects phosphate exchange. The phosphate analogue arsenate inhibits both the exchange reaction and active transport. Both processes are stimulated by K+ and Mg2+, the highest activities being observed with both ions present. Membrane vesicles have also been isolated from Escherichia coli K10, a strain which possesses only a functional PST phosphate transport system. These vesicles perform neither exchange nor active transport of phosphate, although active transport of amino acids is observed in the presence of ascorbate-phenazine methosulphate or D-lactate.


Quantitative aspects of free and esterified sterols in Saccharomyces cerevisiae under various conditions. For extraction of free and esterified sterols from yeast cells, a method was devised in which both forms of sterols were extracted with light petroleum after the treatment of the cells with acetone, and then with dimethylsulfoxide. The content of sterol esters in the cells under aerobic conditions markedly increased with time, amounting to 95% of the total sterols under some conditions. However, the formed sterol esters were decreased, accompanied with an increase of free sterols, when the cells were put under anaerobic conditions. Variations of radioactivities of both sterols which had been labeled in the side chain by incubation of the cells with [Me[-14C]methionine were examined on the cells grown under various conditions. No variation was observed on the cells under aerobic conditions. On the other hand, the labeled esters were hydrolyzed to yield free sterols in the cells under anaerobic conditions. In the cells under aerobic conditions, the free sterols were found to consist mainly of ergosterol, whereas the esterified sterols contained considerable amounts of zymosterol, lanosterol, and other intermediate sterols besides ergosterol.


Regional differences in prostacyclin formation by the kidney. Prostacyclin is a major prostaglandin of renal cortex. Microsomes prepared from rabbit renal cortex were found to synthesize substantial amounts of 6-ketoprostaglandin F1alpha from prostaglandin G2 or arachidonic acid during an incubation. In contrast, no 6-ketoprostaglandin F1alpha was formed by renal medullary microsomes which synthesize predominantly prostaglandin E2. Mass spectral confirmation of the structure of 6-ketoprostaglandin F1alpha from these incubations demonstrates the ability of the renal cortex to synthesize prostacyclin.


Disaccharidase and lysosomal enzyme activities in amniotic fluid, intestinal mucosa and meconium. Correlation between morphology and disaccharidase activities in human fetal small intestine. Brush border membrane bound disaccharidases (sucrase and maltase) and lysosomal enzyme (alpha-glucosidase, beta-D-fucosidase and N-acetyl-beta-glucosaminidase) activities awere studied in amniotic fluid (AF). The above enzymes except N-acetyl-beta-glucosaminidase showed a decrease in activity with gestational age beginning at about the 19th week. The activities of sucrase and maltase correlate with the morphological maturation of fetal intestinal mucosa. The distribution of disaccharidases and lysosomal alpha-glucosidase in AF and intestinal mucosa showed different patterns suggesting that these enzymes originate in diverse fetal tissues.


Effect of luteinizing hormone (LH) and LH-releasing hormone (LHRH) on testosterone production in vivo, in fetal rabbit testis in late gestation. Plasma and tesicular testosterone were measured by radioimmunoassay in the 29-day-old rabbit fetus receiving an injection of saline solution, LH or LHRH. 30 min following the injection of 5 microgram LH into the umbilical vein, testosterone levels were significantly increased by 287% in the plasma and 293% in the testis, compared with controls receiving saline solution. The injection of 2 microgram of LHRH under the same conditions significantly increased testicular testosterone by 256% and plasma testosterone by 746%. The results show that the fetal rabbit testis, at the end of gestation, is capable of responding to LH stimulation. The hypophysio-testicular axis is apparently functional at this stage of gestation, as shown by the response to LHRH.


A model for traveling bands of chemotactic bacteria. A theoretical model is used to study band formation by chemotactic populations of Escherichia coli. The model includes the bacterial response to attractant gradients, the chemotactic sensitivity of the bacteria to the concentration of the attractant, and population growth. For certain values of the parameters in the model, traveling bands of bacteria form and propagate with or without growth. Under specific growth conditions the band profile is maintained and the band propagates at constant speed. These predictions are in general agreement with the experiment results of J. Adler and earlier theoretical work by L. Segel and his collaborators. However, our theory differs in several important respects from the latter efforts. Suggestions are made for further experiments to test the proposed model and to clarify the nature of the processes which lead to band formation.


The measurement of bacterial translation by photon correlation spectroscopy. Photon correlation spectroscopy is shown to be a practical technique for the accurate determination of translational speeds of bacteria. Though other attempts have been made to use light scattering as a probe of various aspects of bacterial motility, no other comprehensive studies to establish firmly the basic capabilities and limitations of the technique have been published. The intrinsic accuracy of the assay of translational speeds by photon correlation spectroscopy is investigated by analysis of synthetic autocorrelation data; consistently accurate estimates of the mean and second moment of the speed distribution can be calculated. Extensive analyses of experimental preparations of Salmonella typhimurium examine the possible sources of experimental difficulty with the assay. Cinematography confirms the bacterial speed estimates obtained by photon correlation techniques.


Environmental applications of mass spectrometry. The 1976 publications reporting organic and spark source mass spectrometric studies on environmental samples were compiled. Emphasis was placed on pollutants identified rather than methods and techniques used, and reports that did not incorporate data obtained by a technique's application were not included. The 349 reports cited vary from those reporting hundreds of identified pollutants to those describing the analysis of only one sample containing one or a few pollutants. The following sample types were not considered to be environment samples: forensic samples, synthetic or 'standards' samples, and samples analyzed for drug residues.


LETS glycoprotein: arrangement and function at the cell surface. LETS is a large surface glycoprotein that is found on normal fibroblasts, but is absent or exists in amounts on transformed cells. Immunofluorescent staining shows LETS protein fibrils arrayed around the cells, particularly concentrated beneath the cells and in the area between neighboring cells. LETS glycoprotein is disulfide-bonded at the cell surface into dimers and higher aggregates. Other surface proteins also appear to participate in disulfide bonding. Reduction of disulfide bonds leads to increased release of LETS protein from the cells, as does the addition of cytochalasin B. Purified LETS protein added to transformed cells binds to the cells in a fibrillar array similar to that seen on normal cells. Addition of LETS protein leads to increased attachment and spreading of cells and causes transformed cells to align like normal ones. It also causes the appearance of actin cables in transformed cells, which normally lack them. These effects are inhibited by specific antisera to LETS protein or by reduction of disulfide bonds in the protein and are blocked or reversed by proteolysis. The results suggest that LETS protein plays a role in adhesion of cells.


Platelet transfusion therapy. Optimal donor selection with a combination of lymphocytotoxicity and platelet fluorescence tests. Although the value of HLA matching for the selection of platelet donors for patients refractory to random platelets is beyond doubt, even perfectly matched combinations sometimes fail to give a satisfactory transfusion response. With HLA typing and negative lymphocytotoxicity crossmatches, 35% of the platelet transfusions administered to 15 patients gave disappointing results (29 of 82). Additional crossmatching with the newly developed platelet fluorescence test described in this paper reduced the unexpected transfusion failures to 7% (6 of 82). Five of these failures were observed in one patient. The target of the antibodies detected with this platelet fluorescence test is not yet fully specified. It seems probable that both HLA and platelet-specific non-HLA antibodies were detected. No correlation of the results of platelet transfusions with the presence or absence of leukoagglutinating antibodies was found.


B lymphocyte antigens in the differential diagnosis of human neoplasia. Human B lymphocyte antigens (HBLA) were detected with fluorescent-labeled antibodies on malignant cells of 102 patients with Hodgkin disease and other lymphomas, plasma cell myeloma, and nonlymphoreticular neoplasms including carcinomas of the breast, lung, and ovary, soft tissue sarcomas, and neuroblastoma. HBLA were present in Hodgkin disease and other lymphomas of B cell or histiocyte derivation. They were absent in plasma cell myeloma and nonlymphoreticular neoplasms. Absorption studies revealed that malignant T cells had smaller amounts of HBLA, usually not detected by immunofluorescence. Expression of HBLA was dependent on both cell differentiation and origin. Detection of HBLA enabled immunologic distinction of Reed-Sternberg and other lymphoma cells from morphologically similar cells of nonlymphoreticular origin. The rapidity, reproducibility, and economy of the immunofluorescence test make this a useful clinical tool for the differential diagnosis of lymphoma from other malignant disorders in man.


Ultrastructural features of the plasma cells in "non-secretory" myeloma. A case of "non-secretory" multiple myeloma is described. The diagnosis was based on the clinical picture, typical radiological findings, and infiltration of the bone marrow by myeloma cells which showed specific immunofluorescence staining mainly with antisera for IgM and kappa light chains. An attempt is made to explain the absence of pathological proteins in the serum, based on the ultrastructural findings of the myeloma cells, which showed "buddings" of the cell membranes containing endoplasmic reticulum and cytoplasmic material. It is suggested that the cells of the "non-secretory" type of multiple myeloma possess a normal excretory mechanism, but the pathological proteins are prevented to be secreted in the serum being surrounded by portions of the cell membrane.


Disseminated toxoplasmosis with brain involvement in a renal allograft recipient. A 47-year-old male with renal failure received a renal transplant which subsequently was rejected. After removal of the transplant the patient went into a catabolic state, and developed fever and hematochezia. The patient became septic, developed respiratory involvement. This is the eighth recorded case of central nervous system toxoplasmosis following renal transplantation.


Microvascular surgery in degloving injuries: an experimental study. Using an experimental model in the rabbit, the importance of direct cutaneous vessels for skin flap survival in skin avulsion injuries with, and without, a crushing injury has been investigated. The results are presented and possible application to the human situation discussed.


Free flap transfer in rabbits using irradiated recipient vessels. In rabbits free flaps anastomsed to irradiated vessels have about a 50:50 chance of survival.


Pre-auricular full-thickness skin grafts. The use of the pre-auricular region as a donor site for full-thickness skin grafts is described. It provides a valuable source of skin for the medial canthal-nose, eyelid-cheek areas, providing a good colour and texture match.


The reversed dermis flap.

The reversed dermis flap. The reversed dermis principle of Hynes has been applied to flaps. There are 2 main varieties: the direct bridge pedicle flap and the turn-over local flap but the same principle might occasionally be useful in free flaps.


The place of the cross-leg flap in reconstructive surgery of the lower leg and foot: a review of 165 cases. In a series of 165 cross-leg flaps, 94 per cent were successful. Some degree of necrosis occurred in almost half of them. Major necrosis requiring split-skin grafting occurred in less than one-fifth. Thrombo-embolic complications were rare and mainly in the older age group. The retunr of sensation was good; better in the flap than in the donor site. The long-term results were good with a low complication rate. On weight-bearing surfaces the cross-leg flap skin stands up well to wear and tear.


The appearances of renal transplant lymphocoeles during dynamic renal scintigraphy. Eight patients are described in whom transplant lymphocoeles were drained. All had 99Tcm-DTPA dynamic renal scintigrams performed pre-operatively; five showed features of obstruction. Photon deficient areas on the scintigrams and bladder deformities were of particular value in detecting lymphocoeles.


Prospective randomized multicentre trial of proximal gastric vagotomy or truncal vagotomy and antrectomy for chronic duodenal ulcer: interim results. In three centres, 222 patients (Birmingham 70, London 87 and Rotterdam 65 patients) with chronic duodenal ulcer were treated by proximal gastrict vagotomy (PGV)  (116 patients) or truncal vagotomy and antrectomy (TVA) (106 patients) in a prospective randomized trial. After 1 year 5 recurrent duodenal ulcers (4.3 per cent) have been recorded in the PGV group, compared with 1 (1 per cent) in the TVA group. The reoperation rate was high in both groups-6 after PGV, usually for recurrent ulcer, and 7 after TVA, mostly for gastric retention. PGV showed a marked superiority in the number of patients with a good clinical result Visick I or II) at 1 year after operation, i.e. 82 per cent compared with 56 per cent for TVA.


Morbidity and mortality in renal transplant patients after incidental surgery. Sixty-five further surgical procedures were carried out in 39 renal transplant patients without mortality and with low morbidity. There was a 9 per cent incidence of clean wound infection, and minor chest infection occurred in another 9 per cent. Stay in hospital for these procedures was not prolonged. The function of the transplanted kidney showed no deterioration after these further surgical procedures. The successfully transplanted patients is thus a good candidate for further surgery despite the previous renal failure and the continuing immunosuppressive therapy.


The use of bulk evacuant in patients with haemorrhoids. Fifty-three patients with symptomatic haemorrhoids have been studied in a double-blind cross-over trial of a bulk forming agent (ispaghula husk) against a placebo. Although only 11 per cent of patients ocmplained of constipation, a significant benefit in symptoms and improved bowel habit was demonstrated.


Pile suture: a new technique for the treatment of haemorrhoids. A new technique for the treatment of haemorrhoids, termed pile suture, is described. It appears to have significant advantages over conventional haemorrhoidectomy both in terms of incidence of complications and patient comfort.


Prolonged antifibrinolysis: an effective non-surgical treatment for ruptured intracranial aneurysms? The outcome of treatment with an antifibrinolytic agent (tranexamic acid) for six weeks after rupture of an intracranial aneurysm was assessed in a randomised controlled trial. Twenty-two out of 25 (88%) treated patients survived at follow-up of three to 33 months compared with 14 out of 25 (56%) control patients. Among the patients who did not undergo operation the survival rate was 81% (13 out of 16) in treated patients and 42% (8 out of 19) in controls. Antifibrinolytic treatment has so far been assumed merely to postpone rebleeding and has been used to enable surgery to be deferred. These findings suggest that tranexamic acid may actually prevent rebleeding without operation. Prolonged antifibrinolysis may therefore prove useful in those patients in good condition whose aneurysms do not lend themselves to surgical obliteration.


Prophylactic effect of cimetidine in duodenal ulcer disease. Fifty-seven symptom-free patients with duodenal ulcer entered a double-blind trial to assess the prophylactic  effect of cimetidine. Patients were randomly allocated to receive cimetidine 400 mg twice daily (29 patients) or placebo (28 patients). The trial was designed to imitate daily clinical practice, so duodenal ulcer disease was diagnosed by means of x-ray examination. Three patients from each group withdrew from the trial. All remaining patients continued to receive treatment for 12 months or until symptoms recurred. Three out of 26 patients suffered relapses during cimetidine treatment, compared with 20 out of 25 receiving placebo. No side effects were attributable to cimetidine. Long-term cimetidine treatment had no curative effect as relapses occurred soon after treatment was stopped. The estimated chance (cumulative remission rate +/- 2 SE) of remaining symptom-free 13 weeks after one year's cimetidine treatment had been completed was 47 +/- 21%. Maintenance treatment with cimetidine is a suitable alternative to elective in surgery in patients with duodenal ulcer subjects frequent relapses. Further study is needed to establish the optimal duration and safety of prolonged cimetidine treatment.


Serum ionised calcium concentration: measurement versus calculation. Four hundred and eighteen measurements of serum ionised calcium, total calcium, and protein concentrations were made from 47 normal volunteers, 104 patients with chronic renal failure (33 being treated conservatively and 71 with regular haemodialysis), and 83 renal transplant recipients. The serum ionised calcium concentration was measured with an Orion SS-20 meter and calculated from the total serum calcium and protein concentrations by using three formulae and a nomogram. In the normal subjects and patients undergoing regular haemodialysis, whose serum calcium concentrations were in or near the normal range, three of the calculations gave results similar to those obtained by direct measurement. In patients with conservatively treated chronic renal failure and those who had received renal transplants, however, there was poor aggrement between the methods. When patients with hypercalcaemia and hypocalcaemia from all the groups were considered separately there was again poor agreement between calculated and measured concentrations of serum ionised calcium. Of the patients whose measured concentrations of serum ionised calcium were high, 69-76% were classified as normal by the four indirect methods. We conclude that calculation of the serum ionised calcium concentrations is not an adequate substitute for direct measurement.


Pituitary-testicular interrelationships in mumps orchitis and other viral infections. Leydig-cell function was assessed in 27 men with acute mumps orchitis by measuring plasma testosterone concentrations before and after the administration of human chorionic gonadotrophin (HCG). The test was also performed on groups of patients with other febrile viral infections and mumps without orchitis and on healthy euspermic men. The concentrations both before and after HCG were significantly lower in patients in the acute phase of mumps-but not in those with other viral infections and mumps without orchitis-than in the healthy men. Basal concentrations of follicle-stimulating hormone (FSH) and luteinising hormone (LH) were significantly increased in patients with acute mumps orchitis, while an exaggerated response to LH-releasing hormone was noted in four patients after the acute phase of the disease. Raised plasma LH concentrations were also found in several patients with viral infections, including mumps without orchitis. There appeared to be no particular merit of any of the treatments used (aspirin, prednisolone, and cold baths). In patients reevaluated three to five and 10 to 12 months after the acute phase of their disease the basal testosterone concentrations were similar to those of the healthy men, but several of the patients showed a severely impaired response to HCG. Mean basal FSH and LH concentrations were significantly increased 10 to 12 months after the acute phase, while the mean LH concentration was also raised at three to five months.It is concluded that mumps orchitis impairs Leydigcell function during the acute phase of the disease but may also have a more permanent damaging effect, similar to that found in the germinal epithelium.


Diagnostic treatment and reporting criteria for gonorrhoea in sexually transmitted disease clinics in England and Wales. 1: Diagnosis. The current methods used in the diagnosis of gonorrhoea are reported. The sites sampled in symptomatic patients who were not gonorrhoea contacts and those sampled in symptomless contacts are described. Urethral specimens were taken routinely from all male heterosexual and active homosexual patients with a urethral discharge but in only 81% and 82% respectively of these patients if they were symptomless gonorrhoea contacts. Not all consultants would repeat investigations (smear and/or cultures) in gonorrhoea contacts if the initial ones were negative; heterosexual male and active homosexual patients were less likely to be seen again. Smears and cultures were performed routinely on women in 97% of clinics, but for men this was so in only 81% of clinics. The wider use of cultures for men, the policy with regard to the taking of urethral specimens from asymptomatic male heterosexual and active homosexual patients who are gonorrhoea contacts, and the number of diagnostic investigations required are discussed.


A trial of adenine arabinoside in genital herpes. Twenty-four episodes of genital herpes in 22 men, all confirmed by virus isolation, were studied in a double blind trial. They were treated either with 3% adenine arabinoside (Ara-A) in petrolatum ointment base or with the base alone applied four times daily for one week. The lesions were counted and sketeched on days 0, 2, and 7. There was no demonstrable advantage to be gained from the use of Ara-A ointment. The results of the Papanicolaou smears and virus isolation agreed in the diagnosis of 75% of cases. The presence of continuing lesions or fresh ones in some patients after the acute phase of the initial or recurrent attack of herpes necessitates the man taking precautions on resuming sexual intercourse.


A DNA endonuclease isolated from yeast nuclear extract. We have isolated and partially purified a DNA endonuclease from nuclei of the yeast Saccharomyces cerevisiae. Although purified on the basis of its ability to degrade denatured DNA, the enzyme can also attack native DNA. Denatured oligonucleotide products of the enzyme are sensitive to venom phosphodiesterase (EC3.1.4.1.) but not to bovine spleen phosphodiesterase (EC3.1.4.18). The enzyme has an estimated molecular weight of 6.6--7.5 X 10(4), more than twice as large as the endonucleases involved in DNA repair in Escherichia coli. When analyzed on glycerol gradients, the endonuclease sedimented as a single activity against both denatured DNA and closed circular DNA duplexes. The enzyme showed a 10-fold preference for denatured over native T7 DNA substrate, and appears to produce random nicks in a supercoiled replicative form of phiX174 DNA (RFI) with no discernable preference for the unpaired bases in the supercoiled duplex. The endonuclease appears to be distinct from the yeast endonucleases previously described.


Reversal of myocardial dysfunction in endotoxin shock with insulin. Recent data reported from this laboratory have documented myocardial functional depression in endotoxin shock. The purpose of the present study was to determine the effects of insulin on the dysfunctioning canine myocardium subjected to lethal endotoxin shock. Experiments were conducted on isolated working left ventricular preparations in which LD90-100 endotoxin was administered prior to, or following, isolation of the heart. Determinations of myocardial performance were conducted under the conditions of controlled mean aortic pressure and cardiac output. Myocardial dysfunction occurred between 2 and 6 h postendotoxin, as evidenced by significantly increased left ventricular end-diastolic pressure, decreased power, and depressed negative dP/dt, although blood glucose concentrations were maintained at control values. Intraatrial infusions of insulin at rates of 6 U/min reversed all signs of myocardial dysfunction. During insulin infusion, heart rates decreased (p less than 0.02) and myocardial lactate uptake increased (p less than 0.02), while oxygen uptake and coronary blood flow were insignificantly altered.


Chlamydiae, rickettsiae, and their cell wall defective variants. Inapparent chlamydial and rickettsial infections are an important source of the dissemination of the parasites and may cause explosive outbreaks of severe diseases in man and animal. However, it is engimatic how these obligate intracellular microbes induce latency and why or how inapparent infections convert into active disease. Currently, microbiologists believe that chlamydiae and rickettsiae are gram-negative bacteria unique in their intracellular habitat. This review presents evidence that these organisms have another peculiarity; namely, defective cell walls present throughout much of their life cycle. In this survey, the properties of the small and large forms of chlamydiae and rickettsiae are reexamined with regard to the current knowledge of cell wall defective variants of free-living bacteria. Data are presented in support of the concept that chlamydiae and rickettsiae are cell wall defective microbes whose small 'bacterial' forms have lost the ability to reproduce as bacteria during evolution; the large forms including ultrafilterable phases of the life cycle of these parasites are responsible for inapparent infections of healthy carriers, whereas conversion into small 'bacterial forms may cause, under appropriate conditions manifest diseases. This concept may provide challenging and profitable directions in the search to explain puzzling phenomena associated with chlamydiae and rickettsiae.


Inhibition of granulocyte phagocytosis of Candida albicans by amphotericin B. Phagocytic activity of PMN's in five healthy and five burned patients were measured in vitro. Addition of 1 microgram per millilitre of amphotericin B to the assay produced a marked inhibitory effect of the phagocytic activity of PMN against C. albicans.


Kinetic analysis of batch and continuous culture of Streptococcus cremoris HP1. The growth of Streptococcus cremoris on a semidefined medium was studied at initial lactose concentrations of 0.2-5.0% in batch culture, and in lactose-limited chemostat cultures at 0.5% lactose. Kinetic analysis of the batch data, using statisitcal techniques, indicated the importance of lactose limitation and lactic acid inhibition of the growth of S. cremoris. A model for the biomass production, lactose utilization, and lactic acid production in batch culture was proposed. In continuous culture, it was found that steady state populations were maintained at higher dilution rates (D = 0.6-0.7 h-1) than the maximum predicted by batch culture (0.56h-1). No evidence for a selection of fast growing mutants was obtained. Copious growth adhering to the walls of the fermentor (i.e. wall growth) occurred very rapidly at higher dilution rates and this undoubtedly affected steady-state growth and wash-out and, as a consequence, the apparent maximum dilution rate.


A method for the isolation of asporogenic mutants of Bacillus thuringiensis. Asporogenic and oligosporogenic mutants of Bacillus thuringiensis can be isolated by streaking the bacteria onto a solid medium, incubating at 42 degrees C, and picking small, raised areas of growth which appear on the streaks after 48 h.


Changes in tumor immunity during therapy determined by leukocyte adherence inhibition and dermal testing. Leukocyte adherence inhibition (LAI) is an easily carried out in vitro test for tumor reactivity which is based on the prevention of adherence of leukocytes incubated with antigen to which the donor is immune. In this study a comparison is made with dermal response to tumor antigen. A total of 234 patients were tested, 74 of whom had melanoma, 111 of whom had squamous cell carcinoma of the head and neck, 18 of whom had neuroblastoma and 31 of whom had other tumors. Forty-two persons without tumors acted as controls for the LAI test. A high degree of correlation was found between LAI and dermal response. Furthermore, LAI exhibited marked tumor specificity and showed a ten-fold greater sensitivity than dermal response. LAI may be used to monitor serial changes in tumor reactivity in cancer patients.


Tetracycline and quinacrine in the control of malignant pleural effusions. A randomized trial. Eighteen patients with advanced metastatic malignancy who had 21 pleural effusions requiring sclerosis for control were randomly allocated to intrapleural therapy with tetracycline or quinacrine. Tetracycline produced partial or complete control of the effusion in ten of 12 trials for a median duration of 6 months (range 1.5 to 22 months). Partial or complete control was obtained in nine of ten trials with quinacrine, for a median duration of 3 months (range 1 to 13 months). All complete responders who died achieved control of their effusions until their terminal admissions despite clinical evidence of overt systemic tumor progression in the intervening period. Single-dose tetracycline therapy was accompanied by less fever (p less than 0.04) and less pleuritic pain (p = 0.09) than quinacrine. Tetracycline is effective, well tolerated, easily administered, and should be considered as the initial therapy for malignant pleural effusions requiring pleural sclerosis.


Immunofluorescent detection of estrogen receptors in breast cancer. Comparison with dextran-coated charcoal and sucrose gradient assays. Biopsy specimens from 106 women with primary operable, recurrent or metastatic breast cancer were analyzed in a double blind study designed to compare the results of a new fluorescent antibody method for detection of estrogen receptors with estrogen receptors measured biochemically with dextran-coated charcoal and sucrose gradient assay techniques. Assay results correlated in 89.4% of tumors analyzed, and molecular receptor forms (8S and 4S) were accurately predicted in 94.7% of neoplasms studied. Divergent results most often occurred in specimens sparsely populated with malignant cells. The new technique permitted recognition of possible sources of false negative results such as necrosis, absence of tumor and, on occasion, estrogen bound in vivo. It was possible to analyze by the immunofluorescence method two specimens of insufficient size for biochemical assay.


Adjuvant chemotherapy in the management of primary malignant melanoma. In a prospective randomized study, the effect of chemotherapy (either systemic or combined intraarterial and systemic) was studied in 117 patients undergoing a curative resection of Clark's level III, IV or V malignant melanoma. Systemic chemotherapy was started one month after surgery one week courses with an I.V. injection of Vinblastin 6 mg/m2, Thiotepa 6 mg/m2, Rufocromomycine 60 microgram/m2, Methotrexate 15 mg/m2 on day one with procarbazine 30 mg/m2 orally daily were given every other week for three months and later every four weeks. Intraarterial chemotherapy of DTIC 80 mg/kg day for ten days was given 28 days prior to surgery. 65 patients with limb malignant melanoma were treated either by surgery only (27 patients), or by systemic chemotherapy (23 patients)  or by preoperative intraarterial chemotherapy and systemic chemotherapy (15 patients): 52 patients with non limb malignant melanoma were treated either by surgery only (28 patients) or by systemic chemotherapy (24 patients). We drew curves of disease free survival following surgery and studied the levelling off of the curves, 24 months after surgery 65% of the patients treated by surgery  alone were alive and free of disease whereas 81% of the patients treated by surgery and chemotherapy were alive and free of disease (p less than 0.05) suggesting a possible benefit of adjuvant chemotherapy. Intraarterial preoperative chemotherapy has not proved of additional benefit to date.


Chemotherapy of malignant hemangiopericytoma. Thirty-nine chemotherapy trials in 16 patients with metastatic hemangiopericytoma treated at MSKCC and 33 trials from the literature are reviewed. Adriamycin, alone or in combination drug regimens, is the most effective agent, producing complete and partial remission in 50% of cases. Other drugs which show some activity include vincristine, cyclophosphamide, actinomycin, methotrexate and DTIC. The available data indicate malignant hemangiopericytoma should be considered chemotherapeutically responsive tumors.


Intrathecal methotrexate overdose without neurotoxicity: case report and literature review. A 24-month-old female developed a central nervous system relapse, while in bone marrow remission, eight months after the diagnosis of acute lymphocytic leukemia was made. Inadvertently, she received 14 times the standard dose of intrathecal methotrexate (170 mg/m2 vs. 12 mg/m2). Treatment with intravenous leucovorin and oral dexamethasone was given. Her only symptomatology was mild headaches. No neurological abnormalities developed. Her cerebrospinal fluid methotrexate levels (5.2 X 10(-6)M at 23 hours and 5.9 X 10(-7)M at 47 hours) and half-life (t 1/2 = 8 hours) were within the range previously reported in patients following standard doses of intrathecal methotrexate who did not develop neurotoxicity. The various manifestations of neurotoxicity associated with the use of intrathecal methotrexate as well as those factors considered to play a part in the development of neurotoxicity are reviewed.


Ultrastructural study of 28 cases of Ewing's sarcoma: typical and atypical forms. The characteristics of 35 round cell sarcomas of bones are analyzed by optical and electron microscopical means, 28 cases of Ewing's sarcoma and 7 cases of malignant lymphomas (reticulum cell sarcoma) being distinguished. The existence of a morphological diversity within the Ewing's sarcoma group allows the authors to differentiate a conventional form of Ewing's sarcoma (21 cases) consisting of principal blastemic cells and secondary degenerative ones (dark cells) from an atypical variant (7 cases of atypical Ewin's sarcoma) whose structure adopts either an immature mesenchymal or histiocytic appearance. The ultrastructure of the atypical Ewing's cells demonstrates variability in size and in the nucleus, which is grooved and possesses prominent nucleoli. In the cytoplasm, in addition to the existence of a variable amount of glycogen, more highly differentiated structures appear when a comparison is made with the principal cells of the conventional Ewing's sarcoma. There exist filaments and mitochondria complexes, desmosomic-like junctions and profiles of endoplasmic reticulum. No transitional forms between the conventional and the atypical variants of Ewing's sarcoma have been observed. According to this analysis, when compared to other bone malignancies, the presence of glycogen as a means for identifying Ewing's sarcoma seems to be of restricted value. No clinical or anatomical differences could be established between either variant of Ewing's sarcoma.


Evaluation of esophageal dysplasia by cytofluorometric analysis. In order to grade objectively and characterize dysplastic and precancerous esophageal epithelium its DNA content was measured by cytofluormetric methods and compared to normal and cancerous esophageal epithelium. This yielded the following results. With transition of the esophageal eipthelium  from mild dysplasia to severe dysplasia and finally to in situ carcinoma, Feulgen-DNA values showed patterns characteristic of a tetraploid population. They lacked prominent peaks which were usually observed with invasive carcinomas. Dominant near-tetraploid population and definite tetraploid-octoploid populations were characteristic of severe dysplasia or carcinoma. The mean Feulgen-DNA values were significantly larger in severe dysplasia than in the lesser grade of dysplasia as well as the normal epithelium. However, this was not the rule in the full blown carcinomas. It would appear that the esophageal cytophotometric patterns are analogous to those previously observed in the skin and uterine cervix.


Fibromatosis of the breast.

Fibromatosis of the breast. A case of fibromatosis of the breast occurring in a 37-year-old woman is described. Only 15 cases of this type have been previously reported. In 5 of these cases there was also involvement of the underlying pectoral muscles, raising the possibility that some of these may have been of pectoral musculoaponeurotic origin. Two of the previously reported cases occurred in patients with Gardner's syndrome and 1 in a patient with "familial muticentric fibromatosis." It is anticipated that fibromatosis of the breast will behave in a similar fashion to fibromatosis occurring in other sites; i.e., as a local aggressive lesion which exhibits a high incidence of local recurrence following incomplete excision.


Progress in the cytological diagnosis of gastric lymphoma: a report of 32 cases. Thirty-two cases of gastric lymphoma have been examined cytologically in our laboratory. In one series (1953-1972), a technique combining washings and abrasion under fluoroscopic control was used. A positive diagnosis of malignancy was made in 7 of 17 cases. In a recent series (1972-1976), 15 cases of gastric lymphoma have been studied by direct abrasion during endoscopy. Malignant cells were identified in 13 cases and a correct diagnosis of lymphoma was made in 11 cases. Biopsy was positive for malignancy in 12 cases and lymphoma was specifically diagnosed in 9 instances. Combining cytology and biopsy, a diagnosis of cancer was made in 14 of 15 cases. Endoscopic cytology appears to be far superior to blind abrasion and washings techniques in the diagnosis of lymphoma of the stomach.


Prognostic significance of parafollicular small lymphocytes in follicular lymphoma: clinicopathological studies of 82 cases of primary nodal origin. Pretreatment biopsy material of 82 cases of follicular lymphoma of lymph node origin was reviewed. According to the amount of small lymphocytes in the parafollicular lymphoid tissue (PSL), tumors were classified: PSL++, abundant lymphocytes with prominent postcapillary venules; PSL+, a number of lymphocytes readily recognizable, postcapillary venules present but not prominent; PSL+/-, lymphocytes barely appreciable or absent. Five-year actuarial survival rates were 82.7% in PSL++, 42.3% in PSL+, and 0% in PSL+/-. Ten-year actuarial survival rates were 51.5% and 4.7% in PSL++ and +, respectively. The PSL++ pattern was often associated with localized disease. Patients surviving more than 5 years with disseminated disease had either PSL++ or +. Survival was better correlated with PSL patterns than histologic tumor types or clinical stages. Transition of the pattern from nodular to diffuse occurred in 17 of 26 cases observed and was concomitant with the progressive loss of parafollicular (or interfollicular) components, namely small lymphocytes and lymphocyte-associated vasculature. Classification of follicular lymphoma based on parafollicular small lymphocytes (PSL) offers a new set of prognostic criteria and a guide to improved clinical management.


Fever and infection in leukemic patients: a study of 494 consecutive patients. All of the febrile episodes occurring in 494 adults with acute leukemia were reviewed. There were an average of 2.39 febrile episodes per patient and the patients spent 28% of their days in the hospital with fever. Sixty-four percent of the febrile episodes were due to infection. The most common types of infection  were disseminated infection and pneumonia, which together accounted for 69% of the total episodes of documented infection. The etiologic agent was identified in 73% of the documented infections and gram-negative bacilli were responsible for the great majority. The most common gram-negative bacilli causing infection were Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa. During the course of their leukemia, 31% of the patients had repeated episodes of infection caused by the same organism and 13% ahd repeated FUO's. Fever occurred most often when the patients had neutropenia (less than 500/mm3). The fatality rate from septicemia decreased from 84% in 1966 to 44% in 1972. The fatality rate for major infections caused by gram-positive cocci was 16%, for gram-negative bacilli was 37% and for fungi was 86%. Although infection remains a serious problem in leukemia patients, considerable progress has been made.


Similarities among factors that render macrophages tumoricidal in lymphokine and interferon preparations. Lymphokine preparations, including supernatants derived from antigen-stimulated Bacillus Calmette-Guérin-immune spleen cell cultures and normal spleen cells incubated with insoluble concanavalin A, were compared with partially purified L-cell interferon for the ability to render resting macrophages nonspecifically tumoricidal in vitro. Significant activation of macrophages by lymphokine preparations occurred at concentrations as low as 0.5 and 0.25% of the assay mixture for antigen-stimulated and concanavalin A-induced lymphokine, respectively. These end point concentrations were each determined to contain 0.3 unit of interferon per ml. Supernatants obtained from unstimulated normal spleen cells, concanavalin A-treated nu/nu spleen cells, or Bacillus Calmette-Guérin-immune spleen cells in the absence of sensitizing antigen did not enhance macrophage tumoricidal function and lacked interferon. Activation by L-cell interferon required at least 1 unit/ml. The macrophage-activating factors contained in lymphokine and interferon preparations were stable at pH 2 and at 56 degrees, but they were destroyed when heated at 80 degrees for 30 min, and were inactivated by trypsin. The data demonstrate common properties for the induction of tumoricidal macrophages by these divese preparations.


Purification and quantitation of preneoplastic antigen from hyperplastic nodules and normal liver. The protein in microsomal membranes of hyperplastic nodules of livers from rats fed a diet containing 2-acetyl-aminofluorene referred to as the preneoplastic antigen has been purified to a nearly homogeneous state. A protein sharing identical immunodeterminants based on double agarose diffusion and immunoelectrophoresis has also been detected in deoxycholate-solubilized microsomes from normal liver, but it cannot be detected by gel immunodiffusion in the absence of detergent. There is approximately 4 times as much of this antigen in hyperplastic nodule microsomes as there is in normal microsomes as determined by electroimmunoassay. The antigen from nodules is not more than one-half the molecular weight of the antigen derived from normal microsomes in 0.2% deoxycholate. These findings are consistent with the hypothesis that an altered state of membranes exists in hyperplastic nodule endoplasmic reticulum, resulting in increased amounts of immunoreactive preneoplastic antigen. The nodule protein has a decreased association with its membrane matrix.


Evaluation of the carcinogenicity of chemicals: a review of the Monograph Program of the International Agency for Research on Cancer (1971 to 1977). In 1971 the International Agency for Research on Cancer initiated a program on the evaluation of the carcinogenic risk of chemicals to humans, which concentrated on the production of monographs on individual chemicals. A review of this ongoing program is presented here as a contribution to the discussion of primary prevention of cancer. A total of 368 chemicals were evaluated in the first 16 volumes of the International Agency for Research on Cancer monographs. For 26 chemicals (or industrial processes), a positive association between exposure and the occurrence of cancer in humans was observed. For 221 chemicals, some evidence of carcinogenicity was found in at least one species of experimental animals. However, no evaluation of the carcinogenic risk of these chemicals to humans was made, either because no epidemiological studies or case reports were available or because the results of available human studies were inconclusive. For the remaining 121 chemicals, the available data were inadequate for an evaluation of the presence or absence of a carcinogenic effect in experimental animals or humans. The criteria on which the carcinogenicity of chemicals to humans and/or experimental animals was assessed, from the initiation of this program in 1971 until 1977, have recently been revised and are briefly discussed.


In vitro responses of peripheral blood and spleen lymphoid cells to mitogens and antigens in childhood Hodgkin's disease. Over the past 5 years, parameters of immunological function have been determined in all children with biopsy-proven Hodgkin's disease in the Department of Pediatrics, Memorial Sloan-Kettering Cancer Center. This report summarizes the in vitro responses of lymphocytes to stimulation by mitogens and antigens (between January 1975 and December 1976) in 33 of these previously untreated patients. In nine of these patients, responses of the splenic lymphocytes were studied concomitantly with the responses of peripheral blood lymphocytes. Peripheral blood from normal children and adults was used as the control. Our results have demonstrated no significant differences between the responses of normal children and adult controls. The absolute necessity for concomitant studies of the controls and the patients was shown. The value of examining multiple concentrations of a single mitogen was also well defined. In the children with Hodgkin's disease, there was a consistent failure of the peripheral blood lymphocytes to respond to the lower concentration dose of phytohemagglutinin. However, this abnormality was not found in the splenic lymphocytes.


Inhibitory effect of reducing agents on N-acetoxy- and N-hydroxy-2-acetylaminofluorene-induced mutagenesis. The effect of cysteine (alpha-amino-beta-mercaptopropionic acid) on the mutagenic activities of the proximate carcinogen, N-hydroxy-2-acetylaminofluorene, and the ultimate carcinogen, N-acetoxy-2-acetylaminofluorene, was examined by estimating the frequency of his+ revertants of Salmonella typhimurium. Nontoxic concentrations of cysteine significantly reduced the formation of revertants when it was applied concurrently with the two carcinogens. Cysteine showed no detectable effect on mutagenesis when added to bacteria before or after exposure to carcinogens. The magnitude of inhibition of mutagenesis depended on the dose of cysteine and the concentration of the carcinogens. Cysteine at equimolar concentrations inhibited to a larger degree the mutagenesis induced by N-hydroxy-2-acetylaminofluorene than it inhibited that elicited by N-acetoxy-2-acetylaminofluorene. The inhibitory action of cysteamine and glutathione was comparable to that of cysteine. The results appear to be consistent with the assumption that cysteine traps electrophiles prior to their action on DNA.


Adjuvant therapy for osteosarcoma: preoperative and postoperative treatment. Seventeen consecutive patients with osteogenic sarcoma participated in a prospective study to ascertain first, whether postoperative adjuvant chemotherapy or chemoimmunotherapy could reduce the incidence of distant metastases and second, whether in situ tumor cell destruction could be achieved with preoperative chemotherapy and radiation therapy. To date 14 of 17 patients (85%) are alive and free of disease for a median survival time of 11 months. Three patients developed recurrent disease, one with local recurrence in the tibia and two with pulmonary metastases. Limb salvage was attained in 12 patients by cadaver allografts and in one patient by radiation alone at 6 months.


cis-Dichlorodiammineplatinum (II) in advanced osteogenic sarcoma. Eight patients with advanced metastatic osteogenic sarcoma were treated with cis-dichlorodiammineplatinum(II) (DDP). Prior to DDP, seven patients had amputations and all had received adjuvant adriamycin (ADR) therapy. In addition, prior to DDP, six patients had received high-dose methotrexate. There was one complete response (pulmonary metastases) and four partial responses (three metastases in the lungs and one in the bone). One additional patient, with local recurrence of osteogenic sarcoma of the mandible following initial resection and adjuvant ADR, was retreated with surgery and DDP and is disease-free for greater than 3 years. The cumulative dose ranged from 300 to 660 mg/m2. Toxicity included irreversible kidney damage in two patients, transient severe hematologic suppression in two patients, and nausea and vomiting in all patients. DDP is a new effective agent in the treatment of osteogenic sarcoma.


Sequential combination chemotherapy (containing high-dose cyclophosphamide) for metastic osteogenic sarcoma. Eleven patients with metastatic osteogenic sarcoma were treated with cyclophosphamide, adriamycin, and, in some cases, high-dose methotrexate. In the event of metastatic progression, the dose of cyclophosphamide was escalated by increasing the number of consecutive daily infusions (dose, 45 mg/kg/day). The results indicate that metastatic osteogenic sarcoma is marginally responsive to adriamycin and cyclophosphamide but rarely responsive to high-dose methotrexate as administered in this trial. The response of metastatic lesions was not improved by escalating the dose of cyclophosphamide.


Combination chemotherapy for osteosarcoma. Because of the great risk for development of pulmonary metastases following amputation for osteosarcoma, 24 consecutive patients with "clinically localized" osteosarcoma of an extremity were given adjuvant combination chemotherapy with adriamycin-cyclophosphamide-high-dose methotrexate-citrovorum factor. Thirteen of these patients remain free of tumor from 11 to 48 months following amputation. The median disease-free survival is estimated to be 18 months and the median survival 27 months. No relapses have been observed in any patients surviving free of disease beyond 23 months. Combination chemotherapy was also given to 16 patients whose disease was not localized; eight with pulmonary metastases at or following diagnosis, one with nodal metastases at diagnosis, two with osteosarcoma following radiation therapy for other malignant tumors, three with osteosarcoma of flat bones, one with parosteal osteosarcoma, and one with multifocal osteosarcoma. Three of this latter group of patients are surviving free of tumor at 8, 17, and 19 months from diagnosis. Two young patients died from complications of methotrexate and adriamycin toxicity.


Adjuvant chemotherapy for osteogenic sarcoma. Twenty-nine evaluable patients with nonmetastatic osteosarcoma were given sequential combination chemotherapy utilizing high-dose methotrexate with citrovorum factor rescue, vincristine, adriamycin, and cyclophosphamide. Fourteen (48%) of 29 patients are currently disease-free for 8--48 months from initiation of chemotherapy with a median disease-free survival of 21 months. The projected 4-year disease-free survival is 13%. At 4 years the projected overall survival is 57%. In this particular study, adjuvant chemotherapy does not appear to significantly prevent the development of overt metastases. In four patients, delayed onset of metastasis was observed at 18--43 months from initiation of treatment.


Adjuvant therapy for nonmetastatic osteogenic sarcoma: an evaluation of transfer factor versus combination chemotherapy. A randomized study compared the effects of combination chemotherapy (high-dose methotrexate, adriamycin, and vincristine) with immunotherapy in the form of transfer factor in the adjuvant treatment of patients with nonmetastatic osteogenic sarcoma after apparent complete surgical ablation of the primary tumor. Thirty-two patients were evaluated. Of 22 patients who received chemotherapy, three died of drug-related complications and six were alive without disease recurrence between 260 and 673 days after operation. Ten patients in the transfer factor group converted their markers, and of these, five were alive without recurrence 420--753 days after operation. Neither treatment program was considered superior with respect to disease-free survival.


Adjuvant treatment of osteogenic sarcoma with high-dose cyclophosphamide. Six patients with osteosarcoma and no evidence of metastases received postoperative adjuvant chemotherapy with high-dose cyclophosphamide (25 mg/kg iv every other day for five doses). Three of these patients are alive without evidence of disease at 2 1/2, 3, and 5 years following diagnosis. The regimen was tolerable in terms of toxicity. Cyclophosphamide in high doses may be effective adjuvant therapy in some patients with osteosarcoma.


Adjuvant whole-lung radiation with or without adriamycin treatment in osteogenic sarcoma. Eighteen consecutive patients with osteogenic sarcoma were treated after initial surgery with 2000 rads of whole-lung radiation for 21--28 days. Eleven of these patients went on to receive adriamycin (20 mg/m2 X 3 days every 6 weeks). Three of seven evaluable patients are free of disease in the radiation group (median time to recurrence, 130 days) while six of ten evaluable patients are free of disease in the radiation + adriamycin group (median time to recurrence, 310+ days). These results are similar to published experience with whole-lung radiation and adriamycin alone.


Treatment of essential hypertension with pindolol. Pindolol was given for 12-15 consecutive weeks to 35 patients for the treatment of essential hypertension. Significant blood pressure reductions were achieved in the group of 28 patients who completed the trial, as tested by the Wilcoxon pair test. There was no difference in antihypertensive effect between a three times a day and a twice a day administration schedule. The incidence of side-effects was not affected by the change in dosage or schedule.


Underestimation of true pulmonary blood volume by the pulmonary artery wedge injection technique in cardiac patients. Pulmonary blood volume measurements were made comparing pulmonary artery with pulmonary artery wedge and left atrial dye dilution curves in 32 patients with cardiac disease. Mean transit times across the lungs were underestimated by the PAW curve technique. Hence calculated PBV by the right heart injections alone underestimates true PBV.


Immunocytochemical study of the hypothalamo-neurohypophysial system. IV. Topographical distribution of neurophysin neurons of the sheep paraventricular and supraoptic nucleus. An antiserum cross-reactive against ovine neurophysins-I-II and -III has been used in conjunction with the immunoperoxidase histochemical procedure to localize the cells of the sheep paraventricular (PVN) and supraoptic nuclei (SON). In order to describe the topographical distribution of the SON and PVN a study was made on the serial sections cut (a) transversely from rostral to caudal positions and (b) sagittally from lateral to medial positions of the hypothalamus. The cells of the SON, when examined in the transverse aspect, extended approximately 1900 mu caudally and when examined in the sagittal plane were contained within a lateral-medial distance of 4830 mu. In each case the SON cells lay adjacent to the optic chiasm. As sections were cut transversely, the cells of the PVN first appeared in a rostral position defined as 0mu and close to the ventral lining of the third ventricle. This general ventral and ventro-lateral distribution of cells maintained up to a caudal distance of approximately 840 mu. From positions 1260-2310mu there was a dramatic dorsal shift of the PVN cells which by this time had also extended laterally. The total rostral-caudal distance occupied by the PVN cells was 3150mu. That the lateral-medial distance occupied by the PVN was small (1050mu) was determined on examining the magnocellular nuclei in sagittal section.


Immunocytochemical identification of an LHRH-producing system originating in the preoptic nucleus of the duck. A fluorescent technique applying specific LHRH and vasotocin antisera was used for the immunocytochemical localization of the respective neurosecretory systems in the hypothalamus of gonadectomized, testosterone-treated and/or serotonin injected male domestic ducks. An immunoreactive (IR) LHRH-producing system, with perikarya located in the preoptic nucleus, could be traced through the ventral hypothalamus down to the external layer of the rostral and caudal ME, in close vicinity to the hypophysial portal system. An IR-vasotocin system originating in the paraventricular and supraoptic nuclei ran through the ventral hypothalamus, but terminated in (i) the external layer of the rostral ME, and (ii) in the posterior lobe of the hypophysis.


Reaction of the anastral mitotic apparatus of endosperm cells of the plant Leucojum aestivum with antibodies to tubulin from porcine brain as revealed by immunofluorescence microscopy. Structures binding an antibody against tubulin from porcine brain were localized in the giant anastral mitotic apparatus of endosperm cells of the monocotyledonous plant, Leucojum aestivum, by indirect immunofluorescence microscopy. Both continuous and chromosomal spindle fibers were strongly stained. Postive fluorescence was also noted in polar cap regions and, in prometaphase stages, to some extent at the fragmented nuclear envelope. Intermingling and branching of subfiber elements was frequently noted.


A method of synchronization of normal and malignant human cells in culture. A method is described for providing reproducible S phase parasynchrony in both normal mesenchyme and transformed epithelia. Cells were seeded at low density in medium containing 10% serum. 24 h later the serum concentration was reduced to 0.5%. After 110th the cells were collected at the G1/S boundary in fresh medium containing 10% serum plus 2.5mM hydroxyurea over 20h. After removal of hydroxyurea and trypsinization the re-plated cells entered the S phase with a high degree of synchrony, as judged by autoradiography, pulse-labelling with 3H-thymidine, cell growth and time lapse cinematography. By 6h after synchronization 80% of the population had entered the S phase and between 10-13h 70% went through mitosis.


An RNA core in the 30S ribosomal subunit of Escherichia coli and its structural and functional significance. 1. Evidence is presented for the occurrence of a very stable RNA core (S4-RNA) in "native" 16S RNA that is also present in the 30S subunit of Escherichia coli. A model giving the approximate location of this RNA core in the 30S subunit is presented. 2. It is proposed (a) that this S4-RNA acts as a nucleus for the assembly of the 30S subunit, and (b) that a small class of "linkage" proteins, including S4, further facilitate the assembly of the proteins to the RNA, thereby explaining some of the "cooperative" effects that are observed during in vitro assembly. 3. Evidence for the importance of the RNA core in the functioning of the ribosome is discussed.


Effect of timolol plus hydrochlorothiazide plus hydralazine on essential hypertension. The effect on hypertension of hydrochlorothiazide 100 mg daily plus timolol 20-60 mg daily versus hydrochlorothiazide plus placebo and of hydrochlorothiazide plus timolol plus hydralazine 40-200 mg daily versus hydrochlorothiazide plus placebo plus hydralazine was evaluated in a double-blind, randomized, crossover study in 38 patients with hypertension. Hydrochlorothiazide plus timolol was more effective than hydrochlorothiazide plus placebo in lowering both supine and standing systolic and diastolic blood pressures. Hydrochlorothiazide plus timolol plus hydralazine was a very effective regimen in lowering both supine and standing systolic and diastolic blood pressure. The patients tolerated this regimen well with greater hypotensive activity and a lower incidence of side effects than on hydrochlorothiazide plus placebo plus hydralazine.


Value and limitations of programmed electrical stimulation of the heart in the study and treatment of tachycardias. A review is given on the use of programmed electrical stimulation of the heart in patients suffering from tachycardia. The application of this technique makes it possible to evaluate mechanisms of tachycardia directly in the human heart. By repeating the same stimulation program following drug administration the effect of drugs on arrhythmia mechanisms can be studied. There are several factors, however, that influence the amount of information on mechanism and pathway of tachycardia and selection of appropriate therapy that can be obtained during the study. These factors as well as how information obtained programmed electrical stimulation of the heart has resulted in a better use of the 12-lead electrocardiogram as a diagnostic tool are discussed.


Epicardial mapping in the Wolff-Parkinson-White syndrome. Epicardial mapping provides a method for defining antegrade and retrograde sites of pre-excitation. It is best undertaken only after a careful, detailed preoperative electrophysiological study has been performed. The potential pitfalls of the technique are many and technical expertise must be constantly available to maintain a functioning system. For these reasons, it is not likely to lend itself to widespread application. The same techniques can be applied to localization of the site of origin of atrial or ventricular dysrhythmias, localization of myocardial ischemia and infarction, as well as to differentiate between epicardial delays due to conduction delay and those caused by intramural myocardial delay.


Prognosis for patients with congenital heart disease and postoperative intraventricular conduction defects. Intraventricular conduction defects are common following repair of various forms of congenital heart disease. Such defects may affect adversely the long-term prognosis of patients in whom cardiac hemodynamics were adequately restored. Review of previously published studies suggests that the site of the conduction defect may be the reason for the different prognoses reported for patients from different institutions. The so-called "trifascicular block" pattern which sometimes occurs following open heart surgery is probably due to a more extensive lesion to the branching and penetrating parts of the His bundle rather than additional injury to the posterior left bundle branch fibers. Transient complete heart block in the immediate postoperative period seems to be a predictor for late development of complete heart block or sudden death at least as powerful as right bundle branch block and left anterior hemiblock.


Depressant effect of digoxin on atrioventricular conduction in man. We examined the effect of chronically administered digoxin on atrioventricular (A-V) conduction in nine cardiac transplant recipients. We assessed A-V conduction by measuring the duration from the pacing stimulus to the onset of the QRS complex (S'R interval) and by determining the occurrence of Wenckebach periodicity during rapid atrial pacing. We made measurements during a control period and during a period of digoxin administration of up to 37 days. During the digoxin period, the cycle length at which Wenckebach block occurred was prolonged by 14% of the control value and the S'R interval was significantly prolonged at paced rates of 110 beats per minute and faster. After digoxin was discontinued, the Wenckebach periodicity and S'R interval returned to control values. Atropine and propranolol did not alter digoxin's effect on A-V conduction. We conclude that digoxin exerts a direct (or non-neurally mediated) depressant effect upon A-V conduction in man, although the stress of tachycardia is necessary to demonstrate the effect.


Unexplained in-hospital fever following cardiac surgery. Natural history, relationship to postpericardiotomy syndrome, and a prospective study of therapy with indomethacin versus placebo. In Part I of this study, the in-hospital course of 219 patients who had undergone a cardiac operation is analyzed. Fever (greater than or equal to 37.8 degrees C, rectal) was present after postoperative day 6 in 159 patients (73%) and was of unexplained cause in 118. Fever decay in the population of unexplained fever patients was exponential. All patients with unexplained postoperative fever were afebrile by postoperative day 19. In-hospital pericardial rub and pleuritic chest pain, widening of the mediastinum on chest film, and pleural effusion were not specifically associated with unexplained postoperative fever. In Part II, 67 patients with unexplained postoperative fever were given indomethacin (100 mg per day) or placebo for 7 days by a randomized, double-blind protocol. Indomethacin resulted in a shorter duration of fever (2.4 vs 3.5 days, P is less than 0.01) and in a shorter duration of chest pain, malaise, and myalgias compared to placebo. Sixty-seven percent of the patients in Part I and all of the patients in Part II were contacted 2-8 months following hospital discharge. Five percent had experienced an illness that we considered to be acute pericarditis, but its occurrence was unrelated to whether the patient had had in-hospital unexplained postoperative fever, in-hospital rub or chest pain, or in-hospital administration of indomethacin.