Giardiasis in mice. I. Prolonged infections in certain mouse strains and hypothymic (nude) mice.

The natural history of Giardia muris has been studied in inbred mouse strains and hypothymic (nude) mice derived from a specific pathogen-free facility. Although giardiasis was readily established in several mouse strains, marked variation was observed in the time course of spontaneous elimination of the parasite. During a 10-week study, fecal excretion of Giardia cysts remained relatively constant in C3H/He mice, but decreased at a variable rate in other mouse strains. Resistance to reinfection was greater in strains in which the duration of primary infection was relatively short. Hypothymic (nude) mice derived from a strain showing a relatively rapid elimination of Giardia (BALB/c) maintained a stable infection with high cyst counts. Nude mice reconstituted with lymphoid cells from syngeneic thymus-intact mice showed a progressive reduction in cyst excretion and reconstitution with limited numbers of lymphoid cells from thymus-intact mice previously exposed to Giardia accelerated resolution of infection. In nude mice, giardiasis was associated with a reduction in the villus-crypt ratio of jejunal mucosa, but the degree of change was greater in nude mice reconstituted with lymphoid cells. This Giardia model involving inbred strains and nude mice permits further dissection of the function of thymus-derived cells in intestinal immune responses and induction of changes in small bowel morphology.


Effects of intravenous vasoactive intestinal peptide (VIP) on gallbladder function in the cat.

The influence of vasoactive intestinal peptide (VIP) on the concentrating mechanism and the motility in the feline gallbladder has been studied in vivo. A perfusion technique made possible a simultaneous study of the motility and of the net transport of water and electrolytes across the gallbladder wall. It was found that an intravenous infusion of VIP relaxes the gallbladder and induces a net fluid secretion into its lumen. The net absorption of chloride ions was markedly reduced, whereas the net transport of sodium, potassium, and bicarbonate was reversed from an absorption into a secretion. Owing to the presence of VIP-containing nerve fibers in the gallbladder wall, a physiological significance for the secretory gallbladder response to VIP is suggested.


Peptidergic (VIP) innervation of the esophagus.

Nerves displaying vasoactive intestinal polypeptide (VIP) immunoreactivity were demonstrated in the esophagus of rats, cats, and pigs. Furthermore, electron microscopy revealed the presence of nerve terminals displaying the features of peptidergic nerves. VIP nerves were abundant within the smooth muscle layer of the lower esophagus of cat and pig. Immunoreactive nerve fibers and nerve cell bodies were found in the plexuses of the esophageal wall. In pig fetuses VIP immunoreactive nerve cell bodies were observed already at crown-rump length of 4 cm. VIP nerves were also observed in human fetal esophagus. For recording of the motor effects of VIP, segments were taken from cat esophagus close to the esophagogastric junction. VIP induced a dose-dependent relaxation upon contraction by carbamylcholine.


Morphological evaluation of opossum lower esophageal sphincter.

Studies were performed in the opossum to evaluate the morphological characteristics of the lower esophageal sphincter. The sphincter and the esophageal body were identified manometrically and fixed in situ by perfusion with aldehyde fixative. Light microscopy revealed that: (1) longitudinal muscle layers of the sphincter and the esophageal body were similar in thickness and compactness, and (2) circular muscle of the sphincter was thicker and was composed of muscle fasciculi with abundant intervening connective tissue as compared to the compact muscle fasciculi of the circular muscle of the esophageal body. Electron microscopy showed the circular muscle fibers of the sphincter to have irregular protuberances from their surfaces, whereas the circular muscle fibers of the esophageal body possessed smooth surfaces. Several types of junctional complexes between adjacent muscle fibers were observed; however, there was no difference in their distribution in the sphincter or esophageal body. The majority of the nerve varicosities contained a mixture of agranular (350 to 450 A) and large dense core vesicles (800 to 1600 A); varicosities containing small granular vesicles were not found in any area of the esophagus. When varicosities were cut along the longitudinal axis of the axon, they often showed grouping of similar vesicle types in different areas along the axon varicosities. There was no difference in the type of varicosities found in the sphincter or the esophageal body. These studies show that: (1) circular muscle of the sphincter can be morphologically distinguished from that of the esophageal body; (2) there is no difference in the morphology of the nerve terminals or the vesicle types in the two areas; and (3) classification of the varicosities based upon the predominance of the vesicle types may be artifactual because of sampling error.


Lithium inhibits basal and food-stimulated gastrin secretion.

Ten psychiatric patients were given a protein-rich meal in periods on and off lithium administration. The concentrations of gastrin in serum were measured radioimmunochemically before and during the meal. The results show that lithium suppresses basal as well as food-stimulated gastrin secretion.


Hepatic taurine concentration and dietary taurine as regulators of bile acid conjugation with taurine.

Taurine concentration in liver biopsies taken from 20 patients undergoing cholecystectomy or laparotomy for obstructive jaundice correlated with percentage of taurine-conjugated bile acids in hepatic bile. In biliary obstruction, taurine concentrations in muscle did not parallel high hepatic taurine concentrations, suggesting selective hepatic taurine accumulation in biliary obstruction. In fasting subjects with an intact bile acid enterohepatic circulation, per cent taurine-conjugated bile acids in bile was the same as per cent taurine conjugation of bile acids by the liver. Ingestion of small amounts of taurine (250 mg) can increase the per cent taurine conjugation by the liver. Of 10 subjects, 7 increased per cent taurine conjugation of bile acids by the liver by 2.5 to 10% at 2 1/2 hr after intraduodenal taurine administration. We conclude that hepatic taurine concentration is a major determinant of per cent taurine conjugation of bile acids by the liver in man. In the fasting subject with an intact enterohepatic circulation, per cent taurine-conjugated bile acid in the bile acid pool is very close to the per cent taurine conjugation of bile acids by the liver. Hepatic bile acid conjugation pattern may differ from that of the bile acid pool as a result of taurine ingested with meals, but the deviation is small, and acute alteration of the per cent taurine conjugation in the bile acid pool does not occur.


Estrogen enhances dietary cholesterol induction of saturated bile in the hamster.

The influence of ethinyl estradiol (EE) on the effects of dietary cholesterol on the biliary saturation index and on the rate-limiting hepatic enzymes of cholesterol synthesis, hydroxymethylglutaryl-CoA-reductase, and bile acid synthesis, 7 alpha-hydroxylase, were determined. Four groups of 12 male hamsters were treated for 1 month with EE, 15 micrograms per kg per day, or placebo vehicle administered intraperitoneally and fed either a standard diet, 0.8 mg of cholesterol per g of food, or high cholesterol diet, 2.4 mg of cholesterol per g. The high cholesterol diet increased the saturation index to 1.00 +/- 0.03 (P less than 0.01) from 0.65 +/- 0.02 in untreated hamsters on the standard diet. EE treatment on the high cholesterol diet further increased (P less than 0.01) the saturation index to 1.15 +/- 0.02. The high cholesterol diet decreased (P less than 0.01) hydroxymethylglutaryl-CoA-reductase activity from 308 +/- 16 pmoles per mg per min in untreated hamsters on the standard diet. The addition of EE treatment had no effect on hydroxymethylglutaryl-CoA-reductase activity. The high cholesterol diet increased (P less than 0.01) 7 alpha-hydroxylase activity from 23 +/- 1.0 pmoles per mg per min in untreated hamsters on the standard diet. The addition of EE decreased (P less than 0.01) 7 alpha-hydroxylase activity from that in untreated hamsters on the standard diet. The conclusions are as follows: (1) EE prevented dietary cholesterol-induced stimulation of cholesterol 7 alpha-hydroxylase activity; (2) EE enhanced the ability of dietary cholesterol to induce saturated bile; and (3) gallstone formation in estrogen-treated women may result from impaired metabolism of dietary cholesterol.


Morphological characterization of Kupffer and endothelial cells of rat liver isolated by counterflow elutriation.

Kupffer and endothelial cells of rat liver were purified by recirculating collagenase perfusion, metrizamide gradient, and counterflow elutriation. Every step of the isolation procedure was followed by light microscopy and histochemistry. The final fractions of purified sinusoidal cells were examined in their isolated state by transmission and scanning electron microscopy. The scope of this manuscript is the detailed documentation and discussion of all technical aspects and problems of a rather new isolation technique, as well as the detailed description of the purified sinusoidal cells of the liver by scanning electron microscopy. Broader acceptance of this isolation procedure should lead to the specific characterization of biochemical and immunological functions of these cells and elucidate their pathophysiological significance.


Hepatic extraction of long- and short-acting narcotics in the isolated perfused rabbit liver.

Hepatic extraction of the long-acting narcotic, methadone, was compared to that of the short-acting narcotics, morphine, diacetylmorphine, and meperidine, using an isolated perfused rabbit liver preparation. Methadone was avidly extracted from portal venous blood (86.1 +/- 0.81%) in a single pass through the liver after a bolus injection (1.5 mg) into a nonrecirculating perfusion system. Hepatic extraction of methadone was independent of rate of hepatic blood flow (0.59 to 1.53 ml per g of liver per min) but was altered by increasing the total amount of methadone injected. After a bolus injection of 15.0 and 75.0 mg, the proportions of methadone extracted were reduced to 75 and 56%, respectively. The hepatic extraction of morphine (1.5 mg) was 25%, of diacetylmorphine (1.5 mg) 59%, and of meperidine (1.5 mg) 66% in a single pass, all significantly lower (P less than 0.01) than that of methadone. Subcellular fractionation of whole liver homogenates after a single pass of drug showed that methadone and its metabolites were localized primarily in the fractions containing nuclei, mitochondria, microsomes, and other membranes, whereas morphine was primarily localized in the supernatant cytosol. Unchanged methadone was shown to be slowly released from the liver into hepatic effluent blood along with small amounts of the inactive pyrrolidine and pyrroline metabolites (identified by gas chromatography and mass spectrometry). These findings suggest that the liver may serve not only as a site of biotransformation of methadone, but also as a major reservoir for storage and subsequent release of unchanged compound.


Effects of vasoactive intestinal peptide on resting and pentagastrin-stimulated lower esophageal sphincter pressure.

Vasoactive intestinal peptide (VIP) administered as an intravenous infusion at different doses (0.8, 1.6, and 3.2 micrograms per kg per hr, respectively) inhibited dose-dependently the response of the lower esophageal sphincter to an intravenous injection of pentagastrin (0.6 microgram per kg) in 4 healthy volunteers. Inhibition ranged from about 20% (not significant) with the low dose to about 55% (P less than 0.05) with the high dose. On the other hand, the VIP doses employed did not substantially decrease basal lower esophageal sphincter pressure. Calculated on the basis of plasma levels of the respective peptides, the inhibitory effect of VIP was about one-third of that of secretin. Even at the smallest dose of VIP, plasma levels of radioimmunoassayable VIP (20 to 100 pmoles per liter) markedly exceeded those encountered normally (1 to 19 pmoles per liter). So, the data presented do not support the suggestion that normally circulating VIP essentially contributes to the physiological regulation of the lower esophageal sphincter pressure; they do not exclude, however, such a role for locally released VIP.


Monitoring of hormonal therapy in patients with metastatic breast carcinoma by plasma marker protein profiles.

Approximately 50% of the present patients with metastatic breast carcinoma, who were treated with hormonal therapy, had increased plasma levels of CEA or GCDFP. With therapy, serially decreasing plasma levels of these marker proteins appeared an accurate indicator of a favorable response, whereas increasing levels indicated disease progression.


Randomized steroid therapy of human kidney transplant rejection.

This randomized, double-blind study failed to show any therapeutic benefit of a 30-mg/kg bolus over a 3-mg/kg bolus of methylprednisolone for the treatment of acute kidney transplant rejection. Since there was a slight associated increase in infections and septic mortality, routine use of high-dose methylprednisolone bolus therapy is not recommended or justified.


Prothesis cement envelope in femoral component total hips.

Loading tests showed wide stem-thin cement envelope systems in valgus orientation placed with distal plug to be significantly more stable at higher loads. Narrow stem-thick cement envelope systems in varus without plug were unstable within a marginal factor of safety for cyclic loading. Four cement failures occurred within the thin stem-thick cement system on the upper lateral aspect of the prosthesis cement envelope.


Preparation of allogeneic cartilage and bone for grafting.

Seroma formation was most apparent in the A-treated groups and was probably related to the continued leakage of methyl alcohol from the graft. Warping in the pinna, fibrosis around grafts, graft resorption, and cellular infiltration were least evident in the FZ and R groups. Both produced better results than storage in BSS or A, but because radiation is far more expensive and less convenient than FZ, the latter is the better preparation and preservation technique.


Preventing the prostaglandin effect on dermal ischemia in the burn wound.

The eventual depth of tissue necrosis after burning is not immediately apparent. In all burn wounds, there exists a zone of stasis which shows progressive microvascular deterioration. These progressive changes have been prevented by methylprednisolone acetate, indomethacin, and ASA. All of these agents are known to inhibit prostaglandin synthesis. These data suggest that prostaglandins have a role in the progressive dermal ischemia after thermal trauma and that their effect can be prevented by specific antiprostaglandins.


A new animal model for testing the effectiveness of chemotherapeutic agents on renal adenocarcinoma.

A renal cell endocarcinoma that arose spontaneously in a Wistar-Lewis rat has been used to screen various chemotherapeutic agents for effectiveness against this tumor. Of the agents so far tested, cyclophosphamide (Cytoxan) and vinblastine have displayed very considerable anti-tumor activity. Adriamycin was marginal, and fluorouracil (5-FU) and Cis-dichlorodiammine Platinum (II) were ineffective.


Comparative effects of azathioprine, cyclophosphamide and frentizole on humoral immunity in mice.

Data is presented comparing the activities of three immunosuppressive agents, cyclosphosphamide, frentizole and azathioprine in models of humoral immunity in mice. Cyclophosphamide and frentizole suppressed the primary and secondary plaque forming cell responses to sheep erythrocytes at lower doses than did azathioprine. Prolonged suppression of serum antibody titers occurred following short-term therapy with cyclophosphamide or frentizole, but not azathioprine. Azathioprine was also the least effective agent in suppressing a primary response to the T-independent antigen, trinitrophenylated lipopolysaccharide. All three agents were found to inhibit the induction and activity of suppressor cells at immunosuppressive doses.


Effect of frentizole on mitogen-induced blastogenesis in human lymphocytes.

Frentizole is a new immunoregulatory agent developed as an alternative to cytotoxic agents. In human lymphocytes, Frentizole inhibits the response to various phytomitogens without decreasing cell viability. Frentizole (500 ng/ml) inhibited thymidine incorporation into DNA most effectively when added to lymphocyte cultures at the same time as the addition of the mitogen. Frentizole (500 ng/ml) markedly inhibited the response to Con A (% inhibition, corporation was dose dependent with 125 ng/ml of Frentizole sufficient to inhibit significantly the response of all three mitogens. Frentizole (62.5 ng/ml) maximally inhibited uridine incorporation, and inhibition of uridine incorporation was independent of the phytomitogen employed. Increasing concentrations of Frentizole were found to have no effect on thymidine or uridine incorporation into unstimulated normal lymphocytes.


Azathioprine treatment of adjuvant arthritis.

Administration of azathioprine in the diet to Lewis rats reduced the lethality of this drug relative to various regimens by gavage. This mode of administration made it possible to administer effective doses with reduced toxicity. Azathioprine blocked the early development of adjuvant arthritis and decreased the joint scores of animals with established adjuvant disease. A combination of azathioprine and prednisolone produced an additive reduction of both developing and established joint scores. A 10 day pulse regimen of prednisolone resulted in a strong, rapid decrease in established joint scores. This decrease was sustained by continuous administration of azathioprine. In all cases removing azathioprine and/or prednisolone from the diet of animals with established adjuvant arthritis resulted in recurrence of disease. The results of these studies support the validity of the adjuvant model for prediction of anti-arthritic activity.


The modulatory effect of exogenously added prostaglandin E1 or E2 on the delayed-type hypersensitivity reaction of normal or tumored mice.

The effect of exogenously added prostaglandin (PG) E1 or E2 over concentration ranges of from 1 x 10(-4) to 1 x 10(-9)M were studied in order to determine their effect on the delayed-type hypersensitivity (DtH) reaction of normal or tumored mice. PGE1 or PGE2 generally caused a stimulation over the control values of normal mice as detected by the footpad swelling assay. However, PGE1 or PGE2 at all concentrations tested were found to significantly inhibit the DtH reaction of CD2F1 tumored mice.


Drug induced modulation of immune responses in mice: effects of 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) and cyclophosphamide (Cy).

Graded doses of Cyclophosphamide (Cy) or 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide (DTIC) were given to CD2F1 or C57Bl/6 mice. One, 45 or 60 days later the animals were tested for allograft responses, competence of producing cytotoxic lymphocytes in vitro and lethal graft-versus-host disease (GVHD) in vivo, delayed-type hypersensitivity (DTH) and humoral antibody responses against sheep red blood cells (SRBC). Both agents produced strong inhibitory effects, except for DTH, when given 1 day before the antigenic stimulus. However immunodepression lasted for at least 60 days after DTIC, whereas relatively rapid recovery of immune responsiveness was detected in mice treated with Cy. When Cy or DTIC were given to allogeneic donor mice 1 day before spleen cell transfer, immunodepressed recipients did not undergo GVHD. However when drugs were administered to recipient mice inoculated with allogeneic spleen cells, lethal GVHD occurred when Cy but not DTIC was given to the hosts. DTH responses were potentiated by Cy when the drug was given 1 day before sensitization. In contrast hypersensitivity reactions were not affected by DTIC treatment. It was concluded that DTIC is a potent and long-lasting immunodepressive agent, capable of affecting various T-cell subpopulations and possibly B lymphocytes in mice. Since the drug inhibits immune response when given before the antigenic stimulation, it was suggested that DTIC acts through a mechanism similar to that of alkylating non phase-specific agents.


The effects of pharmacologic agents on mitogen-induced cellular cytotoxicity in guinea pigs.

Using pharmacologic agents as probes, three aspects of the mitogen-induced cellular cytotoxicity reaction (MICC) were evaluated. These included the requirement for a concomitant lymphoid DNA synthetic response, the role of microtubules and microfilaments in effecting target cell lysis, and the potential inhibitory activity of hydrocortisone. Results, using both PHA and Con A stimulated guinea pig lymph node cells, indicate that this form of cytotoxicity occurs as a phenomenon independent of 3H-Tdr incorporation. Animals treated with cyclophosphamide showed cytotoxic reactions equivalent to untreated controls whereas mitogen-induced proliferative responses were greatly impaired. Further studies indicated that the in vitro exposure of lymph node cells to either mitomycin or cytosine arabinoside markedly reduced DNA synthesis but did not depress the ability of mitogen-stimulated lymphocytes to effect target cell lysis. The microtubular antagonists, vincristine, vinblastine and colchicine, inhibited cytotoxic reactions if the agents were present at the time that lymphocyte-target cell interaction was established. However, the antimicrofilament agent cytochalasin B was not inhibitory; this contrasts to this agent's ability to suppress antigen-induced cell-mediated cytotoxic reactions. In a third series of experiments, hydrocortisone showed a dose-related inhibition of MICC responses. The action of the steroid was apparent only if the drug was present at the onset of the culture; no suppression was observed if it was added after an initial one day incubation.


In vitro effect of an acute nonspecific inflammatory exudate on tritiated-thymidine incorporation by unstimulated and PHA-stimulated spleen cells.

The effect of an acute nonspecific inflammatory exudate with mitogenic activity for macrophages in culture has been tested on the spontaneous and PHA-induced DNA synthesis by spleen cells in vitro. Stimulatory effect of this exudate was observed on the spontaneous DNA synthesis which was detectable over a range of 1:4 to 1:4096 concentrations. After optimal PHA stimulation, an inhibition of mitogen-induced DNA synthesis was observed when the cells were exposed to the highest concentrations (up to 1:128) of the exudate. Thereafter, the phenomenon could be reversed and the stimulation was maximal at the concentration of 1:2048. When a suboptimal dose of PHA was used, the stimulatory effect was more pronounced and detected from 1:8 up to 1:4096 concentrations.


Regulation of the expression of autoimmunity in NZB x NZW F1 mice by sex hormones.

This study examines the role of sex hormones in modulating the expression of autoimmunity in NZB x NZW F1 mice. Male sex hormones were found to retard disease. Differences were noted between prepubertally and postpubertally altered males and females. The presence of male sex hormones prepubertally was associated with marked retardation of the development of antibodies to DNA. Prepubertal but not postpubertal castration of males led to significant acceleration in anti-DNA production. Nevertheless, administration of male sex hormones to females retarded the development of fatal glomerulonephritis, even when given postpubertally. These results suggest that manipulation of sex hormones may be used to modify the expression of autoimmunity.


Increased susceptibility of tumor cells and chicken erythrocytes to lysis by antibody and complement after treatment with aminoethylisothiouronium bromide hydrobromide (AET).

After treatment with aminoethylisothiouronium bromide hydrobromide (AET), the ascites forms of the diethylnitrosamine-induced guinea pig hepatomas, line-1 and line-10, were susceptible or more susceptible to killing in vitro by certain combinations of tumor-specific or IgM anti-Forssman antibody and either human or guinea pig complement. Since AET could be toxic to either cell line, conditions of pH, concentration of AET, and duration of exposure of the cells to the reagent were determined that resulted in enhanced susceptibility without significantly affecting cell viability. Chicken erythrocytes (CE) also were tested and AET-treated cells found to be more susceptible to lysis by IgM anti-Forssman antibody and guinea pig complement. The enhancement apparently was not due to increased ability of AET-treated CE to fix antibody. In contrast to CE, the lytic susceptibility of sheep cells was not affected by AET treatment. In addition to AET, several drugs and enzymes that also can affect the susceptibility of the tumor cells to antibody and complement were tested and found to be ineffective against CE. Since AET reputedly acts directly on the cell surface, it seems reasonable to assume that the increased susceptibility of the tumor cells and CE to antibody and complement may result from a modification of the cell surface.


Suppression of experimental allergic encephalomyelitis by EN3638: dependence on adjuvants and treatment schedules.

Oral administration of 2, 3 or 4 doses of 100 or 250 mg/kg of EN3638 during the incubation period of experimental allergic encephalomyelitis delayed the onset and reduced the incidence and severity of clinical signs and histological lesions. Five doses of 50 or 100 mg/kg effected virtually complete and permanent suppression of clinical signs even after cessation of therapy, and five doses of 250 mg/kg eliminated histological lesions as well. Optimum results required coverage of the entire incubation period regardless of dose level. These results were obtained only when carbonyl iron was used as the adjuvant for production of EAE. When complete Freund's adjuvant was used, EN3638 delayed the onset but had little or no influence on late-developing clinical signs and histologic lesions after cessation of therapy. The permanence of suppression when carbonyl iron was used is related to the absence of an oil depot. Carbonyl iron is a superior adjuvant for drug suppression studies.


Intercellular adhesion and its role in epidermal differentiation.

The differentiation of epidermal keratinocytes is accompanied by a regular sequence of changes in the nature of their adhesive interactions. The basis of these changes is discussed with reference to the more detailed studies of intercellular adhesion of other tissue types. In the early stages, desmosome formation predominates. A sequence of molecular events which may underlie desmosome formation and junctional stability is constructed. At the later stages of differentiation, adhesive interactions between non-junctional membranes are of increasing importance, and cells undergo pronounced flattening. The involvement of the cytoskeleton in these processes is considered. Possibilities for further studies on keratinocyte adhesion in normal and pathological epidermis are suggested.


Teratomas, neoplasia and differentiation: a biological overview. I. The natural history of teratomas.

In this paper I have attempted to outline the natural history of spontaneously occurring teratomas and associated tumours, but without introducing any preconceptions or assumptions as to their histogenesis or mechanisms of internal differentiation. The justification for this omission is that there is presently no direct evidence in respect of either process in human tumours of this type, with the exception of recent work by LINDER et al. (1975a, b). The various histopathological classifications of teratoid lesions have not been discussed in detail either, because for the most part they have been evolved to serve a specific prognostic purpose on either an empirical basis or on certain histogenetic assumptions. In either case there is an inevitable tendency to emphasize extremes of morphological appearance at the expense of possible continuities of structure and behaviour across the spectrum of teratoid lesions. The purpose of this paper, on the contrary, has been to discern features common to these tumours whenever and wherever they occur. Thus, human teratomas are uniquely puritissular lesions composed, potentially at least, of virtually every recognizable (and probably some as yet unrecognizable), type of embryonic, foetal and adult cell and tissue, together with, in some cases, frankly malignant cells of no obvious derivation or differentiation. In spite of the occasional appearance of structures resembling pre-somite embryos (embryoid bodies), there is no compelling evidence that human teratomatous histogenesis recapitulates embryogenesis in any strict fashion. Histologically, the overwhelming impression is of a more or less random association of cells and tissues at different stages of development and differentiation that proceed up to but not beyond organogenesis. Such teratomas are found at a number of well-defined sites, of which the sacrococcyx is the most prominent in infancy and the gonads during adult life. Both gonadal and extragonadal sites are also associated with apparently homogeneous neoplasms containing cells with features reminiscent of early stages of germinal differentiation which evoke, in many cases, a marked stromal and lymphocytic response, the so-called germinomas. In 'mixed' tumours, which are recognized in an increasing proportion of cases, there is karyological evidence of a conjoint rather than separate origin of teratomatous and germinomatous elements in at least some tumours, challenging a long held belief in their invariably separate character (e.g. HALLEY, 1963).


Milk proteins and mammary cancer: a review.

Milk proteins are of potential value in characterizing mammary carcinoma from a functional point of view. The major milk proteins are described with special reference to human milk. The caseins, whey proteins and membrane structures in the milk are discussed in terms of their chemical, biological and immunological properties. In vitro culture systems help to define the hormone dependency of normal mammary tissues and mammary carcinomas. The control of proliferation and milk protein production are partially independent, and this becomes especially evident in experimental tumours. Clinical samples of human tumours and plasma from patients with mammary carcinoma show differences in the level of certain milk proteins. These appear to relate to tumour spread, state of differentiation and the presence of hormone receptors.


The nodular adrenal.

Nodules commonly occur in the human adrenal gland. They are best regarded as part of the ageing process, produced in response to adrenal vascular changes. Nodules exhibit a wide diversity of size and distribution and are seen not only in subjects with normal adrenal function but also in patients with hypercorticalism (Cushing's and Conn's syndromes). In these disorders, the nodules appear to be a consequence of the diseases, rather than being aetiological.


Treatment of mental disorders in India.

1. Mental health gets a low priority all over the world but much more so in developing countries. 2. In India, modern psychiatric facilities are available only in the cities. Mental hospitals are becoming modernized but the backbone of psychiatry is the psychiatric department in the General Hospital where treatment is out-patient and family based except short admissions for crisis intervention. 3. Psychotropic drugs are preferred both by psychiatrists and patients, next being electroconvulsive therapy (ECT) and other physical treatments followed by psychotherapies. 4. In view of paucity of facilities, 80% of the population has to depend on indigenous treatments consisting of Ayurvedic and Unani systems of medicine, religious treatments consisting of prayers, fasting, etc. and various witchcraft and magical rituals.


HLA system, psychiatry and psychopharmacology.

1. A number of antigens of the HLA system showed significant associations with clinical phenotypes of schizophrenia and manic depressive disorders. Even though we emphasize the need to consider these results with caution, we suggest that the findings now available indicate that the chromosomal regions which control the HLA system also contain the genetic material related to schizophrenia. On the other hand, although initial results have been encouraging, more work is needed before we can draw definite conclusions about the relationships between HLA antigens and the genetics of manic depressive disorders. All this recently acquired information is discussed and new lines for research are also suggested, including linkage studies in families, which might offer a more precise understanding of the genetic contribution to psychopathology. 2. Stressed also is the possibility that HLA determinants interfere with the interaction between neurotransmitters and/or psychotropic drugs and specific receptors. In this light, the clinical implications of HLA-A1 reactions to chlorpromazine and haloperidol, and of the HLA-A1 cross-reacting antigens are analyzed. Such studies are as yet very preliminary; however they perhaps help to clarify both the real biological roles of these antigenic membrane structures and the mechanisms by which psychotropic drugs interact with membrane receptors.


Psychopharmacological studies in genetically determined subgroups of psychiatric patients.

1. As a prerequisite for psychopharmacological studies in subgroups of psychiatric patients two approaches will be described: a. A multiaxial classification system for affective disorders (MULTI-CLAD). b. Studies of ABO- and HLA-systems in patients with affective disorders. HLA: In 107 manic-melancholic patients selected according to the very strict MULTI-CLAD criteria confirmatory evidence was obtained that there is a positive association between affective disorders and HLA-Bw 16; the results were also strongly suggestive of a positive association between HLA-7 and such disorders. ABO: In sixty-six manic-melancholic patients selected along the same criteria, the differences between all patients combined versus controls were not significant, but a significantly higher percentage of bipolar patients (70%) than of unipolar patients (22%) had blood group O, while a significantly higher percentage of unipolar patients (65%) than of bipolar patients (23%) had blood group A. 2. The findings are in the process of further study involving some 300 patients from the Psychochemistry out-patient-clinic. The purpose is to see whether less selected groups of patients with affective disorders show less marked profiles for ABO and HLA, as this will have importance for the selection of subgroups of patients for psychopharmacological studies.


Perspectives and practical applications in psychopharmacogenetics.

1. Individual response to drugs is to a great extent influenced by hereditary factors. 2. The interaction between genetic and environmental factors affecting drug metabolism in man is of crucial importance to the understanding of therapeutic response in psychopharmacology. This proposition is illustrated for various psychotropic drugs such as the monoamineoxydase inhibitors (MAOI), tricyclic drugs and lithium salts as well as for enzymes involved in the synthesis and degradation of biogenic amines. 3. New perspectives in pharmacogenetics and their relevance to psychopharmacology are discussed.


Drugs and the developing skeleton.

The skeleton develops from early embryonal stages until the end of the second decade. Normal morphogenesis requires integrated growth, differentiation and morphogenetic movement over prolonged periods of time. The complexity of the processes involved ensures that the potential for drugs to affect the system is very large, and that a number of metabolic pathways may be disturbed. Skeletal abnormalities are thus an important component of many malformation syndromes and are produced by varied genetic mechanisms combined with environmental effects.


Genetic epidemiology and the prevention of functional mental disorders and alcoholism: family study and biological predictors.

1. This review intends to present some theoretical and practical considerations which appear essential for the development of rational research strategies in the field of primary and secondary prevention of mental disorders and alcoholism. 2. The various advances and trends regarding the nosology and diagnosis of these disorders are discussed. Integrative epidemiological models for relating the multifactorial causation and the heterogeneity (multidimensionality) of these disorders are presented. 3. It is emphasized that alcoholism and the functional mental disorders occur in families as shown by (i) the increased incidence of these disorders among relatives and (ii) the existence of various clinical categories genetically associated. 4. Current methodology in clinical diagnosis and genetic epidemiology represent powerful procedures for typing and subtyping of these disorders. Family studies could identify more homogeneous subgroups and generate hypotheses as to the mode of transmission of mental disorders and alcoholism. 5. Real progress could be made in prevention only if the search for predictors is carried out in homogeneous subgroups. 6. There is a lack of knowledge regarding biological predictors. An urgent need for association studies and linkage analysis should be carried out in order to identify genetic markers (causal relationship) and chromosomal markers. These could provide for the specification of a constellation of markers and the development of appropriate tests to identify subjects at risk likely to develop alcoholism and mental disorders. 7. The immediate issues in secondary prevention and the later outcomes in primary prevention are outlined.


Monitoring of antidepressant drug plasma levels: the next ten years.

Future studies of the relationship between plasma level and drug response in depressed patients ought to take the following facts into consideration: 1. Selective drug analytical methods must be used and subjected to quality control. Methods for the major urinary metabolite(s) of the parent drug should also be developed. 2. Each drug has individual pharmacokinetic and pharmacodynamic properties--it is unlikely that one drug will be effective in all patients even under optimal kinetic conditions. 3. The pharmacologic and biochemical effects of hitherto investigated tricyclic antidepressants correlate significantly to the concentrations of parent drug and/or its active metabolite in plasma. 4. It is more likely that a significant correlation will be found between the total tricyclic antidepressant level in plasma and the therapeutic outcome in a patient sample if the range of plasma levels is large--in this case the relatively small interindividual differences in plasma protein binding play a minor role. 5. Concomitant somatic disease may change the kinetics of antidepressant drugs. 6. The clinical methods used for selecting and rating study patients with depressive disorders must be standardized. 7. Novel rapidly acting drugs are desirable because the slow onset of action of tricyclic antidepressant seriously hamper their clinical evaluation. 8. A strong correlation between plasma concentration of an antidepressant drug and clinical outcome is strong evidence that the clinical effect is due to the drug rather than nonpharmacological factors.


The role of plasma concentrations in the use of tricyclic antidepressant drugs.

1. The range of tricyclic antidepressant plasma levels (or doses) needed for therapeutic response remains largely unresolved, since quantal plasma concentration (or dose)--response relationships have not been clearly defined for either therapeutic or nontherapeutic effects. 2. The fact that certain patients apparently became more depressed at higher plasma levels must be balanced against the facts that "depression" is a mixture of disorders as yet poorly distinguishable and that tricyclic antidepressants have multiple pharmacologic effects. 3. There is presently no justification for routinely monitoring tricyclic antidepressant plasma levels, even though, as for any drug, such determinations are justifiable in patients who are unresponsive or show signs of toxicity. 4. Plasma level determinations can never replace sound clinical judgment and dosage adjustment for individual patients.


Negative aspects of psychotherapeutic drug treatment.

Negative effects of psychotropic substances may be divided into seven categories: 1. Physical symptoms, e.g. headache, dry mouth, etc. 2. Somatic complications, i.e. conditions which seriously impair the patient's health, e.g. choleostatic jaundice or tardive dyskinesia. 3. Behavioural toxicity, i.e. noxious modifications of the patient's behaviour as the result of the drug's action, e.g. drug-dependence, psycho-motor retardation, etc. 4. Compliance problems, i.e. irregular or unreliable adherence to the prescribed drug regime by the patient. 5. Restriction of the patient's learning capacity, which may represent an obstacle to the application of other treatment modalities, e.g. behaviour modification, or to the patient's social re-adaptation. 6. Psychodynamic interference with psychotherapy, e.g. by diminishing the patient's motivation to pursue this type of treatment or by disturbing the structure of his defences. 7. Reducing the physicians' therapeutic efficacy if he relies exclusively on psychotropic agents.


The pathogenesis of essential hypertension.

Essential hypertension is a quantitative abnormality, the pathological effects and risks increasing with the blood pressure level. In Western countries blood pressure rises with age in most individuals, so essential hypertension is more frequent in middle and older age groups. It is likely that an individual's blood pressure level is determined by many interacting factors. These include heredity, which probably acts multifactorially, and many environment influences, including psychological stress and obesity. Specific factors may be of varying importance in different individuals and in different populations. Several physiological mechanisms control the blood pressure level and may be altered in essential hypertension. In early hypertension sympathetic nervous activity is sometimes increased, although in long-standing hypertension this is less marked. Cardiac output may be increased in borderline hypertension but is normal in established hypertension, when total peripheral resistance is increased. Total exchangeable sodium is normal, while the renal pressure-natriuresis balance is altered, so that for a given pressure the hypertension kidney excretes less sodium. In some patients, plasma renin is low, probably as a result of renal adaption to prolonged hypertension. The pathogenic sequence in essential hypertension is uncertain. Increased autonomic activity may cause vasoconstriction in renal and other arterioles and increase cardiac output, leading to a rise in blood pressure. Elevated pressure itself produces structural changes in the resistance vessels, including those of the kidney, which eventually maintain the hypertension even when the initiating stimulus is removed. The way in which heredity and environment influence pathogenic mechanism is also uncertain. Heredity might, for example, influence the autonomic response to stress or the liability to irreversible changes in the resistance vessels or in the kidney. Environmental factors may also increase autonomic activity, enhance vascular reactivity or alter renal function.


Endomyocardial biopsy.

Cardiac biopsies are being undertaken with increased frequency in recent years. The present review concentrates mainly upon the role of this technique in the more accurate classification and diagnosis of the cardiomyopathies. In addition the quality of biopsy material and the degree to which it represents the overall cardiac pathological changes are presented.


The relevance of the structural co-factor (chemogenic lesion) in adverse and toxic reactions of neuropsychotropic agents.

1. Multidisciplinary methodologies in human and experimental investigations revealed that neuropsychotropic agents display multiple neural and extraneural "targets" or bioreceptors. 2. The adverse and toxic reactions would be, in essence, the expression of a reversible or irreversible "chemogenic lesion" resulting from the molecular interactions among the chemical agents and the morpho-chemical correlates of the organism at any level of the structural organization. 3. In pathogenic terms, this "chemogenic lesion" appears as a patho-chemical condition or a dynamic state of interacting chemical and biological mechanisms rather than a single cause.


The mechanisms of human tumour-induced osteolysis and hypercalcaemia.

This is a brief resume of the current knowledge regarding the mechanisms whereby tumours may cause the breakdown or increase the turnover of bone matrix resulting in hypercalcaemia. The precise mechanisms and agents still remain to be ascertained. This would appear to be an investigative area worthy of significant research effort in view of the potential benefit to patient care which may then ensue.


Psychotropic drugs and their relationship with psychopathology of affective disorders.

In this paper we discuss the relationship between the psychopathology of depressive behavior and the effectiveness of drugs affecting mood. Particular emphasis is given to the recent contribution of the authors (1975-1977) to the specific items of: 1. non-psychological validation of diagnosis of primary affective disorders 2. predictability of the response to antidepressant drugs 3. factors involved in the effectiveness of long-term lithium treatment. Key words: depression, primary affective disorders, secondary affective disorders, unipolar depression, bipolar depression, N1-methylnicotinamide, 3-methoxy-4-hydroxyphenylglycol, tricyclic antidepressant drugs, lithium prophylaxis, intraerythrocyte/plasma lithium ratio. Cerebral spinal fluid (CSF); intraerythrocyte/plasma lithium ratio (Li ratio); 3-methoxy-4-hydroxyphenylglycol (MHPG): monoamine oxidase (MAO); morbidity risk (MR); N1-methylnicotinamide (N1-MN); norepinephrine (NE); primary affective disorders (PAD); secondary affective disorders (SAD).


The classification of depressions and the activity profile of the antidepressants.

1. Pre-requisiste for a successful treatment of depressions is an accurate diagnosis. 2. The nosological classification proposed by the WHO-ICD (International Classification of Diseases, 9th edn.) differentiates three main groups of depressive states, i.e. somatogenic, endogenous and psychogenic depressions. 3. In somatogenic depressive manifestations, first of all, the organic disease has to be treated. 4. In endogenous and psychogenic depressions, the kind of treatment and the indication for long-term therapy can be derivated by the nosological diagnosis. 5. The syndromal diagnosis determines the choice of the antidepressant with the correct activity pattern and gives also the indication for a combined treatment with beta-blockers. 6. Nosological classification, syndromal diagnosis, activity patterns of the antidepressants, the indication for long-term treatment and combined therapy are discussed.


Psychopharmacological prospectives in the treatment of dementia.

1. Dementias have a complex etiology and pathogenesis which should be carefully evaluated in order to attempt a medical treatment. 2. Drugs are among the most frequent causes of dementias, particularly drugs with anticholinergic properties. 3. A similarity between the mental symptoms of anticholinergic poisoning and senile dementia has been observed. 4. Recent investigations have also presented a decrease of cholinergic activity in postmortem material of subjects with Alzheimer's disease. Also a number of data suggest that recent memory would be related to changes in the metabolism of brain acetylcholine (Ach). 5. The possibility that drugs stimulating brain cholinergic mechanisms might be used in the treatment of dementias is envisaged.


Treatment of epilepsy: with special reference to developing countries.

1. Epilepsy, a common chronic neurological disorder, constitutes an important medical problem especially as in the developing countries there is a great dearth and shortage of health personnel, especially trained ones, in clinical neurosciences. The prevalence of epilepsy in developing countries is probably higher than in the Caucasians although accurate epidemiological data are lacking. 2. Epilepsy is discussed with special regard to the need for accurate diagnosis, and the difficulties encountered in developing countries. 3. Pharmacotherapy should be as simple as possible and suggestions are made on the essential drugs useful in the control of epilepsy with special reference to developing countries and in the context of economics and ready availability. Grand mal and focal epilepsies could be controlled by phenobarbitone, with phenytoin, sulthiame and carbamazepine kept as reserves or adjuncts. Minor (generalised) epilepsies could be controlled by ethosuximide, with clonazepam and sodium valproate (sodium dipropylacetate) as reserve drugs and adjuncts. For status epilepticus, diazepam is effective and readily available, with clonazepam and phenytoin as alternatives. 4. The problems in the management of epilepsy in the developing countries include lack of facilities and personnel to ensure accurate diagnosis and treatment, inadequate supply or non-availability of drugs, high defaulting rate of patients, the adverse and often pernicious social stigmatisation of the epileptic. 5. Possible solutions to some of these problems include integration of management (in simple terms) of convulsive disorders into the basic health system of delivery of health care in developing countries, aggressive pursuit of health education of the public by governmental and non-governmental agencies, active, intensive and sustained promotion of training of health personnel in clinical neurosciences and research aimed at producing long-acting anticonvulsants.


Sites of action of amphetamine intrinsic to catecholaminergic nuclei: catecholaminergic presynaptic dendrites and axons.

1. It is now well established that the behavioral actions of amphetamine, especially locomotor and stereotyped behaviors, are dependent in part upon the release of catecholamines in the central nervous system. 2. A variety of empirical evidence has established that the release of catecholamines by amphetamine leads to changes in neuronal activity in regions postsynaptic to catecholaminergic nerve terminals. In addition, release of catecholamines is accompanied by a marked inhibition of neuronal firing in catecholaminergic neurons. 3. At least two conceptions have been advanced to account for this marked decrease in catecholaminergic neuronal activity. (a) In one of these, release of catecholamines from presynaptic terminals is thought to lead to a compensatory decrease in neuronal firing rate by means of a postsynaptic neuronal feedback loop from regions innervated by catecholaminergic neurons. (b) In the other, decreased neuronal activity is hypothesized to result from local release of catecholamines onto or near catecholaminergic neuronal dendrites and somata, a phenomenon that has been characterized as self-inhibition. 4. For dopaminergic neurons, recent biochemical, neuropharmacological and neuroanatomical evidence suggests that the latter process could be subserved by dopamine released from dopaminergic neuronal dendrites, i.e., "presynaptic" dendrites.


Psychological performance in anxious patients treated with diazepam.

1. After each week of a flexible dosage treatment with either diazepam, amylobarbitone or placebo anxious patients were assessed by a comprehensive battery of psychiatrist's ratings, subjective tests and psychological performance tasks to detect the clinical and psychological effects of the drugs. 2. Self rated anxiety and insomnia were improved significantly by diazepam, while amylobarbitone improved only the self rated insomnia. 3. An impairment of performance relative to placebo was detected on two performance tasks after the barbiturate and on six performance tasks after the benzodiazepine. 4. The patient's reported level of anxiety under each treatment condition was related to the performance on the five tasks showing drug effects, thus confirming the postulated inverted U-shape relationship between drive and performance.


Medico-social evaluation of the long-term pharmacotherapy of schizophrenia. Comparative study of fluphenazine and pimozide.

1. A controlled clinical trial has shown oral pimozide to be clinically at least as effective as fluphenazine decanoate in the continuation treatment of schizophrenia. 2. Pimozide was also associated with more favourable measures of social outcome. 3. Some implications of these findings are discussed.


Consequences of prenatal maternal alcohol exposure including the fetal alcohol syndrome.

1. Some recent findings on fetal alcohol effects are presented under the headings of introduction, classification--clinical signs and symptoms, epidemiology, etiology--possible pathogenesis, diagnosis, prognosis, management, discussion and conclusions. 2. The present level of knowledge suggests that the toxic effects of alcohol on the fetus may be a health hazard of significant proportion and that further clinical investigation and basic science research studies are indicated.


Genetic methods and preventive psychiatry.

1. The meaning of the consistently high estimates of heritability of psychiatric disorders such as affective disorders and schizophrenia is that a small proportion of families accounts for a very large proportion of the population diagnostic variance. 2. This implies that the classic community mental health services model of a randomly distributed risk in a geographically defined catchment area population is inappropriate, and that efficient case finding and follow-up would result from tracing illness within pedigrees of known cases. 3. Application to clinical practice of family study methods developed in genetic research enables efficient identification of unrecognized and untreated cases, and early provision of care (secondary prevention). The use of family study methods will also uncover milder and variant ("spectrum") forms of illness in relatives of known patients, which then become accessible to treatment. 4. A family study of affective illness at the United States National Institute of Mental Health, demonstrated how additional ill persons including previously untreated cases could be identified. Starting with 86 Bipolar probands, we interviewed all available first degree relatives, and saw second degree relatives if there was indicated psychopathology by history. 5. Of the 405 living first degree relatives of 86 Bipolar I patients, the study found 1.2% had lifetime diagnosis of untreated Bipolar illness, 2.7% had untreated Unipolar illness, 4% had less severe personality disorders and 2% suffered from behavioral disorders such as drug abuse or alcoholism.


Identification of high-risk criteria in the framework of W.H.O. collaborative research in the major mental disorders.

1. Primary prevention of psychiatric disorders from the point of view of WHO was discussed. 2. It was emphasized that in contrast to developed countries malnutrition and infection-induced secondary mental deficiencies are still prevalent in the developing world. 3. Some of the relevant WHO projects were briefly reviewed.


Primary and secondary prevention of alcoholism: emerging trends and research strategy.

1. The theoretical and empirical value of a "level conceptualization in prevention" as proposed by the classical 'public health' model is challenged. 2. Although prevention should be related only to reduction of incidence of the disease (new cases), for various reasons the authors also include secondary prevention in the prevention of alcoholism. 3. Two main strategies are proposed in the prevention of alcoholism: (a) the global prevention directed to the population at large, and (b) the oriented or selective prevention directed to specific target groups (high risk groups). 4. In primary prevention a theoretical model, based on system theory "the ecogenetic wheel model" is proposed which tries to integrate the multidimensional (dependent variables), multifactorial and family approaches (independent variables) involved in alcoholic-related problems. 5. The biological predictors (chromosomal and biochemical markers) and psychological predictors to be used in the early detection of alcoholism are discussed. 6. Two theories are suggested for detection of biochemical markers: direct detection in naive subjects and indirect detection (activating theory) in subjects exposed to ethanol. 7. Secondary prevention could presently benefit from a "constellation" of clearly identified biological markers which would allow for the early detection of initial alcoholics. Screening programs could be implemented for selected target groups such as (a) occupational alcoholism programs, (b) programs for alcoholics' families, (c) programs for specific hospitalized patients and (d) alcohol programs related to traffic accidents.


Childhood family influences on risk of alcoholism.

1. The self-destructive behavior of chronic, excessive drinking is motivated by self-hatred in combination with ambivalent expressions of ambition and dependency. These sources of vulnerability to alcoholism develop in early childhood. 2. The protective influence of a favorable, stable self-evaluation is indicated by characteristics of occupational groups with a low incidence of alcoholism, such as monarchs and Presidents of the United States. 3. Characteristics of the personal name may influence development of self-esteem. In a small sample of Presidents and brothers of Presidents with drinking problems, most had a brother with the same first name as the admired, successful father. 4. Primary prevention should help parents to recognize the child's need for love, tolerance, and responsibility. These influences enable the child to develop autonomy and self-esteem.


Early detection of high risk subjects in affective disorders.

1. Family, twin and linkage studies indicate that genetic factors are involved in the etiology of major affective disorders. 2. Recent clinical and biological research suggest that affective disorders are an heterogeneous group of illnesses, with variable genetic determination. 3. Since Lithium carbonate has been proven to be an effective prophylactic treatment in affective disorders, the question arises whether early detection of affective illness is possible and what are the implications for genetic counseling and primary prevention of affective illness.


Genetic markers in depressive disorders.

1. Association or linkage between a known genetic marker and an illness with a presumed genetic etiology supports two conclusions: a) The genetic etiology would be considered definite, and b) the illness should be considered a homogeneous disease. 2. After separating depressions on the basis of gross familial differences, a finding of linkage or association in any subgroup would indicate that the particular illness is autonomous. Data on association between bipolar and unipolar depression and subtypes of the ABO system are given. 3. Methodological problems in association studies are discussed. 4. Preliminary data suggest the possibility of linkage between the alpha-haptoglobin locus and third component of complement locus and depression spectrum disease, a depression which is familially defined by the presence of alcoholism in the first-degree family member.


The coexistence of androgen and glucocorticoid receptors in the DDT1 cloned cell line.

The hamster ductus deferens cloned tumor cell line (DDT1) has been shown to contain both androgen and glucocorticoid binding activity. The androgen receptor binding site concentration is 1.07 x 10(-13) mol of testosterone/mg protein, and testosterone (T) binds with a Kd of 4.3 x 10(-10) M. Dihydrotestosterone (DHT) is also bound to the receptor with a Kd of 2.99 x 10(-10) M and the binding site concentration is 1.33 x 10(-13) mol/mg protein. The order of steroid binding affinity is DHT greater than T greater than Estradiol greater than Progesterone. Cortisol, dexamethasone, and triamcinolone acetonide do not inhibit the androgen binding in vivo or in vitro. In a cell free system antiandrogens inhibit the binding of DHT. The DDT1 cells have a separate receptor for cortisol which binds at saturation 3.44 x 10(-13) mol cortisol/mg protein and has a Kd of 4.54 x 10(-9) M. These studies provide evidence that these endocrine target cells contain specific high affinity receptors for more than one type of steroid. The glucocorticoid receptor may be important for maintaining essential undifferentiated functions while the DHT receptor gives the specific characteristics of sex hormone responsive tissues.


Hormonal control of bone collagen synthesis in vitro. Effects of insulin and glucagon.

The direct effects of porcine insulin and glucagon on bone collagen and non-collagen protein synthesis have been examined in cultures of calvaria obtained from 21-day fetal rats. Bones were incubated for 24 to 96 h and [3H]proline was added for the last 2 h of culture. Incorporation of the label into collagenase-digestible protein (CDP) and noncollagen protein (NCP) was determined using purified bacterial collagenase. Insulin increased the labeling of CDP by 60 to 115% at concentrations of 10(-9) to 10(-6) M. A smaller stimulatory effect was observed on NCP. The effect on CDP appeared after 12 to 24 h of culture, was maintained for 96 h in the continuous presence of the hormone, but was lost within 3 h of removal of insulin from the culture medium. Insulin appeared to have a direct effect on collagen synthesis and not on collagen breakdown. Insulin did not affect the incorporation of [3H]uridine or [3H]thymidine into the RNA and DNA fractions of bone at 24 h. Insulin opposed the inhibitory effects of parathyroid hormone and dibutyryl cyclic-3',5'-adenosine monophosphate and to a lesser extent, the inhibitory effect of isobutylmethylxanthine on the labeling of CDP. Glucagon did not affect the response to insulin and by itself had small and variable inhibitory effects on proline incorporation.


Inhibition of the in vitro pituitary response to luteinizing hormone-releasing hormone by melatonin, serotonin, and 5-methoxytryptamine.

The effects of pineal indole compounds on the response of the neonatal rat anterior pituitary gland to LH-releasing hormone (LHRH) were studied in organ culture. After 24 h of culture under control conditions, pituitary glands from 5-day-old female rats were routinely incubated for an additional 24 h with the test compounds. Medium LH content was determined by double antibody radioimmunoassay. LHRH (10(-9) M) induced a 10-fold increase in LH levels over control values. Melatonin at a concentration of 10(-9) M significantly reduced the LHRH-stimulated release of LH; maximal suppression to 14% was attained with 10(-8) M melatonin. Similarly, 10(-8) M LHRH caused a 26-fold elevation in medium LH which was suppressed to 62, 55, and 47% by 10(-9), 10(-8), and 10(-7) M melatonin, respectively. In short-term experiments, inhibition was evident within 30 min of treatment. A developmental study of the effect of melatonin on LH release revealed significant inhibition with pituitary glands from rats 2, 5, and 10 days of age but not with glands from animals 21 and 30 days of age. Other pineal indoles were tested for their effects on the LH response to a single dose of LHRH (3 x 10(-10) M). Serotonin at a concentration of 10(-9) M significantly suppressed LH release; maximal reduction to 37-53% occurred with 10(-8) to 10(-6) M serotonin. 5-Methoxytryptamine also produced an inhibition which was significant only at 10(-6) M, the highest concentration tested. N-Acetylserotonin, 5-hydroxyindoleacetic acid, 5-methoxyindoleacetic acid, 5-hydroxytryptophol, and 5-methoxytryptophol showed no consistent inhibitory activity at doses up to 10(-7) M. These findings indicate that melatonin, serotonin, and 5-methoxytryptamine can act directly on the neonatal pituitary gland to suppress LHRH-induced release of LH.


Immunohistochemical localization of beta-lipotropic hormone in the pituitary gland.

Identification of the beta-lipotropic hormone (beta-LPH)-producing cells in several species, including man, was performed with the technique involving use of the unlabeled antibody and peroxidase-antiperoxidase complex. Serial paraffin and ultrathin sections were treated for detection of both beta-LPH and ACTH at the light and electron microscopic levels. It was clearly shown that beta-LPH could be found only in the corticotropic cells located in the pars intermedia and pars distalis of all species studied. At the electron microscope level, it could be established that beta-LPH is contained in all the secretory granules of positive cells. These results suggest that beta-LPH is stored in the same secretory granules as ACTH and that both hormones are released together during granule extrusion.


Stimulation of testosterone production in vivo and in vitro in the male rhesus monkey fetus in late gestation.

To assess intrauterine fetal testicular function, the carotid or femoral vessels of rhesus monkey fetuses, 129-145 days gestational age, were catheterized following hysterotomy of the mother. The fetus was returned to the uterus, the catheters were exteriorized through the mother's vagina and the pregnancy was allowed to continue. In this chronic preparation, basal levels of testosterone (measured with an RIA with 65% cross-reactivity with 5 alpha-dihydrotestosterone) in male fetal serum were 0.85 +/- 0.29 (SD) ng/ml. Administration of a 10 or 100 IU intra-arterial bolus of hCG into the fetal circulation stimulated in increase in fetal serum testosterone levels of 70 and 630%, respectively. Other fetuses were challenged with bolus infusions of 10 and 50 micrograms of synthetic gonadotropin releasing hormone (GnRH). The lower dose caused an increase in serum testosterone concentrations in only one of four fetuses, while the higher dose resulted in a positive response in all three experiments performed. With this dose, the mean increase in circulating testosterone concentration after 1 h was 105%. In vitro, specific binding of iodinated hCG was demonstrated in testicular homogenates from rhesus fetuses near term and hCG stimulated testosterone biosynthesis in testicular minces. Maximal stimulation was achieved at hCG concentrations between 5 and 50 ng/ml. The data indicate that the testes of fetal rhesus monkeys during late gestation are capable of androgen biosynthesis and can bind and respond to gonadotropin stimulation. Furthermore, the pituitary-gonadal axis in the fetal male monkey is capable of responding to GnRH stimulation at this stage of gestation.


Newer aspects of pernicious anemia.

Although readily treatable with vitamin B12, pernicious anemia continues to captivate investigative endeavors of those interested in the pathophysiology and pathogenesis of this disorder. Notable advances have been made in understanding properties of intrinsic factor, vitamin B12-binding proteins, structure and de novo synthesis of vitamin B12, mechanism of action of vitamin B12-dependent enzymes in man, and metabolic consequences of reduced activities of these enzymes in pernicious anemia. Similarly, newer morphological observations have given information regarding pathogenesis of some of the cytological abnormalities found in megaloblasts, and recent cytochemical studies have shed light on abnormalities of nuclear and cytoplasmic constituents in vitamin B12-deficient cells. Both cellular and humoral factors may contribute to immune-mediated processes in pernicious anemia, although as yet, it has not been established with certainty that pernicious anemia is an autoimmune disorder. As we look ahead, it will be important to define the process or processes responsible for atrophic gastritis, which is the pathophysiological basis of pernicious anemia. Likewise, advances in biophysics used in the study of cell membranes, cell surface phenomena, and metallic ion transport may find applicability in the study of pernicious anemia and perhaps provide further insights into metabolic abnormalities responsible for the development of megaloblastosis.


Paroxysmal cold hemoglobinuria.

The clinical and hematological features of a rare autoimmune disorder, PCH, are reviewed. Based on the case reports of 24 patients suffering from this disease, the presence of cold hemolysins in the sera of these patients as the main cause for the red cell destruction following exposure to cold is further discussed. However, recent electron microscope and biochemical studies suggest, in addition, that alterations of the red cells, and especially of their membranes, may play a role in the hemolytic process. The role of other factors, such as thermal range, specificity, and the immunological properties of the Donath-Landsteiner antibodies, as well as the role of the complement in the cold and warm phase of the Donath-Landsteiner reaction, is discussed. The differential diagnosis between PCH and the closely related CHD is outlined. While most of the reports deal with the mechanism of red cell destruction, relatively little attention is given to the treatment of the disease. It appears that the oldest remedy, i.e., warming of the patient and prevention of his exposure to cold, remains the best.


The microbiology of paranasal sinus infections: diagnosis and management.

Study of the bacteriology of sinusitis and its diagnosis and treatment has been difficult. One problem is the anatomy of the paranasal sinuses; all communicate with a bacteriologically contaminated cavity. Access to all but the frontal sinus involves traversing either the nasal or oral cavity, both of which are teeming with aerobic and anaerobic bacteria. The criteria used to establish the diagnosis of sinusitis has varied widely. There are a number of examination techniques available, but none are foolproof. Therefore, patient populations may not be comparable. The absolute elimination of the possibility of contamination of culture specimens is impossible. Investigators have taken cultures in several ways: of the purulent secretions within the nose, of the contents lavaged from the sinus into the nose, of material aspirated from the sinus, and of tissue removed from the sinus. In most studies prior to 1974, anaerobic cultures were not performed. Studies of various treatment programs have used differing criteria to monitor the progress of treatment. No single method is completely reliable. Clinical signs and symptoms, radiologic appearance, the results of irrigation, and thermography have been used to follow patients. Many studies have used multiple therapeutic maneuvers concurrently, for example, antibiotics, lavage, and a decongestant. In some there were no controls. Because of these problems, as is true in many clinical areas of investigation, meaningful comparisons of various studies are difficult. Despite this, there are some areas of consensus in the literature.


Classification of lymphomas.

Malignant lymphomas are neoplasms of cells of the lymphoreticular or immune system. Classification of these neoplasms has long been controversial and confusing. In recent years, considerable progress has been made in establishing useful and prognostically significant classifications of lymphomas. Currently, lymphomas may be divided into two main groups: Hodgkin's disease and non-Hodgkin's lymphomas. The Rye classification of Hodgkin's disease is now widely accepted and used throughout most of the world. In contrast, considerable conflict exists about the schemes of non-Hodgkin's lymphomas. The traditional classifications of non-Hodgkin's lymphomas currently used by most pathologists are based purely on morphologic grounds, and, despite the fact that they may be conceptually incorrect, they have often been shown to be useful for clinicopathologic studies. New or modern but yet untested schemes based not only on morphologic criteria, but also on recent immunologic techniques, have been proposed. This work will review the classifications of Hodgkin's disease and the non-Hodgkin's lymphomas, emphasizing the currently used schemes, describe the major modern classifications of lymphomas, and discuss and illustrate the subclasses of lymphomas and the differential diagnoses of the various types of lymphomas from nonlymphomatous proliferations which may mimic them.


Clinical enzymology in cancer.

It is fair to say that so far, and with few exceptions, the application of enzymology to clinical oncology has been disappointing. This is certainly true with regard to cancer screening and diagnosis. It is unlikely that any single enzyme or isoenzyme will emerge as a sufficiently sensitive or specific indicator of cancer, and it would seem more profitable to focus on multivariate or pattern analysis of several enzymes and other measurable body fluid constituents. Another suggested approach would be to establish the normal enzyme levels for individuals and then follow them for changes which might signal the development of a neoplasm. Finally, Weber's concept of key enzymes as the phenotypic markers of neoplasia and targets of chemotherapy would appear to open a new avenue for enzymology in clinical oncology.


Serum ferritin assay.

Ferritin is an iron storage protein of high-molecular weight which is primarily present in the liver, spleen, and bone marrow. A very sensitive immunoradiometric assay has been developed which permits determination of serum concentrations in normal persons and in patients with a variety of different disorders. In normal subjects, the serum ferritin concentration correlates very well with total body iron stores as measured by phlebotomy. The serum ferritin concentration is reduced in patients with iron-deficient anemia and is significantly higher in patients who are anemic for other reasons. Subject areas discussed in this review include the details of the immunoradiometric procedure, the sensitivity and accuracy of the assay, factors influencing the assay, values characteristic of a variety of clinical disorders, and the utility of the assay in clinical medicine and public health.


Discriminant analysis.

Discriminant analysis (DA) is a pattern recognition technique that has been widely applied in medical studies. It allows multivariate observations ("patterns" or points in multidimensional space) to be allocated to previously defined groups (diagnostic categories). The relationships between DA and other multivariate statistical techniques of interest in medical studies will be briefly discussed. The main emphasis is on linear discriminant functions (LDF). The theoretic assumptions underlying DA using LDFs will be presented, and the effect of violations to these assumptions will be reviewed in detail. Alternative methods will be presented when violations cause serious problems. It has been shown that the familiar LDF is fairly robust to departures from the assumptions. The application of the LDF in less than ideal situations therefore often does not cause much harm (if the violations are not too grotesque). Another set of problems reviewed is how to estimate the misallocation probabilities when using discriminant functions. The selection of the "best" subset of variables out of the complete set will be discussed. Practical guide lines are given based on the theoretic studies reviewed. When possible, available computer programs for various problems of DA will be indicated. The review does not aim at covering all medical studies where DA has been applied, since emphasis is on the practical conclusions of the theory of DA.


Methods for detection of hemoglobin variants and hemoglobinopathies in the routine clinical laboratory.

Many mutant hemoglobins and hemoglobinopathies can be identified with a high degree of specificity in the routine clinical laboratory. The most frequent abnormalities--those involving Hb S or C--are usually easily detectable in small amounts of sample analyzed by two simple methods of electrophoresis: cellulose acetate at pH 8.5 and citrate agar at pH 6. Some rarer mutants, e.g., Hb O, Hope, and Camden, can also be recognized by these two methods. Presumptive identification of other relatively frequent mutants, such as Hb D Los Angeles (Punjab) and Hb G Philadelphia, can be accomplished with additional data obtained from globin electrophoresis on cellulose acetate in acidic and alkaline buffers containing urea and 2-mercaptoethanol (or dithioerythritol). Electrophoretic profiles are presented of about a dozen hemoglobins likely to be encountered in screening programs in the U.S. Methods are also presented for identifying other genetic hemoglobin abnormalities--various types of thalassemia, Hb M, unstable hemoglobins, and those of the newborn.


Myoglobin: methods and diagnostic uses.

Myoglobin is the oxygen-binding protein characteristic of skeletal and cardiac muscle. With muscle disease or dysfunction, myoglobin may enter the circulation, and after renal clearance, it may also appear in the urine. Therefore, the presence of myoglobinemia and myoglobinuria may serve as indicators of the presence and severity of muscle disease. With newly developed methods of detection, myoglobinemia and myoglobinuria are now recognized as complications of trauma, ischemia, surgery, states of exertion and stress, metabolic abnormalities, inherited enzyme disorders, toxin and drug actions, and inflammatory states. Infarction of the heart muscle also can be detected by myoglobin assay. Persistent myoglobinuric states may be complicated by renal failure and electrolyte imbalance. The diagnosis of myoglobinemia and myoglobinuria can be now confirmed with the use of immunoassay techniques. Although not yet widely available, they offer the possibility of the specificity and sensitivity needed for clinical use.


Enzyme multiplied immunoassay technique: a review.

A brief review of the various immunoassays is presented before the basic mechanism of the enzyme multiplied immunoassay technique (EMIT) is described. This is followed by a presentation of the specific advantages and disadvantages of this method, as well as its correlation with other methods as applied to qualitative and quantitative determinations of each type of drug for which EMIT technology is available.


Current considerations in digoxin usage.

Basic considerations in biotransformation and pharmacodynamics are presented as a basis for understanding clinical usage. The role of polarity in determining a given glycoside's duration of action and extent of biotransformation is emphasized. The pharmacokinetics are summarized emphasizing the fact that digoxin is not completely absorbed by oral administration. The important relationship of serum digoxin levels to myocardial content and apparently to myocardial response is reviewed. This relationship and the development of precise methods for measurement of digoxin in serum provide the clinician with accurate means to assess myocardial tolerance for digoxin under diverse clinical circumstances. This review includes discussion of methods of digitalization, appropriate use of serum levels, apparent and real resistance to digoxin, and apparent and real sensitivity to digoxin. The limitations of serum levels as a precise guide to toxicity are analyzed. Finally, new developments in use of immunologic therapy for digoxin intoxication are presented.


Counterimmunoelectrophoresis in biology and medicine.

The review will initially focus on the historical development of counterimmunoelectrophoresis (CIE). A part of the manuscript will be devoted to methodological considerations of CIE as well as a discussion of the antisera used. The body of the review will detail each test procedure for which CIE is applicable and discuss unique elements of technique and limits of detection, as well as clinical interpretation of results. The final section will summarize potential applications of CIE in microbiology.


Villous adenoma of the ampulla of Vater. An unusual cause of biliary colic and obstructive jaundice.

An unusual case of biliary obstruction caused by a benign villous adenoma of the ampulla of Vater is reported and the literature reviewed. Of the reported cases, 75% have jaundice or symptoms of cholecystitis. Rarely, gastrointestinal bleeding or pancreatic duct obstruction is a presenting symptom. The tumors are frequently small and can be overlooked. Operative treatment varies from excision of the tumor to pancreatoduodenal resection depending on histological evaluation, intraoperative findings, and the surgeon's philosophy.


Relationships between immunoglobulins and the intestinal epithelium.

The intestinal epithelium is intimately associated with immunoglobulins. This association may begin in neonatal life with the ingestion of large quantities of immunoglobulins in breast fluids. These ingested immunoglobulins probably have a local protective action in the intestinal lumen. In some mammalian species a large portion of the maternal immunoglobulins is translocated intact across the intestinal epithelium into the circulation, providing additional immunological protection. In rodents, the transepithelial translocation of IgG from breast fluids is initiated and critically dependent upon receptors on enterocyte surface membranes for the Fc region of IgG. Close epithelial-immunoglobulin relationships continue throughout life with the transfer of various classes of immunoglobulins across the epithelium into the intestinal fluids. In man and other mammalian species, IgA and IgM are selectively transported through enterocytes, principally in the crypts of intestinal glands. This transfer may involve binding of polymeric forms of these immunoglobulins to receptors on the abluminal surfaces of the enterocytes. The secretory component, a glycoprotein synthesized by enterocytes, may be such a receptor. IgE and IgG enter the gut lumen by mechanisms that are not defined but seem to be distinct from those involved in the translocation of IgA and IgM. Secreted antibodies in intestinal fluids and mucus bathe the luminal surfaces of intestinal epithelial cells but appear not to be firmly bound to their apical plasma membranes or glycocalyces. The intimate association of immunoglobulins with intestinal epithelial cells illustrates the close relationships that exist between the gut and lymphoid cells and their products. These relationships suggest the possibility that the gut epithelium is affected by a large variety of immunological reactions in health and disease; these possibilities, which have been explored only minimally, warrant much attention in the future. Studies on the binding, uptake, and intracellular transport of immunoglobulins by enterocytes could contribute much to the understanding of receptors for immunoglobulins on many other types of cells, such as lymphocytes, macrophages, mast cells, and the lining cells of placental or yolk sac membranes.


Gastrin cell distribution in normal human stomachs and in patients with Zollinger-Ellison syndrome.

Quantitative distribution of gastrin cells was evaluated in three normal human stomachs and in four stomachs from patients with Zollinger-Ellison syndrome. Cells identified by the immunoperoxidase method were counted along the entire length of five mucosal strips parallel to the axis of the lesser curvature and sampled from the posterior to the anterior walls. The number of cells per unit area (2300 microns2) decreased from the pylorus to the borderline of the gastric body from (mean +/- SEM) 50.9 +/- 12.0 to 24.2 +/- 13.0 and from 29.6 +/- 5.6 to 10.4 +/- 2.6 for control and Zollinger-Ellison syndrome, respectively, with large interindividual variations. From factorial analysis no statistical difference was found between the two groups. It is therefore suggested that the number of gastrin cell in antral mucosa may not be a significant criteria in the diagnosis of Zollinger-Ellison syndrome.


Indomethacin in the treatment of ureteral colic.

Based on a theoretical analysis of the genesis of ureteral colic, it was assumed that indomethacin, a potent prostaglandin synthesis inhibitor, ought to be useful in the treatment of patients with an obstructing ureteral stone. Experimental studies and clinical observations have verified this assumption.


The effects of azathioprine and 6 MP on immunity.

The thiopurines, azathioprine and 6 MP are potent inhibitors of both experimental and clinical immune responses. The primary pharmacological activities are mediated by competitive inhibition of enzymes concerned with de novo purine base synthesis; Immunosuppressive activities appear to result from cytotoxic activities directed against antigen-responsive lymphocytes; this inhibition is maximal when the treatment course coincides with the proliferative expansion phase of the response. By contrast, thiopurines are comparatively ineffective if used during an effector phase of an immune response. Furthermore, administration prior to antigenic challenge does not lead to immune inhibition; in fact, it may lead to augmentation of selected immune responses. Treatment with thiopurines does not result in acute lymphopenia; prolonged courses will cause a moderate decrease in circulating lymphocytes. The drug does not selectively deplete peripheral T or B cells but can acutely reduce K (killer) cells, which are effectors in ADCC responses. In addition, short-lived thymocytes and marrow lymphocytes are rapidly depleted by these anti-metabolites. Many in vitro functions of lymphocytes, from treated animals remain normal. Recent studies indicate that, in vitro, azathioprine is specifically able to bind murine T lymphocytes; this can be shown by their ability to inhibit their capacity to rosette with sheep erythrocytes. Azathioprine is also a potent inhibitor of mixed lymphocyte culture responses and can readily suppress the in vitro generation of cytotoxic T cells. These observations suggest that drugs exert preferential toxicities for murine T cells. B lymphocytes for mice appear to vary in their susceptibility for thiopurines. By contrast, the activity of human B cells can be readily suppressed with this drug whereas T helper function is comparatively resistant. In addition to immunosuppressive properties, thiopurines are capable of exerting anti-inflammatory activities, primarily by inhibiting the replication of hematopoietic precursors.


Mechanisms of the immunosuppressive and anti-inflammatory effects of glucocorticosteroids.

Corticosteroids have multifaceted effects on various phases of inflammatory and immunological activity. These include effects on vascular and tissue responses, effects on the movement or traffic of inflammatory or immunologically reactive cells, direct effects on functional capabilities of cells, and direct or indirect effects on various soluble factors mediating inflammation or immunologic activity. It is clear that there is a differential sensitivity of various populations and subpopulations of cells to the corticosteriod modulation of cellular kinetic patterns, cellular interactions, and functional capabilities. In general, corticosteroids have a much greater and more obvious effect on the traffic and kinetics than on the functional properties of cells involved in inflammation and immunologic activity. Hypotheses concerning the precise mechanisms of many of these effects have been proposed, but still await verification and possibly amplification.


DNA arrangement in isometric phage heads.

DNA is wound tightly into phage heads in such a way that it tends to form layers concentric with the rigid protein shell. In P22 and wild-type lambda, DNA completely fills the internal volume, with a highly uniform local packing of adjacent segments; in lambda deletion mutants containing less than a full genome, the local packing distance increases correspondingly.


Lysogeny associated with mucoid variation in Mycobacterium kansasii.

Ten of 200 strains of Mycobacterium kansasii were found to produce very mucoid growth on Löwenstein-Jensen medium. By electronmicroscopy these 10 strains were found to be lysogenic, whereas no phage was observed in cultures of 30 non-mucoid strains. The cultural and biochemical properties of the lysogenic strains are compared with those of non-lysogenic strains, and the morphology of the phages is described.


Cutaneous monitoring of systemic PCO2 on patients in the respiratory intensive care unit being weaned from the ventilator.

A procedure for measuring the partial pressure of CO2 in equilibrium with the epidermis was developed at Hewlett--Packard Laboratories. It consists of determining by infra-red absorption techniques the concentration of CO2 inside a small (50 microliter) chamber applied hermetically over and around an epidermal window (2.25 cm2) stripped of its stratum corneum or horny layer. We have applied the procedure to 25 patients in the Respiratory Intensive Care Unit at Stanford Hospital. Only patients scheduled for weaning from the ventilator were selected for the study. The epidermal windows were on the medial aspect of the forearm and were monitored for 3--6 h. Arterial blood samples were periodically withdrawn from the catheterized radial artery and were analysed by conventional means for subsequent comparison with the cutaneous measurements which were recorded in real time at the rate of one a minute. The range of arterial PCO2 values that were measured varied from 3.33 to 9.30 kPa (25 to 70 mmHg) and correlated well with the corresponding cutaneous PCO2 values that were typically higher than the arterial values by 0.7 kPa (5.2 mmHg) with a standard deviation of 0.2 kPa (1.5 mmHg). Some recordings of cutaneous PCO2 are shown and discussed.


Aneurysm of the membraous septum in ventricular septal defect.

An aneurysm of the membranous septum was found frequently in patients with ventricular septal defect; although appearance at catheterization during infancy was not common, aneurysms were detected in about half of the patients older than 2 years of age. A significant decrease in the left-to-right shunt occurred with the development of an aneurysm, but progression to complete spontaneous closure was not seen in any patient. In three older patients, an aneurysm of the membranous septum "disappeared" with time, even though complete spontaneous closure had not occurred.


Reoperation following direct myocardial revascularization.

Among the 5507 patients who underwent aortocoronary bypass between October 1969 and June 1975, 41 patients (0.007%) developed recurrent angina and required reoperation. The factors necessitating reoperation were graft thrombosis in 10 patients (24%), progression of disease in 12 (29%), graft thrombosis and critical unbypassed lesions in one (2.4%), graft failure and progression of disease in in 12 (29%), graft failure and critical unbypassed lesions in four (10%), and all three factors in two patients (4.8%). Among 10 patients with 50% lesions present but not bypassed at the initial operation, nine of these lesions progressed to significant stenosis and in five patients this was the sole reason for reoperation. At the second operation, total revascularization was achieved in 32 patients (78%). One patient (2%) experienced a perioperative myocardial infarction and one patient (2%) died. This study emphasizes the importance of "complete" revascularization at initial operation, the concept that arteries with 50% obstruction should be routinely bypassed, and the conclusion that risks of reoperation are comparable with those of initial aortocoronary bypass, but that long-term relief of angina is less favorable.


Late development of severe pulmonary venous obstruction following the Mustard operation.

While four patients with d-transposition of the great arteries who had a Mustard operation before 2 years of age developed severe pulmonary venous obstruction 2, 3 1/2, 3 9/12, and 5 years following their operation, initial postoperative catheterization (less than 1 year) revealed only minimal pulmonary artery wedge and right ventricular end-diastolic pressure differences, with normal peak systolic pulmonary artery pressures. Serial clinical examination, including height and weight percentiles, chest X-rays, electrocardiograms, and the presence of a continuous murmur in one patient suggested development of pulmonary venous obstruction. Repeat catheterizations demonstrated pulmonary artery pressures greater than or equal to systemic and pulmonary artery wedge minus right ventricular end-diastolic differences greater than 13. Successful relief of the pulmonary venous obstruction included insertion of a Dacron patch to enlarge the pulmonary venous atrium, incision of the obstructing orifice, and repair of associated intra-atrial defects. Operation and postoperative course have been unremarkable. It is concluded that pulmonary venous obstruction can be both an early and progressively late sequela of the Mustard operation. Serial examinations with a high index of suspicion should allow repeated catheterizations to document the occurrence. Operative revision of the obstruction appears to be effective with minimal risk.


Esophageal spasm: clinical and manometric response to nitroglycerine and long acting nitrites.

The effect of nitroglycerine and long acting nitrites was studied in a group of 8 normal control subjects and 12 patients with esophageal spasm. The objective response of the esophagus to these drugs was recorded by obtaining esophageal manometric studies and was correlated with response in clinical symptoms. In 7 patients who had significant gastroesophageal reflux associated with spasm, the response to nitroglycerine was unpredictable. But in the group of 5 patients with diffuse esophageal spasm without gastroesophageal reflux, the response was uniformly good. All of the patients who responded to nitroglycerine also responded to long acting nitrites. These 5 patients, who were placed on long term management with long acting nitrites, remained symptom-free from 6 months to 4 years. None of them had recurrence of symptoms while they were on long acting nitrite therapy. The study suggests that if esophageal spasm is associated with reflux, the use of nitrites is less effective in controlling spasm than it is in those who do not show this association, and that diffuse esophageal spasm can be effectively managed with long acting nitrites on a long term basis in the absence of reflux. If there is esophageal spasm associated with reflux esophagitis, nitrites may be beneficial as an adjunct to antireflux therapy.


The physical and behavioural complex of dementia.

An inquiry was made into the physical and behavioural problems presented by patients admitted to hospital because of dementia. 81 patients were studied over a period of 3 years, and a comparison was made between the 38 with idiopathic (Alzheimer's) dementia, and the others, most of whom suffered from focal cerebral arteriosclerosis or Parkinson's disease with dementia. The average age was between 70 and 80 years, and the hospital stay averaged 18-28 months. Nursing difficulties ranged from immobility of the patients on the one hand to wandering on the other, especially in the Alzheimer's group. Behaviour disturbances, shouting, incontinence and degenerate habits were found in a high proportion and the incidence of fractures reached 15%. Vascular incidents as complications or causes of death were relatively uncommon; in those who died, the cause was usually infection. The mainstays of treatment were tranquillising drugs, used only when necessary, and in minimal quantities, simple occupational activity, and an awareness by the staff of the high morbidity to which these patients were prone.


Quantitation of blood flow after Le Fort I osteotomy.

Le Fort I maxillary osteotomies were performed on ten macaque monkeys. The particle distribution method (nondiffusible radioactive microspheres) was used to quantitate local blood flow before and after surgery. Significant reduction in blood flow to the osteotomized maxillary segment was noted in those animals (group S) where the descending palatine vessels were transected. Those animals in which the vascular pedicle was intact (group I) showed decreased blood flow to the attached gingiva and alveolar bone, but palatal tissue blood flow was unchanged or increased. The results reinforce the precept of the importance of maintaining an adequate nutrient pedicle when performing orthognathic surgical procedures.


Long-term therapy of myoclonus and other neurologic disorders with L-5-hydroxytryptophan and carbidopa.

We evaluated the therapeutic effect of L-5-hydroxytryptophan (L-5HTP), the precursor of serotonin (5-hydroxytryptamine), combined with carbidopa, a peripheral decarboxylase inhibitor, in patients with intention myoclonus and examined the serotonin metabolites in spinal fluid, blood and urine before and during therapy. In 18 patients with intention myoclonus due to anoxia or other brain damage, 11 derived more than 50% overall improvement during treatment with L-5HTP and carbidopa. Spinal-fluid 5-hydroxyindoleacetic acid was 35% lower in patients with intention myoclonus than in controls (P less than 0.05). Therapy with L-5HTP and carbidopa increased the concentration of serotonin metabolites in urine and spinal fluid. We postulate that a deficiency of brain serotonin is causally related to intention myoclonus and that the therapeutic effect of L-5HTP and carbidopa may be due to the repletion of serotonin in regions of the brain where serotoninergic neurons have degenerated.


Ankle arthrography and ankle distortion.

A ligament rupture is found in some 60% of patients with ankle distortion. The rupture usually involves the anterior talofibular ligament, and there may be associated ruptures of other ankle ligaments. Clinical findings and conventional radiological examination (including stress exposures) are insufficiently reliable for demonstration or exclusion of a ligament lesion. Ankle arthography is a relatively simple method of investigation; interpretation of the images obtained is generally no problem. Surgical exploration has nearly always confirmed the arthrographic diagnosis 'ligament lesion'.