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Thyroid hormone receptor dimerization function maps to a conserved subregion of the ligand binding domain. Thyroid hormone receptors (TRs) bind as dimers to specific DNA response elements. We have used a genetic approach to identify amino acid sequences required for dimerization of the TR beta isoform. Bacteria expressing a chimeric repressor composed of the DNA binding domain of the bacteriophage lambda cl repressor fused to the TR beta ligand binding domain are immune to lambda infection as a consequence of homodimerization activity provided by the receptor sequences. The phenotypes of deletions and point mutations of the TR beta sequences map dimerization activity to a subregion of the ligand binding domain that is highly conserved among all members of the nuclear hormone receptor superfamily. These results confirm and extend previous findings indicating that this subregion plays an important role in the dimerization of TR beta and other superfamily members.

Mobile extracorporeal shockwave lithotripsy. During the last 18 months, extracorporeal shockwave lithotripsy (ESWL) has been provided at Epsom District Hospital using a mobile unit containing a Dornier HM4 lithotriptor. Patients with upper ureteric and renal stones were selected for treatment, which was performed without anaesthesia or sedation as a day-case procedure; 83 patients were treated, 5 of them with bilateral stones. Seventy patients required 1 treatment session, 17 required 2 and 1 patient required 3. There were no serious complications but 3 patients needed ureteroscopy to remove obstructing stones. The overall success rate was 86%. The cost to treat each NHS patient was 253 pounds. Mobile lithotripsy as a day-case procedure is a safe and cost-effective means of treating urolithiasis and can be performed in a District General Hospital.

Cell-bound cations of the moderately halophilic bacterium Vibrio costicola. Over most of the range of salt concentrations in which the moderately halophilic bacterium Vibrio costicola could grow, the sum of the cell-associated Na+ + K+ ions was at least as high as in the external medium. This is in contrast to other moderate halophiles, which have substantially lower internal than external salt concentrations for most of their growth range. The relative amounts of Na+ and K+ in V. costicola varied with environmental conditions. The K+/Na+ ratio fell during anaerobic incubation or when cells were poisoned. As Na+ ions left the cells, K+ ions entered. However, movement of these ions was not tightly coupled, since K+ content of cells could increase without a corresponding decrease in Na+ content. The Mg2+ contents of cells varied little with environmental conditions.

Surgical management of islet-cell adenoma in infancy. Persistent neonatal hypoglycemia is a potentially serious condition which should be recognized promptly, investigated thoroughly, and treated expeditiously. Islet-cell adenoma causing hypoglycemia in infancy is very unusual. Only 23 cases have been reported in the literature. This report documents eight cases of our own and summarizes diagnostic methods, proper medical preparation, and fundamental surgical management. Prompt surgical intervention is emphasized, as this will relieve hypoglycemia and may be important in preventing irreversible central nervous system damage. We are of the opinion that any infant with unremitting hypoglycemia, a high corrected insulin/glucose ratio, and failure to respond to maximum diazoxide therapy will require partial pancreatectomy. Identification of the adenoma at the time of operation is unlikely, and blind pancreatectomy and/or reoperation is not unusual.

Clinical significance of arginase in colorectal cancer. Arginase, a potent immune inhibitor, existed in much greater abundance in the cytoplasm of cancer cells than in normal cells. Serum arginase levels from 31 patients with colorectal adenocarcinoma were determined by using enzyme immunoassay (mean +/- standard error = 18.96 +/- 4.83 ng/ml) and showed to be significantly higher than levels from control subjects (n = 115, 3.09 +/- 0.22 ng/ml) (P less than 0.005). Surgical samples of 15 patients were individually homogenized and assayed by the same method and revealed that the arginase level in tissues with colorectal cancer was two times greater than the level found in normal mucosal tissues (1.74 +/- 0.31 micrograms/g tissue versus 0.77 +/- 0.09 micrograms/g tissue, P less than 0.005). However, the serum arginase levels in patients with colorectal cancer were independent of their carcinoembryonic antigen (CEA) levels (n = 27, arginase 11.81 +/- 1.88 ng/ml, CEA 17.31 +/- 4.24 ng/ml, r = 0.084, P = 0.666). The results suggested that serum arginase level can be a valuable criterion for preoperative evaluation and possibly postoperative follow-up study. It can also combine with CEA determination to intensify the clinical assessment for colorectal cancer.

A PC program for performing multigroup longitudinal comparisons using the Potthoff-Roy analysis and orthogonal polynomials. A PC-program performing the Potthoff-Roy (PR) multigroup (G-sample) analysis of longtidinal data is described and illustrated. This program and the underlying statistical model are useful in the comparison of several longitudinal samples. Applications include the study of growth, development, adaptation, aging, and treatment effects (in short, any phenomenon in which the passage of time is important) for which serial data are available. Specifically, this method fits polynomials to the average growth curves in the samples, and tests hypotheses concerning the curves themselves and the individual coefficients of the polynomials. The program features the utilization of orthogonal polynomial regression coefficients (OPRCs) and is written in GAUSS, a relatively inexpensive yet comprehensive matrix programming language. It is documented that using OPRCs to comprise the within-individual or time design matrix has several advantages over the more usual choice of the successive-powers-of-t form of this matrix and an example of one important such advantage is provided. GAUSS was employed to make the program readily-accessible (i.e., executable code) to biomedical investigators. The GAUSS compiler is not required to run this program. Information regarding the availability of the program is provided in the Appendix.

Prenatal diagnosis and clinical outcome of ovarian cysts. Technical refinements of ultrasound (US) have greatly affected the antenatal diagnosis and treatment of ovarian cysts. From 1985 to 1990 25 consecutive fetuses with ovarian cysts were followed-up by US both during pregnancy and postnatally. All cases were diagnosed between the 28th and 39th weeks of gestation. Deliveries were all at term; cesarean section was required only for obstetric complications. Eight fetuses (32%) showed US patterns of cyst torsion, a finding confirmed at surgery in all. In five patients US patterns suggested complications postnatally that were also confirmed at operation. In six cases cysts increased or remained unchanged in size after 15 days of life: in 50% of these surgery showed ovarian torsion. In the remaining six cases spontaneous resolution occurred within 1 to 4 months. One patient required intrauterine needle aspiration. There were two cases of intestinal obstruction. To date, more than 60% of newborns with ovarian cysts require oophorectomy; however, different treatments (cystectomy, needle aspiration, uncapping) combined with a close US follow-up are likely to reduce this percentage.

Salinomycin effects on mitochondrial ion translocation and respiration. The effects of salinomycin on alkali cation transport and membrane functions in rat liver mitochondria have been investigated. After potassium uptake, stimulated by valinomycin or monazomycin in the presence of adenosine 5'-triphosphate, salinomycin caused rapid release of K(+) from mitochondria. Salinomycin reversed valinomycin- or monazomycin-induced oscillatory swelling of mitochondria preloaded with K(+), Rb(+), and Na(+) but was without effect on Li(+) or Cs(+) preloaded mitochondria. Salinomycin blocked the retention of K(+) more effectively than the retention of Rb(+) or Na(+). Salinomycin inhibited both coupled and uncoupled respiration with strict substrate specificity in medium of low but not in high K(+) concentration. The oxidation of glutamate, alpha-ketoglutarate, and malate plus pyruvate was inhibited by salinomycin, but that of beta-hydroxybutyrate or succinate was not significantly affected. Salinomycin inhibited adenosine triphosphatase activity of mitochondria induced by valinomycin or monazomycin in K(+) and Rb(+) medium without significantly affecting adenosine triphosphatase activity in Li(+), Na(+), or Cs(+) medium. Oxidative phosphorylation in mitochondria was inhibited by salinomycin but the inhibitory effect of salinomycin lacked the substrate specificity observed for respiration. It is proposed that salinomycin perturbs mitochondrial functions by acting as a mobile carrier for alkali cations through membranes.

The serum response factor is extensively modified by phosphorylation following its synthesis in serum-stimulated fibroblasts. Growth factor regulation of c-fos proto-oncogene transcription is mediated by a 20-bp region of dyad symmetry, termed the serum response element. The inner core of this element binds a 67-kDa phosphoprotein, the serum response factor (SRF), that is thought to play a pivotal role in the c-fos transcriptional response. To investigate the mechanism by which SRF regulates c-fos expression, we generated polyclonal anti-SRF antibodies and used these antibodies to analyze the biochemical properties of SRF. These studies indicate that the synthesis of SRF is transient, occurring within 30 min to 4 h after serum stimulation of quiescent fibroblasts. Newly synthesized SRF is transported to the nucleus, where it is increasingly modified by phosphorylation during progression through the cell cycle. Within 2 h of serum stimulation, differentially modified forms of SRF can be distinguished on the basis of the ability to bind a synthetic serum response element. SRF protein exhibits a half-life of greater than 12 h and is predominantly nuclear, with no change occurring in its localization upon serum stimulation. We find that the induction of SRF synthesis is regulated at the transcriptional level and that cytoplasmic SRF mRNA is transiently expressed with somewhat delayed kinetics compared with c-fos mRNA expression. These features of SRF expression suggest a model whereby newly synthesized SRF functions in the shutoff of c-fos transcription.

Delayed suppressive effect of a low dose of caerulein on the grooming behavior induced by the D1-receptor agonist SKF 38393. Caerulein (CLN, 0.8-80 micrograms/kg, s.c.) was administered to male rats 10 min or 24 hr before the injection of SKF 38393 (3 mg/kg, i.p.). The increased mouth movement and grooming behavior by SKF 38393 were suppressed dose-dependently by CLN 10 min before the SKF 38393. CLN at the dose of 0.8 micrograms/kg, given 24 hr before the SKF 38393, suppressed the grooming behavior by SKF 38393. These findings suggest that a low dose of CLN, but not a high dose, had a delayed suppressive effect on the grooming behavior induced by an excess of D1-activity.

Clinical and radiographic "reankylosis" following hip surgery in ankylosing spondylitis. Eleven patients with ankylosing spondylitis underwent reconstructive hip surgery (21 hips). In 10 of these hips multiple surgical procedures had been performed. The final procedure included total hip arthroplasties (16 hips), femoral cup arthroplasties (four hips) and an Austin-Moore prosthetic replacement (one hip). A clinical and radiographic evaluation in the postoperative period revealed a high incidence of decreased joint motion and heterotopic ossification. Clinically moderate to severe restriction of motion was noted in 12 hips, and in six of these "reankylosis" was present. Radiographically moderate to severe new bone formation was seen in 11 hips, and in nine of these "reankylosis" was suggested. An association of excessive ossification and multiple surgical procedures was evident. It would appear that when the prime indication for hip surgery in patients with ankylosing spondylitis is restricted motion, the operation may not be beneficial.

Duodenal intramural nerves in control of pyloric motility and gastric emptying. We have investigated the role of ascending duodenal intramural nerves in the control of isolated pyloric pressure waves (IPPW) and liquid gastric emptying. In six pigs, the proximal duodenum was transected to interrupt intramural nerves. A further six pigs had a sham operation. Four weeks after operation, motility of the antrum, pylorus, and duodenum was recorded by side holes and a sleeve sensor. Gastric emptying of a 1,000-ml test meal was significantly more rapid in duodenum-transected animals (P less than 0.0001) during intraduodenal infusion of each of isosmolar dextrose (424 ml emptied), fatty acid (335 ml), and amino acids (396 ml) than in duodenum-intact animals (dextrose: 128 ml; fatty acid: 57 ml; amino acids: 192 ml). Associated with this, in duodenum-transected animals infusion of each of isosmolar dextrose, fatty acid, amino acids, and hyperosmolar saline failed to produce the stimulation of IPPW seen in duodenum-intact animals. In both duodenum-intact and -transected animals, supramaximal stimulation by intraduodenal infusion of 25% dextrose slowed gastric emptying and stimulated IPPW. Ascending duodenal intramural nerves are a major physiological pathway for nutrient- and osmolar-stimulated feedback control of pyloric motility and gastric emptying.

Transgenic domestic animals provide an animal model for rheumatoid arthritis. Production of transgenic domestic animals by microinjection of egg nuclei has permitted the introduction of exogenous genes into the transgenic animal. Pursell et al (1) report severe synovitis, cardiomegaly, dermatitis, renal disease and gastric ulcers in pigs with an expressed bovine growth hormone transgene. I have hypothesized that rheumatoid arthritis (RA) is a disease with initial symptoms to the gamete (2, 3). This hypothesis is supported by data showing a reduced rate of RA in women using oral contraceptives (4, 5) and remission of RA in pregnancy (6). RA in animals resulting from trauma to the gamete would be consistent with this hypothesis. This paper hypothesizes that some of the pathology associated with genetic engineering of livestock can be attributed to a rheumatoid arthritis-like spectrum of symptoms. This systemic reaction could be sufficiently similar to human RA to permit the transgenic pig to serve as an animal model of the disease.

The binding of low-affinity and high-affinity heparin to antithrombin. Fluorescence studies. The interaction between antithrombin and two forms of heparin, differing in their affinity for the matrix-linked protein, has been studied by fluorescence. The binding of the high-affinity heparin fraction to antithrombin leads to activation of the inhibitor, allowing it to react more rapidly with a number of serine proteases of the coagulation cascade. The interaction with the low-affinity heparin fraction, however, has considerably less influence on this inhibition rate. The binding of either fraction to antithrombin was found to result in an increase of the tryptophan fluorescence of the protein. This increase was much larger for high-affinity heparin than for low-affinity heparin, suggesting a different mode of binding of the two fractions to the protein. The fluorescence enhancement caused by high-affinity heparin is consistent with a conformational change of antithrombin related to its activation. Only the fluorescence enhancement observed on the binding of high-affinity heparin was of a sufficient magnitude to allow quantitative studies. These showed high-affinity heparin to bind to antithrombin with a stoichiometry of about one and with a binding constant at physiological ionic strength of about 8 X 10(7) M-1. At higher ionic strengths, however, the affinity decreased markedly.

Transcervical cannulation of the fallopian tube for the management of ectopic pregnancy: prospective multicenter study. To determine the efficacy of transcervical tubal cannulation and intraluminal methotrexate injection for the management of tubal ectopic pregnancy (EP). Prospective multicenter study of 33 patients with tubal pregnancies. Four university-based gynecology and radiology departments in three different countries: France, England, and Germany. Thirty-three patients who presented with a clinical diagnosis of EP. Patients underwent transcervical tubal cannulation under fluoroscopic or ultrasound control and local injection of methotrexate (up to 50 mg). We evaluate the feasibility of transcervical tubal cannulation for the management of tubal pregnancy. Two patients elected to withdraw from the protocol. In the remaining 31 patients there was complete resolution of the EP in 27 (87%). Surgery was performed in 4 patients. Seventeen patients, 14 of whom desired pregnancies, were available for follow-up to assess the return of reproductive potential. Seven of 7 patients who subsequently underwent hysterosalpingography had patency of the affected tube. Five patients later had an intrauterine pregnancy. One patient had an early miscarriage, two have given birth, and two singleton pregnancies are still ongoing. The remaining patients are symptom free. This study demonstrates that transcervical tubal catheterization in patients with tubal pregnancies is feasible and can be performed without anesthesia or analgesia in most cases. Intraluminal methotrexate per se is capable of causing regression of the EP. This approach offers a new alternative for the treatment of selected patients with tubal EP.

Micrometastases in breast cancer: long-term follow-up of the first patient cohort. "Micrometastases" can be identified in the bone marrow of patients with apparently localised breast cancer using an immunocytochemical stain for epithelial membrane antigen (EMA). Of 39 women who had marrow samples examined at the time of initial presentation (37), or with locally recurrent disease (2), 13 (33%) had samples which contained small numbers of EMA positive cells. 10 out of 23 (44%) lymph-node positive patients were marrow positive, compared to 1 out of 14 (7%) lymph node negative cases (P = 0.03). Long-term follow-up (median 9.5 years) has shown that 11 out of 13 (85%) patients with micrometastases have developed metastatic disease compared to 8 out of 26 (31%) with negative bone marrow aspirates (P less than 0.05). The small number of EMA positive cells detected in bone marrow samples probably reflects the high metastatic potential of primary or recurrent cancers rather than established microscopic deposits; it is not yet clear whether the finding of such micrometastases will act as an independent variable compared to established prognostic factors.

Occupational radiation exposure to interventional radiologists: a prospective study. This study investigates the occupational radiation dose to interventional radiologists and the operator-controlled factors that may affect dose. Thirty interventional radiologists wore radiation badges over and under lead aprons for 2 months and answered a questionnaire. The relationships between dose and caseload, case mix, experience, optional fluoroscopy features, lead apron type, and additional lead shielding were evaluated. Mean projected yearly dose (PYD) over lead was 49.1 mSv (1 mSv = 100 mrem) but was 66.6 mSv for persons performing 1,000 or more cases per year (P = .027). Mean PYD under lead was 0.9 mSv but was 1.3 mSv for persons with 0.5-mm lead coverage and 0.4 mSv for those with 1.0-mm lead coverage (P = .002). No other significant correlation was found. Conclusions are that caseload and apron thickness are the primary determinants of total body dose, that over-lead dose is high enough to warrant additional lead shielding for the head and neck, and that a double-thickness apron lowers under-lead dose by two-thirds. The large difference between under-lead and over-lead doses suggests that use of a collar badge alone for monitoring purposes is not predictive of total-body effective dose for this group of radiation workers.

[Some physicochemical changes in poultry meat caused by Pseudomonas ssp. II]. Studies showed that the reproductive capacity and the biochemical activity of the experimental Pseudomonas ssp. II are manifested to a various extent in the white and red poultry meat. No changes in the meat set in until the microbial count reach 10(8)-10(9) per gram of meat. This critical value is reached on the fifth day for the red meat, and the 7th day for the white meat. Later on the changes in PH, the aminoammonia nitrogen, the volatile fatty acids, the ammonia gas reaction, and the CuSO4 reaction show such values that give grounds to discard the meat. The reaction for the demonstration of H2S is consistently negative, which is referred to as an individual feature of the monoculture used.

Analysis of endocrine active and clinically silent corticotropic adenomas by in situ hybridization. The distribution of pro-opiomelanocortin (POMC) messenger RNA (mRNA) in 7 functional and 17 clinically silent corticotropic adenomas was analyzed by in situ hybridization (ISH) with 35S-labeled oligonucleotide probes using formalin-fixed paraffin-embedded tissue sections cut from blocks that were in storage between 1 to 14 years. All 7 functional adenomas and 4 subtype 1 tumors had detectable POMC mRNA, while 3 of 6 subtype 2 and 1 of 7 subtype 3 silent adenomas contained detectable POMC mRNA. In situ hybridization analysis with an 35S-labeled beta-actin probe showed a positive hybridization signal in 22 of 22 cases, indicating that the absence of detectable POMC mRNA in some adenomas was not due to loss of the mRNAs during processing of the tissues or because of the age of the embedded tissue blocks. Northern hybridization analysis with the oligonucleotide probes in 2 normal pituitaries and an adenoma causing Cushing's disease detected a 1.2-Kb mRNA in all three tissues, indicating that the oligonucleotide probes were very specific. These results indicate that subtype 1 silent adenomas and clinically active adenomas associated with Cushing's disease contain POMC mRNA that is readily detectable by ISH in routinely processed tissue specimens, while only a few of the subtypes 2 and 3 adenomas have POMC mRNA that can be detected in paraffin blocks with the oligonucleotide probes used in this study.

Method for evaluating broth culture media: application to Haemophilus. A method was devised to test the growth-promoting ability of a broth medium. The "dilute to extinction" method determines the inoculum required to develop heavy turbidity in a broth with overnight incubation. A statistical method using Poisson distribution was used to show that a single Haemophilus cell can develop heavy turbidity in an optimal broth. The dilute to extinction method was used to evaluate the shelf life of stored media, to titrate the growth factor requirements of Haemophilus, and to evaluate the use of purified hemin and nicotinamide adenine dinucleotide in a broth medium for the growth of Haemophilus. Of the media tested, the most suitable formulation was Mueller-Hinton broth supplemented with 10 microgram of hemin and 10 microgram of nicotinamide adenine dinucleotide per ml. The dilute to extinction method appears to be especially useful in the development of broth media for fastidious organisms. The method could also be used to assure the quality of other broth media which are required to support the growth of small inocula in the clinical or research laboratory.

[Septic thrombosis of cavernous sinuses. Report of 2 cases]. We report two male adolescents who developed septic thrombosis of the cavernous sinuses after manipulation of a furuncle on the nasal dorsum. We noted in both patients, besides the clinical findings of a generalized infectious process, palpebral edema, proptosis, ptosis, altered pupillary reactivity and bilateral III, IV and VI nerve palsies, as well as dysfunction of the ophthalmic branch of the fifth cranial nerve. One of the patients also had bacterial meningitis. Their cerebral angiograms demonstrated narrowing of the intracavernous portion of both internal carotid arteries. They improved with the antimicrobial treatment, but were left with ptosis and ocular palsies as sequelae. The adequate management of facial furuncle to prevent such a serious complication is emphasized.

11C-SCH 39166, a selective ligand for visualization of dopamine-D1 receptor binding in the monkey brain using PET. The new selective D1-dopamine receptor antagonist SCH 39166 was labelled with the positron emitting isotope 11C and used as ligand for visualization of dopamine-D1 receptor binding in Cynomolgus monkeys by PET. After intravenous administration of the ligand a marked uptake of radioactivity was recorded in the D1-dopamine receptor-rich striatum and neocortex but not in the dopamine receptor-poor cerebellum. The uptake of radioactivity in striatum and neocortex was markedly displaced after the intravenous injection of a high dose of the D1-dopamine receptor antagonist SCH 23390 but not after the 5-HT2 receptor antagonist ketanserine. 11C-SCH 39166 should be a useful tool to explore D1-dopamine receptor characteristics in the living human brain by PET.

The incidence of meconium-stained amniotic fluid from 1980 through 1986, by year and gestational age. The annual incidence of meconium-stained amniotic fluid was analyzed for changes in a total obstetric sample of 45,115 singleton, vertex, liveborn infants over a 7-year study period. The incidence of meconium-stained amniotic fluid for the total obstetric population was calculated for each year of the study period. The sample was then stratified by estimated gestational age, and the incidence of meconium-stained amniotic fluid was calculated for each gestational age group. The incidence of meconium-stained amniotic fluid increased 40.9% over the study period, from 18.8% in 1980 to 26.5% in 1986 (P less than .001). This increase was found to be in a consistent linear trend (P less than .05). The incidence of meconium-stained amniotic fluid was also found to increase significantly in a linear trend as gestational age of the fetus increased. These findings lend support to both the maturational theory and the stress theory of meconium passage in utero.

Cell-mediated immunity to measles, myelin basic protein, and central nervous system extract in multiple sclerosis. A longitudinal study employing direct buffy coat migration inhibition assays. Cell-mediated immunity to myelin basic protein, to an extract of central nervous system white matter, and to measles virus nuclear core, was studied nine patients with multiple sclerosis in a serial longitudinal fashion using in vitro inhibition of buffy coat migration. The mean migration index to all antigens at various times before, during, and after exacerbation of multiple scelrosis in the patients did not differ from the index in a reference group of normal subjects. The incidence of inhibition of migration induced by central nervous system white matter and basic protein was greater than in serially studied normal subjects (p less than 0.05, p less than 0.2 less than 0.1, respectively) but bore no definite relation to clinical course.

Requirement of GTP hydrolysis for dissociation of the signal recognition particle from its receptor. The signal recognition particle (SRP) directs signal sequence specific targeting of ribosomes to the rough endoplasmic reticulum. Displacement of the SRP from the signal sequence of a nascent polypeptide is a guanosine triphosphate (GTP)-dependent reaction mediated by the membrane-bound SRP receptor. A nonhydrolyzable GTP analog can replace GTP in the signal sequence displacement reaction, but the SRP then fails to dissociate from the membrane. Complexes of the SRP with its receptor containing the nonhydrolyzable analog are incompetent for subsequent rounds of protein translocation. Thus, vectorial targeting of ribosomes to the endoplasmic reticulum is controlled by a GTP hydrolysis cycle that regulates the affinity between the SRP, signal sequences, and the SRP receptor.

Frame-of-reference training and cognitive categorization: an empirical investigation of rater memory issues. We considered the effects of frame-of-reference (FOR) training on raters' ability to correctly classify ratee performance as well as their ability to recognize previously observed behaviors. The purpose was to examine the cognitive changes associated with FOR training to better understand why such training generally improves rating accuracy. We trained college students (N = 94) using either FOR or control procedures, had them observe three managers on videotape, and rate the managers on three performance dimensions. Results supported our hypotheses that, compared with control training, FOR training led to better rating accuracy and better classification accuracy. Also consistent with predictions, FOR training resulted in lower decision criteria (i.e., higher bias) and lower behavioral accuracy on a recognition memory task involving impression-consistent behaviors. The implications of these results are discussed, particularly in terms of the ability of FOR-trained raters to provide accurate performance feedback to ratees.

Selective activation of human heat shock gene transcription by nitrosourea antitumor drugs mediated by isocyanate-induced damage and activation of heat shock transcription factor. Treatment of cultured human tumor cells with the chloroethylnitrosourea antitumor drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) selectively induces transcription and protein synthesis of a subset of the human heat shock or stress-induced genes (HSP90 and HSP70) with little effect on other stress genes or on expression of the c-fos, c-myc, or beta-actin genes. The active component of BCNU and related compounds appears to be the isocyanate moiety that causes carbamoylation of proteins and nucleic acids. Transcriptional activation of the human HSP70 gene by BCNU is dependent on the heat shock element and correlates with the level of heat shock transcription factor and its binding to the heat shock element in vivo. Unlike activation by heat or heavy metals, BCNU-mediated activation is strongly dependent upon new protein synthesis. This suggests that BCNU-induced, isocyanate-mediated damage to newly synthesized protein(s) may be responsible for activation of the heat shock transcription factor and increased transcription of the HSP90 and HSP70 genes.

Human upper airway structural cell-derived cytokines support human peripheral blood monocyte survival: a potential mechanism for monocyte/macrophage accumulation in the tissue. A central feature of chronic airway inflammation is accumulation of monocyte/macrophages in the tissue. It is well known that circulating monocytes are short-lived cells whereas tissue macrophages are longer-lived cells. One mechanism that may account for accumulation of inflammatory cells includes enhanced survival and/or differentiation of these cells. Recent studies imply that signals released by tissue structural cells may be crucial in these events. To investigate this notion, human blood monocytes were cultured with either culture medium alone as a control, human nasal epithelial cell-conditioned medium (EpCM), or fibroblast-conditioned medium (FCM) for more than 1 wk. Survival of monocytes in medium alone was 17% at day 7, whereas survival of those cultured with 50% of EpCM or FCM was 62% and 64%, respectively. The effect of EpCM and FCM was dose dependent. Preincubation of either conditioned medium (CM) with an antibody against granulocyte/macrophage colony-stimulating factor (GM-CSF) or an antibody against macrophage colony-stimulating factor (M-CSF) resulted in a partial abrogation of the survival-enhancing effect, to an average of 50% and 30%, respectively. Complete inhibition was obtained by preincubation of the CM with a combination of both antibodies. The effect of CM represented true survival because CM only induced a low profile of [3H]thymidine incorporation and, furthermore, less than 0.3% of the cells cultured with CM underwent DNA synthesis as assessed by autoradiography. In addition, ultrastructural observations demonstrated that most monocytes cultured with either CM but not with control culture medium assumed ultrastructural features of macrophages by day 8 of culture.(ABSTRACT TRUNCATED AT 250 WORDS)

The relevance to protection of three forms of delayed skin-test response evoked by m. leprae and other mycobacteria in mice. Correlation with the classical work in the guinea-pig. The controversy surrounding the protective role of 'delayed hypersensitivity' in tuberculous guinea-pigs has never been resolved. This controversy has arisen because the term 'delayed hypersensitivity' is used indiscriminately to describe both a type of necrotic skin-test reactivity which does not appear until 4-6 weeks after infection, and also non-necrotic reactions which can be elicited within a few days. Responses closely analogous to both have been characterized in mice immunized with mycobacteria. Simple criteria are described which allow these responses to be distinguished from one another, and from the Jones-Mote phenomenon. The relevance of each type to protection, susceptibility and immunopathology in leprosy, tuberculosis, leishmaniasis and listeriosis is discussed.

Isolation and characterization of boar spermatozoa with and without a cytoplasmic droplet. 1. Boar semen was separated on a Percoll density gradient into three populations; a low-density band of immature sperm cells containing a cytoplasmic droplet and a high-density doublet band formed by spermatozoa without a cytoplasmic droplet. 2. In these three cell populations four acid hydrolases were determined, viz. (1) alpha-glucosidase; (2) alpha-mannosidase; (3) beta-galactosidase; (4) beta-hexosaminidase. 3. The release of the hydrolases (1), (2) and (3) from cytoplasmic droplet containing spermatozoa was stimulated whereas the release of beta-hexosaminidase was inhibited by calcium ions. 4. The results suggest that acid alpha-glucosidase, alpha-mannosidase and beta-galactosidase are situated in the acrosome whereas acid beta-hexosaminidase is localized predominantly in the cytoplasmic droplet of boar spermatozoa. 5. We conclude that beta-hexosaminidase should prove useful as a biochemical marker for cytoplasmic droplet containing spermatozoa and hence for the number of immature sperm cells in boar semen.

Reversal of Na+ retention in chronic caval dogs by verapamil: contribution of medullary circulation. The effects of verapamil on papillary plasma flow (PPF) and Na+ excretion were studied in anesthetized chronic caval dogs with low cardiac output and Na+ retention. Infusion of verapamil into the left renal artery (5 and 10 micrograms.kg-1.min-1) caused a dose-dependent ipsilateral increase in renal blood flow and Na+ excretion (from 10 +/- 2 to 171 +/- 32 and 225 +/- 35 mu eq/min, respectively). PPF in the left kidney was 26.6 +/- 4.4 and was significantly greater than that measured in the contralateral kidney (13.3 +/- 2.4 ml.min-1.100 g-1) (P < 0.01). The natriuresis occurred independent of changes in cardiac output and peripheral vascular resistance. In a separate group of caval dogs in which stimulation of the renin-angiotensin and adrenergic systems was intensified with a tighter caval constriction, verapamil failed to induce renal vasodilation or natriuresis and PPF was not altered. Despite the disparate hemodynamic responses, verapamil stimulated renal production of both renin and prostaglandin E2 in both groups of caval dogs. We conclude that the ability of verapamil to induce papillary vasodilation may contribute to the natriuresis seen in the caval dog, in which the site of Na+ retention includes the loop of Henle.

Localization and needle aspiration of breast lesions: complications in 370 cases. A prospective study of the immediate complications of 370 consecutive breast-imaging procedures (203 wire localizations and 167 radiographically or sonographically guided fine-needle aspirations) is reported. Vasovagal reactions occurred in 27 (7%) of 370 cases, ranging in severity from syncope (four of 370, 1%) to mild light-headedness. These vasovagal reactions were independent of procedure type or use of local anesthesia, but were more common in younger patients. Other complications included prolonged (5 min or longer) bleeding (three of 370, 1%) and extreme pain (two of 370, 1%). One patient was found to have malignant hypertension. We conclude that wire localizations and imaging-guided aspirations are generally well tolerated procedures. However, vasovagal reactions are frequent enough to warrant close observation of patients. Radiologists and breast-imaging personnel should be able to recognize and treat vasovagal reactions.

Involvement of pedal peptide in locomotion in Aplysia: modulation of foot muscle contractions. Pedal peptide (Pep) is a 15-amino-acid neuropeptide that is localized within the Aplysia central nervous system (CNS) predominantly to a broad band of neurons in each pedal ganglion. Pep-neurons were identified by intracellular staining and immunocytology or by radioimmunoassay (RIA) of extracts from identified neurons. RIA reveals that 97% of all Pep-like immunoreactivity (IR-Pep) in pedal nerves is found in the three nerves that innervate the foot. Nearly every Pep-neuron sends an axon out at least one of these three nerves. Application of Pep to foot muscle causes an increase in the amplitude and relaxation rate of contractions driven by nerve stimulation or intracellular stimulation of pedal motor neurons. The increase in relaxation rate was the predominant effect. Intracellular recording in "split-foot" preparations reveals that Pep-neurons increase their overall firing rates and fire in bursts with each step during locomotion. Recovery of IR-Pep from foot perfusate following pedal nerve stimulation increases in a frequency-dependent fashion. Thus it appears that one function of Pep-neurons is to modulate foot muscle contractility during locomotion in Aplysia.

Dipeptidyl peptidase IV in the immune system. Effects of specific enzyme inhibitors on activity of dipeptidyl peptidase IV and proliferation of human lymphocytes. Dipeptidyl peptidase IV (DP IV) is a membrane peptidase playing a significant role in the process of activation and proliferation of human thymus-derived lymphocytes. This conclusion is drawn from (1) the induction of this enzyme on mitogen-activated T lymphocytes (cf. Schön, E. & Ansorge, S. (1990) Biol. Chem. Hoppe-Seyler 371, 699-705) and (2) the impairment of different functions of activated T cells in the presence of specific inhibitors and antibodies against DP IV (Schön, E. & al. (1987) Eur. J. Immunol 17, 1821-1826). This paper is aimed at testing new active site-specific peptide inhibitors for their efficiency as inhibitors of lymphocyte DP IV and DNA synthesis of mitogen-stimulated lymphocytes. These inhibitors comprise (i) diacylhydroxylamine derivatives of Xaa-Pro or Xaa-Ala peptides, (ii) different oligopeptides with N-terminal Xaa-Pro-sequences, and (iii) amino-acid amides of the pyrrolidide and the thiazolidide type. The thiazolidides of epsilon-(4-nitrobenzyloxycarbonyl)-L-lysine and of L-isoleucine as well as Ala-Pro-nitrobenzoylhydroxylamine are the most effective inhibitors in both test systems, yielding half-maximal inhibitory concentrations in the micromolar range. Cell viability was not impaired in this effective concentration range. Other inhibitors of DP IV are one to two orders of magnitude less efficient in the suppression of lymphocyte proliferation.

Regulation of cyclic AMP metabolism in bovine adrenal medullary cells. The capacity of cultured bovine adrenal medullary cells to metabolize and export cyclic AMP has been studied. Basal cellular cyclic AMP levels were increased 50% by 100 microM 3-isobutyl-1-methylxanthine (IBMX) and rolipram, a class IV (cyclic AMP-specific) phosphodiesterase (PDE) inhibitor. They were not affected by inhibition of class I (Ca2+/calmodulin-dependent), class III (cyclic GMP-inhibited) or class V PDE (cyclic GMP-specific) with vinpocetine or 3-isobutyl-8-methoxymethyl-1-methylxanthine (8-methoxymethyl-IBMX), SK&F 94120, or MB 22,948, respectively, all at 100 microM. Furthermore, only IBMX and rolipram enhanced the cyclic AMP response to 0.3 microM forskolin. Rolipram had an EC50 of < or = 1 microM and was equally effective at 100 microM and 1 mM. IBMX enhanced cyclic AMP levels significantly more at 1 mM than at 100 microM. Neither vinpocetine nor 8-methoxymethyl-IBMX (100 microM) enhanced the Ca(2+)-dependent cyclic AMP response to K+ depolarization. Elevation of cyclic GMP levels with sodium nitroprusside (10 or 100 microM), to activate any cyclic GMP-stimulated class II PDE and to inhibit any cyclic GMP-inhibited class III PDE, also had no effect on basal or forskolin-stimulated cyclic AMP levels. In the presence of IBMX (1 mM), forskolin (5 microM) caused a rapid and large increase in cellular cyclic AMP levels which was maximal after about 5 min and declined slightly over 3 hr. Over this period, extracellular cyclic AMP levels rose almost linearly reaching levels 2-3 times those in the cells. The results indicate bovine adrenal medullary cells have a high capacity for sustained cyclic AMP export. Furthermore, two PDE isozymes appear to degrade cyclic AMP in these cells, a rolipram-sensitive, cyclic AMP-specific, class IV isozyme and a rolipram-insensitive isoform.

Identification of the viral haemorrhagic disease virus of rabbits as a calicivirus. Liver tissue from rabbits which had died of viral haemorrhagic disease (VHD) was used to identify the causative agent of the disease. After extraction of liver homogenates and density gradient ultracentrifugation, viral particles with buoyant densities between 1.32 to 1.38 g/ml and estimated sedimentation coefficients between 100 S and 175 S were obtained. The isolated virions were determined to have a diameter of 40 nm. The particles morphologically resembled those of the Caliciviridae family, had positive reactions both in ELISA and haemagglutination assays, and were infective for rabbits. By immunoblotting, a major structural protein with a molecular weight of 60 kDa was identified. RNA of high purity and of approximately 8 kb was isolated from virions. Labelled cDNA of virion RNA detected two RNAs of 8 kb and 2 kb in Northern blots of liver RNA from animals infected with the VHD virus (VHDV). Finally, isolated virion RNA injected directly into the liver or rabbits produced a disease with clinical symptoms and pathological findings typical of VHD. A calicivirus originally designated "rabbit haemorrhagic disease virus (RHDV)" was thus identified as the causative agent of VHD. The agent causing the European brown hare syndrome (EBHS) is also a calicivirus (EBHSV). VHDV and EBHSV are different members of the Caliciviridae family; their relationship can be clearly demonstrated by using different approaches of investigation.

Immunotherapy with cytokine gene-transduced tumor cells: the next wave in gene therapy for cancer. Recently, new tumor vaccine approaches were developed in animal systems that modify tumor cells genetically to secrete certain cytokines. Engineering tumor cells to secrete cytokines in a paracrine fashion can induce powerful local cytokine effects without producing significant systemic toxicity. In addition to local inflammation, this approach can alter the presentation of tumor antigens or activation of tumor antigen-specific T lymphocytes, resulting in systemic antitumor immunity. The development of high efficiency gene transfer technologies such as defective retroviral vectors allows for the translation of these preclinical studies to clinical trials. However, before large investments are made in this area of gene therapy, it will be important to demonstrate that the actual gene transfer component of the strategy significantly enhances antitumor immune responses relative to alternative nongenetic approaches.

BCG immunisation in England and Wales: a survey of policy and practice in schoolchildren and neonates. To determine the policy and practice of district health authorities in England and Wales for BCG immunisation in schoolchildren and neonates. Self completion postal questionnaire survey. District immunisation coordinators. 199 district health authorities in England and Wales. Questionnaires were received from 186 districts, a response rate of 94%. Considerable uniformity was observed in many aspects of BCG immunisation policy and practice but some important variations were found. 15 districts no longer carry out a routine schools programme. 148 districts offer BCG to selected groups of neonates and five to all neonates, but 31 districts do not offer BCG to this age group. The recommended action in response to different levels of tuberculin sensitivity in schoolchildren and neonates varied among districts. Despite the recommendations of the Joint Committee on Vaccination and Immunisation some districts do not offer BCG immunisation to neonates at high risk of tuberculosis and there are important variations in other aspects of BCG policy.

Early asbestosis: evaluation with high-resolution CT. To determine the earliest stage at which lesions in asbestosis can be diagnosed and to assess their progression, 23 asbestos-exposed patients with minimal or no abnormalities at plain radiography were examined with high-resolution computed tomography (HRCT) twice, with an interval of 12-37 months between examinations. In 21 of the patients, parenchymal abnormalities were found. Major parenchymal features seen at CT included thickened intralobular and interlobular lines, subpleural curvilinear lines, pleural-based nodular irregularities, hazy patches of increased attenuation, small cystic spaces, and small areas of low attenuation. At paired serial CT, subpleural isolated dots or branching structures connected with the most peripheral branch of the pulmonary artery started to appear in lower subpleural zones and then became confluent to create pleural-based nodular irregularities. CT-pathologic correlation led to the conclusion that the confluence of subpleural peribronchiolar fibrosis creates subpleural fibrosis.

Adjunct hospital emergency toxicology service. A model for a metropolitan area. A feasibility demonstration with a gas chromatograph/mass spectrometer/computer system (GC/MS) was initiated to provide a 24-hour (seven days/week) adjunct emergency toxicology service to the hospitals in the tricounty area comprising Metropolitan Detroit. During June 1, 1974, to April 1, 1975, more than 85 different drugs and other agents were identified in the body fluids of approximately 1,000 victims of accidental or deliberate poisonings. At least one toxic substance was identified in 57% of the cases, and the presence of two or more drugs was established in one of five (19%) of the victims. This study indicates that a centrally located GC/MS/computer system can provide an effective adjunct emergency toxicology service for an entire metropolitan community and thereby provide guidelines for a prompt and rational therapy.

Identification, characterization, and quantitation of soluble HLA antigens in the circulation and peritoneal dialysate of renal patients. Human lymphocyte antigen (HLA) class I and class II antigens and beta 2 microglobulin (B2M) were identified in peritoneal dialysate (PD) and serum from patients with end-stage renal disease (ESRD) using monoclonal antibodies in an enzyme-linked immunoassay. The HLA class I and class II antigens each exhibited approximate molecular weights of 50,000 to 60,000 daltons by chromatography on Sepharose CL 6B. Class I antigens in serum and PD fluid were associated with B2M. Free B2M (Mr 11,500) also was detected in both sera and PD fluids. Unlike class I antigens, class II antigens were not found to have attached B2M. Class I and class II antigens eluted from 2-diethylaminoethanol ion exchange gradient columns at 0.07 mol/L (molar) phosphate buffer pH 7.2 and migrated with alpha 2-beta 1 mobility in agarose electrophoresis. Class I antigens were purified from ESRD patients' PD fluid by solid-phase immunoaffinity chromatography. Enzyme-linked immunoassay demonstrated that this purified protein was composed of a class I heavy chain and B2M. Class I allospecificity was confirmed by neutralization on known HLA typing antisera in a microcytotoxicity assay. Soluble HLA class I antigen preparations specifically inhibited blast transformation of responder lymphocytes in mixed lymphocyte culture reactions. Inhibition was dose dependent and ranged from 0% to 95%. The presence of soluble HLA antigens in body fluids may play an important part in the immunologic tolerance to self. This study demonstrates a ready source of large quantities of soluble HLA for detailed analysis.

Stimulation of thyroid function by several pituitary hormones results in an increase in plasma thyroxine and reverse triiodothyronine in tilapia (Tilapia nilotica). In this study, intravenous injection of several doses of porcine follicle stimulating hormone (pFSH: 0.002, 0.01, 0.05, and 0.5 micrograms/g body wt), bovine TSH (bTSH: 0.5 micrograms/g body wt), and ovine growth hormone (oGH: 0.04, 0.02, and 0.4 microgram/g body wt) stimulated an increase in plasma thyroxine (T4) and reverse triiodothyronine (rT3) in tilapia. This effect occurred in a dose-dependent manner. pFSH was the most potent in stimulating thyroid function. The dose of 0.002 microgram pFSH/g body wt increased plasma levels of T4 over control levels (2.59 +/- 0.16 ng/ml) about 2.5-fold within 4 hr, whereas a concentration of 0.5 micrograms/g body wt caused a great and prolonged increase of T4 and rT3 levels. Control levels (2.59 +/- 0.16 ng/ml for T4 and 40.37 +/- 8.60 pg/ml for rT3) were increased 19- and 22-fold respectively, over 24 hr. An increase of T4 and rT3 levels occurred also after injection of total hypophyseal extract and Con A II glycoprotein fraction of a tilapia pituitary homogenate, whereas the protein fraction failed to alter plasma concentrations of T4 and rT3. rT3 levels were also significantly increased at 2 hr, but not at 1 hr, after injection of T4. Basal T3 levels (1.90 +/- 0.22 ng/ml) were reduced by half over 24 hr in all experiments. These results suggest the existence, in tilapia, of a 5-D pathway deiodination of T4 which is pituitary independent. Stimulation of T4 release is always followed by an increase in plasma rT3 levels.

[Accident causes and prevention of injuries in Enduro-motorbike sport]. 365 participants of the 64. Enduro-World Championship in 1989 reported 232 injuries within a 10-years-period of motorbike driving. The knee was most frequent (21.5 pc., mainly ligament ruptures) injured, followed by fracture of the clavicle (18.5 pc.), hand (15.5 pc.) and damages of the shoulder. Fractures are very common (55.5 pc.) in motorbike sports. Injuries often were produced by collisions with other motorbikes or trees. Driving mistakes, jumps, slipping wheels and overturn were other causes for an accident. During the championship 13 accidents were registered. In a clinical examination defects or alterations of the joints and bones were observed at 91 drivers. Important is the incidence of two malign tumours of the testicles. Preventive measures against accidents are discussed.

Relation between vibration levels and perceptive and appreciative judgements of overhead crane operators. The objective of the study was to determine what conditions of exposure to vibrations were responsible for the complaints by workers and what the maximum acceptable vibration levels should be. Vibration was characterized by the unweighted intensity exceeded during 10% of the time (L10) and by the global weighted equivalent intensity (Leqw) during displacement phases and phases involving successive starts and stops or successive hookings and unhookings of the load. The opinions of the workers concerning the intensities of vibration and of shock, and their appraisal of the vibration, were collected. Results show that workers hardly discriminate between vibrations and shocks, and appear more sensitive to horizontal (X and Y axes) than to vertical (Z axis) vibration. Perception as well as appraisal votes are slightly better correlated with intensities of vibration not weighted according to frequency than with weighted intensities, and more with peak intensities (L10) than with r.m.s. values. The vibration intensity weighted globally, which was normally encountered and unpleasant, appears to be about 115 dB(w), which corresponds to the limit value for the intermediate criterion (efficiency reduced by fatigue) proposed by ISO 2631 (1978).

Treatment of the Lennox syndrome with ACTH: a clinical and electroencephalographic study. In 45 cases of Lennox syndrome treated with ACTH, the immediate and long-term effects and the various factors affecting them were investigated by a follow-up study. 1) Regarding the immediate effect, 23 (51.1%) of the 45 cases became "seizure free" for over 10 days. 2) As to the long-term prognosis of these 23 cases, 10 cases relapsed into Lennox syndrome within 6 months and in the remaining 13 cases, seizures were suppressed for over 6 months; out of these 13, seizure relapse was observed in eight cases from 9 months to 7 years later, and the other five cases followed a very favorable course without relapse. 3) The favorable factors related to the effect of ACTH for Lennox syndrome are: a) age at ACTH treatment: up to 4 years old, b) time lag between onset of Lennox syndrome and initiation of ACTH treatment: the shorter the better; at least within 1 year, preferably within 3 months, c) presumptive causes and underlying diseases: idiopathic cases are best, d) mental defects before treatment: the slighter the better, e) seizure patterns: without tonic seizures, and f) EEG findings: disorganized diffuse slow spike-waves without asymmetry. 4) It is desirable to continue the ACTH treatment as long as possible, with the goal of the disappearance of seizure discharges, or at least the disappearance of diffuse seizure discharges.

Characterization of antigens on murine tumor cells reacting with alloantisera against foreign H-2 specificities: analysis by absorption with purified murine leukemia virus and normal lymphoid cells of different H-2 haplotypes. A spontaneous T cell lymphoma of DBA/2 (H-2-d) mice, SL2, was found to react with anti H-2 typing sera raised against certain foreign haplotypes as well as with anti H-2d sera. The cytotoxic anti-SL2 activity of the anti-foreign H-2 sera was detected in a newly developed microradioassay, not however, in a conventional 51Cr release test. Upon culture in vitro the reactivity of the tumor cells with the anti H-2 sera decreased. The anomalous cytotoxic anti-tumor activity of the anti-foreign H-2 sera appeared to be distinct from anti-murine leukemia virus activity, since it was not removed by absorption with either Friend of AKR leukemia virus. Partial absorption was observed with normal lymphoid cells carrying the respective foreign H-2 antigens, but not with cells of unrelated H-2 haplotypes. In each serum tested, the anti-tumor activity could also be absorbed with syngeneic H-2d lymphoid cells. These results show that the anomalous anti-tumor reactivity of certain anti H-2 typing sera, in particular of sera raised in recipients differing in H-2 from the tumor host strains, is not due to the presence of foreign (derepressed) H-2 molecules on the tumor cells. The differences observed between the tumor cells and normal cells seem to be due to unexpected antibodies in the sera reacting with public H-2 specificities which are better exposed on the tumor cells than on normal cells.

[Experience in developing and introducing a system of defect-free work as a stage in creating a complex system of production quality control]. An experience in working out and introduction of a system of failure-free performance work as one of the most important steps in creating a complex system for the production quality control at the Leningrad combine "Krasnogvardeets" is described. Issues related to elaborating, introduction and further improving the system of the failure-free work, its pecuniary stimulation and setting up standards for the enterprise are discussed. Under consideration are also problems of organizing a unitized service for the quantity control, as an organ called to secure coordination and quidance over these operations at the combine in this industry.

Inhibition of the interaction between lipoproteins and amphotericin B by some delivery systems. Amphotericin B (AmB) is a potent antifungal agent used to treat patients with systemic mycoses. The clinical usefulness of the drug is limited by its high toxicity and several new less toxic formulations of AmB have been recently developed. In order to understand the mechanism of the decreases of toxicity caused by various new delivery systems, we have investigated by uv-visible spectroscopy the interaction of two of these formulations with human blood lipoproteins. The results were compared with those obtained with the commonly used pharmaceutical form of AmB (Fungizone). This study shows that AmB-lipoprotein interaction is hindered when the drug is in a monomeric form and/or when it is included in phospholipid-surfactant micelles. In an in vivo study on mice it is shown here that AmB monomerized by surfactant is less toxic to animals than the same concentration of Fungizone, where the polyene is strongly aggregated. It may be concluded from the present study that the AmB species which is responsible for the in vivo toxicity is a complex of the antibiotic with the low density and the very low density blood lipoproteins and that hindering of this complex formation results in a decrease of AmB toxicity.

Gastric emptying of indigestible tablets in relation to composition and time of ingestion of meals studied by metal detector. Enteric-coated tablets leave the stomach mainly during the interdigestive phase. Composition as well as time of ingestion of meals may influence their gastric emptying considerably. In 12 normal volunteers gastric emptying of a plastic tablet with a metal core was followed by a metal detector in relation to different compositions and various times of ingestion of meals. With an empty stomach and after ingestion of 250 ml water, the mean time for gastric emptying of the tablet was 38 +/- 11 min (mean +/- SEM) and 38 +/- 8 min. Two hundred fifty milliliters of milk (652 kJ) and a formula diet (1000 kJ) delayed gastric emptying time to 128 +/- 14 and 152 +/- 6 min, respectively (P less than 0.05). Breakfast (2200 kJ) further retarded gastric emptying compared with both liquids to 249 +/- 24 min (P less than 0.05). There was a close correlation between nutritive density and gastric emptying of the tablet (r = 0.92; P less than 0.001). Main meals also delayed gastric emptying of tablets when compared to empty stomach (P less than 0.05). A snack after breakfast further delayed gastric emptying from 201 +/- 10 to 278 +/- 19 min (P less than 0.05). The largest delay was observed following ingestion of breakfast, lunch, dinner, and additional snacks (509 +/- 220 min). We conclude that the delay of gastric emptying of enteric-coated tablets by food is related to its nutritive density and eating habits. The gastric emptying of an enteric coated tablet that is ingested early in the morning may be delayed until late at night when several meals and snacks are ingested during the day, leading to unwanted alterations in bioavailability and to possible adverse effects.

[Mechanical studies on the dental bridges. (XI) Studies on the apportionment loads to be affected by the supporting conditions of two abutment teeth (author's transl)]. Abutment teeth have been treated as the elastic behavior at the supported conditions and apportionment loads are depended upon the elastic properties of the pontics and abutment teeth. So, this paper shows the apportionment loads of dental bridges and the dependence of the elastic constants of abutment teeth. Abutment teeth are rotated and sinked with digestive power on the pontics. So, the elastic constants of abutment teeth are given with k and K, which k, K are the sinked and rotated coefficients, which are expressed the elastic properties of these abutment teeth. Apportionment loads to be connected with the flexural rigidity of the pontics are calculated for two numerical examples (for the values of 3.6 x 10(3) kg-mm2 and 3.6 x 10(8) kg-mm2 of the concentrated and distributed loads).

An assessment of the validity of densitometric measures of striatal tyrosine hydroxylase-positive fibers: relationship to apomorphine-induced rotations in 6-hydroxydopamine lesioned rats. The power of immunohistochemical staining as a tool for the study of the neurochemical anatomy of the brain would be greatly enhanced if quantitative measures of staining were to be developed. We have here assessed the reliability and validity of two population measures of extent of fiber innervation: percent area occupied by staining, and average optical density (AOD) of staining. We have evaluated these measures for tyrosine hydroxylase-positive staining of the striatum in relation to apomorphine-induced rotational behavior in 6-hydroxydopamine lesioned rats. We have found that inter-operator reliability for the area measure is high (r = 0.98). Apomorphine-induced rotations were observed when the area measured was reduced to 2% or less of the control side, and when the density measure was reduced to 15% or less. These results are similar to those obtained previously for biochemical assay of TH activity, which showed rotations at reductions to 10% or less. We conclude that these density measures provide valid relative indices of extent of fiber innervation on the same section. The AOD measure appears to be more sensitive at lower levels of innervation.

Prevention of distal embolism during arterial reconstruction. Distal embolization of fragmented laminated thrombus and atheroma producing peripheral ischemia or gangrene is an underemphasized complication of arterial reconstruction. A set of techniques has been developed to minimize this important complication. To assess their effectiveness, the incidence of distal embolism in patients undergoing resection of abdominal aortic aneurysm with and without the use of these techniques was studied. In the 434 patients who underwent elective resection of abdominal aneurysm, measures to prevent distal embolism were used in all cases. The incidence of distal embolism was only 0.23 per cent (1 of 434), in contrast to reported incidences of up to 11 per cent. In the 21 patients who underwent emergency resection of ruptured aneurysm, these techniques were not used due to the need for early proximal control for resuscitation; distal embolism of atheromatous material occurred in 2 cases, an incidence of 9 per cent. The application of these techniques to other peripheral vascular procedures has resulted in similar low rates of postoperative distal ischemia.

Lobular involvement in human breast carcinoma. One hundred twenty-nine cases of breast carcinoma were examined in order to clarify the occurrence of lobular involvement with regard to stromal invasion. Lobular involvement was clearly recognized in 56 cases (43%) having discernible portions of intraductal carcinoma components. The process of lobular involvement was first recognizable as an extension of a few carcinoma cells from intralobular ducts into the acinar lumina. Progressive accumulation of the carcinoma cells resulted in marked swelling and distortion of the involved lobules. During the process, perilobular myoepithelial cells (actin-positive cells) were stretched and disappeared. Subsequently, breaks in the basement membranes were also observed, resulting in stromal invasion of carcinoma cells. The lobular involvement was classified into common and round varieties, possibly reflecting different growth activities of the carcinoma cells. The stromal invasion was initiated by peripheral budding or focal necrosis of the involved lobules. The latter pattern was often observed in comedo carcinoma. It was thus revealed that in breast carcinomas the terminal ductal-lobular units are quite often involved and can become sites of extraductal invasion.

Comparison of the in vivo anticoagulant properties of standard heparin and the highly selective factor Xa inhibitors antistasin and tick anticoagulant peptide (TAP) in a rabbit model of venous thrombosis. An in vivo thromboplastin (TP)-induced venous stasis thrombosis model in rabbits was used to compare the efficacy of standard heparin with the selective factor Xa inhibitors, recombinant tick anticoagulant peptide (rTAP) and recombinant antistasin (rATS), in prophylactic prevention of thrombus formation. Heparin significantly reduced TP-induced clot formation at doses of 55 and 100 U kg-1h-1 yielding clot weights of 9 +/- 4 and 6 +/- 2%, respectively. Clot formation was significantly decreased by i.v. infusions of rTAP at doses of 21, 37 and 64 micrograms kg-1 min-1 resulting in normalized clot weights of 13 +/- 3, 8 +/- 2 and 2 +/- 1%, respectively. rATS was approximately 10-fold more potent than rTAP, reducing normalized clot weights to 16 +/- 5, 2 +/- 1 and 1 +/- 0.8% at rATS doses of 1.25, 2.5 and 5.0 micrograms kg-1 min-1, respectively. These data suggest that factor Xa-mediated inhibition of coagulation with rTAP and rATS is as effective as conventional anticoagulant treatment with heparin in preventing venous thrombosis.

Doppler echocardiographic study of porcine bioprosthetic heart valves in the aortic valve position in patients without evidence of cardiac dysfunction. To study the natural history of the hemodynamic performance of bioprosthetic heart valves, Doppler echocardiograms were recorded in a group of clinically stable patients at 2 and 5 years after replacement of native aortic valves with bioprosthetic valves. Eighteen patients completed a 2-year and 26 patients a 5-year follow-up examination. The effective orifice areas of identical models of bioprosthetic valves (Hancock II) were determined in vitro in a left-sided heart pulse duplicator system. In vivo Doppler-derived effective orifice areas were compared with the in vitro measurements for the same valve size. At both the 2- and 5-year follow-up examinations, the Doppler-derived effective orifice area was significantly less than the in vitro area (p less than 0.0001 at each interval). Ten of 16 valves evaluated serially decreased greater than 0.20 cm2 in the Doppler-derived effective orifice area between studies. The mean decrease in effective orifice area in valves evaluated serially was 0.25 +/- 0.29 cm2 (p less than 0.005). The peak transaortic gradient increased from 21 +/- 6 to 27 +/- 8 mm Hg (p less than 0.01). The mean transaortic gradient increased from 12 +/- 4 to 15 +/- 7 mm Hg (p less than 0.05). It is concluded that serial Doppler echocardiographic studies demonstrate a deterioration in the hemodynamic performance of bioprosthetic valves over time in patients with no symptoms or signs of valvular dysfunction and that Doppler echocardiography may be useful for identifying subclinical bioprosthetic valvular dysfunction.

Prolonged apnoea after suxamethonium: an analysis of the first 225 cases reported to the Danish Cholinesterase Research Unit. During the last 4 years, 225 patients have been referred to the Danish Cholinesterase Research Unit following an episode of prolonged apnoea after suxamethonium. Fourteen patients (6.2%) were found to have a low serum cholinesterase activity due to an acquired deficiency (for instance, liver disease, chronic debilitating disease or carcinoma). One hundred and forty-eight patients (65.8%) had an inherited abnormal serum cholinesterase, and 105 of these patients (46.7%) were homozygous for the atypical enzyme (E1 Ea1). The mean period of apnoea in this latter group was 92 min (range: 25--240). Seventeen patients (7.6%) were heterozygous for the normal and the atypical enzyme (Eu1 Ea1), with a mean apnoea period of 25 min (range: 7--60 min). Twelve patients were found to be heterozygous for the atypical and the silent gene (E(a)1 E(s)1). The mean period of apnoea was 126 min (range: 45--210 min). Fourteen patients had other rare genotypes. The longest mean period of apnoea (170 min, range: 70--330) was found in patients homozygous for the silent gene (Es1 Es1). The silent gene and the fluoride-resistant gene were found in 8.9% and 2.7% of the patients, respectively. In 63 patients (28.1%) both the type and quantity of serum cholinesterase were normal. In 34 of these patients (15.2%), the prolonged apnoea was due to other causes; for example, suxamethonium overdose, hyperventilation and central as well as peripheral respiratory depression. However, in the other 29 patients (12.9%), the reason for the prolonged apnoea could not be established. The possibility therefore exists that these cases represent unknown genotypes.

Systemic mannitol increases retinal adhesiveness measured in vitro. Pigmented rabbits were given mannitol intravenously, and at various times thereafter blood osmolality was measured and eyes were enucleated to measure retinal adhesiveness to the retinal pigment epithelium. Both blood osmolality and retinal adhesion increased in proportion to the dose of mannitol. We found a measurable increase in retinal adhesion as early as 10 minutes and as late as 4 hours after mannitol injection. We suspect that mannitol dehydrates the subretinal space and thereby enhances the adhesive properties of the interphotoreceptor matrix or tightens the interdigitation between photoreceptors and pigment epithelial cells. Our data suggest that mannitol could have clinical application in the management of retinal detachments.

[Purulent arthritis]. At all ages, Staphylococcus aureus is the most common microorganism responsible for septic arthritis, but in children below five years of age Haemophilus influenzae is frequently found. In about 1/3 of the cases cultures are negative, primarily because of initiation of antibiotic therapy prior to sampling. A distended joint should be treated as infection until otherwise proved. Today repeated aspirations of the infected joint are recommended as initial treatment, if possible with additional joint lavage, together with systemic antibiotic therapy. In case with no clinical response within 2-4 days, surgical debridement of the joint with synovectomy is of utmost importance. Exercises without weight-bearing are initiated at an early stage and weight-bearing avoided for six weeks.

[Catamnestic studies in hemiplegics]. 61 patients with hemiplegia who had undergone hospital rehabilitation were examined 1 year later and 29 patients after an interval of 10--11 years. Special attention was paid to improvements and relapses with respect to walking ability, personal care, and social situation. The investigation showed that 62% of personal living on their own made progress in the activities of daily life; there were no relapses. 14% of those living in a family showed improvement while 29% relapsed. Of patients living in nursing homes only 5% showed improvement, while there were relapses in 42% of cases. The percentages of cases showing improvement (or relapses) with respect to walking ability are as follows: 20% (7.5%), 30% (22%) and 0% (21%). 32% of the patients had regular physiotherapy sessions. A change in the social situation had resulted for 50%; many of these were lonely and missed visitors. Persons looking after themselves showed the best prognosis following rehabilitation.

[A case of strongyloidiasis accompanied by duodenal ulcer]. A 58-year-old chronic alcoholism patient, who complained of epigastric discomfort, nausea, and frequent loose stool was diagnosed as strongyloidiasis accompanied by duodenal ulcer. The symptoms first appeared two years ago and aggravated during the recent 3 months, and he lost 4 kg of his body weight. Stool examination revealed rhabditoid nematode larvae, which were confirmed as those of Strongyloides stercoralis after cultivation of them to filariform larvae. At duodenoscopy, duodenal ulcer was found. The patient was treated with albendazole (200 mg, bid, for 14 days) for strongyloidiasis and with colloidal bismuth sulfate (240 mg, bid, for 6 weeks) for duodenal ulcer. After the medication, the symptoms of loose stool and epigastric discomfort were much improved and he was discharged with no clinical problems. This is an interesting case which suggests that S. stercoralis infection could be related with ulceration of the duodenal mucosa.

Cellular aspects of conjunctival inflammation induced by the synergistic action of histamine and prostaglandins. Histamine or prostaglandin (PG) E1 or E2 administered to rabbits topically alone in high doses produced conjunctival vasodilation associated with little or no edema while their mixture at lower concentrations produced conjunctival vasodilation associated with profound edema. Sections of tissues treated with the mixture of histamine and PGE1 or PGE2 showed widespread epithelial and subepithelial inflammatory cellular infiltration. Conjunctival smears from eyes treated with the histamine/PG mixture contained small lymphocytes and polymorphonuclear leukocytes, including eosinophilic and occasionally basophilic cells. Differential staining of the polymorphs demonstrated both eosinophils and pseudoeosinophils. Histological examination of the conjunctival smears and sections of the lids obtained from eyes treated with either histamine or PGE1 or PGE2 alone did not show any detectable increase of inflammatory cells when compared to normal controls. The clinical and histological results indicate that the synergistic effect of histamine with PGs of the E-type in the conjunctiva produces an inflammatory response similar to that seen in various clinical forms of human allergic conjunctivitis. Such a response could not be produced by histamine or PGE1 or PGE2 alone even at much higher doses than in the mixture. The data indicate that an interplay of several different mediators may be crucial in the conjunctival response in allergy.

Ethanol decreases progesterone synthesis in human placental cells: mechanism of ethanol effect. Fetal alcohol syndrome (FAS) is a set of signs and symptoms in offsprings born to mothers who abuse alcohol during pregnancy. We postulated that impairment in the placental endocrine function contribute to FAS. In this study, we examined in vitro effects of ethanol on the placental cells' (cytotrophoblast cells) capacity to synthesize progesterone. Cytotrophoblast cells were isolated from normal term placenta and were incubated (2 x 10(6)) with 20-, 30-, and 40-mM doses of ethanol for 6 h. Progesterone was measured in the incubate by RIA. The results showed that, at the 20-mM dose of ethanol, progesterone synthesis was significantly decreased (p less than 0.01), at the 30-mM dose level there was a further decrease of 20%. The differences between 30- and 40-mM ethanol dose levels were not significant. To determine the mechanism of ethanol effects on progesterone synthesis, cytotrophoblast cells were preincubated with 30 mM ethanol followed by 10 microliters of LDL (10 microliters LDL = 80 micrograms cholesterol) and vice versa. The results showed that ethanol effects on progesterone synthesis was dependent on whether ethanol was added prior to or following the addition of LDL in the medium. If ethanol was added in the medium prior to LDL, progesterone synthesis was decreased significantly (p greater than 0.01); however, when ethanol was added after the LDL, ethanol had no effect on progesterone synthesis. In the experiment where ethanol and LDL were added simultaneously in the medium, ethanol blunted the stimulatory effect of LDL on progesterone synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship among vesicoureteral reflux, P-fimbriated Escherichia coli, and acute pyelonephritis in children with febrile urinary tract infection. Ninety-four children with febrile urinary tract infection were studied prospectively to determine the relationship between vesicoureteral reflux, P-fimbriated Escherichia coli, and acute pyelonephritis, and to evaluate the diagnostic reliability of commonly used clinical and laboratory observations. By using renal scan with dimercaptosuccinic acid labeled with technetium 99m as the standard of reference, we documented acute pyelonephritis in 62 (66%) of 94 patients. Vesicoureteral reflux was demonstrated in 29 (31%) of the total group and in only 23 (37%) of 62 patients with pyelonephritis. Of the 70 E. coli urinary isolates, 48 (69%) were P-fimbriated, including 30 (64%) of 47 isolates from patients with pyelonephritis and 18 (78%) of 23 isolates from patients with normal renal scans. The prevalence of P-fimbriated E. coli in patients with pyelonephritis and vesicoureteral reflux was 46%, compared with 71% in those with pyelonephritis who had no concurrent vesicoureteral reflux (p = 0.222). Multiple clinical and laboratory variables commonly used in the diagnosis of acute pyelonephritis did not adequately predict the presence or absence of parenchymal involvement. These data show the following: (1) Acute pyelonephritis in the absence of demonstrable vesicoureteral reflux is common. (2) Febrile urinary tract infections in children are commonly associated with P-fimbriated E. coli, both in the presence and absence of vesicoureteral reflux. (3) The presence of P fimbriae alone does not fully explain the pathophysiology of renal parenchymal invasion by bacteria in the absence of vesicoureteral reflux. (4) The diagnosis of acute pyelonephritis in children with febrile urinary tract infections on the basis of clinical and laboratory observations is unreliable.

Effect of velocity and mechanical history on the forces of motor units in the cat medial gastrocnemius muscle. 1. Two fundamental aspects of the dynamic behavior of motor units of the cat medial gastrocnemius (MG) muscle were measured. Force-velocity (FV) relationships were measured with the use of constant velocity shortening and lengthening movements. Effects of mechanical history were assessed via comparisons of forces immediately after or during slow movements with standard isometric forces. Isometric force-length (FL) relations were also measured, and the effect of different stimulation rates on both FV and FL data was assessed. 2. Prior or concurrent movement greatly potentiated motor-unit force, but this movement potentiation was highly dependent on the amplitude of the unit's force. The smallest twitch forces of type S units (< 10 mN) were potentiated more than threefold, but no potentiation occurred for unit forces > 200 mN. It was tentatively concluded that movement potentiation may play little role in normal movements because it does not occur at forces > 1% of maximal isometric force of the MG. 3. During shortening, the normalized FV relations of type S units were relatively steeper than those of type FR or FF units. For lengthening, there was no evident relation between FV steepness and motor-unit type. 4. Stimulation rate affected both the FV and FL relationships of the motor units. The peak of the FL relationship (Lo) clearly shifted to shorter muscle lengths as stimulation rate was increased. The steepness of the FV relationship for shortening was decreased by increasing stimulation rate, but this effect was modest. 5. The shift in motor-unit Lo and the differences in motor-unit FV relationships were hypothesized to play significant roles during normal motor behavior. Realistic computer simulations of FL and FV functions for a population of motor units undergoing normal steady-state recruitment and rate modulation supported these hypotheses. As the level of simulated neural drive increased, the population Lo shifted to considerably shorter lengths, and the normalized FV function became much less steep. The significance of these results for models of muscle are discussed.

Physicochemical properties of reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase from bovine adrenocortical microsomes. Adrenocortical NADPH-cytochrome P-450 reductase (EC. 1.6.2.4) was purified from bovine adrenocortical microsomes by detergent solubilization and affinity chromatography. The purified cytochrome P-450 reductase was a single protein band in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, being electrophoretically homogeneous and pure. The cytochrome P-450 reductase was optically a typical flavoprotein. The absorption peaks were at 274, 380 and 45 nm with shoulders at 290, 360 and 480 nm. The NADPH-cytochrome P-450 reductase was capable of reconstituting the 21-hydroxylase activity of 17 alpha-hydroxyprogesterone in the presence of cytochrome P-45021 of adrenocortical microsomes. The specific activity of the 21-hydroxylase of 17 alpha-hydroxyprogesterone in the reconstituted system using the excess concentration of the cytochrome P-450 reductase, was 15.8 nmol/min per nmol of cytochrome P-45021 at 37 degrees C. The NADPH-cytochrome P-450 reductase, like hepatic microsomal NADPH-cytochrome P-450 reductase, could directly reduce the cytochrome P-45021. The physicochemical properties of the NADPH-cytochrome P-450 reductase were investigated. Its molecular weight was estimated to be 80 000 +/- 1000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analytical ultracentrifugation. The cytochrome P-450 reductase contained 1 mol each FAD and FMN as coenzymes. Iron, manganese, molybdenum and copper were not detected. The Km values of NADPH and NADH for the NADPH-cytochrome c reductase activity and those of cytochrome c for the activity of NADPH-cytochrome P-450 reductase were determined kinetically. They were 5.3 microM for NADPH, 1.1 mM for NADH, and 9-24 microM for cytochrome c. Chemical modification of the amino acid residues showed that a histidyl and cysteinyl residue are essential for the binding site of NADPH of NADPH-cytochrome P-450 reductase.

The other who is also the same: the relevance of epidemics in space and time for prevention of HIV infection. The history of epidemics reveals the imposition of controls over time and space on the sick and powerless other in the interests of the well and powerful same. In contrast, effective prevention requires the sharing of values, space, and time: coevality in the broadest sense. Adolescents are seen as merely transitional: they were children in the recent past, they will be adults in the recent future. Thus as an other who must become the same, they are seen as out of time and threatening. Conventional adults fear uncontrolled sexuality, especially if it is perceived as taking place out of time and is therefore anachronistic or in the wrong places, out of bed and through the wrong orifices (anatopistic). These unshared cultural perceptions are a barrier against both education for life and effective prevention of HIV infection.

Influence of central obesity and obesity level on the prevalence of NIDDM and impaired glucose tolerance. The purpose of this study was to determine the association of the prevalence of non-insulin-dependent diabetes (NIDDM) with central obesity, obesity, and family history of diabetes. This survey consisted of 1590 subjects (646 men, 944 women) aged 30 years or more from the Sun-Ming district of Kaoshiung city. Glucose tolerance status was ascertained by both medical history and a 75-g oral glucose tolerance test according to World Health Organization criteria. In men and women with central obesity (WHR > or = 0.92 in men and > or = 0.85 in women) or obesity (BMI > or = 27.6 kg/m2 in men and > or = 28.3 kg/m2 in women) (WHR: waist-hip ratio; BMI: body mass index), the prevalence of impaired glucose tolerance (IGT) and diabetes was significantly higher, except the prevalence of diabetes in both sexes with obesity and the prevalence of IGT in women with central obesity were not statistically different, as compared with nonobese subjects. The prevalence of diabetes in men significantly increased from the first quartile to the fourth quartile of BMI and the waist-hip ratio (WHR) (4.48% to 9.21% in BMI, 3.67% to 13.61% in WHR), while the prevalence in women also significantly increased from the first to fourth quartile (2.45% to 11.76% in BMI, 2.04% to 13.49% in WHR). Multiple logistic regression analyses revealed similar increase in the prevalence of diabetes among both men and women for every 1 kg/m2 increase in BMI and every 0.05 increase in WHR (1.07-fold and 1.09-fold in BMI, 1.34-fold and 1.32-fold in WHR, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of naltrindole and nor-binaltorphimine treatment on antinociception induced by sub-acute selective mu opioid receptor blockade. When administered repeatedly, in conjunction with hot plate testing, naloxone and naltrexone have the paradoxical effect of producing antinociception in rats and mice. Recently, we have found that the sub-acute selective blockade of mu opioid receptors leads to the development of antinociception and an augmentation of kappa receptor-mediated antinociception. In this study, acute delta/kappa antagonist treatment produced a significant decrease in paw lick latency in rats displaying antinociception induced by sub-acute mu blockade, however, the response level of these animals was still significantly above the baseline. In addition, rats receiving sub-acute combined mu and delta antagonist treatment took longer to develop an antinociceptive response than those treated with a mu antagonist alone. Sub-acute selective blockade of kappa or delta opioid receptors had no overall effect on paw lick latency during the course of 5 days of hot plate testing. The results indicate that delta receptor activity may play a role in the antinociception induced by sub-acute mu blockade. However, while delta antagonist treatment effected the expression, it did not completely attenuate the antinociception induced by sub-acute mu blockade suggesting that there is still a significant non-opioid component to this analgesic response. The results of a final experiment, in which acute delta antagonist treatment had no effect on antinociception induced by repeated systemic injections of naloxone, supported this hypothesis.

Measuring the neuromodulatory effects of drugs in man with positron emission tomography. Cognitive activation in conjunction with pharmacological challenge was used to demonstrate neuromodulation in man. Using positron emission tomography (PET), measurements of regional cerebral blood flow were made during the performance of memory tasks, before and after the administration of apomorphine (dopamine agonist), buspirone (5-HT1A partial agonist) or placebo. Drug effects on memory-induced increases in regional cerebral blood flow were assessed, on a voxel-by-voxel basis, using statistical parametric mapping. Increases of regional cerebral blood flow in response to the memory challenge were attenuated by apomorphine in the dorsolateral prefrontal cortex and augmented in the retrosplenial region of the posterior cingulate. Conversely, buspirone attenuated blood flow increases in the retrosplenial region. These interactions between drugs and a cognitive challenge can best be interpreted as neuromodulatory effects.

Multiple forms of beta-ketoacyl-acyl carrier protein synthetase in Escherichia coli. Two forms of beta-ketoacyl-acyl carrier protein (ACP) synthetase (designated I and II) have been identified in extracts of Escherichia coli. Synthetase I corresponds to the condensing enzyme that was studied earlier (GREENSPAN, M.D., ALBERTS, A.W., and VAGELOS, P.R. (1969) J. Biol. Chem. 244, 6477-6485); synthetase II represents a new form of the enzyme. Synthetase II was isolated as a homogeneous protein. It differs from synthetase I in having a higher molecular weight (76,999 versus 66,000), a lower pH optimum (5.5 to 6.1 versus 7.2), and a greater resistance to denaturation by heat. Synthetase II is similar to synthetase I in that both are inactivated by iodoacetamide, and prior incubation of the enzymes with fatty acyl thioesters prevents the inhibitory effect of iodoacetamide. Both also react with a fatty acyl thioester to form an acyl-enzyme intermediate, and the latter reacts with malonyl-ACP to form a beta-ketoacyl thioester. Specificity studies indicated that synthetase II, like synthetase I, has similar affinities with saturated and cis unsaturated fatty acyl thioesters of ACP that are intermediates in the synthesis of saturated and unsaturated fatty acids, respectively. The two synthetases differ only with respect to reactivity with palmitoleyl thioesters: synthetase II has a lower Km and higher Vmax than synthetase I with palmitoleyl-ACP. This finding suggests that synthetase II functions specifically in the elongation of palmitoleyl-ACP to form cis-vaccenyl-ACP. An investigation of synthetases I and II in two classes of unsaturated fatty acid auxotrophs revealed that synthetase I is absent in one class, fabB. Addition of wild type synthetase I to fabB fatty acid synthetase, which synthesizes only saturated fatty acids, permitted this fatty acid synthetase to synthesize unsaturated fatty acids. These experiments indicate that synthetase I plays a critical role in the synthesis of unsaturated fatty acids.

Low dose prednisone treatment does not reduce the severity of osteoarthritis in dogs after anterior cruciate ligament transection. It was reported recently that oral administration of prednisone, 0.3 mg/kg/day, decreased osteophyte size and cartilage ulceration in dogs with osteoarthritis (OA) produced by "stab" transection of the anterior cruciate ligament. Since this dose would be equivalent to 17 mg/day for a 70-kg human, our study was performed to determine whether a lower, clinically more realistic, dose of prednisone also had ameliorating effects on OA in the canine model. Following arthrotomy and transection of the anterior cruciate ligament 10 adult mongrel dogs were each given prednisone, 0.1 mg/kg/day, begun either 0, 2, or 4 weeks after arthrotomy and continued until sacrifice 12 weeks after surgery; 7 others underwent the identical surgical procedure but received no prednisone and served as OA controls. No differences were noted between dogs treated with prednisone and the controls with respect to size or extent of osteophytes, severity of synovial inflammation, morphologic changes of OA in articular cartilage, or in vitro synthesis of glycosaminoglycans. Increases in cartilage thickness in the OA knee were similar in the 2 groups, as were increases in H2O content and uronic acid concentration. Regardless of the interval between arthrotomy and start of treatment, the low dose of prednisone used here did not reduce the severity of OA in this model.

Variations in gamma-glutamyl transpeptidase glycosylation and kinetic parameters in cultured liver cells. In rat hepatocytes; the tumorigenic rat liver cell line ARL-16; and the human hepatoma line, Hep G2, 50% of the total gamma-glutamyl transpeptidase (GGT) activity was bound by a Concanavalin-A Sepharose 4B column, calling for alpha-methylmannoside elution (Peak I). Non-binding GGT was distributed between a rapidly eluting Peak II and a slightly retained Peak III. The Km for gamma-glutamyl-p-nitroanalide for either hydrolysis or transpeptidation, or glutathione (GSH) transpeptidation did not vary with peak number or cell type. The GSH hydrolysis Km was essentially constant in Peak I and II GGT. Peak III GGT exhibited a lower Km for GSH hydrolysis with Hep G2 Peak III GGT being the lowest. Peak III GGT increased to 50% of the GGT activity in Hep G2 cells cultured with GSH as the sole cysteine source.

Paraventricular hypothalamic clonidine increases rather than decreases susceptibility to activity-based anorexia in the rat. Anorexia has been related to reduced activity of the paraventricular hypothalamic (PVN) noradrenergic-feeding system. In this study we determined whether clonidine (an alpha 2-adrenergic agonist) infused into the PVN reduced susceptibility to activity-based anorexia (ABA) in the rat. In Experiment 1, clonidine (6 doses) was chronically infused into the PVN of male Sprague-Dawley rats. All animals were exposed to ABA (1.5 hr/day food access; 22.5 hr/day running wheel access) until a 25% body weight loss was reached. Dose-related increases in susceptibility to ABA and decreases in food intake were observed. In Experiment 2, for which heavier animals and 3 doses of clonidine were used, we found no difference in food intake and wheel activity but increased susceptibility to ABA. Chronic clonidine infused into the PVN does not produce hyperphagia and exacerbates rather than attenuates susceptibility to ABA.

Initiation of precocious sexual maturation in the immature rat treated with dehydroepiandrosterone. Administration of dehydroepiandrosterone (DHA) to immature female rats on day 27 for 3 days resulted in an increase in uterine weight within 6 h of injection and a surge of FSH, LH and prolactin occurred on day 30 resulting in premature ovulation. Increase in ovarian weight and vaginal patency also occurred on day 30. Ovulations occurred at various times on day 30 and some as late as day 33 and these could be synchronized by the administration of pregnant mare serum gonadotropin (PMSG). The gonadotropin surge resulting in ovulation could be blocked by central nervous system blocking agents like phenobarbital and reserpine. The action of DHA in inducing precocious ovulation appeared to be mediated through conversion to estrogens because DHA and testosterone both of which can be aromatized to estrogens at appropriate dose elvels caused potentiation of the effect of PMSG on the secretion of gonadotropins. They also induced vaginal patency in the castrated immature rat. Dihydrotestosterone, an androgen not aromatized to estrogens did not induce precocious ovulation, vaginal patency or potentiation of the effect of PMSG in the release of gonadotropins. Furthermore, cyanoketone an inhibitor of 3beta-hydroxysteroid dehydrogenase and thus the conversion of DHA to estrogens, prevented vaginal patency and DHA-induced precocious ovulation.

Spontaneous rupture of bicuspid aortic valve. An unusual cause of aortic insufficiency. This report documents the clinicopathologic correlation between pure aortic regurgitation and an exceptional form of congenitally bicuspid aortic valve. The patient was known for many years to have mild aortic insufficiency. His condition suddenly deteriorated, with signs of an aggravated aortic regurgitation. Infectious endocarditis was considered, but the diagnosis was never established. Surgery revealed an exceptional form of a bicuspid aortic valve in which the conjoined cusp had prolapsed, due to rupture of a fibrous strand which previously had anchored the free rim of the cusp to the inner wall of the aorta. There were no signs of infectious endocarditis. It is suggested that spontaneous rupture of the cord caused the sudden aggravation of aortic regurgitation.

Auscultatory measurement of blood pressure performed by the doctor on duty. A review is presented of the measurements of blood pressure on admission of 600 patients to the wards in a department of general medicine. Three doctors each examined 200 patients, distributed over two periods with an interval of one year. Large differences were found between the doctors as regards the distribution of the BPs, particularly the diastolic pressures. On the other hand, no differences were observed in the distributions during the two periods as far as the individual doctors were concerned. Great preference was shown for zero as the terminal digit and also for certain BP values. It is concluded that the observer introduces a considerable subjective factor in measuring the BP by auscultation. Correct performance of this simple procedure requires meticulous instruction.

Comparison of firing patterns and sensory responsiveness between supraoptic and other hypothalamic neurons in the unanesthetized sheep. Adult Southdown ewes were surgically prepared with pituitary stimulating electrodes, carotid and jugular cannulae, and a cranial platform-cylinder arrangement for chronic single unit recording. Isolated neurons (n = 112) in the region of the supraoptic nucleus (SON) were identified by pituitary stalk stimulastion as AD + (antidromically invaded) SON neuroendocrine cells (n = 75) or AD--(not antidromically invaded) SON neurons (n = 37). Spontaneous firing pattern distribution and sensory evoked behavior of these SON region neurons were compared with activity recorded from 112 randomly located non-identified neurons of extra-SON areas of the hypothalamus. Spontaneous discharge activity was categorized into six distinct firing pattern types: continuously active slow (CAS), continuously active fast (CAF), continuously active bursting (CAB), continuously active regular (CAR), low frequency bursting (LFB), and high frequency bursting (HFB). These 6 firing pattern types were characterized by computer analysis and their mean order independent statistical parameters compared. Bursting discharge patterns (LFB, HFB, and CAB) were compared with respect to mean burst duration, burst mean firing rate, and interburst interavls. Ninety-three per cent of all neurons maintained a stable discharge pattern in the absence of apparent stimuli. Occasionally CAS and CAF neurons spontaneously generated spike clusters sufficient to give the transient appearance of a bursting discharge pattern and LFB neurons lapsed spontaneously into CAS acitivity. All 6 firing pattern types recorded from non-identified extra-SON neurons were also recorded in the SON region. However, spontaneously discharging AD+ SON neurons exhibited only continuously active slow (CAS), continuously active fast (CAF), and low frequency bursting (LFB) activity. The total absence of high frequency bursting (HFB), continuously active regular (CAR), and continuously active bursting (CAB) patterns of discharge from AD+ SON neurons suggests that AD- SON neurons exhibiting these firing patterns may function as interneurons, pacemaker neurons, or receptor neurons. A significant number of LFB discharging neurons were recorded in widespread extra-SON regions of the hypothalamus, indicating this discharge pattern may not be unique to magnocellular neuroendocrine cells. AD+ SON LFB neurons sampled in this study demonstrated a significantly longer mean interburst interval (20.86 sec) compared to extra-SON LFB neurons (12.43 sec). No AD+ SON neuron tested was significantly sensitive to non-specific sensory arousal or sleep-waking state changes. In extra-SON areas of the hypothalamus, 11 of 75 neurons tested to sensory arousal and 6 of 19 neurons tested to sleep-waking changes responded with significant changes in mean firing rate (MFR); no significant difference between firing pattern types was demonstrated in arousal or sleep-waking sensitivity...

The reproducibility of dietary intake data in a prospective study of gastrointestinal cancer. To test the reproducibility of the dietary questionnaire used in the Japan-Hawaii Cancer Study and to measure the consistency of dietary patterns over time, 109 men were reinterviewed with the same questionnaire after a 6-month interval and 111 men were reinterviewed after a 2-year interval. The responses for intake of the 33 food items in the questionnaire were fairly reproducible. Food items with substantial correlation coefficients in both groups of men tended to be consumed on a more habitual basis. This finding suggests that if habitually consumed foods are linked to specific cancers, it is less likely that such associations occur by chance. This is of particular importance because when many food items are considered in a dietary study, chance association between a specific food and cancer is not an infrequent event.

Fat and glycogen utilization in the larynx Muscles of fire-bellied toads (Bombina bombina L.) during calling activity. Both fat and glycogen are present in abundance in the larynx muscles of anurans. To clarify their role, the Musculus dilatator laryngis of the male fire-bellied toad, Bombina bombina was studied. In untreated males, the mean fat content of this larynx muscle was 14%; the muscle contained glycogen amounting to 57% of that measured in the liver tissue of the same animal. After thirteen days of continual calling activity induced by administration of a gonadotropin, the fat content fell to 6%, the glycogen to 34%. The fat content was essentially unchanged (13%) by four hours of electrical stimulation of the muscle; the glycogen content, however, had fallen to 42% after this treatment. Neither component was altered in amount by castration, the fat content being about 13% and that of glycogen, 52%. Nor did treatment with gonadotropic hormone reduce either the fat content (13%) or the amount of glycogen (59%). From these results it was concluded that fats represent a direct source of energy for the larynx muscles, which is used up gradually over long periods of calling. The glycogen in these muscles, on the other hand, is a short-term store sufficient to supply energy for only a few hours of calling activity.

Environmental stress and blood glucose change in insulin-dependent diabetes mellitus. Blood glucose (BG) response to psychological stress in insulin-dependent diabetes mellitus (IDDM) patients has not been firmly established. We report a study designed to address the gaps and methodological difficulties reviewed. Subjects with IDDM were exposed to two sessions (12 weeks apart) of two 20-min standardized stressors (active and passive) and a control condition administered in counterbalanced order. To measure BG response, subjects were connected to a glucose/insulin infusion system providing continuous BG measurement. Mood checklist measures were obtained at prestressor, poststressor, and recovery periods. During the first session of testing, the active stressor was associated with significantly more absolute change in BG response than the passive stressor. Results also indicate that IDDM subjects' BG response to this active stressor was idiosyncratic but significantly reliable over time.

Independence of the central nervous and the peripheral renin-angiotensin systems in the dog. What regulates the activity of the central nervous renin-angiotensin system is not known. To define whether control of this central system is linked to that in the periphery, simultaneous blood and cerebrospinal fluid (CSF) samples for measurement of immunoreactive angiotensin II were drawn from anesthetized dogs during hemorrhage, furosemide-induced volume depletion, insulin-hypoglycemia, beta-adrenergic blockade and saline infusion. Despite vigorous increments or decrements in plasma innunoreactive angiotensin II, CSF levels remained stable. Since immunoreactive angiotensin II in dog CSF is claimed to be mainly the heptapeptide des-Asp1-angiotensin II (angiotensin III), the possibility that the level of this peptide within CSF simply reflects plasma concentrations was assessed by infusing angiotensin III (2.5 and 25 ng/kg/min intravenously, each for 60 minutes) and monitoring plasma and CSF peptide levels. Whereas plasma immunoreactive angiotensin II levels increased appropriately across the infusions, no change in CSF levels was observed. These studies indicate the angiotensin III does not cross the blood-CSF barrier, at least in the short term.

Effects of growth hormone-releasing factor and feed intake on energy metabolism in growing beef steers: net hormone metabolism by portal-drained viscera and liver. Effects of growth hormone-releasing factor (GRF) and intake on arterial concentrations and net visceral metabolism of hormones were measured in six growing Hereford x Angus steers using a split-plot design with 4-wk injection periods within 8-wk intake periods. Steers were fed a 75% concentrate diet at two intakes and were injected s.c. twice daily with saline or GRF (10 micrograms/kg of BW). Arterial concentrations of growth hormone (GH) were measured on d 1 and d 8 to 10 of injections. Eleven measurements, obtained at 30-min intervals, of arterial concentration and net flux of hormones across portal-drained viscera (PDV) and liver were obtained on d 8 to 10 of injections (six hourly measurements were used for insulin-like growth factor-I [IGF-I] and somatostatin). The area under the GH curve and average and peak GH concentrations were increased (P less than .01) by GRF and were greater (P less than .10) at low than at high intake. Liver removal of GH was not affected by GRF or intake. Arterial IGF-I concentration was increased (P less than .05) by GRF and not affected by intake. Treatments did not affect IGF-I flux across the liver. Arterial insulin concentration was greater (P less than .05) at high than at low intake, in part because of greater (P less than .01) PDV release. Increased (P less than .10) arterial insulin concentration in GRF-treated steers was not attributable to significant changes in PDV or liver net flux. Arterial glucagon concentration was greater (P less than .01) at high than at low intake, in part because of greater (P less than .05) PDV glucagon release and decreased (P less than .10) liver extraction ratio. Effects of intake on arterial concentration of insulin and glucagon were in part due to changes in visceral metabolism, but GRF did not affect PDV or liver hormone metabolism.

Characterization of cytokines present in middle ear effusions. Retention of inflammatory mediators and cells in the middle ear cleft during chronic otitis media with effusion (COME), results in ongoing inflammation with the potential for pathologic changes and hearing loss. Cytokines are glycoproteins produced by macrophages and other cells. Activities of cytokines include fever production, osteoclast, fibroblast, phagocyte and cytotoxic cell activation, regulation of antibody formation, and inhibition of cartilage, bone and endothelial cell growth. Using enzyme-linked immunospecific assays we measured levels of six cytokines in middle ear effusions (MEE) from children with COME. Significant levels of four cytokines: interleukin-1-beta (greater than 50 pg/ml), interleukin-2 (greater than 300 pg/ml), tumor necrosis factor-alpha (greater than 40 pg/ml), and gamma-interferon (greater than 6.25 pg/ml) were found in 51%, 54%, 63%, and 19% of MEE, respectively. In contrast, levels of a fifth cytokine, granulocyte-macrophage colony-stimulating factor, and a sixth cytokine, interleukin-4, were undetectable. Age was observed to have a significant effect on the levels of specific cytokines. Interleukin-1 (IL-1) correlated inversely (P less than .02) with age such that the younger the child, the higher the level of IL-1 in MEE. Tumor necrosis factor-alpha (TNF) correlated directly (P less than .005) with age such that the older the child, the higher the level of TNF in MEE. Children undergoing tympanostomy on multiple occasions had average MEE TNF levels (234.2 +/- 109.1 pg/mg total protein) that were nearly 14 times higher (P less than .005) than those from children undergoing their first tympanostomy (16.9 +/- 3.0 pg/mg total protein). Thus IL-1 correlated with the early stages of COME, while TNF correlated with persistence of disease. The presence of these cytokines in MEE may be responsible for the mucosal damage, bone erosion, fibrosis, and resulting hearing loss seen in some cases of COME.

Pharmacotherapy for cocaine-abusing methadone-maintained patients using amantadine or desipramine. In a double-blind, placebo-controlled 12-week randomized clinical trial, we compared amantadine hydrochloride (300 mg/d; n = 33), desipramine hydrochloride (150 mg/d; n = 30), and placebo (n = 31) in the treatment of cocaine-abusing methadone-maintained patients. Treatment retention and medication compliance were excellent, with more than 75% of the patients completing the full 12-week trial. Although reported cocaine abuse was significantly lower in the medicated groups compared with the placebo group at week 4, this difference became nonsignificant at week 8, and no difference was found in cocaine-free urine samples. Future studies of amantadine and desipramine treatment in these patients should consider alternatives to methadone hydrochloride, such as buprenorphine hydrochloride, and the selection of more homogeneous patient subgroups, such as depressed cocaine abusers.

The effect of Corynebacterium parvum in combination with 5-fluorouracil, L-phenylalanine mustard, or methotrexate on the inhibition of tumor growth. Previous reports from this laboratory have demonstrated conclusively that cyclophosphamide administered asynchronously with Corynebacterium parvum (CP) results in greater C3H mammary tumor inhibition than that observed with either agent alone. An analysis of this combination has revelaed that the chemotherapeutic component contributes more significantly to tumor inhibition than does the immunotherapeutic one. This study was conducted to investigate the inhibition of C3H mammary tumors by other chemotherapeutic agents when used with CP. The results have demonstrated that 60 mg of cyclophosphamide per kg, 90 mg of 5-fluorouracil per kg, and 10 mg of L-phenylalanine mustard per kg administrated weekly have similar tumor-inhibiting properties. The addition of CP enhanced the tumor-inhibiting properties of each agent but to differing degrees. The effect of the immunopotentiator when used in combination with alkylating agents was greater than that seen when it was used with the antimetabolite 5-fluorouracil. The tumor inhibition observed when cyclophosphamide was administered asynchronously with CP was significantly greater than that observed when L-phenylalanine mustard was similarly used. Of particular interest was the finding that the addition of CP to a combination of chemotherapeutic agents resulted in no greater tumor growth inhibition than that which occurred when CP was used along with the most effective single agent in the combination. The data have indicated that, contrary to clinical impression, there is no evidence that CP through its toxicity-sparing effect permits the utilization of larger doses of chemotherapy. Consideration has been given to the mechanisms that might account for the differences in tumor growth inhibition encountered when CP was used with different chemotherapeutic agents.

Specific identification of fibrin(ogen) degradation products in plasma and serum using blotting and peroxidase labeled antiserum. We describe a method for identifying fibrinogen and fibrin split products using electrophoresis on agarose gel with sodium dodecyl sulfate (SDS) followed by blotting in nitrocellulose paper. Detection of these derivatives after blotting is accomplished with peroxidase-conjugated rather than by isotopically labeled antibodies. This technique can detect diverse fibrinogen derivatives produced in vivo or in vitro by the combined action of thrombin, plasmin, and factor XIII. This methodology is applicable to plasma, serum, and other body fluids including urine and ascitic fluid. This sensitive and specific assay, distinguishing the products of cross-linked fibrin from those of fibrinogen and detecting fibrin polymers in plasma, can be achieved without the use of radioactivity.

The lovastatin-treated rodent: a new model of barrier disruption and epidermal hyperplasia. Recent studies have linked epidermal cholesterol synthesis with maintenance of the permeability barrier. To assess directly the importance of cholesterol synthesis, we applied lovastatin, a potent inhibitor of cholesterol synthesis, to hairless mouse skin. Transepidermal water loss (TEWL) began to increase after four to six daily applications. Co-application of cholesterol blocked the expected increase in TEWL, demonstrating the importance of cholesterol for development of the lesion. The histology of lovastatin-treated skin revealed epidermal hyperplasia, accompanied by accelerated DNA synthesis. Whereas cholesterol synthesis initially was reduced in lovastatin-treated epidermis, with further treatment cholesterol synthesis normalized, while fatty acid synthesis accelerated greatly. Although the total free sterol content of lovastatin-treated epidermis remained normal, the fatty acid content increased coincident with barrier disruption. Finally, morphologic abnormalities of both lamellar body structure and their deposited, intercellular contents occurred coincident with the emerging biochemical abnormalities. Thus, the abnormal barrier function in this model can be ascribed to an initial inhibition of epidermal sterol synthesis followed by an alteration in cholesterol and fatty acid synthesis, leading to an imbalance in stratum corneum lipid composition and abnormal membrane bilayer structure.

Exposure to ozone and erythrocyte osmotic resistance in the rat. In order to learn the biological effect of photochemical oxidants on living bodies, we exposed newborn and adult rats, of both sexes, to ozone at a concentration of 0.25 ppm, which can be encountered in an urban environment, and then measured the osmotic resistance of their erythrocytes. The results of experiments using newborn rats indicated a positive increase in the osmotic resistance of erythrocytes in whole blood following ozone exposure for 4 weeks. An increase in the osmotic resistance of erythrocytes in the top part obtained by centrifugation was observed following ozone exposure for 12 weeks. This tendency was especially evident among male rats. On the other hand, no increase in the osmotic resistance of erythrocytes was recognized in the adult animals which had been exposed to the same concentration of ozone for 18 months.

Resting heart rate in apparently healthy middle-aged men. Resting heart rate (fcrest) was measured by a standardized technique in 2,014 men aged 40-59 years during a cardiovascular survey. All men were thought to be healthy prior to the survey examination. According to the survey findings, the material was subdivided into 5 clinical subgroups, according to survey findings of coronary heart disease (CHD), or suspect symptoms, or signs. Coronary angiography was performed in 105 subjects with particularly strong suspicions of CHD. FCrest varied between 61-63 among the 5 groups (p greater than 0.10). In 1832/2014 defined as "normals" the following findings were made: 1. Mean fcrest 61 (SD 9.7), and almost identical values obtained by auscultation and from resting ECGs in the same persons. 2. Linear drop in fcrest by age (-0.126 beats/year, p less than 0.001). 3. Increase in fcrest with increasing systolic blood pressure. Since there is no generally accepted technique for measuring fcrest it is suggested that the wide variation in fcrest reported in the literature at least in part may be due to differences in techniques.

Molecular structure of human protamine P4 (HP4), a minor basic protein of human sperm nuclei. Protamine HP4 is a minor protein which was purified from human sperm nuclei. It was characterized by its amino acid composition, peptide mapping after digestion with highly specific endoproteinases and finally by its amino acid sequence. Protamine HP4 contains high amounts of arginine, cysteine and histidine. The primary structure of the protein was established by sequence analysis of intact protamine and of its fragments. HP4 is a P2-type protamine of 58 residues (Mr 7783) structurally related to human protamines HP2 and HP3 from which it only differs by an amino-terminal extension of one and four residues, respectively. These three protamines exhibit a close structural relationship with mouse protamine mP2. The heterogeneity of protamines in human sperm nuclei is discussed.

The effect of spiny lobster shell powder on bone metabolism in ovariectomized osteoporotic model rats. Calcium has been found to be indispensable in the prevention of osteoporosis. Recently, there has been a great deal of research into the best way to consume calcium. In this study, the effect of "powdered lobster shell" on bone metabolism was examined in ovariectomized osteoporotic model rats. This powder has a good flavor and taste, and contains high quantities of calcium. Six-week-old SD-strain female rats were ovariectomized and were fed a low Ca diet (0.01% Ca and 0.3% P) for 32 days. Thereafter, the rats were divided into two groups; the control group was fed a control diet (0.3% Ca and 0.3% P) and an experimental group, the lobster group, was fed a lobster shell powder diet (0.3% Ca and 0.3% P) ad libitum for 30 days. The results were as follows: in comparison with the control group, the lobster group had significant increases in (1) bone mineral density [BMD (DEXA Hologic's QDR-1000] of lumbar spines and tibial proximal metaphyses, which are mainly trabecular bones, and BMD of tibial diaphyses, which is a mainly cortical bone, (2) the breaking force and energy of femur. These results suggests the lobster shell powder could be a valuable source of dietary calcium in increasing BMD, breaking force and energy in osteoporotic model rats.

Morphometric distinction of sclerosing adenosis from tubular carcinoma of the breast. Objective features have been identified that assist in distinguishing sclerosing adenosis from tubular carcinoma of the breast. Hematoxylin and eosin stained paraffin sections of 18 sclerosing adenoses and 18 tubular carcinomas were studied using a TAS Plus image analysis system. Histological measurements from lumens and glands included stereologic features of architecture and morphometry of size and shape (the latter by Fourier coefficients). Cytological measurements included nuclear area, perimeter, diameter and formfactor. Initial analysis suggested utility for several individual features. However, after a modified Bonferroni procedure only two of the features were statistically significant, i.e. the coefficient of variation of luminal form factor and the surface density of glands. Multivariate discriminant analysis using these two variables correctly classified 86% of the cases, with three adenoses and two carcinomas misclassified. Validity of the discriminant rules was supported by classification using measurements from a separate, independent set of cases (ten sclerosing adenoses and nine tubular carcinomas). The classification function computed from the first set misclassified only one case from the second set, a tubular carcinoma, leaving 95% of the cases successfully categorized. Chi square test for 2 x 2 contingency tables gave a p-value < 0.001 for both sets of cases. The results suggest that morphometric features are helpful in distinguishing tubular carcinoma from sclerosing adenosis and point out the need for conservative analysis of high-dimensional data sets.

Ontogenetic dissociation of two classes of habituation. The rates of decrement of two classes of response (an elicited startle reflex and emitted exploratory behavior) were determined in rats of two different ages (15 and 36 days). The rate of decrement in the startle reflex was not clearly differentiated as a function of age. In contrast, there was no evidence of habituation of exploration in the younger animals, whereas the older rats uniformly showed profound response decrements. This ontogenetic dissociation of the two instances of response decrement indicates that accounts of both instances in terms of a common process called habituation may be unwarranted. In addition, these data, in conjunction with earlier findings, indirectly support the possibility that reflex decrements may be relatively more dependent on brain serotonin whereas decrements in exploration may be more dependent on normal cholinergic activity in brain.

Characterization of myosin isoforms in satellite cell cultures from adult rat diaphragm, soleus and tibialis anterior muscles. Satellite cells were isolated by enzymatic dissociation and Percoll gradient centrifugation from adult rat diaphragm, soleus, and tibialis anterior muscles with fairly reproducible yields. Diaphragm and soleus muscle yielded approximately five times more satellite cells than tibialis anterior muscle. According to light microscopic criteria, no morphological differences existed between the satellite cell cultures of different origin. Contrary to the donor muscles, myotubes from the 10-day-cultured satellite cells contained a uniform myosin heavy chain (MHC) pattern with predominance of an immunochemically identified embryonic heavy chain. The three types of cultures displayed a typical embryonic light chain (LC) pattern with LC1emb, LC1f, LC2f, and traces of LC3f. The isomyosin pattern was characterized by four embryonic isomyosins, eM1-eM4, with similar distributions in the three cultures. In summary, these myosin analyses provide no evidence for the existence of satellite cell diversity among three rat muscles of different fiber-type composition, at least not under the applied in vitro conditions.

General pharmacology of the four gastrointestinal motility stimulants bethanechol, metoclopramide, trimebutine, and cisapride. The pharmacological profile of bethanechol (CAS 674-38-4), metoclopramide (CAS 364-62-5), trimebutine (CAS 39133-31-8) and cisapride (CAS 81098-60-4) was studied in a series of simple pharmacological tests in rats and dogs. Bethanechol stimulated both gastric emptying and intestinal propulsion but displayed also the well-known behavioral effects of a direct muscarinic acetylcholine receptor agonist. Metoclopramide showed the profile of a centrally active dopamine D2 antagonist. In addition, metoclopramide displayed a stimulant effect on spontaneous gastric emptying in rats, an effect that could not be related to dopamine D2 antagonism. The only effect observed with trimebutine was protection from castor oil diarrhea, probably due to its reported interaction with peripheral opiate receptors. Cisapride was a potent stimulant of gastric emptying in rats, 7 times more potent than metoclopramide. Cisapride was also a very specific gastrokinetic, over a large dose range (specificity ratio: greater than or equal to 20) devoid of effects indicative for direct interaction with dopamine or acetylcholine receptors. The relationship between the differential activity profiles of the compounds in the present study and differences in their mechanism of action and side-effect liability is discussed.

Enhancement of epidermal growth factor receptor expression on glioma cells by recombinant tumor necrosis factor alpha. Recombinant tumor necrosis factor alpha (rTNF alpha; optimal dose 1000 U/ml) significantly increased the density of epidermal growth factor receptor (EGF-R) in three of four glioma cell lines in culture as determined by binding analysis of anti-EGF-R monoclonal antibody (mAb) 425. Since enhancement of EGF-R expression by rTNF-alpha was inhibited when cells were treated with the protein synthesis inhibitor cycloheximide, the effects of rTNF alpha may be protein-synthesis-dependent. The dose of rTNF alpha that was optimal for up-regulation of EGF-R on glioma cells did not inhibit the growth of these cells. 125I-labeled mAb 425 lysed glioma cells in culture following its internalization into the cells. After glioma cells had been treated with rTNF alpha, the growth-inhibitory effects of the mAb were significantly enhanced, probably a reflection of the increase in EGF-R density on the tumor cell surfaces. The rTNF alpha effects were specific to the EGF-R and did not affect unrelated glioma-associated antigens. In our previous clinical trials, 125I-labeled mAb 425 showed immunotherapeutic effects in glioma patients. The present study provides the basis for considerations of combined immunotherapy of glioma patients with 125I-labeled mAb 425 and rTNF alpha.

Membrane cofactor protein of the complement system. A HindIII restriction fragment length polymorphism that correlates with the expression polymorphism. An RFLP was found in the DNA of 25 unrelated persons, two families, and five cell lines that correlated with their membrane cofactor protein phenotype. If restricted with HindIII, DNA derived from upper band predominant protein (U) phenotypes had a band at 2 kb, whereas DNA of lower band predominant (L) phenotypes had a 4-kb band. The equal band protein phenotype, in which equal quantities of the two species are expressed, had bands at both 4 and 2 kb. The polymorphic HindIII site was localized to an intron within the membrane cofactor protein gene between exon 1 (codes for 5'UT/signal peptide) and exon 2 (codes for the first short consensus repeat). Using the polymerase chain reaction (PCR), sequences around this site were amplified and a single band of 260 bp was produced. In the U phenotype, the PCR product was restricted with HindIII into 200- and 60-bp fragments. In the L phenotype, there was no change in the size of 260 bp upon restriction with HindIII. For the equal band protein phenotype, the PCR product was partially cleaved. The 260-bp PCR product was subcloned and sequenced. DNA from the U phenotype demonstrated an intact HindIII site (AAGCTT), whereas in the DNA of the L phenotype, this site was altered because a "G" was substituted for a "C" (AAGGTT).

Electrogenic sodium pumping in rabbit small intestinal smooth muscle. Oscillations in the activity of an electrogenic Na pump has been suggested as the ionic mechanism underlying the intestinal control potential (slow wave). We investigated the electrogenicity of this pump in rabbit jejunal smooth muscle. Potassium admission to Na-rich tissues caused a large increase in membrane potential which after 10--20 min decreased toward values comparable with those of normal tissues. This hyperpolarization far exceeded EK and could be prevented by cooling or by ouabain. No hyperpolarization occurred upon K admission to Li-rich tissues in the absence of Na. Thus, the pump in this tissue can operate electrogenically. Goldman's equation was modified so as to account for the pump's contribution to the membrane potential. Using this equation, the calculated contribution of the pump, under normal "steady-state" conditions, is unlikely to exceed a few millivolts. It is concluded that although the pump in this tissue can be electrogenic, its contribution may be smaller than that required if the intestinal control potential resulted from rhythmic turning off and on of the electrogenic Na pump.

Glycine levels in the degenerated human spinal cord. Tissues from non-degenerated tissue of 18 patients were assayed for glycine concentration in grey and white matter in the thoracic, cervical and lumbar regions. Confirming earlier results, glycine concentration was found to be maximal in the grey matter of the lumbar segments of the lateral column. Analysis of tissue from 11 human spinal cords showing unilateral Wallerian degeneration, 4 cords with amyotrophic sclerosis and 4 cords with bilateral Wallerian degeneration failed to show statistically significant differences when compared with control values. The results argue against a supraspinal origin of glycine and suggest that glycine levels are regulated locally or at a segmental level in the spinal cord in man.

Unstable angina. Unstable angina can manifest as an array of symptom complexes. In some patients, medical therapy will stabilize the episodes of angina, and only predismissal exercise testing or angiography (or both) will be necessary. At the other end of the spectrum are patients with rest angina or multiple episodes of silent ischemia who are refractory to medical therapy and experience undetected microinfarction. Most of these patients require immediate catheterization and subsequent intervention with intra-aortic balloon pulsation, percutaneous transluminal coronary angioplasty, or coronary artery bypass grafting. An entire spectrum of manifestations exists between these two extremes. One challenge during the 1990s will be better stratification of patients with unstable angina so that safe, efficient, cost-effective treatment strategies can be appropriately applied to all patients.