[Inhibition of stimulated gastric secretion with simultaneous administration of cimetidine and somatostatin].

In four gastric fistula dogs we studied the effect of cimetidine (5 mg/kg/h) and somatostatin (10 microgram/kg/h), alone or in combination, on gastric secretion stimulated by histamine (160 microgram/kg/h) or pentagastrin (6 microgram/kg/h). Acid and pepsin output after histamine stimulation was more reduced by cimetidine than after pentagastrin stimulation. Somatostatin showed an inhibitory effect only after pentagastrin stimulation. The most effective reduction, both on the degree of inhibition and on duration after cessation of the inhibitors, was seen after the combination of cimetidine/somatostatin. These results give some clinical aspects for the use of these two agents.


[Elimination of bone defects with the aid of a transplant (bone morphogenetic protein BMP) prepared according to Urist's method. Animal experimenst compared with Kieler spongiosa].

In two groups of six beagle dogs a standardized bone defect of 1 cm was replaced by a) "Kieler Spongiosa", and b) autologous bone material, prepared according to the formula of Urist. Instead of mechanical insufficiency an impressive osteogenetic potency and periosteosis was noticed in group b.


[Comparative studies on the incorporation of autologous and homologous spongiosa in the compact layer of long bones].

The healing of fresh autologous and homologous cancellous bone graft in gaps made in diaphysis was checked in a comparative test series of dogs. The general revascularization comes from the medulla. During the 2nd week the newly formed vessels in the homograft are obliterated. These are rebuilt during the 3rd week. At the same time new bone formation and reabsorption of the implanted bone by osteoclasts cease temporarily. After 6 weeks both grafts are remodeled in lamellar bone. The osseous trabeculae do not yet run parallel to Havers' system of the corticalis. The results verify the superiority of the autologous cancellous bone grafts.


[Immunologic monitoring of transplantation patients: study of the reactivity of cytotoxic precursor cells].

Proliferative and cytotoxic T-cell reactivity subsequent to in vitro stimulation by a lymphocyte pool were studied in ten patients with well-accepted cadaver renal allografts and eight healthy controls. Whereas the proliferative reactivity was about equal in both groups, the cytotoxic responsiveness was markedly reduced in the allograft recipients. We conclude from these results that immunosuppressive drugs as well as specific adaptation processes act preferentially on the cytotoxic precursor cell population.


[Preservation of kidneys with ischemic injury using hypothermic storage and mechanical prolonged perfusion].

Dog kidneys were flushed and stored in Collins (n = 30) and Sacks (n = 32) solution under hypothermia. These results were compared with those gained by mechanical perfusion (n = 21). Before preservation, the kidneys were subjected to 15 - 60 min of warm ischemia then stored for 12 - 24 h. It was concluded that 12-h preservation time after 15-min ischemic injury was the limit of hypothermic storage preservation. Sacks' solution gave better results than Collins' solution as regards the immediate function after transplantation. In contrast, mechanical perfusion was well tolerated for 24-h preservation time after a warm ischemia of 30 min. In case of warm ischemic damage, mechanical perfusion should be preferred to hypothermic storage.


[The effect of high-dosage prednisolone administration on antibody formation and graft survival time following allogenic rat kidney transplantation].

The dose and time dependence of the immunosuppressive effect of prednisolone on renal allograft survival and antibody formation was studied in inbred rats. A single injection of 50 - 300 mg prednisolone/kg body wt. on the day of transplantation resulted in a dose-dependent prolongation of mean graft survival to 12.8 days as compared to 7.8 days for untreated controls. The daily postoperative administration of 10 and 30 mg prednisolone/kg prolonged the mean survival time to a lesser extent. A single bolus injection of 300 mg prednisolone/kg at different times after transplantatin resulted in a significant prolongation of graft survival and suppression of cytotoxic antibody only when given no later than 2 days postoperatively or following antigen injection.


[In vivo determination of local tissue pO2 in renal cortex in kidney transplantation].

From measurement of local tissue PO2 in human kidney grafts after restoration of renal circulation, a correlation between initial microcirculation and kidney function can be drawn. PO2-histograms of kidney grafts with sufficient function are normal, whereas PO2-histograms of kidneys with delayed onset of function (congruent to 3 weeks) show distinct disturbances of microcirculation. These preliminary results suggest that measuring local tissue PO2 in transplanted kidneys may be of value for the prognosis of the graft.


[Nontraumatic perforations of the small intestine].

From 1970 to 1978, 14 patients with nontraumatic perforations of the small intestine were treated in the Department of General and Abdominal Surgery of the University Frankfurt am Main. In eight cases suture and bypass and/or interval operation with enterostomy was performed. Seven patients survived, one died. In the six other patients resection with primary anastomosis or suture were performed. One patient survived and five patients died following peritonitis due to insufficiency of the anastomosis. The problem of nontraumatic perforation of the small intestine is discussed and the literature reviewed. It is suggested that the operation of choice is suture of the perforation with bypass or the two-stage operation with enterostomy.


[Effect of methylprednisolone on bacterial infection of the peritoneal cavity in the guinea pig].

There is clinical proof of the decisive therapeutic effect of bolus injection of corticosteroids in septic shock. Our own studies, in which sublethal doses of bacterial suspensions were introduced into the peritoneal cavity of guinea pigs, demonstrate that a simultaneously applied solution of methylprednisolone (MP) has no influence on the intraperitoneal number of bacteria. Even the rapid initial decrease of bacterial counts, which, according to our studies, can be inhibited by Liquoid and is, therefore, caused by complement, is not influenced by the addition of MP. There was no indication of a change of tissue reactions in gut or mesenterium. The therapeutic effect of corticosteroids seems to depend on its influence on peripheral vessels.


Yeast chromosomal DNA molecules have strands which are cross-linked at their termini.

The microbial eukaryote Saccharomyces cerevisiae has 18 chromosomes, each consisting of a DNA molecule of 1 x 15 x 10(8) daltons (150 to 2,300 kilobase pairs). Interstand cross-links have now been found in molecules of all sizes by examining the ability of high molecular weight DNA to snap back, i.e., to rapidly renature after denaturation. Experiments in which snap back was assessed for molecules broken by shearing indicate that there are probably two cross-links in each chromosome. Evidence that the cross-links occur at specific sites in the genome was obtained by treating total chromosomal DNA with the endonuclease EcoRI which cleaves the yeast genome into approximately 2,000 discrete fragments. Cross-link containing fragments were separated from fragments without cross-links. This purification resulted in enrichment for about 18 specific fragments. To determine whether the cross-links are terminal or at internal sites in chromosomal DNA, large shear-produced fragments were examined by electron microsopy. With complete denaturation few fragments exhibit the X-shaped single strand configuration expected for internal cross-links. When partially denatured fragments were examined some ends had single strand loops as expected for (AT-rich) cross-linked termini. We propose that a duplex chromosomal DNA molecules have cross-linked termini. We propose that a duplex chromosomal DNA molecule in this eukaryote consists of a continuous, single, self-complementary strand of DNA. This structure has implications for the mechanism of chromosome replication and may be the basis of telomere behavior.


A study of heterochromatin in Drosophila nasuta by the 5-bromodeoxyuridine-Giemsa staining technique.

Larval brain ganglia of Drosophila nasuta were cultured in vitro in the presence of 5-bromodeoxyuridine for 1 or 5 h at 24 degrees C and the air-dried chromosome preparations stained by the Hoechst 33258-Giemsa technique to reveal bromodeoxyuridine induced sister chromatid differentiation. In 1 h as well as 5 h preparations, 10-15% of well spread metaphase plates show a sister chromatid differentiation in only C-band heterochromatin regions of different chromosomes. We infer that this sister chromatid differentiation in all heterochromatic regions is seen after bromodeoxyuridine incorporation for only one replication cycle and is related to the presence of asymmetric A-T rich satellite sequences in all the C-band regions of D. nasuta karyotype.


Endoscopic identification and removal of an unusual symptomatic colonic foreign body.

The discovery and removal of a life-threatening colonic wire suture using the flexible fiberoptic colonoscope has been described. Such reports demonstrate the versatility and usefulness of diagnostic and therapeutic endoscopic procedures.


L-Dopa inhibits metoclopramide stimulation of the lower esophageal sphincter in man.

Opossum lower esophageal sphincter smooth muscle contains inhibitory dopaminergic receptors. Since metoclopramide is a dopaminergic antagonist in many experimental situations, the present study was designed to investigate whether this mechanism could explain the lower esophageal sphincter (LES) stimulating action of metoclopramide in man. The interactions of (1) oral L-dopa, a dopamine precursor, and metoclopramide; and (2) L-dopa and the cholinergic agent, bethanechol, on lower esophageal sphincter pressure (LESP) in normal subjects were examined. Oral L-dopa significantly inhibited LESP response to either oral metoclopramide 20 mg (P less than 0.05), or intravenous metoclopramide 20 mg (P less than 0.05). In contrast, L-dopa did not inhibit the LESP response to subcutaneous bethanechol (0.07 mg/kg). Mean basal LESP measured 50 min after ingestion of 1000 mg L-dopa, 19.3 +/- 3.1 mm Hg, was significantly less than basal LESP after L-dopa placebo, 29.3 +/- 4 mm Hg (P less than 0.01). It is concluded that (1) L-dopa inhibited the metoclopramide-induced rise in LESP but not peak stimulation of LESP by bethanechol; (2) there is evidence for the possibility of LES dopaminergic inhibitory receptors in man; and (3) these data are consistent with the hypothesis that metoclopramide acts on the LES by blocking a dopaminergic pressure-lowering mechanism.


The relationship between conventional liver tests, quantitative function tests, and histopathology in cirrhosis.

Thirty patients with cirrhosis were evaluated with the 2-hr [14C]aminopyrine breath test (score) and with conventional liver tests. Of the 30 patients, 24 also had current liver biopsies. There was a good correlation between necroinflammatory activity in the 24 cirrhotic liver biopsies and the 2-hr aminopyrine scores. All five patients who had at least grade 2 necroinflammatory activity on their biopsy had an abnormal prothrombin time (greater than 3.5 sec above control) and their aminopyrine score was less than 2%. The correlation was good between the 2-hr aminopyrine score and the prothrombin time (seconds over control). No correlation was found between the 2-hr aminopyrine score and either the serum aspartate aminotransferase (SGOT) or any other liver test except for the prothrombin time. It seems that the 2-hr aminopyrine score and prothrombin time are more likely to give a quantitative estimate of total functioning parenchymal mass which is left unaffected by hepatocellular disease in cirrhosis, than the other commonly used liver tests.


Clinical perspectives in the care of the pregnant diabetic patient.

Despite the considerable improvement in the care of the diabetic mother and the prognosis for her baby, a number of clinical problems remain unresolved. Apart from the increased incidence of major and minor fetal anomalies, morbidity amongst the newborn and the high incidence of diabetes in later life of women who have had relatively minor carbohydrate intolerance during pregnancy are a cause for concern. In this paper the outstanding clinical problems and thier possible solutions are considered. The elucidation of the origin of congenital malformations is discussed. The prevention of congenital anomalies in the diabetic requires a precise knowledge of their aetiology which is currently not available. However, on the hypothesis that diabetes creates an abnormal biochemical environment which may well disturb embryogenesis, it is logical to try and control maternal blood sugar as soon as possible in pregnancy or even before conception. To extend this argument further, it follows naturally that the maintenance of normoglycaemia throughout pregnancy until delivery is also desirable. The practicalities of various methods of screening for diabetes in pregnancy and new approaches in the medical and obstetric problems of the pregnant diabetic are also considered. Finally, the question of contraception and its implication for the woman who is known to have carbohydrate intolerance in pregnancy is discussed.


Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12.

Protein- (chicken serum) bound [57Co]cyanocobalamin absorption was evaluated in five hypochlorhydric patients who had developed B12 deficiency despite having normal absorption of unbound crystalline vitamin B12. All five patients had decreased urinary excretion of protein-bound B12 (0.06--0.34%) as compared to twelve normal controls (0.61--5.6%), P less than .001. Improvement in protein-bound B12 absorption in four of the five patients occurred with the exogenous administration of hydrochloric acid, pepsin, gastric intrinsic factor, or a combination thereof. Vitamin B12 deficiency developing in the setting of hypochlorhydria may result from deficiency of acid-peptic digestion of B12 bound to protein and/or a relative deficiency of intrinsic factor. This digestive defect is not detected with tests which measure the absorption of unbound crystalline B12 but is detected by a simple test which employs B12 bound to chicken serum as the form of protein-bound B12.


The influence of hormonal changes of pregnancy on maternal metabolism.

Mammalian pregnancy is characterized by progressive hyperinsulinaemia, raised plasma lipids and increased vulnerability to ketosis after food deprivation. The present investigations were performed to assess the role of two placental steroids, oestradiol and progesterone, in the development of these changes, since plasma titres of these hormones progressively increase during human gestation. In both human subjects and adult female rats it was demonstrated that these two steroids, separately or in combination, augment plasma insulin concentration in vivo, cause hypertrophy of pancreatic islets and promote exaggerated secretion of insulin, but not glucagon, by pancreatic islets in vitro. Hypertriglyceridaemia induced by oestrogen alone or combined with progesterone was associated with increased splanchnic production of triglyceride as well as altered tissue lipoprotein lipase (EC 3.1.1.34) and circulating apoproteins that influence activity of this enzyme. The combined regimen also increased hepatic glycogen storage and suppressed gluconeogenesis in vivo in the rat while accelerating the onset of ketosis during starvation in human subjects and in the animal model. Oestradiol and progesterone appear to effect metabolic changes in nonpregnant animals and human subjects that simulate maternal adaptations to advancing gestation, including altered endocrine pancreatic function, triglyceride metabolism and metabolic fuel storage and mobilization.


Long-term cimetidine in duodenal ulcer disease.

Forty patients with chronic duodenal ulcer who had healed endoscopically with a 6-week course of cimetidine were randomized double blind to 1 year of either placebo or cimetidine tablets 400 mg bid (20 patients in each group). Patients were seen at monthly intervals, and endoscopy was performed at clinical relapse or on completion of 1 year. One of 20 patients on active cimetidine relapsed clinically and endoscopically at 3 months; 16 of 20 patients on placebo relapsed clinically and endoscopically within 9 months, the majority within 3 months, and 2 were shown to have asymptomatic chronic ulcers at routine 12-month endoscopy. None of the 19 patients on active cimetidine routinely endoscoped at 12 months showed evidence of ulceration. This study confirms a high relapse rate when short-term cimetidine is ceased and indicates that maintenance treatment with cimetidine prevents relapse.


Differences in intrahepatic portal-systemic shunting in alcoholic and nonalcoholic liver disease as assessed by liver scan, portal pressure, and E. coli antibodies.

The interrelationship among portal vein pressure, 99mTc sulfur colloid liver/spleen scan abnormality, and serum E. coli antibody titers has been examined in 33 patients with alcoholic liver disease (ALD) and compared with 24 patients with liver disease not related to alcohol (non-ALD). A correlation between portal vein pressure and liver scan abnormality is seen in both groups, but for a given degree of portal hypertension there is a much greater redistribution of sulfur colloid in the ALD group (P less than 0.01). E. coli antibody titers are significantly higher in the ALD patients compared with the non-ALD patients (P less than 0.02), and they show a positive correlation with scan abnormality but not with portal vein pressure. It is suggested that the differences in scan appearance and E. coli antibody titers in these two groups of liver disease patients may be related to differences in intrahepatic shunting.


[Lidocaine prophylaxis in the pre-hospital phase of acute myocardial infarction (author's transl)].

In a double blind study performed in cooperation with 69 emergency doctors and general practitioners in the catchment areas of the university and of the city hospital in Lübeck the action of intramuscular lidocaine on mortality and on the incidence of arrhythmias was investigated in patients with acute myocardial infarction aged less than 70 years. The mortality in the lidocaine group was significantly lower than in the placebo group. The incidence of ventricular arrhythmias up to 120 minutes after the lidocaine injection was also lower than in the placebo group. However, the only case of primary ventricular fibrillation was in the lidocaine group. As the difference in mortality between the two groups appeared at a time when an antifibrillatory action of lidocaine can no longer be assumed one must question whether the positively beneficial effect was real or whether the lower mortality was in fact due to primarily milder disease in the lidocaine group.


Drug prescribing in renal failure.

Drug prescribing for patients with renal failure should incorporate adjustment of dosage regimens in order to avoid accumulation and thus adverse effects. Drugs usually eliminated by the kidneys require the most modification. Since immediate therapeutic efficacy is of importance, the initial or loading dose is essentially unaltered for patients with renal dysfunction. Maintenance doses can be adjusted by either lengthening the interval between doses of by reducing the size of individual doses. In clinical practice, a combination of both methods is used. Serum levels should be used as guides whenever possible. In interpreting these levels, recognition of decreased plasma protein binding and prolonged elimination half-lives in renal failure is imperative. In patients requiring dialysis, consideration must be given to adjustments for drug removal by the artificial membrane. Small molecules unbound to proteins are most easily removed. Specific guidelines for therapy with common drugs prescribed for patients with renal failure are given. These include: (1) narcotics and analgesics; (2) psychotherapeutic drugs; (3) cardiovascular drugs; and (4) antimicrobial agents.


Buprenorphine: a review of its pharmacological properties and therapeutic efficacy.

Buprenorphine, a derivative of the morphine alkaloid thebaine, is a strong analgesic with marked narcotic antagonist activity. In studies in relatively small groups of postoperative patients with moderate to severe pain, one or a few doses of buprenorphine parenterally (by intramuscular or slow intravenous injection) or sublingually were at least as effective as standard doses of other strong analgesics such as morphine, pethidine or pentazocine, and buprenorphine was longer acting than these agents. Only a small number of patients with chronic pain have received repeated doses, but in such patients there was no need for increased doses during several weeks to months of treatment. Buprenorphine appears to produce side effects which are similar to those seen with other morphine-like compounds, including respiratory depression. There is apparently no completely reliable specific antagonist for buprenorphine's respiratory depressant effect, since even very high doses of the antagonist drug naloxone may produce only a partial reversal. The respiratory stimulant drug doxapram has overcome respiratory depression in volunteers and in a few patients in a clinical setting, but such studies have not been done in an overdose situation. Animal studies and a direct addiction study in a few volunteers suggest that the dependence liability of buprenorphine may be lower than that of other older morphine-like drugs. However, a slowly emerging abstinence syndrome did occur on withdrawal after very high doses administered for 1 to 2 months. A definitive statement on the drug's dependence liability and abuse potential cannot be made until it has had much wider use for a longer period of time.


Mexiletine: a review of its pharmacological properties and therapeutic efficacy in arrhythmias.

Mexiletine is a new local anaesthetic antiarrhythmic agent whose chemical structure and electrophysiological properties closely resemble those of lignocaine although its anticonvulsant and pharmacokinetic properties differ from that drug. Unlike lignocaine (lidocaine) it is active following oral administration with a plasma half-life varying between 8 and 20 hours so that it can be administered twice or three times daily to sustain therapeutic plasma levels. The drug is effective when given intravenously or by the oral route in controlling ventricular arrhythmias especially following acute myocardial infarction but the side effects are greater during parenteral administration. Side effects during chronic oral therapy with mexiletine have not posed a serious problem. Mexiletine has the pharmacodynamic and pharmacokinetic properties of an agent suitable for the chronic oral prophylaxis of serious ventricular arrhythmias in patients with ischaemic heart disease.


Drug prescribing in hepatobiliary disease.

Liver disease in man is associated with a variety of pathophysiological processes which may influence the disposition of drugs in several ways. Interpretation of the observed pharmacokinetic changes in liver disease requires an understanding of the relationship between systemic drug clearance (Cls), volume of distribution (Vd) and the elimination half-life [t1/2(beta)], i.e. t1/2(beta) = 0.693 . Vd/Cls. Half-life will be a measure of the fluctuation in drug level one may expect with continued administration of a drug while clearance will determine the dose required to achieve a particular steady state level. Liver disease may affect clearance and volume of distribution and so produce changes in half-life; in addition, alterations in plasma binding of drugs may occur and so influence free (unbound) drug levels. It is also possible that the end organ response, particularly in the case of sedative drugs, may be affected by liver disease. Other factors such as age, nutrition, smoking, and concomitant drug therapy may also influence drug elimination in patients with liver disease. At the present time, caution should be exercised in prescribing drugs to patients with liver disease and the dose should be titrated to the clinical response. The development of liver 'function' tests using model or marker drugs may offer some help to the prescriber in the future and enable a less empirical approach.


Use of bromocriptine in hyperprolactinaemic anovulation and related disorders.

Bromocriptine has been successfully used to treat hyperprolactinaemic disorders of ovulation; treatment with 5.0 to 7.5 mg daily results in normalisation of serum prolactin concentration and restoration of ovulatory menstruation in most patients with hyperprolactinaemic amenorrhoea or oligomenorrhoea. It is equally effective in hyperprolactinaemic patients with pituitary tumours as in those with normal pituitary x-rays, but the choice of bromocriptine as primary treatment in the former group (especially in those patients who desire pregnancy) is a matter of some controversy and requires careful judgement. Bromocriptine has also been used, with reported success, in infertility associated with luteal insufficiency, the polycystic ovary syndrome, normoprolactinaemic amenorhoea and ovulatory infertility. However, its role in the treatment of these disorders will remain uncertain until more extensive, adequately controlled clinical trials are availabe.


Bromocriptine in the treatment of hypogonadism and male impotence.

A rapid, practical diagnostic scheme is the key to selecting proper candidates for treatment with bromocriptine. The evaluation centres around assays for prolactin and follicle stimulating hormone, polytomography and computerised axial tomography of the sella turcica and parasellar regions, and the ergot alkaloid, bromocriptine. Additionally, bromocriptine is of significant value in the treatment of men and women with hypogonadotrophic hypogonadism. Approximately 80% of patients with hypogonadotrophic hypogadism and hyperprolactinaemia will respond favorably to bromocriptine therapy. In women who conceive during such treatment there appears to be no increase in the rate of spontaneous abortion, of multiple gestations or of congenital anomalies. Bromocriptine appears to be of little value in the treatment of male impotence unless hyperprolactinaemia is a component of the disease. Side affects are usually mild and transient. Following the discontinuation of therapy most patients have a recurrence of hyperprolactinaemia and hypogonadism.


[Therapy of chronic hepatitis (author's transl)].

The favorable effect of glucocorticoids on the development of the chronic active hepatitis is statistically proved on the basis of the amelioration of the survival rate in controlled studies. The so-called lupoid hepatitis is significantly better influenced than the HBs-Ag positive chronic hepatitis. By additional therapy with azathioprine it is possible to reduce the dose of glucocorticoids. Therefore it is better to combine glucocorticoids and azathioprine in some cases, especially in those with a high dosed glucocorticoid therapy. Further prospective studies are necessary to check more precisely the therapeutic effect of the different remedies. The effect of D-penicillamine is vague. A treatment with chloroquine is indicated in cases with contraindications again glucocorticoids and azathioprine.


Glicentin immunoreactive cells: their relationship to glucagon-producing cells.

The cellular and subcellular localization of one of the gut glucagon-like immunoreactants (GLI-1 or glicentin) and the relative distribution of glicentin- and glucagon-containing cells were investigated by immunocytochemistry. By immunofluorescence, the antiglicentin serum, which does not react with glucagon, revealed positive cells in the islets of Langerhans and in the gut mucosa, particularly in the terminal ileum and colon. In the intestinal mucosa, it was proven ultrastructurally that the glicentin immunoreactive cells correspond to the L cell and that the secretory granules represent the storage compartment of the immunoreactive material. In pancreatic islets, consecutive semithin sections treated with antiglicentin and specific antiglucagon sera showed that the same A cell population reacted with both sera, while immunoperoxidase staining on thin sections revealed that the immunoreactive material was confined to the secretory granules. The same results were obtained on dog oxyntic mucosa, where the glicentin- and glucagon-containing cells were identified as the gastric A cell. The immunocytochemical demonstration of a common glicentin-like material in the A and L cells together with the known presence of a common immunoreactant in glicentin and glucagon strongly support the idea that the A and L cells are ontogenetically related and synthesize their secretory product via a glicentin-like precursor which, by specific cleavage, could yield glucagon and gut glucagon-like immunoreactants.


The Ninth Sir Hans Krebs Lecture. Compartmentation and communication in living systems. Ligand conduction: a general catalytic principle in chemical, osmotic and chemiosmotic reaction systems.

Chemical reactions, like osmotic reactions, are transport processes when looked at in detail. Chemical catalysis by enzymes or catalytic carriers, and osmotic catalysis by porters, may be conceived as occurring by specific ligand-conduction mechanisms. In chemiosmotic reaction systems, the pathways of specific ligand conduction are spatially orientated through anisotropic enzyme and catalytic carrier complexes in which the reactions of chemical group transfer occur as vectorial diffusion processes of group translocation down gradients of group potential that represent real spatially-directed fields of chemical force. Thus, it is easier to explain biochemistry in terms of transport than it is to explain transport in terms of biochemistry.


Degradation of the DNA-binding domain of wild-type and i-d lac repressors in Escherichia coli.

It has been shown that 28 transdominant mutant lac repressors which have lost operator DNA-binding ability in vivo and in vitro, but still bind inducer and are able to form tetramers (i-d repressors), could be divided into two groups by their capacity or incapacity to bind non-specifically to the phosphate groups of the DNA backbone. All but one of 15 analysed i-d repressors with amino acid substitutions to the C-terminal of residue 52 showed uneffected non-specific DNA binding. All 13 tested i-d repressors with amino acid substitutions to the N-terminal of residue 53 did not bind to double-stranded DNA, and 11 of these repressors derived from missense mutations in the lacI gene were endogenously degraded. The degradation in vivo only affects the amino-terminal 50-60 residues producing a mutant-specific pattern of stable repressor fragments. These fragments are tetrameric and capable of binding inducer in vivo and in vitro. The proteolytic attack presumably takes place during synthesis of the i-d repressors, since the resulting fragments are stable, both in vivo (as shown by a pulse-chase experiment) and in vitro. The proteolysis in vivo depends on the growth conditions of the bacteria and is higher in cells grown in minimal media than in rich media. Wild-type repressor is only susceptible to limited proteolysis in cells grown in minimal media but not in cells grown in rich media. The results suggest that the majority of the sequence alterations before residue 53 in missense mutant i-d lac repressor proteins affect the three-dimensional structure of the amino-terminal DNA-binding domain of the repressor protein, making it susceptible to proteolytic attack by one or several intracellular proteases.


Respiratory nitrate reductase: its localization in the cytoplasmic membrane of Klebsiella aerogenes and Bacillus licheniformis.

The sidedness of the respiratory nitrate reductase in the cytoplasmic membrane of Bacillus licheniformis and Klebsiella aerogenes was studied by indirect immunofluorescence and by lactoperoxidase-catalyzed iodination. It was shown that the two subunits (Mr 150000 and 57000, respectively) of nitrate reductase of B. licheniformis are localized on the cytoplasmic side of the membrane, whereas the K. aerogenes enzyme is a transmembrane protein. The different localization of nitrate reductase in the membranes of these organisms may be related to their different rôle in oxidative phosphorylation.


Demonstration by membrane reconstitution of a butanol-soluble intermediate in the biosynthesis of the O9 antigen of Escherichia coli.

The activity in vitro of the mannan-synthesizing system of Escherichia coli O9 depends on the presence of glucose in the growth medium of the bacteria. Inactive membranes of E. coli strain F988 grown without gain mannan-synthesizing activity by reconstitution with a butanol extract obtained from the same bacteria grown with glucose. Inactive membranes could also be restored to biosynthetic activity by incubation with UDP-glucose in the presence of magnesium chloride. In this magnesium-ion-dependent reaction, a glucolipid was formed which was extractable with butanol. It could be used for the reconstitution of inactive membranes. The products of incubations with GDP-mannose of reconstituted and active membranes were analysed for electrophoretic mobility in sodium dodecylsulfate/polyacrylamide gel electrophoresis, molecular weight and composition. In all cases they proved to be the mannan attached to a hydrophobic mannose carrier, presumably a glucolipid. These results suggest that a glucolipid is the intermediary mannose acceptor in the biosynthesis of the O9 antigen.


Reversible inactivation of tRNA nucleotidyltransferase from baker's yeast by tRNAPhe containing iodoacetamide-alkylated 2-thiocytidine in normal and additional positions.

2-Thiocytidine 5'-triphosphate, s2CTP, is able to replace CTP as a substrate for tRNA nucleotidyltransferase. s2CMP can be incorporated into both cytidine sites of the C-C-A terminus common to all tRNAs, and in the absence of ATP into at least two additional positions. This was shown by alkylation of the 2-thiocytidine residues with iodo[14C]acetamide, total nucleoside analysis, microgel electrophoresis and analysis of RNase T1 fragments of these tRNAs. The incorporation of the 3'-terminal AMP is not influenced by the additional s2CMP residues at pH 9.0. However, at pH 7.6 the additional s2CMP residues are hydrolysed and AMP can be incorporated into the normal position. Two different tRNAs with terminal 2-thiocytidine alkylated by iodoacetamide inhibit tRNA nucleotidyltransferase. This inhibition is significantly slower if an elongated species is used compared to a tRNA with alkylated 2-thiocytidine in the normal position 75. The addition of 2-mercaptoethanol reactivates the enzyme and leads to a cytidine containing tRNA. This reaction identifies the attacking nucleophile of the enzyme as cysteine residue, which is probably identical to a cysteine residue found in a similar experiment reported previously. The mechanism of the enzymatic and chemical reactions is discussed.


Protein S1 from Escherichia coli ribosomes: an improved isolation procedure and shape determination by small-angle X-ray scattering.

Ribosomal protein S1 from Escherichia coli was studied in solution by small-angle X-ray scattering and the following parameters were obtained. The radius of gyration R = 8.0 +/- 0.2 nm; largest diameter D = 28 nm; molecular weight = (8--9) x 10(4). The data also yielded (with the assumption of a rigid particle with almost constant electron density) two radii of gyration of cross-section Rq1 = 2.5 +/- 0.1 nm and Rq2 = 1.05 +/- 0.05 nm and molecular volume = 140 nm3. The experimental scattering curve of S1 was compared with the theoretical scattering curves for several rigid triaxial homogeneous bodies and the closest fit was given by that of a flat elliptical cylinder with the dimensions of 4.5 nm and 0.88 nm for the two semiaxes and 26.5 nm for height. The results from the present X-ray scattering studies and those from limited proteolytic digestion of protein S1 [J. Mol. Biol. 127, 41--54, (1979)] support the notion that the structure of protein S1 is organized into two distinct subdomains within its elongated overall shape. Protein S1 was purified for this study by an efficient procedure which yielded 12 mg S1/g ribosomes. The isolated protein was fully active in functional tests both before and after X-ray irradiation.


Procaine, a local anesthetic interacting with the cell membrane, inhibits the processing of precursor forms of periplasmic proteins in Escherichia coli.

Treatment of Escherichia coli cells with procaine (0.55%, w/v) results in the accumulation of precursor in addition to mature forms of two periplasmic proteins, alkaline phosphatase and glutamine-binding protein. The precursor form of alkaline phosphatase has a higher molecular weight than the mature form by about 2600. An experimental technique is described to isolate and purify precursor forms of any presumably exported protein. After the membrane solubilization step in the presence of nonionic detergent, a peptidase is stimulated, resulting in partial cleavage of the precursors. The products of this cleavage have been identified as the mature protein and presumably the signal peptide in the case of alkaline phosphatase. The amino acid composition of this peptide, which is comprised of 25 residues, has been determined. Procaine (0.55%, w/v) causes an increase in molecular packing of lipid molecules in the membrane which might result in an alteration of membrane fluidity sufficient for selective inhibition of processing of precursors of exported proteins.


Affinity chromatography of tryptophan synthase from Escherichia coli. Systematic studies with immobilized tryptophanol phosphate.

Inhibition studies and affinity chromatography indicate that derivatives of tryptophanol phosphate are suitable ligands for the affinity chromatography of tryptophan synthase. A phenyl group on the spacer arm strengthens the interaction of immobilized tryptophanol phosphate with the enzyme. The alpha 2 beta 2 complex specifically requires the presence of 0.3--0.5 M phosphate ions for binding. The alpha subunit binds in dilute Tris buffer, but its binding is also enhanced by the presence of phosphate ions. The beta 2 subunit binds unspecifically but strongly to the affinity material and to a variety of other immobilized hydrophobic ligands. Binding studies with suspensions of affinity material show that the alpha subunit interacts rapidly and reversibly. Indoleglycerol phosphate and indolepropanol phosphate release bound alpha 2 beta 2 complex and alpha subunit in a competitive manner, indicating that the interaction occurs biospecifically, i.e. via the active site of alpha subunit. L-Serine is a non-competitive inhibitor of binding. These results are discussed with regard to the composite-active-site hypothesis [T. E. Creighton (1970) Eur. J. Biochem, 13, 1--10]. Both the alpha subunit and the alpha 2 beta 2 complex of tryptophan synthase from Escherichia coli can be obtained with high yields and in homogenous form by absorption to the affinity material from partially purified preparations. Elution is achieved with linear gradients either of indolepropanol phosphate or of indoleglycerol phosphate or, in the case of the complex, of L-serine. At the low concentrations of the complex found in crude extracts of wild-type E. coli cells, the unexpectedly high affinity of the beta 2 subunit for hydrophobic ligands leads to partial dissociation of the complex.


IgE in patients with glomerulonephritis and minimal-change nephrotic syndrome.

Serum levels of IgE were studied in 30 children with minimal-change nephrotic syndrome and 32 children with mesangioproliferative glomerulonephritis during different stages of the disease and treatment. In addition, tissue obtained by renal biopsy was investigated by immunofluorescence histology; no deposits of IgE could be found. The serum IgE levels, however, were increased, particularly in patients with minimal-change nephrotic syndrome. It is concluded that IgE does not play a pathogenic role in the development of the renal disease, but that increased IgE levels are an indication of a disturbance of the immune system.


Creutzfeldt-Jakob disease. Infection of infancy or childhood?

A 51-year-old man who died of Creutzfeldt-Jakob disease (CJD), had transient dyskinesias with intention myoclonus and exaggerated startle reaction in early life. This may suggest a link between myoclonic encephalopathy of infants and CJD, and an incubation period of more than 40 years of the transmissible agent of CJD.


Subacute sclerosing panencephalitis. Immunological findings in saliva and salivary glands.

Antimeasles antibody was detected in the saliva of 14 patients with subacute sclerosing panencephalitis. Immunofluorescent staining showed antibody in salvary gland biopsy of 7 patients.


Dose response relationship of clenbuterol (NAB 365) as a solution for inhalation.

The dose-response relationship of the new bronchodilator Clenbuterol (NAB 365, Boehringer Ingelheim) was tested in 12 patients with chronic obstructive lung disease. Clenbuterol is a beta-2-sympathicomimetic, from a series of substituted phenylethanolamines, and it is characterised by good absorption and prolonged action after systemic administration. The action of four different doses of Clenbuterol inhalation solution (6, 12, 24, and 48 microgram corresponding to 2, 4, 8 and 16 drops of a 0.006% solution) was assessed after a single inhalation on 4 successive days. The parameters monitored were bronchial resistance and FEV. The effect of all four doses was the same, both in respect of improvement in FEV and of decrease in bronchial resistance. The increase in expiratory volume and the decrease in bronchial resistance lasted for 6 h. The results show that for inhalation therapy Clenbuterol is a potent, selective bronchodilator, which is largely free of sideeffects. It has still to be determined whether a maximal effect could be achieved with a lower dose 6 microgram.


Comparison of once and twice daily administration of sotalol in the treatment of hypertension.

Thirty patients with mild to sever essential hypertension, satisfactorily controlled by twice daily Sotalol 80 to 320mg/day, entered a double-blind, crossover study comparing the efficacy, tolerability and safety of their usual twice daily dose of Sotalol with the same total dose given once a daily. Each double-blind period was eight weeks long; during it blood pressure and pulse rate were measured in each patient's home at 8-10 a.m., 12-2 p.m. and 8-10 p.m., on alternate days during the last week of each treatment period. There was no significant difference in bloodpressure or pulse rate betwen each regime for the three readings during the day. The mean serum concentration of Sotalol twenty-four hours after once daily administration was not sigificantly lower than the concentration 12 h after twice daily administration. Once daily dosage did not cause any problems of tolerance.


Comparative antiarrhythmic efficacy of intravenous N-acetylprocainamide and procainamide.

Ten patients with persistent ventricular arrhythmia were studied in a comparison of the antiarrhythmic efficacy of N-acetylprocainamide (NAPA) and procainamide (PA). Each patient performed three exercise tests for 40 min., on different days, with submaximal and fixed work loads. During the first exercise test no drug was administered. During the following two tests PA and NAPA, respectively, were administered by intravenous infusion. The electrocardiogram was continously recorded and was analyzed minute by minute. Blood samples for determination of plasma drug concentration were frequently collected. Exercise alone did not significantly change the incidence of arrhythmia. Both PA and NAPA showed a similar and significant antiarrhythmic effect. A blood pressure fall was seen in two patients after administration of each drug. No other adverse reaction was observed.


Factors affecting warfarin requirements. A prospective population study.

In 228 ambulatory patients receiving treatment with warfarin, there was a progressive decline in the dose required to produce an equivalent degree of anticoagulant control with increasing age from the third decade onwards. However, the relationship between age and dose was significant only in patients receiving warfarin after episodes of venous thromboembolism or because of coronary artery disease. Patient weight was also related to warfarin requirements, although it was less important a determinant than age.


An annotated bibliography of the remarried, the living together, and their children.

This bibliography was developed by the Remarried Consultation Center of the Jewish Board of Family and Children's Services of New York City for our own use. Because there is a growing interest in remarriage and the new types of families this social phenomenon creates, we became convinced that the meager number of articles and books in this area would be of interest to others. We have focused our attention on the now common phenomenon of the remarried and those living together in a committed relationship situation. Some articles that were not designed as studies of remarriage situations are included because their content is pertinent to our subject. The bibliography is divided into six sections to facilitated reference use. It should be noted, however, that these sections are not rigid and that some items could readily have been included under two or more sections. Articles included cover publication dates through April 1978. The six sections are: I. Demography; II. Remarried Couples; III. Stepparents and Stepchildren; IV. Divorce as a Precursor to Remarriage; V. Children of Divorce in Relation to Remarriage; VI. Remarriage-Prophylactic and Therapeutic Aspects. Unfortunately we did not find sufficient material to warrant a section on theoretical aspects. We have tried to make this bibliography as complete as possible using two computer retrieval systems as well as our own search of the literature. If you are familiar with references we have missed, we should appreciate hearing from you.


Evolutionary relationships of the gut hormones.

Peptides identical or related to mammalian gut hormones occur widely, not just in gut endocrine cells but also in central or peripheral nerves, amphibian skin glands, and a variety of invertebrate tissues. The dual distribution in brain and gut was probably already established early in the vertebrate line; representatives of the oldest vertebrate group, the cyclostomes, have cholecystokinin-like factors in gut endocrine cells and in brain. The related sequences of certain gut peptides, notably gastrin and cholecystokinin (CCK), and secretin, glucagon, vasoactive intestinal polypeptide (VIP), and gastric inhibitory peptide (GIP), indicate evolution from common ancestral molecules by gene duplication and divergence. Functionally important residues are conserved. Thus the COOH-terminal pentapeptide common to gastrin and CCK also contains their minimal active fragment. There are also evolutionary changes at the level of the target organ receptor mechanisms: these are also evolutionary changes at the level of the target organ receptor mechanisms; these are illustrated by evidence suggesting that secretin regulates the flow of pancreatic juice in mammals whereas the structurally related peptide VIP has a similar role in birds.


Progress and therapy of stress amenorrhea.

Thirty-two patients with stress amenorrhea of less than 1 years duration were found to have withdrawal bleeding after progestin administration, normal serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and good responsiveness to LH-releasing hormone (LH-RH); ovulation was induced following the admininstration of clomiphene citrate. On the other hand, in 11 of 14 patients with stress amenorrhea of longer than 1 years duration, no bleeding followed the administration of progestin, and there were noted high serum FSH and LH levels, exaggerated release responsiveness to LH-RH, and atrophic vaginal smears and endometrium. In addition, it was difficult to induce ovulation by various treatments. The findings suggest that dysfunction in the hypothalamic cyclic (not tonic) center regulating ovulation was the originating factor in the amenorrhea in question and that ovulation should be induced at least once yearly to prevent ovarian function from declining in this type of anovulatory state existing for more than 1 year.


A method for specific detection of autoantibodies to the zona pellucida in infertile women.

Human antibodies to porcine erythrocytes were found to bind to porcine but not to human zonae pellucidae, whereas human isohemagglutinins bound to human but not to porcine zonae. On the basis of the binding behavior of agglutinins, it was found that the immunofluorescence of porcine zonae produced by selected sera from infertile women was due to an antibody of different specifity from that which agglutinated pig red blood cells. However, no serum component other than heteroagglutinin was contained in selected sera from control subjects which fluoresced porcine zonae. Since the component was present in the immunoglobulin G fraction, bound to human zonae, and was reactive with zona-specific antigen(s), it was judged an autoantibody to zonae. Thus a method for specific detection of autoantibodies to zonae has been developed by indirect membrane immunofluorescence using porcine ova as targets.


Morphologic characteristics of the chemically induced acrosome reaction in human spermatozoa.

The morphologic changes accompanying the acrosome reaction in human spermatozoa, as it is induced by the antibiotic A23187 and calcium ions, are described. The reaction is shown to be similar to that observed in other species when the reaction occurs spontaneously or is induced by physiologic fluids. The reaction in human spermatozoa differs from the chemically induced reaction in other species in that plasma membrane microfilaments, prominent in the boar, and tubular-like elements prominent in boar, rabbit, and monkey sperm, are not observed. Motility remains high when human spermatozoa are treated with A23187 and calcium and it is possible that these agents may be useful in the study of certain causes of infertility.


In vitro lymphocytes stimulation with scarlet fever toxin.

Rabbit peripheral blood, spleen and thymus lymphocytes were stimulated in vitro with scarlet fever toxin. The ultrastructure of stimulated blast cells was described; the morphological features of these cells are similar to those of T-lymphoblasts. 3H-thymidine incorporation into lymphocytes stimulated with ET or PHA was studied in correlation with blast formation. Some quantitative discrepancies between both parameters are discussed.


Resistance of transplantation tolerance to X-irradiation.

With regard to the previous finding that suppressor cells participating in the state of transplantation tolerance were radiosensitive, the possibility was investigated whether tolerance can be abolished by irradiation. In the rat model used (AVN recipients, Lewis donors), both neonatally induced tolerance and tolerance induced in adult life by the transfer of suppressor cells were found to be radioresistant.


Are histocompatibility antigens in neonatal skin grafts truly tolerogenic?

Neonatal skin grafts across a weak histocompatibility barrier (MSA-incompatible) were used only for sensitization of the recipients whose responsiveness was then tested in two different assays. On the basis of 1. functional inactivation of PEC in a PEC transfer system and 2. inhibition of macrophage migration. The difference between neonatal and adult skin grafts turned out to be quantitative rather than qualitative, i.e., both induced sensitization whose demonstration with the neonatal grafts required more sensitive techniques and/or more favourable timing because it was weaker. The possible nature of the difference, which was occasionally interpreted as being due to a tolerogenic rather than immunogenic activity of neonatal grafts, is discussed.


The use of model life tables to estimate mortality for the United States in the late nineteenth century.

This paper seeks to extend our knowledge about mortality in the late nineteenth century United States by using census mortality data for older children and teenagers to fit model tables. The same method can also be used with partially underregistered death data. The most commonly used model tables, the Coale and Demeny West Model, apparently do not adequately depict the changing shape of mortality over the period 1850--1910. An alternative model life table system is presented, based on the Brass two parameter logit system and available reliable life tables from the period 1850--1910. The two parameter system must be reduced to a one parameter system by means of estimated relationships between the parameters so that the fitting procedure can be used. The resulting model system is, however, heavily dependent on the experience of northern, industrial states, especially Massachusetts.


[Attempts at developing a syphilis vaccine (author's transl)].

Numerous investigators tried over the years to induce artifically immunity against syphilis by use of a variety of treponema preparations. None of these immunization experiments performed by different means and routes provided clear evidence of acquired immunity in animals and humans given various vaccine preparations against challenge with even minimal doses of virulent T. pallidum. In recent years, however, promising results have been obtained in the immunization study. Two types of syphilis vaccine have been developed which were found very effective in conferring a protection against syphilitic infection on rabbits: (1) the first vaccine contains T. pallidum attenuated by gamma irradiation, and the other one (2) contains T. pallidum killed by penicillin. In addition, it has been demonstrated that the immunogenic activity of T. pallidum is related to their very labile protein component. Pretty much is also known on the factors influencing the immune response of artificially immunized rabbits, and on the immunological mechanisms underlying the development of syphilis immunity.


Alcohol withdrawal syndrome: treatment and assessment of therapeutic efficacy.

The acute alcohol withdrawal syndrome is a disease of many different symptoms. Although the metabolism of ethanol is well-known, no specific treatment of the withdrawal syndrome has been developed. When assessing the therapeutic efficacy of drugs in this syndrome one of the main symptoms to be followed is sleep disturbances, because inability to sleep often maintains the drinking cycle. Besides different target symptoms, the visual analogue scale and the ability to work are useful parameters. The assessment of the efficacy relies mainly on subjective parameters and comparisons with placebo are needed.


Comparison of clinical effects of propranolol (Inderal) with once daily slow-release oxprenolol (Slow Trasicor) in angina pectoris.

In a double-blind, crossover, randomized study, the therapeutic effectiveness of a single daily dose of slow-release oxprenolol (160 mg/day) was compared with a conventional dosage schedule of propranolol (40 mg three times daily) in eighteen patients with uncomplicated, stable exercise-induced angina pectoris. Compared to control values both drugs produced equipotent reduction in the frequency and severity of anginal attacks accompanied by a significant increase in exercise tolerance, a significant suppression of exercising heart rate and an appreciable reduction in the electrocardiographic evidence of myocardial ischaemia when tested on a treadmill. The possible advantages offered by a single dose treatment with slow-release oxprenolol are discussed.


Clinical use of rifampicin in combination for non-mycobacterial infections: a survey of published evidence.

The literature on the clinical use of rifampicin in combination for the treatment of non-mycobacterial diseases is reviewed. From the published evidence, the most promising associations are, for staphylococcal infections, gentamicin, erythromycin, kanamycin and fusidic acid. In the field of Gram-negative infections, Psuedomonas-induced sepsis in particular, data are not so impressive but promising results have been obtained with the associated use of rifampicin and gentamicin or colistin. Some systemic fungal diseases may be successfully treated with rifampicin in combination with amphotericin-B. Although only few reports are available on this subject, the importance of such an application is stressed in view of the severity of these diseases and of the lack of appropriate treatments.


Comparison of a once daily long-acting formulation of propranolol with conventional propranolol given twice daily in patients with mild to moderate hypertension.

The effect of conventional propranolol tablets given twice daily has been compared with an equivalent dosage of a long-acting formulation of propranolol ('Inderal' LA)p given once daily in twenty-nine patients with mild to moderate hypertension. The study lasted 10 weeks. There was no significant difference in clinical response to the two treatments which were equally effective and well tolerated. A once daily dosage schedule should greatly aid patient compliance.


Double-blind comparison of maternal analgesia and neonatal neurobehaviour following intravenous butorphanol and meperidine.

Butorphanol (1 mg and 2 mg) and meperidine (40 mg and 80 mg), given intravenously, were evaluated for analgesic efficacy and safety in a double-blind randomized study employing 200 consenting pre-partum patients in moderate to severe pain during the late first stage of labour. Both drugs provided adequate relief of pain to the mothers. There was no significant difference in the rate of cervical dilation, the foetal heart rate, the Apgar score, pain relief or neonatal neurobehavioural scores betweeen those receiving butorphanol and those receiving meperidine. Twenty-two mothers who received butorphanol and eleven who received meperidine nursed their infants with no adverse effects observed. Side-effects were generally infrequent in this study; however, more side-effects were reported by the patients and observed by the investigator in the meperidine-treated cases (13%) than in the cases treated with butorphanol (2%).


A double-blind clinical study with Monydrin tablets in patients with non-allergic chronic rhinitis.

Oral combination preparations (antihistamine + sympathomimetic) are widely used for nasal and sinus congestion without the presence of allergy. The use of antihistamine in these cases may be questioned. Evaluation of the clinical effect of only a sympathomimetic agent on patients with nonallergic rhinitis is performed in a double-blind clinical study on seventy patients. Phenylpropanolamine (50 mg and 100 mg) was compared with placebo. It was found that 100 mg phenylpropanolamine was significantly more active than 50 mg or placebo administered orally as a sustained-release tablet twice daily. No side-effects such as CNS stimulation and influence on blood pressure were seen at any of the dose levels.


Analgesic combinations with orphenadrine in oral post-surgical pain.

Two hundred male and female patients underwent a variety of oral surgical procedures and were treated afterwards in four test groups. They took a combination of orphenadrine (25 mg) and acetaminophen (325 mg), either drug alone, or placebo. A double-blind study design was used. All patients had moderately severe baseline pain intensity; post-treatment pain relief was recorded at 30 minutes, one, two, four and six hours. A back-up analgesic (codeine-ASA) was made available if needed. Pain intensity difference (PID) and sums of pain intensity difference (SPID) were calculated using established analgesic study techniques. Statistical analyses indicated better analgesic efficacy in both PID and SPID scores for the orphenadrine-acetaminophen combination over the three other treatments. This was evident at 30 minutes and continued through the sixth hour. Each active drug, in turn, was also significantly better throughout than placebo for pain relief. Sub-groups in each treatment regimen required additional pain relief prior to six hours, with significantly more placebo than orphenadrine-acetaminophen patients needing remedication. Side-effect incidence was very low and randomly distributed among the four groups.


Comparative clinical trial of amoxycillin and chloramphenicol in the treatment of typhoid in adults.

A randomized clinical trial in sixty-two adult patients suffering from typhoid fever, proved by blood and marrow culture, showed that amoxycillin in a dosage schedule of 1 g 8-hourly orally for fourteen days was better than chloramphenicol with regard to clinical and temperature response and in respect of carriers and relapse rates. One patient developed a hypersensitivity reaction to amoxycillin which cleared on withdrawal of the drug. Success was achieved in 90% of cases. These findings lend very strong support to the value of amoxycillin as a superior alternative to chloramphenicol in the treatment of typhoid fever.


Interaction of luteinizing hormone-releasing hormone, cyproterone acetate and arginine vasotocin on plasma levels of luteinizing hormone in intact and castrated adult male rats.

Treatment of unanesthetized castrated adult male rats every 3 h for 48 h with either 5 microgram of arginine vasotocin (AVT) and/or 1 microgram luteinizing hormone-releasing hormone (LRH) caused a significant inhibition of plasma levels of luteinizing hormone (LH) and compared to castrated control rats receiving diluent only. However, the intravenous (iv) injection of 1 microgram of AVT into urethane-anesthetized male rats which had been castrated for 0, 24 or 48 h did not affect plasma levels of LH at 10, 20 or 60 min following injection compared to their respective diluent-treated castrated control rats. Similarly, the iv injection of either 100 ng, 1 microgram or 10 microgram AVT was unable to acutely affect plasma levels of LH in intact male rats. Following the iv injection of 2 doses of 50 ng LRH spaced 1 h apart in anesthetized castrated male rats, 2 peaks of equal magnitude in plasma LH were noted. Castrated rats treated with 2 injections spaced 1 h apart of LRH + AVT had significantly higher plasma levels of LH than did rats treated with LRH alone. In subsequent studies, both AVT and arginine vasopressin were observed to augment the plasma response of LH to an injection of LRH whereas oxytocin had no effect. A single injection of AVT + LRH significantly augmented the plasma titers of LH compared to levels observed in LRH-treated control rats as did a second injection 1 h later. The administration of cyproterone acetate sc for 2 days by itself had no effect on plasma LH but in conjunction with LRH caused a marked rise in plasma LH compared to intact rats treated with LRH alone. AVT in combination with LRH and cyproterone acetate caused a significant elevation in plasma LH at 60 min post-injection when compared to plasma levels of rats treated with LRH alone or the combination of LRH and cyproterone acetate. It is concluded that acute intravenous injections of AVT augment the LH-releasing activity of LRH; chronic treatment for 48 h, however, with LRH + AVT leads to a significant depression of plasma LH perhaps due to an exhaustion of the releasable pool of LH in the anterior pituitary.


Digestion of gliadin peptides by intestinal mucosa from control or coeliac children.

Gliadin, subsequently treated with pepsin, trypsin and pancreatic extract was further digested by small-intestinal mucosal homogenates from 10 control or 8 coeliac children. The amino acids liberated in the incubation mixture were measured and corrected for mucosal damage. In accordance with the data from the literature on adults, the total amount of amino acids released from gliadin peptides by the intestinal mucosa from children with active coeliac disease is significantly lower than that by the mucosa from control subjects. Qualitatively, however, no significant differences for the individual amino acids are observed with the exception of glutamine and proline, so that damaged coeliac mucosa liberates relatively more glutamine but less proline.


Microvascular permeability to albumin and glomerular filtration rate in diabetic and normal children.

In order to examine the permeability of microvessels in diabetic children, the glomerular filtration rate, urinary excretion rates of albumin and beta 2-microglobulin, intravascular mass of albumin, and transcapillary escape rate of albumin were studied in 26 diabetic children without clinical signs of microangiopathy (age: 7-14 years; duration of disease: 3-14 years). Similar measurements were made in 28 healthy school children (age: 8-14 years). Mean glomerular filtration rate in the diabetic children was higher than in the normal children (138 versus 109 ml/min per 1.73 m2, p less than 0.01). Urinary excretion rates of albumin and beta 2-microglobulin did not differ in diabetics. Mean intravascular albumin mass in the diabetic girls (1.64 g/kg body weight) was lower (p less than 0.01) than in the diabetic boys (1.89 g/kg body weight) and also lower (p less than 0.02) than in the normal girls (1.94 g/kg body weight). Mean transcapillary escape rate of albumin in the twenty diabetics with duration of diabetes less than 10 years (7.14%/h) was lower (p less than 0.01) than that in normal children (8.90%/h); the escape rate showed a positive correlation with duration of diabetes (r=0.47; p less than 0.02). Thus glomerular filtration rate in diabetic children is elevated to the same extent as in adult short-term juvenile diabetics while the permeability of the glomerular membrane to macromolecules is normal. Interpretation of the results on intravascular albumin mass and transcapillary escape rate of albumin requires further investigation.


Long-term hormonal secretion from the autotransplanted sheep pancreas.

Seventy-five duct-ligated pancreatic segmental autotransplants were made into bipedicled skin loops on the necks of merino ewes by vascular suture to the carotid artery and jugular vein; the in situ pancreatic remnants apparently continued to function normally. Thirty-seven were found to be active hormone secretors (secretion-rate responses to Na butyrate greater than 1 mU/min for insulin or 5 ng/min for glucagon) when first tested approximately 1 month after transplantation; 12 remained active at 1 year, 5 at 2 years, and 4 at 3 years. At first testing, the responses were (mean +/- standard errors): insulin, 12.3 +/- 2.52 mU/min; glucagon, 52.6 +/- 13.5 ng/min. It is concluded that this autotransplant can, on occasion, be relatively long-lived and that it is a useful model with which to study not only pancreatic physiology but also non-immunological factors involved in survival of endocrine function in pancreatic transplants.


Substance P-, VIP-, and enkephalin-like immunoreactivity in the human vagus nerve.

The human vagus nerve has been investigated for the presence of substance P (SP), vasoactive intestinal polypeptide (VIP), and enkephalin (ENK) using immunohistochemistry. After 0.5-4 hr of nerve ligation during surgical operations two right thoracic main truncs, two anterior subdiaphragmal trunks, and four anterior nerves of Latarjet were found to contain accumulation of immunoreactive material in nerve fibers above the ligation. Very high numbers of SP-, medium numbers of ENK-, and low number of VIP-immunoreactive fibers were seen. The relative proportions were similar at all levels studied. These data thus indicate the presence and axonal transport of SP-, ENK-, and VIP-like peptides in the human vagus nerve. Our observations in humans correlate well with results obtained from other species. Thus gastrointestinal vagal sensory mechanisms may be mediated by SP (and possibly VIP) and some motor mechanisms by ENK.


Treatment of cirrhosis with colchicine. A double-blind randomized trial.

As part of a double-blind, randomized, controlled trial to evaluate the effect of colchicine on liver cirrhosis, 43 cirrhotic patients were assigned to either a placebo (20 patients) or a colchicine (23 patients) treatment group. Colchicine 1 mg and an indistinguishable placebo were administered orally on a daily dose 5 days a week. In the colchicine group, 12 were males and 11 females, while in the control group 13 were males and 7 females. The time elapsed between diagnosis and inclusion in the study was 14.1 mo for the controls and 14.5 mo for the patients on colchicine. Mortality related to the liver disease occurred in 4 patients on colchicine and 8 patients on placebo. Although the probability of surviving in the colchicine group was greater than that of the placebo, the difference did not reach statistically significant levels. Of the colchicine-treated patients, in three a remarkable decrease in liver fibrosis was observed in serial biopsies. In two other patients, carcinoma of the liver developed. Six of the survivors on colchicine have improved clinically, noticing disappearance of ascites and edema, as well as a decrease in the size of the spleen. All the survivors on placebo continue to show clinical deterioration. In contrast to the usual drop of serum albumin seen in the cirrhotic patients, those receiving colchicine increased and maintained their serum albumin levels throughout the study. Serum proline values were elevated only in the alcohol cirrhotic patients. Serum alkaline phosphatase increased only in those patients receiving colchicine. The results indicate that in some cases, liver fibrosis could be modified by treatment with antifibrotic drugs. The use of colchicine at present should remain within controlled studies.


Transfer of drug resistance factors to the dimorphic bacterium Caulobacter crescentus.

The P-type drug resistance factors RP4, RK2, R702, R68.45, and the N-type drug resistance factor R46 are transferred to Caulobacter crescentus at high frequencies. They are stably maintained and their antibiotic resistances are expressed. Experiments with RP4 have shown that intergeneric transfer of RP4 occur at a frequency of 10(-1). C. crescentus strains maintain RP4 as a plasmid, are sensitive to RP4-specific phage, and segregate phage-resistant cells at a frequency of 10(-4) to 10(-5). The RP4 plasmid can be used in several ways: (1) the RP4 plasmid will promote chromosomal exchange between C. crescentus strains at frequencies ranging from 10(-6) to 10(-8); (2) RP4 will promote the transfer of nonconjugative colE1 plasmids from E. coli to C. crescentus; once transferred, the colE1 plasmid is stably maintained under nonselective conditions, can be transferred serially, and segregates independently from RP4; and (3) RP4 can be used to introduce transposons into the C. crescentus chromosome, providing the basis for additional genetic techniques.


Fine-structure mapping of the acetamidase structural gene and its controlling region in Aspergillus nidulans.

A large number of amdS mutants altered in acetamide utilization have been used to construct a fine-structure map of the amdS locus. The mutagen diepoxyoctane generated most of the deletion strains used for mapping. A minimum of 14 sites within the amdS gene were found. Biochemical analysis of amdS mutants defined the extent of the probable coding region. A new mutant, amd-205, which did not produce detectable inactive gene product, was found to be inseparable by recombination from the "up-promoter" mutation amdI18 and was located outside of the apparent amdS coding region. The cis-dominant mutation, amdI9, was also located at this end of the gene. This work, therefore, provides evidence for the separation of a eukaryotic gene into controlling and structural regions.


[Mutagenic effect of a tetrahydrodiazopyrene derivative on bacteria].

Mutagenic action of 3,7-diamino-4,9-dioxy-5,10-dioxo-4,5,9,10-tetrahydro-4,9-diazapiren (DDDTDP) was shown using indicator strains Salmonella typhimurium TA 1534, TA 1536, TA 1537, TA 1538. The drug-induced mutations in strains TA 1534 and TA 1538, and it can be used as a positive control in testing mutagens capable of inducing frameshift mutations. No significant differences was observed between DDDTDP effects on strains TA 1534 and TA 1538 which did or did not bear rfa mutation causing defects of cell wall lypopolysacharide complex. Within the range of concentrations tested DDDTDP had mutagenic effect without causing essential killing of bacteria. The mutagenic effect was decreased in the in vitro system of metabolic activation (Ames' plate test in Salmonella microsomes).


[Comparative study of mutator-gene prv and several other mutator-genes of Escherichia coli K-12].

Mutations prv1, prv2 and mutR34, increasing frequencies of intragenic recombinations, are found not to complement and therefore to be alleles of one gene. Checking for the influence of mutator genes mutS3, mutT1 and uvrE502 on the intragenic recombination in conjugational crossings has shown that mutators mutS3 and uvrE502 increase the frequency of intragenic recombinations while mutT1 does not change it. None of the examined mutator genes influence the conjugational frequencies of recombination. A supplementary analysis for the mutability of the mutant prv1 has been carried out. The prv1 mutation can induce mutations of the frameshift type. Mutations uvrA6, recB21, recC22 and lexA produce no influence on the display of a mutator effect of the prv1 mutation.


[Effect of ftorafur and 5-fluorouracil on the chromosomes of human tumor cell cultures].

The effect of two antitumour drugs, ftorafur (Ft) and 5-fluorouracil (5-FU) on chromosomes of human tumour cells (strain CA-1) was studied in vitro. Since no data on the karyotype of this tumour strain had been published, the chromosome set of the model was investigated at first. Significant quantitative and structural divergence from the normal human male karyotype were observed. Steam line cells contained 47-49 chromosomes, including 9 permanent markers. No Y-chromosome was revealed. Ft and 5-FU hardly injured the chromosomes of CA-1 cells; the level of aberrant metaphases reached 94%. Chromatid deletions and gaps formed the major part of drug-induced cytogenetic abnormalities.


Practical application of generic growth theory and the significance of the growth curve parameters.

The generic growth curve is developed by plausibility arguments based on simple growth models. Parameters of the generic curve include the maximum size, maximum specific growth rate, and a dimensionless velocity constant which can be related to metabolic efficiency in the case of nutrient-limited growth. Parameter estimates are obtained from estimates of the size and time at the point of inflection, the size and time at any other arbitrarily selected point, and the maximum size. Parameter estimates thus obtained and used as initial estimates in nonlinear least squares analysis often give rapid convergence to a minimum error mean square. [For the growth of Escherichia coli K-12 in liquid medium, the generic curve could be simplified to a form containing only three parameters: the maximum specific growth rate, the maximum size, and the time required to reach maximum size. When the bacteria were inhibited by the addition of increasing amounts of the lactoperoxidase antimicrobial factor, there was no significant change in viable counts or maximum specific growth rate, but the time required to reach maximum growth increased linearly with increasing amounts of added antimicrobial factor.] Analysis of growth in terms of the generic growth curve can be a powerful technique for finding relationships which may not be apparent from qualitative consideration of the data.


Rate of disappearance in plasma of synthetic LH-RH intravenously injected in man.

The rate of disappearance of intravenously injected LH-RH was studied in 6 human volunteers. The blood samples were taken every 20 sec from the time of injection to time +5 min and every 30 sec from time +5 min to time +10 min. The half-life of LH-RH was calculated in the interval of 3-10 min, and was found to be 2.4 +/- 0.4 min. The amounts of LH-RH estimated in the vascular compartment were relatively low when compared to the total amount of injected LH-RH. This observation suggests a rapid and important passage towards the extravascular compartment.


Investigations on intravascular coagulation in liver disease: souble fibrin monomer complexes in liver cirrhosis.

Souble fibrin monomer complexes (SFMC) have been quantitated in 18 patients with liver cirrhosis by means of plasma gel filtration on an agarose column. The concentration of SFMC (as related to total fibrinogen) was increased in cirrhotic patients. The difference between controls and patients, as well as the difference between compensated and decompensated cirrhotic subjects, was statisically significant. Although these data, together with the results of heparin administration in one reported case, suggest intravascular coagulation, some alternative explanations should also be considered.


High-level resistance to streptomycin in Escherichia coli with R1 plasmid and the analysis of genetic determinants.

Some properties of streptomycin-resistant mutants of Escherichia coli were analyzed. In a R+ culture, the phenotype under study may be significantly selected at a frequency of 10(-5) on media with higher streptomycin level. The lrs mutation is present in the cells prior to the action of streptomycin and remains in the cells even after curing of the R1 plasmid. The mapping of the lrs gene by conjugation with a concomitant transfer of chromosome and the R1 plasmid in different Hfr strains of E. coli failed to establish the localization of this gene in the tested chromosome regions. The presence of a cryptic plasmid was detected in cells with the lrs mutation after curing of the R1 plasmid. This plasmid codes neither fertility functions nor chloramphenicol-acetyltransferase, streptomycin-adenyltransferase, or ampicillin-beta-lactamase.


The bactericidal activity of sera of healthy neonates and of newborns with hyperbilirubinaemia to Escherichia coli.

Cord and newborn sera were found to possess a significantly decreased in vitro bactericidal activity to Escherichia coli as compared to sera of adult individuals. Hyperbilirubinaemia in neonates suffering from both Rh and ABO incompatibility results in a further significant impairment of the bactericidal activity of their sera in comparison with healthy newborn infants. Exchange transfusion improved considerably the serum bactericidal activity. The possible mechanism of toxic action of unconjugated bilirubin on cells of the immune system is discussed.


Antimicrobial and cytolytic activity of N,N-dimethyl-l-methyldodecylamine oxide.

N,N-Dimethyl-l-methyldodecylamine oxide inhibited the growth of bacteria, yeast and filamentous fungi; further it induced lysis of osmotically stabilized protoplasts of Saccharomyces cerevisiae and human erythrocytes. This effect is based evidently on a change in the organization and function of cell membranes.


Selection of a yeast strain with optimal utilization of straw hydrolyzates.

The dry nonseparated straw hydrolyzates prepared by mild acid hydrolysis of milled straw contains 25--30% of reducing substances, mostly saccharides with prevalence of xylose. A strain utilizing the neutralized nonseparated hydrolyzates without any growth substances added was obtained by selection and long-term adaptation of an array of yeast strains. The strain, identified as Candida tropicalis 2838, exhibited high cell-growth rate and considerable yield of protein-rich biomass.


Antimicrobial efficacy of some N,N'-dialkyl-N,N'-dimethyl-1,6-hexanediamine dioxides.

A total of 17 N,N'-dialkyl-N,N'-dimethyl-1,6-hexanediamine dioxides were tested for activity against three microorganisms. A relationship was found between the length of the alkyl substituent and antimicrobial activity.


[Therapy of so-called shock lung. Experimental animal studies of the lung in shock].

1. Under hemorrhagic-traumatic shock conditions the depression of the flow and the pressure in pulmonary arteria and of the pressure in the left atrium was significant. The elevation of the pulmonary vessel resistance was significant, the pulmonary circulation time was longer. The depression of the oxygen partial pressure in arterial and venous blood was significant. 2. In comparison to single re-transfusion of the taken blood, the re-transfusion and application of 6-Methylprednisolone (Urbason; 30 mg/kg) could raise the pulmonary pressure and the flow in the pulmonary arteria and the oxygen pressure in the arterial and venous blood over their basic level. 3. After re-transfusion and simultaneous addition of phenoxybenzamine a renewing shock took place caused by a relative hypovolemia. 4. The hemodynamic circulation in the pulmonary and peripherial vessels was restored by hemodilution. While a single infusion of Haemaccel intensified the hypoxemia in comparison to shock conditions, the infusion of albumin (4%) caused no change in measured values. The application of Urbason (30 mg/kg) combined with Haemaccel-infusions raised the arterial and venous oxygen pressure significantly, in comparison to the hypotonic-phase they exceeded the basic values.


[Local corticoid therapy in pediatrics].

During 1978 I carried out a clinical trial in my pediatric practice with the new corticoid dermaticum Alfason, which contains the active substance hydrocortisone-17 abutyrate--an ester of hydrocortisone not previously used therapeutically. To begin with Alfason was given in an open trial to 100 children and later, because of the favourable results obtained, it was employed in another group of 100 children in a double-blind trial against a fluorinated corticoid, a substance which up to then I had most often prescribed. The results showed a good to very good effect in over 90% of the cases treated with either drug, there was no substance related statistical difference. According to the literature the ratio of success regarding side effects is particularly favourable for Alfason so that its use in the treatment of corticoid-requiring dermatoses in childhood can be recommended.


[Experimental pancreas transplantation].

Pancreatic auto- and allotransplantation of the pancreas tail were successfully performed in dogs. Malnutrition related to pancreatic exocrine hypofunction occurs initially in pancreatic-autotransplantation but gradual recovery by 3 months is normal. Tolbutamide showed a significant prolongation of hypoglycemia, glucose tolerance curves were normal in pancreatic autotransplantation. Denervation and lymphatic interruption of the pancreas may cause a transient but not definitive influence on pancreatic functions. In pancreatic allotransplantations there was a slight extension of survival time in the immunosuppressive treated group (Imuran 6 mg/kg). The results suggest that hyperglycemia, a poor response of the islets after glucose stimulation and a low circulating plasma-insulin level along with a low amylase level indicated the end point of rejection. The canine pancreas has been perfused for 3 hours with a membrane oxygenator, a pulsatile pump and a heat exchanger at a temperature of 37 degrees C. Among the criteria used in this study the insulin output into the venous blood in response to glucose administration as well as a pancreas secretion after secretin stimulation were found to be the most reliable indicators as to the viability of the pancreas. This is further supported by an average oxygen consumption of 0,77 ml O2/100 g/min at a constant flow of 80 ml/min and a pressure of 75 mmHg.


[Investigations of iron and folate levels in serum after implantation of heart valve prostheses (author's transl)].

In 90 patients with prosthetic heart valves, the presence of iron and folate deficiencies was assessed in a double-blind study. Anemia was found in 18 cases. Average serum iron levels were below the normal range and could be incremented significantly through the administration of 193 mg Fe++ daily during a 4-week period. No evidence of folate deficiency was found.


Secretory B-cell activity in insulin dependent maturity-onset diabetic.

In 10 insulin dependent maturity onset diabetics we found elevated basal C-Peptide levels (4.78 +/- 0.5 ng/ml. Normal range 1.1--3.6 ng/ml), which could be suppressed by insulin injection to the same extent as in sulfonylurea treated diabetics could be demonstrated. C-Peptide immunoreactivity in these patients therefore seems to be newly secreted rather than accumulated material. Since adrenalectomized patients could be suppressed in the same way, it is likely, that catecholamines are not the major factor in the mechanism of suppression. Therefore only decrease of bloodsugar levels seems to be accountable for the decrease of C-Petide levels. High C-Petide levels in insulin dependent maturity onset diabetics which cannot be stimulated but suppressed may be explained by a loss of glucoreceptor molecules.


Inactivation of two hyperactive LH-RH analogues by rat hypothalamic peptidases.

Hyperactive analogues of luteinizing hormone-releasing hormone (LH-RH) are beleived to derive their properties from either increased binding affinity to anterior pituitary receptor sites or through decreased susceptibility to enzymic degradation. To investigate the latter suggestion and to examine the possible sites of hypothalamic peptidases inactivating LH-RH, D-Ser(TBU)6-EA10-LH-RH and D-Leu6-EA10-LH-RH, which are known to have considerably greater activity than LH-RH, were incubated with a hypothalamic supernatant fraction containing active peptidases degrading LH-RH, and their gonadotrophin-releasing ability after incubation with the enzymes was tested in normal, adult male rats; LH-RH was also tested in the same way. From a comparison of the relative losses of biological activity, both the LH-RH analogues treated proved to be more resistant to the hypothalamic peptidases than LH-RH itself; the D-Leu6-EA10-LH-RH retained its gonadotrophin-releasing activity longer than the D-Ser(TUB)6-EA10-LH-RH. These findings indicate that increased activity of the analogues may, in part be due to increased resistance to enzymic inactivation and suggest initial sites of cleavage at the Gly-leu and Pro-Gly NH2 bonds in the LH-RH decapeptide by the hypothalamic enzymes. Studies on the action of peptidases on LH-RH and its analogues may yield useful information in the design of peptidase with increased biological activity.


Sheltering Arms: the last of its kind.

Sheltering Arms Hospital, Richmond, VA, is probably the last free private general hospital in the United States/Now, after 90 years, the forces of change have claimed it.


Social worker gains seat on health panel.

Rep. Barbara Mikulski deals with health care issues in terms of the people affected. She is concerned about the impact of cost containment legislation on uncompensated charity care.


An automatic system for chromosomal analysis applied to prenatal diagnosis.

Computer-assisted metaphase analysis for prenatal diagnosis can be economically performed by a preexisting hardware-software system. The program can be run by technician-level (i.e. nonspecialist) personnel who can opt for the automatic operational mode for good quality metaphases or for the semimanual mode for problem metaphases (numerous superpositions, artifacts, etc.). The karyotype can be obtained in conversational mode. Hardcopy output is available for all modes.


Improved technique for human leukocyte cultures.

An improved technique for cultivation of peripheral human lymphocytes is presented. The setting of the blood cells is replaced by a wash in Ficoll to remove the polymorphonucleocytes.


The approach of the European communities to the assessment of the carcinogenic risk of environmental chemicals, in particular, artificial colourings.

A brief outline is given of the rationale of the Environmental Research Programme of the European Economic Community and of its implementation. The major part of the programme is devoted to research on the exposure-effect relationships for mutagens and carcinogens and to the establishment of criteria. As a first step, a battery of test systems for mutagenicity screening is being established. These will be evaluated in a comparative test programme. The second part of the paper describes the specific legislative actions of the European Communities on food colourings. The historical background is given; and the criteria used by the Scientific Committee for Food for classifying and evaluating colouring matters are listed. Proposed regulatory action, on the basis of the report of the Committe, includes lists of colouring matters which are 'unacceptable', 'temporarily acceptable' and 'acceptable'.


The identification and control of occupational bladder cancer.

The recognition of an increasing number of environmental and occupational factors imvolved in cancer etiology indicates the urgent need for more effective identification and control procedures. On the evidence of experience derived from the historical example of occupational bladder cancer, it is suggested that the problems of identification and control require an integrated approach which must involve the toxicity screening of industrial materials, the environmental screening of the industrial process and the epidemiological screening of those who work in industry. Such a programme will depend for its success upon the cooperation and understanding of all concerned, and the need for consultation and the full provision of information is stressed. Benefits are indicated which might ultimately accrue from the establishment of a computerized data bank in which the results of toxicological, epidemiological and carcinogenicity investigations have been accumulated and collated under the auspices of an international agency.


The asbestos industry and statutory control of its hazards.

The difficulties of balancing the possible hazards of asbestos against its useful properties, the cost of control measures and the availability of adequate substitutes are described. The history of the asbestos industry, of recognition of the association between asbestos and respiratory disease and of the develpment of control regulations in the UK are outlined. The present provisions for inspection of work places, for medical services to workers and for environmental control within and outside the workplace have been reviewed and a Health and Safety Commission set up to implement them; their work is described. Although the regulations are being implemented, however, public anxiety has increased. Justification for such anxiety comes from reports of still-existing hazards and from the fact that the current standard was established on faulty grounds. Three studies are described which indicate that a dose-response relationship may exist in relation to the carcinogenicity of asbestos; however, there is still not enough evidence to set standards. Further studies have shown that the different types of asbestos incur different degrees of risk. The UK Asbestos Standards are thus undergoing revision, this time in consultation not only with physicians and hygienists, but also with members of industry, trades union members, academics and local authorities.


Long-term culture of pancreatic islet cells with special reference to the beta-cell function.

Islet cells of adult rat pancreas, dissociated with EDTA-Dispase, were cultivated in Microtest wells for over 2 months. In our cultures, islet cells were free-floating and cohered with each other to reorganize histotypic aggregates resembling the nondissociated islets. Morphologically, excellent preservation of islet cells in the aggregates was confirmed during the culture using both light and electron microscopy. The function of islet beta-cells, as demonstrated by the synthesis and release of insulin, also was retained throughout the culture period. Islet beta-cells cultured for long periods exhibited better response to the short-term stimulation of theophylline than to a high concentration of glucose, as observed in the islets of fetal or newborn rat pancreas.


Development in vitro of epithelial-cell monolayers derived from fetal rat pancreas.

Purified epithelial-cell monolayers were generated in vitro from explants of fetal rat pancreas. The extent of the development of the epithelial monolayer, as determined by planimetric analysis, was enhanced by the application of two methodological procedures: (a) preincubation of fetal pancreas in situ at 27 degrees C for 5 hr prior to dissection and explantation; and (b) incubation of the explants in medium containing a high concentration (50% to 70%) of fetal bovine serum. By utilizing such culture conditions, sheets of contiguous epithelial cells, with little or no peripheral fibroblastic contamination, were maintained for 9 days. Whereas the majority of cells within the monolayer had morphological characteristics of pancreatic ductal cells, endocrine cells were identified by the specific immunocytochemical localization of insulin and glucagon. In addition, insulin could be detected in the incubation medium throughout the course of experiment. The simplicity of this preparation offers some advantages over other techniques including reduced chance of contamination and reduced cellular damage or death. It provides a model for future studies directed toward developing individual cell strains derived from pancreatic epithelial cells.


[Investigation comparing the methods of serological differentiation of streptococci by precipitation, co-agglutination and fluorescence test (author's transl)].

Three methods for the serological determination of streptococci were compared: immunoprecipitation, immunofluorescence and co-agglutination. The results of the immunoprecipitation were the basis of evaluation. The deviating results in immunofluorescence and co-agglutination deviate among one another. With immunofluorescence relatively too many strains were determined as group B, with co-agglutination as group C.


Protection of cotton rats against experimental Echinococcus multilocularis infections with BCG cell walls.

Previous works has indicated that cotton rats treated with Mycobacterium bovis strain BCG are effectively protected against an infection with the metastatically proliferating metacestodes of Echinococcus multilocularis. In an attempt to induce a similar protection in the absence of tubercular granulomatous lesions, cotton rats were treated with BCG cell walls. A single injection of 150 micrograms of cell walls, emulsified in mineral oil-Tween-saline, 2 weeks before the inoculation of the parasite completely protected the animals against infection with E. multilocularis. This protection was correlated with an increase in the numbers of monocytes and, as judged by acid phosphatase activity, an activation of these cells. This study shows that BCG cell walls are as effective in protecting animals against E. multilocularis as the viable organism.


Bactericidal activity of fractionated granule contents from human polymorphonuclear leukocytes.

Proteins from human polymorphonuclear leukocyte granules were extracted with 0.2 M acetate, pH 4.0, and fractionated by Sephadex G-100 column chromatography. The fractions demonstrated selective bactericidal action against a deep rough cell wall mutant of Escherichia coli O111:B4 with rough lipopolysacharide and cell wall mutants of Salmonella typhimurium LT-2 with lipoplysacharide of Ra, Rc, Rd1, Rd2, and Re types. Smooth parent strains were most resistant to the bactericidal action. Fractions with greatest activity for the mutants were from valley regions (regions of low protein concentration) between three high protein peaks comprising myeloperoxidase, protease, and lysozyme, respectively. Susceptibility of the mutants to bactericidal action increased as sugar residues decreased in lipopolysaccharide. Gram-positive bacteria were susceptible to different fractions than were the gram-negative bacteria.


Protective effect of active immunization with purified Escherichia coli heat-labile enterotoxin in rats.

The protective effect of active immunization by different routes with a purified preparation of the polymyxin-release form of Escherichia coli heat-labile toxin was evaluated in rats. Immunized animals were challenged by placing toxin into ligated ileal loops at dosages which produced either 50% or the maximum secretory response in unimmunized rats. Immunization exclusively by the parenteral route yielded significant protection. Rats were also protected when parenteral priming was followed by boosting given either directly into the duodenum or perorally 2 h after intragastric cimetidine, but not when the peroral boosts were given with bicarbonate. Immunization administered entirely by the peroral route with cimetidine yielded protection but only when the immunizing dosage was fivefold greater than that found effective in the parenteral-peroral approach. Rats immunized exclusively by the parenteral route and those boosted perorally with cimetidine were also tested, and found to be protected, against challenge with viable organisms of strains that produce either heat-labile toxin alone or both heat-labile and heat-stable toxin, but they were not protected against a strain which produces just heat-stable toxin. Geometric mean serum antibody titers were increased by 16-fold or more over control values in those groups of rats in which protection was achieved, with the exception of those immunized exclusively by the peroral route. These observations demonstrate that (i) active immunization with purified E. coli heat-labile toxin results in significant protection against both this toxin as well as viable organisms which produce it, but not against viable strains which produce heat-stable toxin only, and (ii) concomitant ablation of gastric secretion by the use of cimetidine renders the peroral route of immunization effective. They suggest that prophylactic immunization against diarrheal disease caused by heat-labile toxin-producing strains of E. coli may be feasible in humans.