Screening for congenital hypothyroidism: results of screening one million North American infants. Pilot programs for screening of newborn infants for congenital hypothyroidism began in North America in 1972. To date, the five oldest programs (Quebec, Pittsburgh, Toronto, Oregon Regional, and New England Regional) have screened 1,046,362 infants. A total of 277 infants with congenital hypothyroidism have been detected and seven have been missed, resulting in a total of 284 affected infants in the screened population and an overall incidence of one in 3,684 live births. Of the affected infants, 246 were determined to have primary hypothyroidism, an incidence of one in 4,254 births. Ten infants with secondary-tertiary hypothyroidism were detected in Quebec, Oregon, and Toronto, an incidence of one in 68,200 births. Of all the infants with primary hypothyroidism who were adequately studied, 63% were determined to have aplastic or hypoplastic glands, 14% normal or enlarged glands, and 23% ectopic thyroid tissue. The estimated minimum incidence of infants with TBG deficiency is one in 8,913 births. Only 8 of the 277 detected infants were suspected clinically to have congenital hypothyroidism prior to the time of confirmation of the diagnosis at 4 to 8 weeks of age. The cost of screening varied from $0.70 to $1.60 per infant, depending on which costs were included in the estimate. Preliminary evidence from Quebec suggests that infants treated in the program have normal developmental testing scores at 18 months of age.


Spontaneous histamine secretion from leukocytes in the presence of strontium. Basophil leukocytes from human blood secrete histamine in the absence of a membrane stimulus when incubated in a medium containing Sr++, 1 to 10 mM. Spontaneous histamine secretion in the presence of Sr++ is inhibited by La+++, 1 to 1000 nM and 2 deoxy-D-glucose, 30 to 300 microM. Spontaneous secretion in the presence of Sr++ increases with increasing pH in the range 6.5 to 8.5. Agents which cause a rise of intracellular cyclic AMP level increase the spontaneous secretion in 194th presence of Sr++. The results suggest that spontaneous histamine release is a secretory response of the cells, and evidence is provided for a dual role of cyclic AMP in the control of histamine secretion.


Conformational changes of membrane-bound (Na+-K+)-ATPase as revealed by antibody inhibition. As different structural states of the (Na+-K+)-ATPase (EC 3.6.1.3) may lead to a changed reactivity to antibodies, the influence of Na+, K+, Mg++, Pi and ATP on the reaction between highly purified (Na+-K+)-ATPase and antibodies directed against the membrane-bound enzyme was measured. The antigen antibody reaction was registered by measuring the antibody inhibition of (Na+-K+)-ATPase activity. In the membrane-bound but not in the solubilized enzyme four different degrees of antibody inhibition were obtained at equilibrium of the antigen antibody reaction if different combinations of Na+, K+, Mg++ and ATP were present during the incubation with the antibodies. Corresponding to the different degrees of inhibition, different rates of enzyme inhibition were measured. (a) The smallest degree of enzyme inhibition was obtained when (i) only Mg++, (ii) Mg++ and Na+ or (iii) Mg++ and K+ were present during the antigen antibody reaction. (b) The enzyme activity was inhibited more strongly if Na+, Mg++ and ATP were present together. (c) It was inhibited even more if only (i) Na+, (ii) K+, (iii) ATP or both (iv) ATP and Na+, (v) ATP and K+, (vi) ATP and Mg++, or if (vii) no ATP and activating ions were present. (d) The highest degree of antibody inhibition was obtained if Mg++, ATP and K+ were present together. In the presence of Mg++ plus ADP and in the presence of Mg++ plus the ATP analog adenylyl (beta-gamma-methylene) diphosphonate, Na+ and K+ did not influence the degree of antibody inhibition as they did in the presence of Mg++ plus ATP. It was further found that the degree of antibody inhibition in the presence of Mg++, ATP and K+ was affected by the sequence of which K+ and ATP were added to the enzyme prior to the addition of the antibodies. It is suggested that by antibody inhibition different conformations of the (Na+-K+)-ATPase could be detected. These conformations may possibly not occur in the solubilized enzyme and therefore do not seem to be necessarily linked to the intermediary steps of the ATP hydrolysis of the enzyme. The structural changes which are induced by Na+ and K+ in the presence of Mg++ plus ATP are proposed to occur during the Na+-K+ transport.


RNA-directed DNA polymerase from particles released by normal goose cells. Cells from a goose embryo were shown to release particle-associated RNA-directed DNA polymerase and RNase H activities that required the presence of Nonidet P-40 for detection. The particles were not infectious and did not have endogenous DNA synthesis. The goose particle DNA polymerase was related to the DNA polymerase of spleen necrosis virus with respect to size and was inhibited by immunoglobulin G to spleen necrosis virus DNA polymerase. However, goose cells producing DNA polymerase-containing particles did not contain reticuloendotheliosis virus-related nucleotide sequences in their DNA.


Translation of bovine leukemia virus virion RNAs in heterologous protein-synthesizing systems. Bovine leukemia virus 60 to 70S RNA was heat denatured, the polyadenylic acid-containing species were separated by velocity sedimentation, and several size classes were translated in a micrococcal nuclease-treated cell-free system from rabbit reticulocytes. The major RNA species sedimented at 38S and migrated as a single component of molecular weight 2.95 x 10(6) when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The predominant polypeptides of the in vitro translation of bovine leukemia virus 38S RNA were products with molecular weights of 70,000 and 45,000; minor components with molecular weights of 145,000 and 18,000 were also observed. Two lines of evidence indicate that the 70,000- and 45,000-molecular weight polypeptides represent translation products of the gag gene of the bovine leukemia virus genome (Pr70gag and Pr45gag). First, they are specifically precipitated by a monospecific antiserum to the major internal protein, p24, and second, they are synthesized and correctly processed into virion proteins p24, p15, and p10 in Xenopus laevis oocytes microinjected with bovine leukemia virus 38S RNA. The 145,000-molecular weight polypeptide was immunoprecipitated by the anti-p24 serum and not by an antiserum to the major envelope glycoprotein, gp60. It contained all the tryptic peptides of Pr70gag and additional peptides unique to it, and thus represents in elongation product of Pr70gag in an adjacent gene, presumably the pol gene. The 18,000-molecular weight product was antigenically unrelated to p24 and gp60 and shared no peptides in common with Pr70gag, Pr45gag, or the 145,000-molecular weight polypeptide. It was maximally synthesized on a polyadenylic acid-containing virion 16 to 18S RNA, and we present evidence that this RNA is a 3' end-derived subgenomic fragment of the bovine leukemia virus genome rather than a contaminating cellular RNA.


Reticuloendotheliosis virus: detection of immunological relationship to mammalian type C retroviruses. Reticuloendotheliosis virus (REV) p30 shares cross-reactive determinants and a common NH2-terminal tripeptide with mammalian type C viral p30's. An interspecies competition radioimmunoassay was developed, using iodinated REV p30 and a broadly reactive antiserum to mammalian virus p30's. The avian leukosis-sarcoma viruses and mammalian non-type C retroviruses did not compete in this assay. Previous data indicating that the REV group is not represented completely in normal avian cell DNA lead us to speculate that this may be the first example of interclass transmission, albeit in the remote past, among the Retroviridae.


Formation of Rous associated virus-60: origin of the polymerase gene. The DNA of normal chicken embryos contains sequences related to the avian leukosis-sarcoma viruses. RNA-dependent DNA polymerase of these viruses is encoded by a genetic element known as the pol gene. The nature of the endogenous virus pol gene in chicken cells was investigated by testing its ability to participate in genetic recombination. Rous-associated virus-60-type recombinant viruses isolated after infection of chicken cells with strains tsLA337PR-B or tsNY21SR-A, both of which produce a temperature-sensitive DNA polymerase, also possessed the temperature-sensitive lesion. These results are consistent with the hypothesis that the endogenous viral information used for the generation of Rous-associated virus-60 is deficient in at least part of the pol gene and that the defect includes that portion represented by the lesions in NY21 and LA337. The frequency of polymerase-negative BH-Rous sarcoma virus alpha formation was not affected by the levels of endogenous viral expression, which suggests that the alpha defect is not derived from the endogenous pol gene.


Comparison of the small RNAs of polymerase-deficient and polymerase-positive Rous sarcoma virus and another species of avian retrovirus. The small RNAs contained in virions of avian leukosis and sarcoma viruses are a virus-specific subset of the total small RNA population of the host cell. The reverse transcriptase protein must be present in the budding virion for this selection to take place. Virions of the alpha form of the Bryan strain of Rous sarcoma virus, which lack detectable reverse transcriptase, incorporated an unselected population of small RNAs identical to total chicken cell small RNA. Virions of reticuloendotheliosis virus, which contain a reverse transcriptase unrelated to that of the avian leukosis and sarcoma viruses, contained a distinctly different population of small RNAs although both the avian leukosis and sarcoma and the reticuloendotheliosis viruses were grown in chicken cells. Because the primer for avian leukosis and sarcoma virus RNA-dependent DNA synthesis is a host cell tRNA, the differences in reverse transcriptase small RNA selection may help explain the failure of different species of retrovirus to complement for the reverse transcriptase.


Synthesis of long complementary DNA in the endogenous reaction by equine infectious anemia virus. In the endogenous reverse transcriptase reaction, equine infectious anemia virus is able to synthesize complementary DNA (cDNA) of 8,000 nucleotides in high yield. After 2 h in 50 muM dNTP, about 2.8 mug of cDNA per mg of protein is produced, almost 30% of which is long cDNA. The system thus compares favorably with the other two well-characterized endogenous reaction systems, Moloney murine leukemia virus and avian sarcoma virus. Elongation rates of 100 to 150 nucleotides per min have been observed; these rates are comparable to those seen with purified avian myeloblastosis virus reverse transcriptase and significantly higher than those observed in vivo. In the absence of actinomycin D, equine infectious anemia virus does not require high dNTP levels for either optimal incorporation or long cDNA synthesis. The amount of long cDNA synthesized is maximal at 2 h in 50 muM dNTP; neither longer time nor higher dNTP levels (through 1.8 mM) increased this yield. Half-maximum yield in 2 h was achieved at about 15 muM dNTP, which is very similar to the published K(M)'s for isolated avian and murine reverse transcriptases. Total incorporation, on the other hand, continues to rise slowly through 1 mM dNTP; the half-maximum was 30 to 50 muM dNTP. In the presence of 100 mug of actinomycin D per ml, however, higher dNTP levels are required for long cDNA synthesis. We conclude that equine infectious anemia virus is exceptionally well-suited to studies of the physical organization of the retrovirus genome and to investigations of the mechanism of synthesis of the double-standard cDNA endogenous reaction product.


Effects of nerve stimulation and drugs on the release of histamine and norepinephrine from the isolated heart. Compound 48/80 and polymyxin B elicited prompt and sharp increases in histamine output from the isolated guinea pig heart and had no effect on norepinephrine output. Dextran decreased histamine output without affecting norepinephrine output. Bradykinin increased both histamine and norepinephrine output; the histamine output increased only after a latent period. Stimulation of both left and right stellate ganglia increased norepinephrine output, but only right ganglion stimulation increased histamine output, after a latency. Stimulation of the right but not the left vagus nerve decreased histamine output first, then increased it moderately, the peak of which came later than norepinephrine release. It was suggested that histamine release following nerve stimulation and bradykinin was secondary to norepinephrine release. Isoniazid decreased the output of both histamine and norepinephrine. Aminoguanidine increased histamine output but decreased norepinephrine output.


Combined treatment with by-pass operation, irradiation and immunochemotherapy for advanced thoracic esophageal cancer. Based on the experimental results that operative stress of thoracotomy or laparothoracotomy has enhanced tumor growth remarkably in rats compared with laparotomy, a new combined treatment with by-pass operation, irradiation and immunochemotherapy was investigated in 39 advanced thoracic esophageal cancer patients. At by-pass operation, abdominal esophagus was divided and its proximal stump was closed immediately. Cervical esophagus was then divided and its distal stump was pulled out to the right supraclavicular region to make outer fistula. Thus, anticancer drug was poured into the esophagus through outer fistula very easily just before irradiation and then irradiation was performed under the condition that the lesion was immersed in the drugs. As anticancer agent, Mitomycin-C, 5-Fluorouracil or Bleomycin was given alternately. Lately, the combination of 5-Fluorouracil and Vitamin A was preferably used. The changes of immunological parameters and the survival after the onset of treatment was reported.


[Experiments towards the viral etiology of a preleukemic syndrome: osteomyelofibrosis (author's transl)]. The present study describes the separation and purification of a reverse transcriptase and cellular DNA polymerases from the human spleen of a patient with myelofibrotic syndrome. The specific requirements with respect to bivalent cations and templateprimers for DNA polymerase-alpha, DNA polymerase-beta and DNA polymerase-gamma, as well as for the reverse transcriptase, are reported. Sedimentation velocity measurements of the purified enzymes gave values of 150 000, 40 000, 100 000 and 70 000 daltons for DNA polymerase-alpha, DNA polymerase-beta, and DNA polymerase-gamma and the reverse transcriptase respectively. The purified reverse transcriptase was specifically inhibited by antisera to the reverse transcriptases of the two primate viruses, SiSV and GaLV. Antisera raised against the myelofibrotic spleen reverse transcriptase inhibited the homologous enzyme and also the reverse transcriptase from SiSV and GaLV. DNA polymerases alpha, beta and gamma from the same spleen were not inhibited by the antisera. These results constitute the first indication of a possible retroviral etiology for myelofibrotic syndrome. Since SiSV and GaLV are exogenous to all primates the results indicate that this polymerase was acquired and the results are most simply interpreted as indicating that virus related to the SiSV-GaLV group is present in man.


Mallory bodies. Horseradish peroxidase: specific cytochemical and biochemical marker for alcoholic hyalin. Horseradish peroxidase (HRP), a glycoprotein enzyme, bound specifically to Mallory bodies (MBs) in cryostat sections of autopsy liver and liver biopsies. In contrast, HRP did not bind to cryostat sections of normal liver. The specificity of HRP binding was also observed using light and electron microscopy in autopsy liver-derived subcell fractions prepared by the MB isolation procedure. In order to quantitate HRP binding, a solid phase colorimetric assay was developed. This assay involves immobilizing purified MBs or homogenized tissue fractions in glass tubes, incubating with HRP, and measuring the enzymatic activity of bound HRP. A linear relationship between MB concentration and HRP binding was observed. The assay was capable of detecting as little as 1 microgram of MB protein. The specificity of HRP binding was also investigated using the solid phase assay. The specific activity (HRP bound per milligram of protein) of purified MBs was 10 to 15 times that of a glass wool-filtered liver homogenate suggesting that the solid phase assay may be of use in monitoring the purification of MBs. HRP did not bind to normal liver homogenate even when large loads were assayed. The results of this study indicate that HRP binding, employed cytochemically, represents a rapid and facile procedure for ascertaining the presence of MBs in tissue. In some cases, those structures may not be easily visualized by conventional staining procedures. Furthermore, quantitation of MBs in tissue may be possible by using a solid phase enzyme-linked assay.


Histochemical change of the endothelial basal lamina of the diabetic lymphatic vessel. Electron micrsocopic periodic acid methenamine silver staining of lymphatic endothelial basal lamina taken from diabetic patient has shown a positively changed basal lamina, which is an early sign of the changes and plays an important role in pathological tissue changes in the disease.


[Pathogenesis of Sudeck's syndrom and a new possibility for its treatment (author's transl)]. Authors describe the microcircular haemodynamics of Sudeck's syndrom together with the characteristic vitious circle of pain, rigidity, oedema and osteoporosis. Based on theoretical considerations and own results the infusion of dextran (Rheomacrodex 10%) as a pathogenetic base therapy is recommended. For increasing efficiency according to their experiences early treatment is suggested.


Surgical treatment of pancreatic cancer. The problems encountered in the surgical treatment of pancreatic cancer are outlined on the basis of a review of the literature published in the last 15 years and the authors' experience with 157 patients over the period 1970 to 1977. The overwhelming evidence favors resection as opposed to any palliative procedure. Although the number of patients eligible for 5-year follow-up is small, the data suggest that total pancreatectomy with regional lymphadenectomy may be the most appropriate operation.


Serum-myelin-basic-protein assay in diagnosis and prognosis of patients with head injury. Serum levels of myelin basic protein (M.B.P.), a nervous-system-specific protein, were measured in 157 patients after head injury and related both to the type of brain damage and to the clinical outcome assessed three months after injury. Mean concentrations of M.B.P. in patients with severe intracerebral damage, with or without associated extracerebral haematoma, were significantly raised at the time of admission and remained high for two weeks after injury. In patients with extracerebral haematoma not associated with severe intracerebral damage mean M.B.P. values rose four to six days after injury and were significantly raised only in patients with poor eventual outcome. Mean serum-M.B.P. concentrations in patients with a good outcome after injury were similar to those in controls. In patients with a poor outcome the mean M.B.P. levels between two and six days after injury were significantly higher than in those with a good outcome. The assay of serum-M.B.P. may be valuable in assessment of severity of brain damage in patients after head injury and in prediction of outcome.


Significance of loin pain in women. A study of 100 consecutive cases referred to a urological clinic. Of 100 consecutive female patients referred to a urology clinic in Sheffield with suspected renal pain, only 22% has upper-urinary-tract lesions. A full history and examination, an analysis of a midstream specimen of urine, and a straight X-ray examination of the renal tract indicated or excluded an upper-urinary-tract lesion in 94% of the cases. In the remaining 6%, where an upper-urinary-tract abnormality was diagnosed only after urography, the findings were incidental in most cases and no treatment was necessary.


Oral versus intravenous high-dose steroid treatment of renal allograft rejection. The big shot or not? 50 episodes of renal allograft rejection were treated by oral prednisolone and 49 by intravenous methylprednisolone. Both treatments achieved reversal of rejection in approximately 60% of episodes. Morbidity-rates, as assessed by hypertension, oliguria, fluid retention, and infection, tended to be greater after oral treatment. When the results were reexamined for accelerated, acute, and chronic rejection episodes the only difference demonstrated was an increased frequency of fluid retention in patients treated by oral prednisolone for an acute rejection episode. There was no evidence that intravenous methylprednisolone was nephrotoxic.


Is azathioprine necessary in renal transplantation? In renal-transplant patients in whom azathioprine therapy was withdrawn early because of bone-marrow suppression no rebound graft rejection was noted. Any subsequent rejection episodes were satisfactorily treated with methylprednisolone pulse therapy. Of 15 patients in whom azathioprine was stopped electively after at least 2 years, only 1 had a subsequent cellular rejection. It is concluded that azathioprine may not have a major role in the immunosuppressive management of renal-transplant patients. If azathioprine has to be stopped there seems to be no good indication for restarting it.


Wiskott-Aldrich syndrome: detection of carrier state by metabolic stress of platelets. A stress test has been designed which shows a consistent abnormality in platelets from carriers of the Wiskott-Aldrich-syndrome (W.A.S.) gene. 2-deoxy-D-glucose (D.D.G.), an inhibitor of glycolysis, completely inhibited second-wave adrenaline (epinephrine)-induced aggregation of platelets from 10 W.A.S. carriers, whereas it had no effect on the response of control platelets. Antimycin A (Ant A), an inhibitor of oxidative phosphorylation, had no effect on adrenaline-induced platelet aggregation of either carriers or controls. Incubation of control platelets with a combination of Ant A and D.D.G. inhibited aggregation in a way comparable to the effect of D.D.G. alone on carrier cells. Thus, W.A.S. carriers have a defect in platelet metabolism similar to that produced in normal platelets with Ant A. The D.D.G. stress test is a simple reproducible assay for detection of W.A.S. carriers.


Uptake of iron by duodenal biopsy specimens from patients with iron-deficiency anaemia and primary haemochromatosis. Iron uptake by human duodenal mucosa in vitro was considerably higher in iron-deficient patients than in controls. In biopsy specimens taken after treatment with iron, uptake fell to normal levels, although total iron in the mucosa remained low. In iron-overloaded patients with primary haemochromatosis, there was inappropriately high uptake of iron by the biopsy specimens. Kinetic analysis suggested that this was the result of affinity for iron being increased in a carrier in the enterocyte.


Early detection of cancer of oesophagus along Caspian Littoral. Report of a pilot project. A simple mass-screening procedure for the early detection by brush cytology of oesophageal cancer in 280 adults in high-incidence villages of the Caspian Littoral is described. The presence of atypical cells in 7%, and the discovery of frank carcinoma in 3 symptom-free people encourages continuation of the project.


Carnitine deficiency induced during intermittent haemodialysis for renal failure. Carnitine concentration was measured in plasma, muscle, and dialysate before and after haemodialysis in patients with renal failure and in plasma and muscle of healthy controls. In eight of the nine patients carnitine concentration in muscle after haemodialysis was only 10% of the concentration in controls. Plasma-carnitine varied in patients before dialysis and in all of them was reduced by dialysis. The loss of carnitine into the dialysate (190--2100 mumol/treatment) greatly exceeded the normal loss in urine for most of patients, and was only partly compensated for. In some patients normal or high plasma-carnitine and low concentrations in muscle indicated that the carnitine-concentrating mechanisms in the muscle cell had failed. The reduction in carnitine will interfere seriously with normal cellular functions and this may help to explain the clinical syndrome of cardiomyopathy and cardiac failure which has been observed in some patients treated for a long time with intermittent haemodialysis.


Bacterial contamination in traditional Gambian weaning foods. Although emphasis on infant feeding is rightly being placed on breast-feeding, the need for safe weaning foods for the developing world must also receive its due attention. Traditional weaning foods used for young infants in a typical West African village can be as hazardous, bacteriologically, as commercial milk products, and providing a breast-fed child with supplements under the conditions which prevail in much of the developing world is potentially dangerous, whatever the source of the food.


Combination chemotherapy with cis-diammine-dichloro-platinum, vinblastine, and bleomycin in advanced testicular non-seminoma. 40 patients with disseminated testicular non-seminoma were treated with cis-diammine-dichloro-platinum, vinblastine, and bleomycin. Complete remission was achieved in 24 (60%) patients and partial remission in 11 (28%). 22 of the 24 complete responders, who have been followed-up for a median of 11 months, have been tumour-free for 5--30 months. There were 3 drug-related deaths. This regimen is the most effective remission-induction treatment available for disseminated testicular non-seminoma. Patients should be treated in centres experienced in the specialised management of this potentia-ly curable disease.


Cure of aplastic anaemia in paroxysmal nocturnal haemoglobinuria by marrow transfusion from identical twin: Failure of peripheral-leucocyte transfusion to correct marrow aplasia. The ability of syngeneic peripheral leucocytes to cure marrow aplasia was tested in a patient with paroxysmal nocturnal haemoglobinuria (P.N.H.). Transfusion of 7.1X10(10) white cells obtained by leucopheresis from an identical-twin donor, providing 3.4X10(4) myeloid progenitors (C.F.U.-C)/kg, failed to improve marrow function within two months. In contrast, transfusion of 1.3X10(10) nucleated bone-marrow cells, representing 6.4X10(4) C.F.U.-C/kg, from the same donor resulted in prompt bone-marrow recovery. These observations support the hypothesis that aplastic anaemia in P.N.H. is a stem-cell defect that may be corrected by the simple infusion of relatively small numbers of normal bone-marrow cells. They also seem to indicate a distinct advantage of marrow cells over peripheral-blood mononuclear cells in their ability to correct marrow aplasia.


Cytochrome b is present in neutrophils from patients with chronic granulomatous disease. Analysis of dithionite difference spectra demonstrated that cytochrome b was present in neutrophil homogenates from a 17-year-old girl and her 25-year-old brother who had the autosomal recessive form of chronic granulomatous disease, and from an 18-year-old boy with the X-linked form of chronic granulomatous disease. These results indicate that the postulated importance of cytochrome b in the oxygen burst during phagocytosis is questionable.


Improvement in iron status and liver function in patients with transfusional iron overload with long-term subcutaneous desferrioxamine. Subcutaneous desferrioxamine (2--4 g over 12 h) was administered 6 nights each week to 34 patients with transfusional iron overloads who continued to receive regular blood-transfusions. All 34 patients showed a fall in serum-ferritin after 5 to 12 months. In some patients serum-ferritin fell almost to normal. Liver function improved in all the patients, serum-aspartate-transaminase levels fell in all 17 patients tested, and liver-iron fell in 5 of 6 patients tested. These studies show that body-iron stores can be substantially reduced, to normal or near normal levels, by long-term subcutaneous desferrioxamine in patients with transfusional iron overload despite the need for continued blood-transfusion. They also show that removal of iron is accompanied by improved organ function.


Non-A non-B hepatitis associated with chronic liver disease in a haemodialysis unit. To clarify the aetiology of an outbreak of HBsAg-negative acute hepatitis in the renal unit at Fulham Hospital in 1968--70, serological tests for antibody to hepatitis-A virus (anti-H.A.V.) were done retrospectively on serum samples obtained at the time of the outbreak. 7 patients had had two previous episodes of clinical HBsAg-negative hepatitis. Serum samples were available from 24 of the 29 infected patients, and these were paired in 12 instances. There was a slight increase in the titre of anti-H.A.V. in 1 patient, and a further 2 patients who subsequently developed chronic hepatitis showed a decrease in titre, but no changes in titre were detected in the remaining 21 cases. These findings do not provide evidence for the involvement of hepatitis-A virus in the outbreak of hepatitis and effectively exclude a role for this virus in the chrnoic liver disease which developed subsequently in 8 (28%) of the patients. This outbreak is therefore probably non-A non-B hepatitis, which has not been reported previously in Great Britain in a haemodialysis unit. The results confirm that this form of hepatitis may be related to a high frequency of persistent hepatic dysfunction.


Dependence on chlormethiazole and effects of its withdrawal. Five cases of physical dependence on chlormethiazole are reported. Because sudden withdrawal may precipitate an acute "organic psychosis", chlormethiazole should only be used in hospitals and, even then, only for a maximum of 9 days.


Therapeutic efficacy of apomorphine combined with an extracerebral inhibitor of dopamine receptors in Parkinson's disease. Apomorphine in combination with a peripheral dopamine receptor blocker (domeperidone) was administered to four parkinsonian patients in a double-blind placebo-controlled study. The therapeutic efficacy of apomorphine was not reduced by domperidone, while nausea, drowsiness, sedation, and arterial hypotension were prevented. Combination of domperidone with dopamine agonists may result in more effective treatment of Parkinson's disease.


A waterborne outbreak of gastroenteritis with secondary person-to-person spread. Association with a viral agent. In December, 1976, an outbreak of gastroenteritis occurred at a resort camp in Colorado. Data obtained by questionnaire from 760 persons indicated that 418 (55%) had had gastroenteritis at the camp or within a week of leaving it, with peak onset within a two-day period. Symptoms included vomiting (81%), diarrhoea (65%), and fever (49%); median duration of illness was twenty-four hours. The attack-rate increased with consumption of water or ice-containing beverages. The camp water supply was found to be inadequately chlorinated and contaminated by a leaking septic tank. Although routine laboratory tests did not reveal bacterial, viral, or parasitic pathogens, immune electron microscopy detected virus-like particles in two of five diarrhoeal stool filtrates. Oral administration of one of these bacteria-free filtrates to two volunteers induced a gastrointestinal illness similar to that observed in the camp visitors.


Food allergies and migraine.

Food allergies and migraine. 60 migraine patients completed elimination diets after a 5-day period of withdrawal from their normal diet. 52 (87%) of these patients had been using oral contraceptive steroids, tobacco, and/or ergotamine for an average of 3 years, 22 years, and 7.4 years respectively. The commonest foods causing reactions were wheat (78%), orange (65%), eggs (45%), tea and coffee (40% each), chocolate and milk (37%) each), beef (35%), and corn, cane sugar, and yeast (33% each). When an average of ten common foods were avoided there was a dramatic fall in the number of headaches per month, 85% of patients becoming headache-free. The 25% of patients with hypertension became normotensive. Chemicals in the home environment can make this testing difficult for outpatients. Both immunological and non-immunological mechanisms may play a part in the pathogenesis of migraine caused by food intolerance.


Increased hepatic copper concentration in Indian childhood cirrhosis. 19 Indian children with liver disease were studied. 5 in whom a clinical and histological diagnosis of Indian Childhood Cirrhosis was made had massive orcein-staining deposits in liver cells. The hepatic copper content in these 5 cases was strikingly high (1389 microgram/g dry tissue, range 1045--2303) the normal range being 15--55 microgram/g. Of the other 14 cases, only 2 had hepatic copper levels above normal (170 and 262 microgram/g.) This high hepatic copper concentration may be caused by excessive copper ingestion or an abnormality of copper metabolism.


Cytoplasmic copper and its toxic effects. Studies in Indian childhood cirrhosis. Morphological, histochemical, and chemical study of three necropsy specimens of liver in the terminal stage of Indian Childhood Cirrhosis revealed a strikingly high copper content. it is proposed that excess accumulation of copper in the cytoplasm of hepatocytes disturbs the microtubular system, causing hydropic swelling and the formation of Mallory's hyalin. Copper and copper-binding protein showed topographical association with Mallory's hyalin. Diffuse cytoplasmic staining and the lysosomal copper distribution also suggested that copper had a cytotoxic effect. The pattern of copper distribution in Indian Childhood Cirrhosis differs from that in Wilson's disease and in prolonged cholestasis with excessive hepatic copper deposition, indicating a different mechanism of the copper accumulation.


Genetic marker for insulin-dependent diabetes mellitus. A rare genetic type (Bf F1) of properdin factor B is found in 22.6% of patients with insulin-dependent diabetes mellitus but in only 1.9% of the general population, yielding a relative risk of 15.0. This indicates that a genetic locus for insulin-dependent diabetes mellitus is very close on chromosome 6 to Bf, and that Bf F1 is a marker for nearly 1 out of 4 insulin-dependent diabetic patients.


Influence of once-daily administration of beta-adrenoceptor antagonists on arterial pressure and its variability. Intra-arterial pressure was recorded over 24 h in hypertensive patients before and during long-term treatment with beta-adrenoceptor antagonists given once daily under standardised conditions. Arterial pressure was reduced throughout the 24 h after the last dose as was variability of pressure during physical activity; variability during sleep and rest did not change significantly.


Improvement of chronic congestive heart-failure by oral captopril. Catopril, an inhibitor of angiotensin converting enzyme, was given orally during cardiac catheterisation to 6 normotensive patients with refractory congestive heart-failure. 60--180 minutes after administration of 25 mg captopril, arterial pressure fell by 25%, cardiac index rose by 38%, and left-ventricular pressure and right-atrial pressure fell by 25% and 40% respectively. Plasma-renin activity rose while plasma noradrenaline and aldosterone fell. These data suggest that, in the short term, captopril can reduce both preload and afterload, and improve cardiac function, in refractory congestive heart-failure.


Is arterial hypertension crucial for the development of cerebral haemorrhage in premature infants? Computerised tomography has revealed that more than 40% of premature neonates (birth weight smaller than 1500 g) have cerebral bleeds in the first 3 or 4 days of extrauterine life. Injection studies done at necropsy have shown that they usually originate in the capillaries of the germinal matrix. It is suggested that premature neonates are hypertensive when their blood-pressure is compared with that in utero, and that events that lead to further rises in pressure are common. Their capillaries are not protected against rises in arterial pressure because autoregulation is impaired. Furthermore, the capillaries in the germinal matrix are not supported by firm glial structures. Arterial pressure rises are therefore likely to be responsible for germinal matrix haemorrhage in the premature neonate, and the risk of haemorrhage probably diminishes as autoregulation of cerebral blood-flow is restored a few days after birth.


Effect of rubella vaccination programme on serological status of young adults in United Kingdom. Antibody to rubella virus was measured in over 10,000 serum samples collected in 1976, 1977, and 1978 from young adult blood donors and university students. The incidence of seronegatives was lower (4--7%) among females born in 1956 and subsequently--i.e., among the age groups offered rubella vaccine at school--than among females born before 1654 (11--20%). The incidence of seronegatives among males in the 1977 and 1978 surveys had the opposite trend, with a higher proportion of seronegatives in younger males, born in 1956 and subsequently, than in older males. The findings provide evidence that the rubella vaccination programme in the U.K. is having a significant impact on the immunological status of young females of childbearing age. Nevertheless too high a proportion of young females remains potentially susceptible to rubella.


How district hospitals see acute colitis. Acute colitis was an uncommon cause of admission to twenty-two district hospitals in 1975--77. The overall mortality in this series of 130 patients was 5.2%, 1.8% during medical treatment and 20% after urgent surgical treatment. A third of the patients were admitted without previous diagnosis. Four-fifths responded to medical treatment and the rest were treated by urgent colectomy. Four of the six related deaths and half the urgent operations occurred among 18 patients iwth colonic dilatation. This complication was often detected within two days of admission by abdominal X-ray; symptoms and signs were unhelpful in its recognition. Early admission to hospital of patients with severe unexplained diarrhoea or a sharp attack of colitis, rapid investigation to exclude infection, and energetic treatment of colitis, monitored by abdominal X-rays to detect colonic dilatation at its earliest stage, might reduce the frequency and danger of this complication.


Survey of operating room pollution within an N.H.S. district. Pollution by waste anaesthetic gases was measured in all operating departments in a typical N.H.S. district. Methods were chosen to provide time-weighted average levels over the period of each operating session. The results showed that air-conditioning alone could not guarantee pollution levels below suggested maximum levels and that to meet those requirements air-conditioning plus scavenging was necessary. Background pollution levels were found to be representative of the personal exposure of nursing staff but approximated to only one third of the anaesthetists' personal exposure. Dental clinics presented special problems, namely the very high levels of pollution to which the dentist and his assistants were exposed.


Continuous subcutaneous insulin infusion: improved blood-glucose and intermediary-metabolite control in diabetics. Blood-levels of glucose and the major intermediary metabolites, lactate, pyruvate, 3-hydroxybutyrate, and alanine, were measured in 7 insulin-dependent diabetics during 24 h of continuous subcutaneous insulin infusion (C.S.I.I.) from a portable dual-rate syringe pump. Results were compared with metabolic profiles during the patients' conventional insulin treatment and with those of 17 non-diabetics. The mean 24 h plasma-glucose during C.S.I.I. was not significantly different from that in non-diabetics. During infusion blood concentrations of lactate, pyruvate, 3-hydroxybutyrate, and alanine were also close to those in the non-diabetic state. Thus, C.S.I.I. provides strict control not only of blood-glucose but also of major metabolites, an essential prerequisite for investigating the influence of good metabolic control on diabetic microangiography.


Restoration of normal lipid and aminoacid metabolism in diabetic patients treated with a portable insulin-infusion pump. To determine whether abnormalities of lipid and aminoacid metabolism observed in diabetes are corrected when plasma-glucose levels are restored to normal, eight insulin-dependent diabetics were treated for 7-14 days with a portable infusion pump which delivers insulin subcutaneously in basal (between-meal) doses with pulse-dose increments before meals. Mean plasma-glucose (206 +/- 24 mg/dl during conventional insulin treatment) fell to 89 +/- 3 mg/dl at day 7 and 84 +/- 2 mg/dl at day 14 of pump treatment; glycosuria was eliminated. Plasma cholesterol, triglycerides, and free fatty acids were elevated during conventional insulin treatment but fell to normal after 7 days of pump treatment. Plasma-levels of branched-chain aminoacids were 50-60% above control levels during conventional treatment but fell to normal after 7 days of pump therapy. Aminoacids were reduced from their high postprandial levels to normal values after insulin-pump treatment. In addition to restoring plasma-glucose to normal, treatment of diabetes with a portable insulin-infusion system results in restoration of normal lipid and aminoacid metabolism. Long-term use of this system may determine whether metabolic changes resulting from insulin lack cause the complications of diabetes.


Ultrasound detection of brain damage in preterm infants. A linear-array real-time ultrasound scanner with a 5 MHz probe was used to examine the brains of 31 infants born at less than 33 weeks of gestation. The equipment was mounted on a small trolley and the infants could easily be scanned in their incubators. 7 of the 31 infants were shown to have cerebral lesions, including haemorrhages into the germinal layer and ventricles, hydrocephalus, and infarction of the periventricular region and cerebral cortex. The type and extent of the lesions were conformed by computerised tomography and at necropsy. Ultrasound scanning is a safe, simple, non-invasive technique that provides valuable information for the diagnosis, investigation, and treatment of lesions in the brains of newborn infants.


Circulating immune complexes in non-A, non-B hepatitis. Possible masking of viral antigen. Serial serum samples from 22 patients with transfusion-associated non-A, non-B hepatitis and 2 chimpanzees with the experimentally induced disease were tested for circulating immune complexes by Raji-cell radioimmunoassay. 13 patients (59%) and 1 chimpanzee had circulating immune complexes immediately before, coincident with, or during the return to normal of raised aminotransferase activity. 7 of the 10 patients with chronic non-A, non-B hepatitis had detectable complexes at levels which waxed and waned in parallel with changes in serum aminotransferase activity. Immune complexes may contain and mask viral antigens, and their presence may explain the failure of conventional immunological techniques to detect virus antigens.


Production of IgE complexes by allergen challenge in atopic patients and the effect of sodium cromoglycate. Specific IgE complexes and symptoms of asthma and eczema were produced in two allergic patients by oral challenge with food allergen. Both symptoms and IgE complexes could be prevented by pre-treatment with oral sodium cromoglycate. The IgE complexes can fix complement and may therefore provide the vehicle of the "late" responses seen in immediate hypersensitivity. The central role of gut sensitivity is emphasised by the protection afforded by sodium cromoglycate both when given acutely, against the effects of an oral challenge, and when given continuously for asthma and eczema due to food allergy.


Immune complexes containing food proteins in normal and atopic subjects after oral challenge and effect of sodium cromoglycate on antigen absorption. After ingestion of food, immune complexes containing food proteins as antigens were demonstrated in the serum of normal and atopic subjects. In the atopic patients challenged with the food to which they were sensitive, abnormal levels were detected. The same atopic patients pretreated with oral sodium cromoglycate had less antigen entry, diminished immune-complex formation, and no atopic symptoms. Tests for antigen entry and immune-complex formation after oral challenge may permit objective assessment of food allergy and may show whether drugs such as oral sodium cromoglycate are likely to benefit individual patients.


Significance of elevated mid-trimester maternal plasma-alpha-fetoprotein values. In a prospective trial of 15,481 pregnancies, 667 women (4.3%) had two sequential mid-trimester plasma-alpha-fetoprotein (A.F.P.) values above 2 times the median. The outcome of these pregnancies was open neural-tube defect (12.4%), birthweight less than 2.5 kg (10.3%), twins (9.8%), fetal wastage (9.5%), perinatal death (2.6%), other (1.3%), and "normal" singleton (54.1%). At higher A.F.P. cutoffs the proportion of "normal" singleton pregnancies declined rapidly, being 19% at 3 times the median and 9% at 4 times the median. If it is assumed that ultrasonography and amniotic-fluid A.F.P. assay can detect twins and most cases of neural-tube defect, the outcome of the residual pregnancies is still strongly influenced by plasma-A.F.P. level. Thus at a cut-off of 4 times the median two-thirds of the pregnancies in this residual group will end in spontaneous abortion, stillbirth, or neonatal death. It is suggested that counselling of women taking part in A.F.P. screening programmes should be strongly influenced by maternal plasma-A.F.P. levels, even if ultrasonographic findings and amniotic-fluid levels are normal.


Plasma assay of fetal factors VIIIC and IX for prenatal diagnosis of haemophilia. Fetal blood unmixed with maternal blood or amniotic fluid was obtained by direct-vision fetoscopy in 22 consecutive cases at 15--22 weeks' gestation; the investigation was done either for prenatal diagnosis or before therapeutic abortion. Fetal plasma factors VIIIC and IX averaged 50 I.U./dl (S.D. 12.8) and 12.5 I.U./dl (S.D. 2.4), respectively. Two male fetuses at risk of haemophilia had normal factor VIIIC levels by these criteria, and both pregnancies ended in the birth of a normal boy. Five others gave 3 normal and 2 haemophilic results, which were confirmed in two of the three terminated pregnancies.


Defective reticuloendothelial system function in rheumatoid arthritis. The function of the splenic reticuloendothelial system in patients with rheumatoid arthritis (R.A.) was assessed by determining the clearance of autologous heat-damaged erythrocytes from the circulation. 11/13 patients with active R.A. had a defect in the clearance of red cells and there was a significant inverse correlation between splenic function and the level of circulating immune complexes detected by a Clq-binding assay. Splenic function was normal in 13 patients with inactive disease who had been treated with either gold or prednisone. A serial study on 1 patient with active R.A. showed a clear correlation between fluctuations in disease activity, splenic function, and the level of circulating immune complexes.


Korean haemorrhagic fever in staff in an animal laboratory. In March, 1975, and January, 1978, there were outbreaks of Korean haemorrhagic fever (K.H.F.) among staff in the animal laboratory of the clinical research building of Tohoku University hospital. 13 doctors and 1 veterinarian had K.H.F., and all except 1 had a mild but typical clinical course. K.H.F. antibody titres were significantly raised in all 14 patients. 12 other doctors working in the same room had no symptoms and no K.H.F. antibody. K.H.F. antibody was also detected in 3 animal technicians who had not been ill, but who had worked in the same room. Antibody was not detected in any of the 4 technicians who worked in different animal rooms in another building. Epidemiological studies suggest that laboratory rats were the source of the infection. High titres of K.H.F. antibody were most common in rats reared in the animal laboratory associated with the outbreak.


Undifferentiated carcinoma in young men: the atypical teratoma syndrome. In 5 young men with apparent undifferentiated carcinoma involving lung, mediastinum, and lymph-nodes subsequent response to treatment, tumour-marker analysis, and histology review suggested a diagnosis of embryonal-cell carcinoma. It is suggested that atypical presentation of extragonadal germ-cell tumours may be common. Because such tumours respond to chemotherapy, accurate diagnosis is essential.


Detection of extracranial carotid stenosis by computed tomography. Ten patients with transient ischaemic attacks (T.I.A.) within the carotid territory were examined by aortic-arch angiography and computed tomography (C.T.) of the neck. C.T. showed evidence of carotid calcifications in all 17 angiographically abnormal arteries, and there was no evidence of calcification in the 3 normal arteries. C.T. of the neck promises to be a useful technique for the investigation of patients with T.I.A.s.


Liposomes in arthritis: a new approach.

Liposomes in arthritis: a new approach. Intra-articular liposomal cortisol palmitate in a dose equivalent to 2 mg of cortisol produced a worthwhile therapeutic response in patients with rheumatoid arthritis. This may represent a valuable new approach to treatment.


Correlation between computed tomographic values and liver iron content in thalassaemia major with iron overload. Computer tomographic (CT) scans of the liver were obtained in six thalassaemic patients with iron overload confirmed by liver biopsy. Mean CT values for the liver in individual patients were linearly related to the iron content estimated by liver biopsy (correlation coefficient = 0.995).


Dacron bypass grafting in the relief of obstructive jaundice. A new technique using a 'Dacron' tube bypass graft for relief of obstructive jaundice due to malignant disease is described. This method is applicable when a conventional bypass operation is technically impossible. Good palliation was achieved in all seven patients who survived the immediate postoperative period.


Infants of very low birthweight. A 15-year analysis. 357 babies weighing 501--1500 g were born alive at Hammersmith Hospital in 1961--75. 58.5% died in the neonatal period and 1.4% at 4--25 months of age. 1.4% of the total are untraced, 5.3% have major handicap, 5.6% have minor handicap, and 27.8% are apparently normal. There was no significant improvement in neonatal mortality in three 5-year periods, 1961--65, 1966--70, and 1971--75, except that more small-for-gestational-age babies survived in the last period than in the first. More of these babies survived than did babies whose birthweight was appropriate for gestational age. There was no significant improvement in the proportion of handicapped children among the very-low-weight liveborn babies throughout the 15-year period, despite increasing complexity of care.


Diagnostic decision-process in suspected pulmonary embolism. Report of the Herlev hospital study group. An analysis was made of how a diagnosis was arrived at in 60 consecutive patients with suspected pulmonary embolism. Patients underwent an initial clinical assessment, a chest X-ray examination, pulmonary scintiphotography, and final clinical assessment. Later, chest films and scintiphotos from these patients and from 120 controls were mixed and reread "blind". The results suggest that clinical physiologists were biased by the clinical information when interpreting the scintiphotos and that clinicians in turn believed implicitly in the scintigraphic report when they made the final diagnosis. The degree of agreement between the first and the second readings of the scintiphotos was unsatisfactory. The radiological findings did not correlate with the clinical and scintigraphic assessments. The study reveals some of the problems which arise in routine clinical practice, when the true diagnosis cannot be established by independent means.


Sputum-smear-negative pulmonary tuberculosis: controlled trial of 3-month and 2-month regimens of chemotherapy. Of 1072 Chinese patients with radiographically active pulmonary tuberculosis and no microscopic evidence of acid-fast bacilli in sputum examinations, only 691 (64%) were sputum-culture negative. All patients were randomly allocated to selective chemotherapy (antituberculosis chemotherapy not being started until the activity of the disease had been confirmed), to daily streptomycin, isoniazid, rifampicin, and pyrazinamide for 2 months or 3 months, or to a standard 12-month control regimen. During the subsequent 12 months, 64% of the patients in the selective chemotherapy series started antituberculosis chemotherapy. Both 2-month and 3-month regimens were inadequate for patients whose pretreatment sputum cultures were positive (relapse-rates 14% and 7%, respectively, in patients with drug-sensitive strains) but in the patients whose first cultures were negative the relapse-rate was only 1% after both short-term regimens.


Reactions and antibody responses to reinforcing doses of adsorbed and plain tetanus vaccines. In children aged 15--16 years receiving routine reinforcement tetanus immunisation, adsorbed vaccine caused more severe and more frequent local reactions than did plain formol toxoid, and a higher incidence of pyrexia. The incidence of swelling and erythema at the inoculation site increased with serum antitoxin titre at the time of inoculation, whereas pain and tenderness were related to the presence of the aluminium hydroxide adjuvant. Both vaccines gave satisfactory antibody responses over a 5-month observation period; plain formol toxoid induced higher mean titres than did the adsorbed vaccine. It is recommended that plain and not adsorbed vaccine be used when reinforcement of immunity to tetanus alone is desired.


Plasma-triglycerides do not regulate high-density lipoprotein concentrations. Diets high in carbohydrate and diets restricted in fat and calories were used to induce large fluctuations in plasma-triglycerides in patients with severe familial hypertriglyceridaemia. High-density-lipoprotein (HDL) concentrations were estimated by radioimmunoassay of the major HDL apoprotein, apo A-I, and were correlated with plasma cholesterol and triglyceride concentrations. Patients with type-1 hyperlipoproteinaemia had apo A-I concentrations about 50% of normal, and no increase in apo A-1 concentrations was observed even when plasmatriglycerides were reduced to the normal range. Apo A-I concentrations in type-5 hyperlipoproteinaemia were not consistently low and did not correlate with plasma-lipid concentrations. It does not seem that hypertriglyceridaemia reduces HDL in either disorder.


Karyotypic conversion in Ph1-positive chronic myeloid leukaemia with combination chemotherapy. Twelve previously untreated patients with Ph1-positive chronic myeloid leukaemia received combination chemotherapy soon after diagnosis. There was karyotypic conversion in five: in four, the percentage of Ph1-positive cells fell to 10 or less. In two other patients, who had mosaic karyotypes at presentation, the percentage fell to 5% and zero.


Diabetic twin pregnancy: an unequal result. A diabetic mother produced twins dissimilar in both appearance and blood biochemistry--one being clearly macrosomic and "hyperinsulinised" at delivery, the other apparently normal. It is suggested that the development of fetal hyperinsulinism may depend not only on maternal blood-glucose control but also on fetal blood-supply or genetic factors.


Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. 24 patients with congestive cardiomyopathy (group I) were compared with a group of 13 controls with similar clinical findings and myocardial function who were selected retrospectively (group II) . All patients received digitalis and diuretics, but group I patients received beta-blockers as well. The survival-rate in group I patients (83%, 66%, and 52% after one, two, and three years respectively) differed significantly from that in group II subjects (46%, 19%, and 10%, respectively). This finding is supported by the demonstration that beta-blockade improved myocardial function in group I subjects. It is therefore suggested that beta-blockade prolongs survival in patients with congestive cardiomyopathy.


Inhibition of sebum excretion by an H2 blocker. Cimetidine, 1g orally per day, partially inhibited sebum excretion in patients with acne. Whether this was the result of H2-receptor blockade or an antiandrogen action is unknown.


Normal plasma-1,25-(OH)2-vitamin-D concentrations in nutritional osteomalacia. Three patients with advanced untreated nutritional osteomalacia had low plasma concentrations of 25-OHD and 24, 25-(OH)2D, and a raised concentration of immuno-assayable parathyroid hormone. The plasma concentration of 1, 25-(OH)2D was normal in all 3 patients.


Innovation in medical diagnosis--the Scandinavian curiosity. Fine-needle aspiration biopsy is a major diagnostic tool in Scandinavia, where 8000 such biopsies may be done in a large metropolitan hospital each year. The procedure is rapid, inexpensive, and technologically simple, yet it has found only limited, albeit increasing, acceptance in medical practice outside Scandinavia. Although the differences between Scandinavian and other medical systems may explain why the technique is not used more widely, there seems to be an underlying reluctance among medical communities to accept subjective types of innovation compared with objective innovation.


The safest place of birth: further evidence. The distribution of births for each place of delivery was studied with a composite antenatal prediction score, incorporating the most important risk factors, which was developed for the second volume of British Births 1970. Although consultant hospitals are seen to have the greatest share of births at moderate and high risk, this is not sufficient to account for the whole amount by which perinatal mortality in these hospitals exceeds that in other places of delivery.


Lymphomas and occupational benzene exposure. There was a significant excess of deaths caused by major lymphomas in men employed in occupations where benzene and/or coal tar fractions are used. The increase in risk was limited to those who were 45 years of age and older at death, an observation which is consistent with the possibility that chronic exposure might be important. Evidence from other studies suggests that benzene may adversely affect the immunological system.


Does screening by "Pap" smears help prevent cervical cancer? A case-control study. The Papanicolaou (Pap)-smear history of 212 cases of invasive cervical cancer was compared with that of 1060 age-matched controls drawn from neighbours. In the 5 years before the year of diagnosis 32% of the cases had been screened by Pap smear, compared with 56% of the controls. This difference was statistically highly significant (p less than 0.0001) and indicated a relative risk of invasive cancer of 2.7 in women who had not been screened by Pap smear, compared with those who had. Differences in Pap-smear history between cases and controls persisted when the data were stratified by age, income, education, marital history, smoking habit, employment status, and access to medical care. These results support the belief that the Pap smear is an effective screening procedure for invasive cervical cancer.


Chlamydia, cytomegalovirus, and Yersinia in inflammatory bowel disease. The relationship of three infectious agents, Chlamydia, cytomegalovirus, and Yersinia enterocolitica, to the aetiology, clinical course, and diagnosis of Crohn's disease was studied. There was no evidence of chlamydial infection in Crohn's disease and no indication either that cytomegalovirus alters the outcome of acute attacks or that infection with Y. enterocolitica is being misdiagnosed as Crohn's disease.


New method for measuring milk intakes in breast-fed babies. A method for the measurement of milk intake in young breast-fed babies is described in which heavy water (2H2O) enrichment in saliva is measured on only two occasions after a single oral dose of 2H2O. Values obtained by this method are compared with those obtained by test-weighing. This new method is ideal for routine surveys since it does not interfere with feeding habits and maternal life style, and no technical expertise is required of the mother.


Resorption of bone.

Resorption of bone. The cell-system responsible for resorption of bone is now considered to be a derivative of haematopoietic bone-marrow, not skeletal connective tissue. Consideration of mutant mice and rats, with defects of bone resorption giving osteopetrosis, suggests that the primary defect is of the professional scavengers, the mononuclear-phagocyte system, failing to recognise effete bone. To explain associated defects of thymic lymphocytes it is postulated that the mononuclear-phagocyte system may be activated to a major or minor extent by professional recognisers, thymic lymphocytes, as happens in some inflammatory reactions.


Postgraduate examinations for general practice in Canada and the United Kingdom. The membership examination of the Royal College of General Practitioners (M.R.C.G.P.) emphasises factual knowledge, and it is suggested that a clinical component should be included, perhaps using simulated patients as in the certificate examination of the Canadian College of Family Physicians (C.C.F.P.).


Early detection of idiopathic haemochromatosis: relative value of serum-ferritin and HLA typing. A study of 18 unrelated families with idiopathic haemochromatosis (I.H.C.) was undertaken to define the relative values of HLA typing and serum-ferritin estimation in the early detection of the disease. Sharing of both HLA haplotypes with the proband indicated a high risk of I.H.C. in siblings; but HLA typing was of limited value in detecting affected offspring. Non-identical HLA indicated a low risk of I.H.C. in both siblings and offspring. The presence of HLA A3 was not clinically useful as a marker for I.H.C., since this antigen was also present in 40% of unaffected relatives. In contrast, the serum-ferritin concentration was elevated in 96% of patients with I.H.C. and in only 5% of unaffected relatives. HLA typing provides some indication of the risk of I.H.C. in first-degree relatives, but the combination of serum-ferritin, serum-iron, and transferrin saturation remains the most reliable screening regimen for early diagnosis of I.H.C.


Antenatal diagnosis of congenital adrenal hyperplasia. The concentration of 17-OH-progesterone (17-OHP) was measured retrospectively in a second-trimester amniotic-fluid sample obtained from a mother who had an infant with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The concentration was more than three times the mean amniotic-fluid-17OHP concentration determined in pregnancies of comparable gestational age with normal outcome. In four further pregnancies tested, where the parents were heterozygous for CAH, amniotic-fluid concentrations of 17-OHP were normal. To date, three of the mothers have delivered normal infants. CAH can be detected in early pregnancy by specific radioimmunoassay techniques for steroid-hormone analysis in amniotic fluid. This antenatal test could be useful in those cases in which parents do not wish to risk having affected offspring.


Potassium depletion and tissue loss in chronic heart-disease. Weight-loss, total body-potassium, and total body-nitrogen were measured in 12 men and 15 women with severe chronic heart-disease. Compared with age-matched healthy controls, the men had lost an average of 13 kg in weight, 915 mmol of potassium, and 354 g of nitrogen, whereas the women had lost 5.6 kg of weight, 327 mmol of potassium, and 66 g of nitrogen. Although the potassium/nitrogen ratio in the lost tissue is not precisely known, the loss of nitrogen indicates that most of the potassium loss in men is due to tissue loss and that there is little fall in the intracellular concentration of potassium in either the men or the women.


Pattern of milk flow in breast-fed infants. 122 six-day-old infants were test-weighed during breast feeding. Cross-sectional data collection avoided repeated interruptions of individual feeds. Milk flow conformed to a definite pattern: a mean of 50% of the feed from each breast was taken in the first two minutes of sucking and a mean of 80-90% was taken by four minutes. The second half of a ten-minute feed from either breast was almost non-nutritive. Preliminary studies suggest that the pattern is the same after one month of lactation.


New bacterial agent of pneumonia isolated from renal-transplant recipients. A gram-negative, weakly acid-fast bacillus has been isolated in embryonated eggs and in guineapigs from lung tissue of two renal-transplant recipients with acute purulent pneumonia. Culture of infected lung tissue and subculture of the egg isolate on artificial media, including media for legionnaires' disease bacterium (Legionella pneumophila), failed to produce growth. Ultrastructural analysis showed that the organism is a prokaryote with a cell-wall structure typical of a gram-negative bacillus but different from that of L. pneumophila. In both patients serum antibody to both isolates developed in high titre. In its microbiological, tinctorial, and ultrastructural characteristics this bacterium differs sufficiently from L. pneumophila and other pulmonary pathogens to indicate that it may be a new agent of bacterial pneumonia.


Thyroid-stimulating immunoglobulins do not cause non-autonomous, autonomous, or toxic multinodular goitres. Thyroid-stimulating immunoglobulins (TSIs) were measured by radioreceptor assay in serum from 51 patients with a multinodular goitre, divided into four groups according to thyroid function, and in 30 normal people. In 9 patients who were euthyroid and had non-autonomous thyroid function and in 6 patients who were hyperthyroid, TSI index was normal . Of 21 euthyroid patients with autonomous function only 2 had a slightly abnormal TSI index (66 in both, normal greater than or equal to 68). Another series of 15 clinically euthyroid patients also had a normal TSI index. These results suggest that TSIs do not contribute to the pathogenesis of multinodular goitre, as has been suggested by others.


Short-term triiodothyronine in prevention of temporary hypothyroidism after subtotal thyroidectomy for Graves' disease. To determine whether short-term thyroid hormone replacement prevents or merely delays temporary hypothyroidism after surgery for Graves' disease, serum T3, thyroid-stimulating hormone, and T4 were measured every 2 months for 18 months in two groups of Graves' disease patients who had had subtotal thyroidectomy. Group I (18 patients) were given T3 20 microgram four times daily from surgery through the twelfth postoperative month. Group II (18 patients) received no treatment. Hypothyroidism occurred at some time during the 18-month period in 10 group-II patients, but was temporary in 7. Temporary hypothyroidism did not occur in group-I patients, whose mean T4 level rose to that in group II within 2 months of T3 withdrawal. Short-term T3 replacement after surgery for Graves' disease thus prevents (and does not simply delay) temporary postoperative hypothyroidism without increasing the frequency of permanent hypothyroidism.


Reduction of pituitary-tumour size in patients with prolactinomas and acromegaly treated with bromocriptine with or without radiotherapy. 69 patients with prolactin-secreting or growth-hormone-secreting pituitary tumours were treated with bromocriptine with or without pituitary irradiation and followed up for 6 months to 6 1/2 years. Of 26 patients with prolactinomas, 11 had external pituitary irradiation in addition to bromocriptine. There was evidence of shrinkage of the pituitary tumour (either a reduction in fossa size or loss of visual-field defects) in 6 of these patients (23%), 3 of whom had been treated with bromocriptine alone. Of 43 acromegalic patients, 30 received external pituitary irradiation. 8 (19%) showed evidence of shrinkage of the pituitary tumour, including 2 who had received no radiotherapy. 1 patient treated with bromocriptine alone showed striking reduction in the size of his suprasellar extension, as assessed by serial computed-tomography scans over 11 months. At the same time his visual-field defects resolved and his deficient corticotrophin and thyrotrophin reserves returned to normal. Bromocriptine can reduce the size of both prolactin-secreting and growth-hormone-secreting pituitary tumours, and this is of potential importance in their management.


Measurement of tissue pH in skin by glass microelectrodes. Alterations in metabolic activity may be used as an indicator of tissue perfusion and haemodynamic status in peripheral ischaemia. A new type of microelectrode was used to measure pH in the skin of patients with vascular disease, and a decrease in pH was demonstrated along the leg, commensurate with the severity of the disease. Measurement of skin pH by this technique is easy and may be useful for assessing tissue perfusion or skin viability in other conditions.


Early clinical evaluation of minaxolone: a new intravenous steroid anaesthetic agent. Minaxolone has been used for the induction and maintenance of anaesthesia in 60 patients undergoing minor surgical procedures. With nitrous oxide as the only supplement, satisfactory conditions were obtained in 56 patients. Patient acceptance was high.


Minaxolone: a new water-soluble steroid anaesthetic. The induction characteristics of minaxolone, a water-soluble steroid anaesthetic, were studied in fit patients undergoing minor urological or gynaecological operations. Minaxolone acted as rapidly as thiopentone. A dose of 0.25 mg kg-1 did not always produce anaesthesia in patients who had not received premedication but 0.5 mg kg-1 was an adequate dose. Excitatory effects were less common with the higher doses of anaesthetic. These effects were usually slight and rarely interfered with the course of anaesthesia. Unlike propanidid, minaxolone did not prolong the duration of action of suxamethonium. Minaxolone is easy to administer and causes little venous damage.


Preoperative chest radiology. National study by the Royal College of Radiologists. Over a period of four to five months, eight hospitals in England, Wales, and Scotland took part in an investigation into the use of preoperative chest radiography (POCR) in 10,619 patients undergoing non-acute, non-cardiopulmonary surgery. Wide variations in the use of POCR were recorded both between centres (11.5--54.2%, mean 29.7%) and and between specialties, and this variation could not be explained on clinical grounds. POCR did not seem to influence the decision to operate or the choice of anaesthetic; nor was there any evidence that POCR, at the levels of utilisation observed in this study, would be of much value as a baseline against which subsequent radiographs in patients with postoperative pulmonary complications could be judged. In view of the absence of clinical usefulness of routine POCR in patients scheduled for non-emergency operations, other than those on heart and lung, and on financial grounds, there is a case for setting a temporary norm for POCR in non acute, non-cardiopulmonary surgery at the lowest level of utilisation found in the eight centres (12%). This norm could be used while the policy of abandoning routine POCR in such cases was discussed.


An outbreak of hepatitis B from tattooing. An outbreak of 34 cases of hepatitis B not all of them notified, is described. 31 was tattooed by one artist; 3 were secondary infections. All primary infections occurred in males aged 16-28 years. Several defects in hygiene in the tattooing procedure were noticed. Recommendations are made for the licensing and routine inspection of all tattoo parlours.


The ultrastructural cytochemistry of peroxisomes in the guinea pig cochlea: a metabolic hypothesis for the stria vascularis. The roles of catalase and alpha-hydroxyacid oxidase activities are studied in the peroxisomes of the guinea pig inner ear. The major activities are located primarily in the intermediate cells of the stria vascularis. The peroxisomes of the stria vascularis behave cytochemically in a similar fashion to those found in the proximal convoluted tubules of the kidney. This study indicates that the stria vascularis may behave as a compartmentalized metabolic system.


Characteristics of tumor associated antigens in squamous cell carcinoma. For centuries physicians have been intrigued by the variable biologic behavior of cancer in humans. In recent years, attention has focused upon the host immune response as an indicator of patient prognosis and for potential use in tumor detection. In this study, tumor associated antigens were extracted from fresh squamous cell carcinoma and their biologic properties were characterized. Using the Leukocyte Migration Inhibition (LMI) assay, considerable sharing of antigenic determinates was noted among the 12 carcinomas and 18 patients studied, though none cross-reacted with each of the others which were studied. Immune assays using pooled tumor extracts successfully differentiated between tumor patients and control subjects, though further development will be necessary before small aggregates of tumor may be consistently detected.


[Diagnostic value of laboratory and scintigraphic investigations in young infants with cholestatic jaundice (author's transl)]. The diagnostic value of laboratory and scintigraphic examination techniques in young infants with cholestatic jaundice will be discussed. The correct diagnosis of neonatal hepatitis or extrahepatic biliary atresia cannot be derived from such investigations as determination of bilirubin, enzyme activities, immunologic or serologic parameters or scintigraphy of the liver. Only quantitative changes of serum LP-X before and after administration of cholestyramin and the modified rose-bengal test may help to establish a correct diagnosis in cholestatic jaundice during the first 6 weeks of life.


[Surgical treatment of congenital obstructive biliary disease (author's transl)]. The results of surgical treatment of bile duct atresia and hypoplasia are disappointing; no improval of long-term survival could be observed. With Kasai's hepato-jejuno-enterostomy which is not suited for the management of complete atresia. A new surgical procedure was evaluated in animal experimentation and in some patients: the bile was drained through the lymph system of the liver into the intestinal tract. Morphology, surgical procedure and indications as pertinent to this new approach are described and discussed. On the basis of the data available at present no conclusions can as yet be drawn, if the good results obtained in animal experimentation will be achieved in man as well. Surgical treatment of choledochus cysts is discussed. The procedure chosen depends upon the site of the cyst. Surgery is aimed at extirpation of the cyst and reconstruction of bile flow through the papilla Vateri. Curative and palliative procedures are discussed.


Effect of double infection of cowpox virus-infected cells with paramyxovirus (Sendai virus) on formation of cowpox virus-specific cell surface antigen. The formation of cowpox virus-specific cell surface antigen (CPV S-ag) was significantly enhanced by double infection with HVJ (Sendai virus). Simultaneous double infection, superinfection with HVJ and superinfection with CPV of cells persistently infected with HVJ similarly enhanced the formation of CPV S-ag, while pre-infection with HVJ was ineffective. To be effective, cells must be infected at a m.o.i. of greater than or equal to 1.0 and HVJ gene functions had to be expressed. The HVJ-infected cell extracts had an ability to accelerate uncoating (or degradation) of CPV, causing an early increase and a subsequent decrease in the infectivity of CPV. This activity reached a maximum 4--6 hr after HVJ infection, the increase paralleling enhancement of the total activity of several cellular enzymes. Addition of puromycin abolished the increase of these activities and the formation of CPV S-ag. Thus, the double infection with HVJ of CPV-infected cells induces an enhancement of CPV S-ag formation presumably as a consequence of activation of cellular enzymes which in turn accelerates uncoating of CPV.


Inhibition of reverse transcriptase activity by benzophenanthridine alkaloids. Benzophenanthridine alkaloids, fagaronine 4, O-methylfagaronine 5,nitidine 1, allonitidine 3 and methoxydihydronitidine 2 have been shown to possess inhibitory activity against reverse transcriptase of RNA tumor viruses. The enzyme inhibition (50%) by these alkaloids was found in the range of 6-60 microgram per milliliter of the reaction mixture when polynucleotide-oligodeoxynucleotide complexes were used as template primers. The results suggested that the benzophenanthridine alkaloids interacted with the template primers (particularly of the A:T base pairs) and not with the enzyme proteins. Kinetics reaction of the reverse transciptase inhibition showed that the alkaloids stopped the DNA polymerase synthesis instantly, probably by interacting with the template primer.


[Immunologic aspects of preparation of antiserum to the reverse transcriptase from avian myeloblastosis virus]. After immunization of rabbits the antiserum was prepared against purified reverse transcriptase (revertase) from avian myeloblastosis virus (AMV). The antiserum demonstrated enzymeneutralizing antibody activity that was associated with ummunoglobulin G fraction but not with IgM. The high antigenicity of AMV revertase for rabbits was shown. The active antiserum was obtained after 4 immunizations of rabbit with approximately 20 microgram of the enzyme. Non-specific revertase inhibitors were found in normal rabbit serum, which were absent in IgG fraction from this serum. The revertase activity of Rauscher leukemia virus (RLV) and Visna virus was not neutralized by antisera against AMV polymerase. This work was supported by the project "Revertase".


[Purification and various biochemical and immunological properties of wild and mutant forms of Drosophila melanogaster 6-phosphogluconate dehydrogenase]. A 1500--2000-fold purification procedure using substrate elution from phosphocellulose is described for two isozymes of 6-phosphogluconate dehydrogenase (6PGD) coded for by the corresponding allelic genes. Taking into account the data of gel filtration and of SDS polyacrylamide gel electrophoresis both isozymes are shown to be dimers containing identical polypeptides of mol. weight 50 000. Antisera against the highly purified sample of 6PGD, inactivated by lyophilization completely inhibited the enzyme activity. Antigens reacting to antisera were revealed by Ouchterlony immunodiffusion tests in extracts of flies carrying the wild type or mutant Pgd allele, coding for 6PGD. In addition to 6PGD antigen (antigen 1) another protein (antigen 2) which shared no common antigenic precipitative determinants with the antigen 1 was revealed in extracts of the normal flies. Antigen 2 was demonstrated also in the six different mutants which expressed zero level of 6PGD activity and had no antigen 1. Mol weight of a 6PGD subunit and of antigen 2 purified by immobilized antibodies were shown to be identical by SDS-polyacrilamide gel electrophoresis. A transformation of "antigen 2" to "antigen 1" was performed by treatment of the former in 2% SDS-mercaptoethanol solution. As a result of SDS treatment no changes of antigenic properties of the inactivated and dissociated 6PGD dimers were observed in immunodiffusion tests.


[Nature of mutations disrupting the formation of 6-phosphogluconate dehydrogenase in Drosophila melanogaster, and their suppression]. Molecular nature of lethal and semilethal mutations in the Pgd locus of D. melanogaster coding for 6-phosphogluconate dehydrogenase (6tpgd) was studied. All these mutations affect the structural gene of the Pgd locus: 3 semilethal mutations resulted in altered 6PGD molecules with the decreased catalytic activity; the remaining 8 lethals were "zero" alleles possessing mutant polypeptides inactive but capable to react with antisera against highly purified 6PGD. "Zero" or low activity alleles for glucose-6-phosphate dehydrogenase induced by ethyl methansulfonate were shown to be supressors for the lethal mutations in the Pgd locus. A monocistronic type of organization of the Pgd locus is suggested taking into account the biochemical mechanism of supression of the Pgd-lethals and their location in the structural gene coding for 6GPD.


A new stain for quantitative measurement of sprouting at neuromuscular junctions. A new combined stain for the simultaneous demonstration of motor nerve terminals and cholinesterase at neuromuscular junctions is described. It employs bromoindoxyl acetate dye-staining for cholinesterase and silver-gold impregnation for nerve terminals. The clarity and reliability of the stain permit quantitative measurements of neuromuscular junctions in order to evaluate nerve terminal sprouting as well as other pathological changes. The method is rapid, reproducible, and simple, and it is well suited for the processing of large numbers of frozen sections.


Mitochondrial ATPase of Zajdela hepatoma. V. Mitochondria of Zajdela hepatoma contain membrane sectors of ATPase complex unassociated with F1. Relative content of membrane sectors of ATPase complex in rat liver and Zajdela hepatoma mitochondria and the ability of mitochondrial membrane of the two sources to bind isolated soluble (F1) ATPase were examined. Approximately equal concentrations of oligomycin were required for 50% inhibition of ATPase activity in submitochondrial particles of rat liver and Zajdela hepatoma indicating practically identical content of membrane sectors of ATPase complex in both types of mitochondria. As detected by the increase in oligomycin-sensitive ATPase activity of submitochondrial particles incubated with isolated F1, the submitochondrial particles of Zajdela hepatoma in contrast to those of rat liver were able to bind specifically considerable amounts of exogenously added F1. The results indicate that mitochondria of Zajdela hepatoma contain membrane sectors of ATPase complex unassociated with F1 but capable of association with this enzyme.


Cerebrospinal fluid markers in central nervous system metastases from testicular carcinoma. Serum values of alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) have been used to monitor disseminated testicular carcinoma. Serial measurements of these markers have been used to monitor the response to therapy, to follow the progress of disease, and to detect subclinical recurrences. With increasingly effective chemotherapy for systemic disease, central nervous system (CNS) metastases in testicular carcinoma are becoming increasingly important as a cause of treatment failure. Cerebrospinal fluid (CSF) values of AFP and HCG seem to be important ancillary acids in the neurosurgical management of CNS metastases from testicular cancer. Our preliminary experience with three cases suggests that these CSF markers (plus computerized tomograhic scanning) should be evaluated in patients with this disease.


Isoprinosine in subacute sclerosing panencephalitis. An open therapeutic trial of isoprinosine was conducted in 15 patients with subacute sclerosing panencephalitis (SSPE). Long-term remissions occurred in 5 (33 percent), with documented improvement sustained for 2 or more years. Another patient was in remission 9 months after starting treatment, and three patients had transient remissions or stabilization. The disease was unaltered in five patients who had rapidly progressive SSPE when treatment started. These results compare with an average remission rate of about 5 percent in several series of untreated cases of SSPE or in cases treated with other antiviral agents. Patients in remission continued to have elevated cerebrospinal fluid (CSF) IgG and measles antibody titers, with one exception. Isoprinosine was tolerated for several years without side effects, except for mild hyperuricemia.


[Telethermographic evaluation of the use of acupuncture in fibrocystic dysplasia in the painful phase]. With this preliminary note the writers propose an objective documentation of acupuncture's effects in fibrocystic mastopathia during the painful phase, using thermography. Five patients have been treated with the following points: 6R, 5MP, 6MP, 4F all in the same session. In four cases clinic remission of symptoms and syntomatic change of the thermography picture have been obtained. In the treated cases menstruations have always been remarked in advance.


Histological staining of hepatitis B antigen in paraffin embedded liver tissue. Two hundred and six unselected liver biopsies were stained with Gomori's aldehyde fuschin, aldehyde thionine, and a modified orcein stain, according to Shikata and others (1974). Six cases showed positive cytoplasmatic staining indicative of hepatitis B antigen. It is suggested that one of these methods should be used in the study of liver biopsies, as an additional tool in the detection of hepatitis B carriers.


Alpha-fetoprotein levels in placenta, maternal, and cord blood in normal and pathologic pregnancy. The level of placental alpha-fetoprotein (AFP) in normal pregnancy at term was found to be 5050 +/- ng/g fresh tissue. A significant increase was noted in the toxemic placenta associated with a rise in circulating maternal AFP level and a nonsignificant increase in cord blood. The increase in maternal AFP level in cases of premature delivery before 33 weeks' gestation and postmature delivery after 40 weeks' gestation predicted that maternal AFP measurement throughout the second and third trimester of pregnancy could be clinically established as an index of placental function.


Effect of bromodeoxyuridine and interferon on cellular and viral functions in human prostatic cells. Some of the human prostatic cells in culture apparently produce oncornavirus-like particles. Bromodeoxyuridine does not enhance the production of these particles. On the contrary, this drug depresses such production. This depression is likely to be due to the cytotoxic effects of bromodeoxyuridine for these cells. These results can be interpreted to suggest that the human prostatic cells used in this study do not contain endogenous oncornavirus genetic information that is inducible. Purified human interferon inhibits the production of oncornavirus-like particles by these prostatic cells. It is also inhibits the rate of cellular DNA synthesis in these cells. These results are consistent with the notion that the inhibitory effects of interferon are mediated through its effect on cellular biosynthetic machinery.


The validity of parental reporting of infant development. A developmental questionnaire, encompassing the ages from 4 weeks to 36 months, has been  devised that, when completed by parents, can be used to screen children as being developmentally normal, questionable, or abnormal. A total of 526 infants were screened by this questionnaire at 28 weeks of age and then examined at 40 weeks of age by a full Gesell Developmental and Neurologic Examination. Underscreening of those with major abnormalities was 2.6%, and of those with minor abnormalities, 10%. Overscreening was 6%. In view of the demonstrated high reliability and validity of the full Gesell Developmental and Neurologic Examination on which the questionnaire is based, the relatively small percentages of overscreening and underscreening make it the most accurate and useful screening questionnaire to date.


Polyadenylation and reverse transcription of influenza viral RNA. The polyadenylation of Fowl Plague Viral RNA and of Influenza A/Victoria Viral RNA using E. coli poly (A) polymerase and the subsequent reverse transcription of the polyadenylated species is reported. We have shown that all 8 genome fragments are adenylated and that an average of 25--30 adenylic acid residues per molecule is sufficient for maximal transcription with reverse transcriptase. The cDNA product is 95% sensitive to Sl-nuclease and hybridisation analysis against viral RNA reveals it to be a faithful copy of the RNA. Amongst the transcription products are long, discrete copies of genes 1--8, the lengths of which are comparable with those of the vRNA determined by electrophoresis on formamide acrylamide gels. These single-stranded cDNAs have been further transcribed to form double-stranded products with hair-pin structures at one end. Analysis of this material on native acrylamide gels revealed some DNA bands corresponding to the predicted sizes for genes 4--8.


A new method for the size estimation of the RNA genome segments of influenza virus. Previous estimates of the size of the RNA genome segments of influenza virus have been unreliable because of a lack of suitable RNA species as size markers. We have attempted to overcome this problem by utilising the ability of AMV reverse transcriptase to synthesise full length DNA copies of RNA molecules in the presence of a suitable primer. By comparing such DNA copies of the RNA segments of the influenza virus genome with sequenced restriction fragments from the E. coli plasmid pBR322, we have made more reliable estimates of the sizes of the eight genome segments from influenza virus A/NT/60/68.


Pyrophosphate-condensing activity linked to nucleic acid synthesis. In some preparations of DNA dependent RNA polymerase a new enzymatic activity has been found which catalyzes the condensation of two pyrophosphate molecules, liberated in the process of RNA synthesis, to one molecule of orthophosphate and one molecule of Mg (or Mn) - chelate complex with trimetaphosphate. This activity can also cooperate with DNA-polymerase, on condition that both enzymes originate from the same cells. These results point to two general conclusions. First, energy is conserved in the overall process of nucleic acid synthesis and turnover, so that the process does not require an energy influx from the cell's general resources. Second, the synthesis of nucleic acids is catalyzed by a complex enzyme system which contains at least two separate enzymes, one responsible for nucleic acid polymerization and the other for energy conservation via pyrophosphate condensation.


Effect of toyocamycin on the synthesis of the 70S RNA of a murine retrovirus. The murine Eveline cell line chronically infected by Friend virus was treated with Toyocamycin (TMC), an adenosin analog and the virions released in the presence of the drug were examined for their RNA. It was found that 70S RNA which was synthesized incorporated Toyocamycin. However, its subunit structure and its poly (A) content were apparently preserved. This incorporation may explain loss of endogenous reverse transcriptase activity.


The response of ataxia telangiectasia cells to bleomycin. The autosomal recessive disorder, ataxia telangiectasia (AT) is characterised by cellular sensitivity to ionizing radiation. The molecular basis of this radiosensitivity is the subject of controversy. We report here that cultured fibroblasts from AT patients are also sensitive to the lethal effects of bleomycin. As with ionizing radiation, no defect has been observed in the overall rejoining of single or double-strand breaks produced by bleomycin. Since, however, only apyrimidinic (and to a lesser extent apurinic) sites and strand breaks are known to be produced by bleomycin, we tentatively suggest that AT cells are unable to rejoin a very small fraction of the total strand breaks. We attribute our inability to detect such unrejoined strand breaks to the relative insensitivity of the sucrose gradient procedures normally used to detect strand breaks.


Detection and partial sequence analysis of gastrin mRNA by using an oligodeoxynucleotide probe. We have used a specific deoxyoligonucleotide probe to detect gastrin mRNA in poly(A)-enriched RNA preparations from hog antrum. The nucleotide sequence of the oligonucleotide, d(C-T-C-C-T-C-C-A-T-C-C-A), was deduced from the unique amino acid sequence Trp-Met-Glu-Glu of gastrin. When used with hog antral RNA, the dodecanucleotide is an effective primer for the synthesis of gastrin-specific cDNA as judged by nucleotide sequence analysis of cDNA isolated by polyacrylamide gel electrophoresis. We have determined an 81-nucleotide sequence corresponding to the region of the gastrin mRNA that codes for the known amino acid sequence of the G34 progastrin intermediate species, and we have demonstrated the presence of two consecutive basic residues preceding the G34 sequence in the prohormone. Hybridization of gastrin cDNA or synthetic dodecanucleotide to hog antral RNA separated by gel electrophoresis on agarose gels in the presence of methylmercuric hydroxide indicates that the mRNA coding for gastrin is about 620 nucleotides long. These results suggest that the gastrin precursor peptide contains 110-140 amino acids. This method should be of general application for detection and characterization of mRNAs corresponding to proteins of known amino acid sequence.


Superinduction of alpha 2u globulin by actinomycin D: evidence for drug-mediated increase in alpha 2u mRNA. Actinomycin D, an inhibitor of DNA-dependent RNA synthesis, increased the hepatic concentration of alpha 2u globulin, an androgen-inducible protein in the rat. Spayed female rats with a marginally induced state of alpha 2u synthesis showed an approximately 5-fold increase in hepatic alpha 2u globulin within 3-6 hr after treatment with actinomycin D. Initial treatment of these animals with 5 alpha-dihydrotestosterone, followed by actinomycin D, resulted within 2-3 hr in a more than 2-fold increase in hepatic alpha 2u globulin compared to animals treated with the androgen alone. In spite of inhibition of hepatic synthesis of poly(A)-containing RNA to less than 25% of control, superinduction with actinomycin D resulted in a parallel increase in the translatable mRNA for alpha 2u globulin. These results showing increase in both alpha 2u globulin and its translatable mRNA after superinduction with actinomycin D support the concept of post-transcriptional repression of alpha2u synthesis.


Cytotoxic T cells: Lyt phenotype and blocking of killing activity by Lyt antisera. WE REEXAMINED TWO QUESTIONS CONCERNING LYT ANTIGENS OF CYTOTOXIC T CELLS OF THE MOUSE: is Lyt-1 antigen expressed on cytotoxic effector cells and can cytotoxicity be blocked by antibody to Lyt antigens in the absence of added complement? A 3-hr (51)Cr-release assay with splenic effector cells and leukemia or myeloma target cells was used to measure cell-mediated cytotoxicity. The cytotoxic activity of effector cells against allogeneic targets was abolished by exposure to Lyt-1, Lyt-2, or Lyt-3 antiserum and complement. Specificity was established by tests with C57BL/6 Lyt congenic mice and absorption studies with thymocytes. Similarly, the cytotoxicity of effector cells directed against semisyngeneic myeloma targets was reduced by Lyt-1, -2, or -3 antiserum and complement. Effector cell cytotoxicity against another semisyngeneic target was only marginally affected by Lyt-1 antiserum and complement, but was abolished by Lyt-2 or -3 antiserum and complement. It appears likely that cytotoxic T cells are a heterogeneous population with regard to Lyt-1 expression and that past studies indicating an apparent absence of Lyt-1 on cytotoxic T cells revealed a quantitative, not qualitative, feature of these cells. With regard to the activity of Lyt antisera in the absence of added complement, selective blocking of effector cell cytotoxicity for allogeneic and semisyngeneic targets was found with Lyt-2 and Lyt-3 antisera but not with Lyt-1 antiserum. The specificity of blocking was established by tests with Lyt congenic mice and absorption studies with thymocytes. With the exception of blocking by antisera to the H-2 haplotype expressed by the target cell, no effector cell blocking was observed with alloantisera or heteroantisera to a range of other cell surface molecules present on mouse lymphoid cells. One possibility to account for the selective blocking by Lyt-2 and Lyt-3 antisera is that Lyt-2,3 determinants on the surface of cytotoxic T cells have a close spatial relation to the T cell receptor.


Major histocompatibility complex products restrict the adherence of cytolytic T lymphocytes to minor histocompatibility antigens or to trinitrophenyl determinants on schistosomula of Schistosoma mansoni. We have previously shown that schistosomula passaged through mice acquire histocompatibility (H) antigens that can be recognized either by alloantibody or by alloreactive cytolytic T lymphocytes (CTL). The latter specifically adhere to but fail to damage the parasite. In this paper we describe the use of trinitrophenyl (TNP)-labeled schistosomula to show that the adherence of CTL with specificity for TNP-modified syngeneic cells is restricted by the major histocompatibility complex (MHC) in a fashion similar to that seen in the lysis of TNP-labeled tumor targets. Thus, these CTL adhere only to schistosomula that have both the appropriate H antigens and TNP determinants on their surface, and not to schistosomula bearing either of these antigens by themselves. We note a significant degree of adherence to schistosomula bearing TNP determinants and H antigens allogeneic to the CTL. Anti-minor H antigen CTL are also restricted by the MHC in their adherence; thus, they only adhere to schistosomula that carry both the major and minor H antigens of the stimulator cells. These antigens can be acquired either by a single passage in vivo of schistosomula through congenic strains that possess both the relevant antigens or by sequential passage through two different strains, each contributing one of the antigens in question.