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Elevated cerebrospinal fluid (CSF) levels of the glia-derived N-methyl-D-aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant—associated with reduced SNX7 expression—to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.

An ultra-low power wake-up radio receiver using no oscillators is described. The radio utilizes an envelope detector followed by a baseband amplifier and is fabricated in a 130-nm complementary metal-oxide-semiconductor process. The receiver is preceded by a passive radio-frequency voltage transformer, also providing 50 Ω antenna matching, fabricated as transmission lines on the FR4 chip carrier. A sensitivity of -47 dBm with 200 kb/s on-off keying modulation is measured at a current consumption of 2.3 μ A from a 1 V supply. No trimming is used. The receiver accepts a -13 dBm continuous wave blocking signal, or modulated blockers 6 dB below the sensitivity limit, with no loss of sensitivity.

BaF2 detectors for picosecond gamma-ray decay lifetime measurements have been installed into the 8π gamma-ray spectrometer as a proof-of-principle for a possible installation of a full array of ten detectors. Using four detectors a test measurement of the half-life of the 2+ state in 152Sm resulted in a value of 1.33(6) ns, compared with a published value of 1.396 ns. Measurements with a 26Na stopped beam were performed with various master-trigger conditions. Using a master trigger of germanium–SCEPTAR–BaF2 OR BaF2–BaF2, the FWHM of the BaF2–BaF2 triggered events was found to be ∼290 ps compared with ∼1.9 ns for the germanium–SCEPTAR–BaF2 triggered events. Simulations using GEANT4 of a suggested BaF2 lifetime measurement system have been carried out. These illustrate the considerable gain in spectrum quality which can be expected using simple add-back protocols.

The TRIUMF-ISAC gamma-ray escape-suppressed spectrometer (TIGRESS) is a new γ-ray detector array being developed for use at TRIUMF's Isotope Separator and Accelerator (ISAC) radioactive ion beam facility. TIGRESS will comprise 12 32-fold segmented clover-type HPGe detectors coupled with 20-fold segmented modular Compton suppression shields and custom digital signal processing electronics. This paper provides an overview of the TIGRESS project and progress in its development to date.

A measurement of the half-life of 62Ga was made as part of a programme of high-precision superallowed Fermi β decay studies at the ISAC radioactive beam facility. The experiment was conducted by counting β+ particles from the decay of 62Ga in a 4π gas proportional counter. The half-life was measured to be 116.01 ± 0.19 ms. Several parameters were varied during the experiment to test for systematic effects, but no significant effects were found.

High-resolution γ-ray spectroscopy is essential to fully exploit the unique, high-quality beams available at the next generation of radioactive ion beam facilities such as the TRIUMF isotope separator and accelerator (ISAC). The 8π spectrometer, which consists of 20 Compton-suppressed HPGe detectors, has recently been reconfigured for a vigorous research programme in weak interaction and nuclear structure physics. With the addition of a variety of ancillary detectors it has become the world's most powerful device dedicated to β-decay studies. This paper provides a brief overview of the apparatus and highlights from recent experiments.

The calcium channel alpha2delta-1 subunit is a structural subunit important for functional calcium channel assembly. In vitro studies have shown that this subunit is the binding site for gabapentin, an anticonvulsant that exerts antihyperalgesic effects by unknown mechanisms. Increased expression of this subunit in the spinal cord and dorsal root ganglia (DRG) has been suggested to play a role in enhanced nociceptive responses of spinal nerve-injured rats to innocuous mechanical stimulation (allodynia). To investigate whether a common mechanism underlies allodynic states derived from different etiologies, and if so, whether similar alpha2delta-1 subunit up-regulation correlates with these allodynic states, we compared DRG and spinal cord alpha2delta-1 subunit levels and gabapentin sensitivity in allodynic rats with mechanical nerve injuries (sciatic nerve chronic constriction injury, spinal nerve transection, or ligation), a metabolic disorder (diabetes), or chemical neuropathy (vincristine neurotoxicity). Our data indicated that even though allodynia occurred in all types of nerve injury investigated, DRG and/or spinal cord alpha2delta-1 subunit up-regulation and gabapentin sensitivity only coexisted in the mechanical and diabetic neuropathies. Thus, induction of the alpha2delta-1 subunit in the DRG and spinal cord is likely regulated by factors that are specific for individual neuropathies and may contribute to gabapentin-sensitive allodynia. However, the calcium channel alpha2delta-1 subunit is not the sole molecular change that uniformly characterizes the neuropathic pain states.

The synthesis and biological test results of a series of enkephalin analogues incorporating the lanthionine modification are presented. The syntheses of four monosulfide-bridged analogues of enkephalins, Tyr-c[d-AlaL-Gly-Phe-d-AlaL]-OH (1a), Tyr-c[d-ValL-Gly-Phe-d-AlaL]-OH (1b), Tyr-c[d-AlaL-Gly-Phe-AlaL]-OH (1c), and Tyr-c[d-ValL-Gly-Phe-AlaL]-OH (1d), where AlaL and ValL denote the lanthionine amino acid ends linked by a monosulfide bridge to form the lanthionine structure, were successfully carried out via preparation of the linear peptide on solid support and cyclization in solution. In vitro binding assays against μ-, δ-, and κ-opioid receptors and in vitro tests using GPI and MVD assays revealed that the dimethyl lanthionine analogues 1b and 1d, denoted as d-ValL in position 2, show substantial selectivity toward the δ-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as d-AlaL in position 2, bind to both μ- and δ-opioid receptors. The in vivo thermal escape assay by intrathecal administration showed that the analogues 1b and 1d are among the most potent ligands at producing antinociception through the δ-opioid receptor. The picomolar potencies of analogues 1a and 1c in the intrathecal (it.) assay strongly indicate that μ- and δ-opioid receptors interact synergistically to modulate the antinociceptive responses.

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Cutaneous drug reactions are the most frequently occurring adverse reactions to drugs. Among hospitalized patients, the incidence of these reactions ranges from 1 to 3%. The frequency of cutaneous reactions to specific drugs may exceed 10%. These reactions may range from mildly discomforting to those that are life-threatening. Anti-infective and anticonvulsant agents are among the drugs most commonly associated with adverse reactions in the skin. We describe and illustrate the clinical morphology of the most common cutaneous drug reactions, as well as drugs that most commonly precipitate specific reactions. The varied nature of the reactions that do occur, even with specific agents, indicates a multiplicity of mechanisms available whereby cutaneous drug reactions may be initiated. Although a variety of terms have been proposed for categorizing cutaneous drug reactions, we propose that reactions are best defined based upon mechanisms, where known. In this review, we assess the current knowledge of four categories of cutaneous drug reactions: immediate-type immune-mediated reactions, delayed-type immune-mediated reactions, photosensitivity reactions, and autoimmune syndromes. Moreover, we describe evidence that viral infection is an important predisposing factor for the development of cutaneous drug reactions upon drug administration. Finally, we review the current knowledge of the type and mechanisms of cutaneous drug reactions to several categories of drugs.

The cross-linked chain cobalt oxychloride Ba5Co5ClO13is reported. Single crystals were obtained by a flux method with BaCl2. A hexagonal unit cell (P63/mmc, a=5.6980(8) Å and c=24.469(5) Å) was found. The +3 and +4 valence cobalt ions were formally distributed into octahedral and tetrahedral sites coordinated by oxide ions. The compound was electrically insulating with a gap of 0.25 eV along the chain. Antiferromagnetism was found, with substantial ferromagnetic character, suggesting that the magnetic ground state is complex.

Hypersensitivity (HS) reactions to sulfonamides and sulfones continue to limit their use in human immunodeficiency virus (HIV)-infected individuals. In vitro cytotoxicity of hydroxylamine metabolites toward peripheral blood mononuclear cells (PBMCs) has been proposed as a marker for these HS reactions. To test the validity of this in vitro system, we determined the selective susceptibility of PBMCs from HIV-infected patients to the cytotoxic effects of hydroxylamine metabolites of sulfamethoxazole (SMX) and dapsone (DDS). Concentration-cytotoxic response data were collected using PBMCs from 12 sulfa-HS (10 SMX-HS and 2 SMX/DDS-HS) and 10 sulfa-tolerant HIV-infected individuals. Although sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) both caused concentration-dependent increases in cell death, DDS-NOH was significantly more potent in each subject (P <.0001). A comparison of a variety of mean data for sulfa-HS and -tolerant patient populations failed to demonstrate the increased susceptibility of PBMCs from HS patients, noted by others, to either SMX-NOH or DDS-NOH. Moreover, any trend toward an increased susceptibility of PBMCs from HS patients was eliminated when adjusted for control cell death. PBMCs from sulfa-HS patients showed significantly greater susceptibility to the stress of short term in vitro incubation (P <. 02). Mean (S.D.) vehicle control cell death values were 24.1% (7.6%) for HS patients and 17.1% (4.4%) for tolerant patients. No significant correlation was observed between hydroxylamine-induced or control cell death and any of the recorded clinical parameters. Although several potential reasons are proposed to explain the disparity with past investigations, the data suggest that in vitro cytotoxicity is not a valid marker for HS reactions in HIV-infected individuals using currently accepted experimental procedures.

Differences in the incidence of adverse drug reactions to trimethoprim-sulfamethoxazole and dapsone may result from differences in the formation, disposition, toxicity, and/or detoxification of their hydroxylamine metabolites. In this study, we examine whether differences in the biochemical processing of sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) by erythrocytes [red blood cells (RBCs)] contribute to this differential incidence. The methemoglobin (MetHgb)-forming capacity of both metabolites was compared after a 60-min incubation with washed RBCs from four healthy human volunteers. DDS-NOH was significantly more potent (P =.004) but equally efficacious with SMX-NOH in its ability to form MetHgb. The elimination of potential differences in disposition by lysing RBCs did not change the MetHgb-forming potency of either hydroxylamine. At pharmacologically relevant concentrations, greater reduction to the parent amine occurred with DDS-NOH. Maintenance of MetHgb-forming potency was dependent on recycling with glutathione, but no difference in cycling efficiency was observed between DDS-NOH and SMX-NOH. In contrast, the pharmacodynamics of hydroxylamine-induced MetHgb formation were not changed by pretreatment with the glucose 6-phosphate dehydrogenase inhibitor epiandrosterone or by compounds that alter normal antioxidant enzyme activity. Methylene blue, which stimulates NADPH-dependent MetHgb reductase activity, decreased MetHgb levels but did not alter the differential potency of these hydroxylamines. DDS-NOH was also significantly more potent when incubated with purified human hemoglobin A0. Collectively, these data suggest that the inherently greater reactivity of DDS-NOH with hemoglobin, the greater conversion of DDS-NOH to its parent amine, and potential differences in disposition of hydroxylamine metabolites may contribute to the preferential development of dapsone-induced hemotoxicity and sulfamethoxazole-induced hypersensitivity reactions.

High-Q active MMIC filters have very low tolerances for temperature drift and process parameter deviations. A theoretical analysis of how these problems limit the Q-value of recursive active MMIC filters is presented. Given that the highest tolerable deviation in filter gain is equal to 1 dB for a temperature drift of 5°C, the Q-value is shown to be limited to 30 if one assumes perfectly impedance matched circuit components. For a non-ideal matching of circuit components, the highest possible Q-value is shown to be also limited by the impedance matching of the filter. It is also found that the maximum allowed deviation in amplifier gain due to on-wafer process parameter deviations when high Q-values, and a stable filter gain are required is very small, even if an automatic Q-controlling system is included. In this analysis, a first-order recursive active filter with a loop electrical length equal to 2π is assumed. The analysis shows that by cascading two first-order filters or by choosing a filter with a loop electrical length equal to n times 2π, a decreased filter gain sensitivity can be achieved.

The peroxisome proliferator-activated receptors (PPAR) are members of the nuclear receptor supergene family and are considered as key sensors of both lipid and glucose homeostasis. The role of the PPARgamma isoform in glucose metabolism is illustrated by the fact that anti-diabetic thiazolidinediones have been shown to be bona fide PPARgamma ligands. Here we report the crystal structure of apo-PPARgamma ligand binding domain (LBD) determined to 2.9-A resolution. Although the structure of apo-PPARgamma-LBD retains the overall fold described previously for other nuclear receptor LBDs, three distinct structural differences are evident. 1) The core AF-2 activation domain of apo-PPARgamma LBD is folded back toward the predicted ligand binding pocket similar to that observed in the holo-forms of other nuclear receptors. 2) The proposed ligand binding pocket of apo-PPARgamma-LBD is larger and more accessible to the surface in contrast to other LBDs. 3) The region of the LBD called the omega-loop is extended in PPARgamma and contains additional structural elements. Taken together, the apo-PPARgamma-LBD structure is in several aspects different from previously described LBDs. Given the central role of PPARgamma as a mediator in glucose regulation, the structure should be an important tool in the development of improved anti-diabetic agents.

Investigations over two major tectonic zones in the Hallandsås Horst, Southern Sweden were carried out in connection with a railway tunnelling project. A combination of resistivity imaging, core drilling and geophysical logging was found to provide a good overview of the variation in rock quality and detailed information on the engineering geological characteristics and genesis of the strata. Resistivity data, acquired along parallel lines over the zones using multi-electrode equipment, were processed by means of automatic inversion software to generate sections showing the variation of resistivity with depth. Wireline core drilling at selected points gave an almost complete core recovery, which revealed major sedimentary sequences and heavily weathered crystalline rocks that were previously unknown or only partially known despite conventional core drilling and percussion drilling. Geophysical borehole logging confirms the resistivity imaging results, and would be a particularly valuable complement to core logging in cases where significant core loss occurs.

To investigate the safety and practicality of an acidic concentrate in milk fever prevention, the pH, carbon dioxide, standard bicarbonate, and base excess of whole blood and the pH in the urine were measured in three treatment groups of dry cows after 14 and 21 d of feeding an acidogenic diet (experiment 1). The dietary cation-anion differences (DCAD) of cows on treatments 1 (n = 11), 2 (n = 13), and 3 (n = 12) were +2275, –262, and –1185 meq/d, respectively. No changes in any parameters were found from the beginning to the end of the experiment in cows on treatment 1. In cows on treatment 2, a significant reduction in urine pH was observed, and in cows on treatment 3 significant decreases in all parameters except blood pH were observed. Mineral analyses of grass samples from fields fertilized with N from NH4NO3, Ca(NO3) 2, or (NH4) 2SO4, with S from (NH4) 2SO4, from KCl or K2SO4 and of Cl from KCl revealed DCAD ranging from –14 to +726 meq/kg of dry matter (experiment 2). Fertilization with Cl increased the chloride concentration in the crop and had the largest effect on DCAD. The results indicate that the use of acidic concentrates is not a health hazard for dry cows, at least not when the DCAD is greater than about –1200 meq/d or about –140 meq/kg of dry matter.

The underlying aim of this study was to obtain knowledge about the questions which could be of interest for a qualitative interview study, and for the planning and construction of a comparative study. The immediate aim was, however, to investigate whether the diary was of importance to patients after their discharge from the ICU or for relatives, following patients' deaths in the ICU. A diary was kept for nine months concerning ten patients together with eight patients who later died in the ICU. All of the ten patients, and four of the eight deceased patients' relatives, answered a questionnaire consisting of five close-ended and two open-ended questions. The participants were encouraged to comment upon all the questions. All participants read the diary. Seven patients stated that it helped them to remember their ICU stay and two that it did not. It helped them to re-live and come to terms with their serious illness/injury and recall what had happened. For those who could not recollect their ICU stay, the diary helped them to remember 'the lost time'. All the relatives except one stated that it helped them to return and adjust to everyday life; made it easier to accept what had happened; and to understand the seriousness of the patient's injury or disease.

Background Patients with seasonal allergic rhinitis may develop bronchial hyperresponsiveness during the active disease period. Eosinophil activation may occur in the bronchial mucosa and may be reflected by increased sputum levels of eosinophil cationic protein (ECP), especially when ECP binding proteins such as α₂-macroglobulin pass through the lamina propria and across the epithelium into the airway lumen. A study was therefore undertaken to determine histamine airway responsiveness (FEV ₁) and bronchovascular responsiveness (exudation of α₂-macroglobulin) to histamine in subjects with seasonal allergic rhinitis, and to explore whether sputum ECP levels are increased by the use of induced exudation followed by induced sputum. Method Eleven patients with seasonal allergic rhinitis were examined before and during a birch pollen season. Sputum was induced by inhalation of 4.5% saline twice before and twice during the pollen season. Histamine inhalations were given before the second of each pair of sputum inductions at increasing concentrations until FEV ₁ was reduced by 20%. Sputum levels of α₂-macroglobulin and ECP were determined as indices of bronchial exudation of plasma and activation of bronchial eosinophils, respectively. ResultsBronchomotor responsiveness increased during the pollen season (median difference in the reduction of FEV ₁ 9% (95% confidence interval (CI) -3 to 26)) but histamine induced exudation of plasma was not increased. Baseline sputum levels of α₂-macroglobulin and ECP did not increase. Histamine induced exudation of α₂-macroglobulin was associated with increased sputum levels of ECP exclusively during the pollen season (median difference 8.2 ng/ml (95% CI 0.4 to 562.0)). Conclusion Bronchial hyperresponsiveness in seasonal allergic rhinitis may not be associated with bronchovascular exudative hyperresponsiveness. Sputum levels of ECP were increased only during the season, and only after induced exudation (potentially moving ECP to the mucosal surface). It is suggested that the combined method of induced exudation and induced sputum may significantly improve the yield of some markers of inflammation in sputum samples.

Abstract Background A number of studies have shown that β ₂ agonists, including formoterol, inhibit plasma exudation induced by the inflammatory stimulus in animal airways. Whether clinical doses of β ₂ agonists inhibit plasma exudation in human bronchial airways is unknown. Methods In order to explore the microvascular permeability and its potential inhibition by β ₂ agonists in human bronchial airways a dual induction method was developed: plasma exudation induced by histamine inhalation followed by sputum induction by hypertonic saline (4.5%) inhalation. Sixteen healthy subjects received formoterol (18 μg) in a placebo controlled, double blind, crossover study. Sputum was induced on five occasions: once at baseline and four times after histamine challenge (30 minutes and eight hours after both formoterol and placebo treatments). Sputum levels of α ₂-macroglobulin were determined to indicate microvascular-epithelial exudation of bulk plasma. ResultsHistamine induced plasma exudation 30 minutes after placebo was considerably greater than at baseline (median difference 11.3 μg/ml (95% confidence interval 0.9 to 90.0)). At 30 minutes after formoterol the effect of histamine was reduced by 5.1 (0.9 to 61.9) μg/ml compared with placebo. At eight hours histamine produced less exudation and inhibition by formoterol was not demonstrated. Conclusion This study shows for the first time an anti-exudative effect of a β ₂ agonist in healthy human bronchial airways. Through its physical and biological effects, plasma exudation is of multipotential pathogenic importance in asthma. If the present findings translate to disease conditions, it suggests that an anti-exudative effect may contribute to the anti-asthmatic activity of formoterol.

Abstract: Formation of new beta cells can take place by two pathways: replication of already differentiated beta cells or neogenesis from putative islet stem cells. Under physiological conditions both processes are most pronounced during the fetal and neonatal development of the pancreas. In adulthood little increase in the beta cell number seems to occur. In pregnancy, however, a marked hyperplasia of the beta cells is observed both in rodents and man. Increased mitotic activity has been seen both in vivo and in vitro in islets exposed to placental lactogen (PL), prolactin (PRL) and growth hormone (GH). Receptors for both GH and PRL are expressed in islet cells and are upregulated during pregnancy. By mutational analysis we have identified different functional domains of the cytoplasmic part of the GH receptor. Thus the mitotic signaling only requires the membrane proximal part of the receptor and activation of the tyrosine kinase JAK2 and the transcription factors STAT1 and 3. The activation of the insulin gene however also requires the distal part of the receptor and activation of calcium uptake and STAT5. In order to identify putative autocrine growth factors or targets for growth factors we have cloned a novel GH/PRL stimulated rat islet gene product, Pref-1 (preadipocyte factor-1). This protein contains six EGF-like motifs and may play a role both in embryonic pancreas differentiation and in beta cell growth and function. In summary, the increasing knowledge about the mechanisms involved in beta cell differentiation and proliferation may lead to new ways of forming beta cells for treatment of diabetes in man.

‘Tomudex’ (ZD 1694), a direct and specific thymidylate synthase (TS) inhibitor entered phase III studies in November 1993. We present here the first analysis of a randomised multicentre, international phase III study. 439 patients with previously untreated advanced colorectal cancer were randomised to Tomudex 3.0 mg/m2given once every 3 weeks or 5-fluorouracil (5-FXJ) 425 mg/m2and leucovorin (LV) 20 mg/m2for 5 days (the Mayo regimen), given every 4–5 weeks. Patients were evaluated weekly for toxicity and every 12 weeks for objective response. The two groups were well matched in terms of demographic characteristics. The mean age of the patients was 61 years and most had either liver (78%) or lung (25–29%) metastases. Ninety seven per cent of patients allocated to Tomudex and 94% of those allocated to 5-FU plus LV had measurable disease. Response was assessed using WHO/UICC criteria; all response data were source validated; 19.8% of patients who received Tomudex and 12.7% of patients who received 5-FU plus LV had complete or partial responses (P= 0.059, odds ratio 1.7, 95% confidence limits 0.98–2.81). There were no statistically significant differences in time to progression or survival between the two groups. Patients who received Tomudex spent a substantially shorter time in hospital for dosing and had significantly lower rates of grade 3 and 4 toxicities such as leucopenia and mucositis. Patients who received Tomudex had a significantly higher incidence of reversible grade 3 or 4 increase in transaminases, which appear to be of limited clinical significance. Improvement in quality of life, weight gain and performance status was seen in both groups. Tomudex has benefits in terms of higher response rates, reduced toxicity and more frequent palliative benefits when compared with 5-FU plus LV in the management of advanced colorectal cancer, and has a more convenient administration schedule.

Hyper-reactivity to non-specific challenges has been considered a hallmark of asthma and is defined as an abnormal responsiveness of the bronchial airways to a variety of provocative agents. The mechanisms underlying hyper-reactivity in the upper and lower airways are not known. By using the nose to study the inflammatory response possible abnormalities can be investigated carefully and pathophysiology of specific airway hyper-reactivities can be better understood. Other factors than merely constriction of the bronchial smooth muscles can cause narrowing of the free lumen to airflow. Functionally different and very distinct mucosal end-organ reactivities may also be increased. If these reactivities can be well assessed, specific airway hyper-reactivity can be defined. In the present report, specific mucosal end-organ hyper-reactivites in the allergic nasal mucosa are presented. Certain widespread hypotheses, such as the role of the eosinophil and the “increased absorption permeability theory”, are disputed.

Experimental data suggest the possibility that common bronchodilators, such as the xanthines and ß2-adrenoceptor agonists, may produce microvascular anti-permeability effects in the subepithelial microcirculation of the airways.

The prognostic significance of pre-treatment serum concentration of squamous cell carcinoma antigen (SCCAg) was investigated in a population of 60 patients with anal epidermoid cancer. Serum concentration was determined during the period 1985–90. The patients were followed until December 1991. An antigen level above 2.0 ng/ml was classified as elevated. Thirty-eight patients had T1–2 tumours, while 22 had T3–4 tumours. Sixteen of the 20 patients (80%) with an elevated SCCAg concentration relapsed or had residual tumour after conclusion of primary therapy, compared to 8 of 40 (20%) with a normal concentration (P=0.00001). Six patients of 40 (15%) with a normal SCCAg had died at the end of follow-up compared to 10 of 20 (50%) with an elevated value (P=0.006). For patients with T1–2 tumours 2 of 29 (7%) with a normal SCCAg had died with or from their cancer compared to 3 of 9 (33%) with an elevated value (P=0.14); for T3–4 tumours these figures were 3 of 11 (27%) and 7 of 11 (64%) respectively (P=0.009). Actuarial survival analyses for patients with normal vs elevated SCCAg concentration showed that the projected five year overal survival was 81% for those with a normal level and 43% for those with an elevated level (P=0.004). For tumour specific survival the figures were 83% vs 45% (P=0.004). In multivariate Cox regression analyses SCCAg concentration was found to be the most significant determinant of risk for overall and tumour specific death as well as for residual or recurrent tumour. SCCAg serum concentration may be a useful prognostic indicator which could be used in selecting high risk patients for a more aggressive primary treatment.

Previous studies have shown that 4 weeks after syngeneic transplantation of a suboptimal number of islets into either C57BL/6J (BL/6J) or C57BL/KsJ (BL/KsJ) diabetic mice there is an impaired insulin secretion by the perfused grafts. After normalization of the blood glucose level with a second islet graft, the BL/6J strain showed restored insulin secretion whilst that of the BL/KsJ strain remained impaired. The aim of the present work was to study the effects of glucose on the in-vitro function of islet β-cells from these two mouse strains, with different sensitivities of their β-cells to glucose in vivo. Isolated pancreatic islets from each strain were kept for 1 week in tissue culture at 5·6, 11, 28 or 56 mmol glucose/l and were subsequently analysed with regard to insulin release, (pro)-insulin and total protein biosynthesis, insulin, DNA and insulin mRNA contents and glucose metabolism. Islets from both strains cultured at 28 or 56 mmol glucose/l showed an increased accumulation of insulin in the culture medium and an enhanced glucose-stimulated insulin release compared with corresponding control islets cultured at 11 mmol glucose/l. After culture at either 5·6 or 56 mmol/l, rates of (pro)insulin biosynthesis were decreased in BL/KsJ islets in short-term incubations at 17 mmol glucose/l, whereas islets cultured at 56 mmol glucose/l showed a marked increase at 1·7 mmol glucose/l. In BL/6J islets, the (pro)insulin biosynthesis rates were similar to those of the BL/KsJ islets with one exception, namely that no decrease was observed at 56 mmol glucose/l. Islets of both strains showed a decreased insulin content after culture with 56 mmol glucose/l. Insulin mRNA content was increased in islets cultured in 28 or 56 mmol glucose/l from both mouse strains. Glucose metabolism showed no differences in the rates of glucose oxidation, however, in islets cultured in 56 mmol glucose/l the utilization of glucose was increased in both BL/6J and BL/KsJ animals. There were no differences in DNA content in islets cultured at different glucose concentrations, suggesting no enhancement of cell death.The present study indicates that, irrespective of genetic background, murine β-cells can adapt to very high glucose concentrations in vitrowithout any obvious signs of so-called glucotoxicity. Previously observed signs of glucotoxicity in vivoin BL/KsJ islets appear not to be related only to glucose but rather to an additional factor in the diabetic environment.Journal of Endocrinology(1993) 136,289–296

The adenovirus‐2 E1A 289R transcription activator protein contains a 49 amino acid sequence (designated CR3) that has been suggested to represent the minimal domain required for E1A‐induced activation of viral early transcription. We show here that the non‐conserved carboxy‐terminal E1A exon contains two interchangeable elements that are required for efficient CR3‐dependent transactivation of the adenovirus E4 promoter in HeLa cells. These two elements do not encode independent transactivation functions and have been designated auxiliary regions (ARs) 1 and 2. The effects of AR1 and AR2 are not additive, suggesting that they contribute a mechanistically analogous function in transcription. Previous studies have suggested that two cellular transcription factors, ATF‐2 and E4F, can function together with E1A to induce transcription of the E4 promoter. The importance of respective factors for E4 transcription has not been resolved. We find that E1A activation of E4F, but not ATF‐2 (or other ATF factors), is AR1‐ and AR2‐dependent. This result suggests that E1A induction of the E4 promoter in HeLa cells is primarily mediated by E4F.

The ability of products from the adenovirus early region 1A to stimulate viral and cellular gene expression has been studied, using a transient expression assay in HeLa cells. We show that the E1A 13S mRNA encodes a diffusible product which is capable of stimulating transcription of adenovirus genes as well as the rabbit beta‐globin gene. The E1A 12S mRNA has no detectable stimulatory effect on either cellular or viral genes. Although being able to stimulate both types of genes, we find that the E1A regulatory protein enhances viral gene expression approximately 10 times more than beta‐globin gene expression. We also find that when connected to the cis‐acting SV40 enhancer element, the beta‐globin gene cannot be further stimulated by the trans‐acting E1A product. Finally, we find that transfection of either adenovirus or the beta‐globin gene into 293 cells, which constitutively expresses the E1A gene products, leads to an enhanced expression which is 10‐ to 20‐fold higher than obtained by co‐transfection of HeLa cells. The 293 cells thus provide a simple assay to demonstrate E1A‐mediated transcriptional regulation.

The effect of adenovirus VA RNAI on the translation of mRNAs expressing the bacterial chloramphenicol acetyltransferase (CAT) enzyme was studied by a transient expression assay in 293 cells. The CAT activity was determined in extracts prepared from cells transfected with mixtures of plasmids encoding CAT and VA RNA. The results showed that VA RNAI co‐transfection resulted in a significant increase in CAT expression from a variety of constructs. Thus, expression of CAT from a SV40 mRNA, a beta‐globin mRNA and a chimeric mRNA containing the adenovirus‐2 tripartite leader were all stimulated approximately 6‐fold by VA RNAI. Based on these results we conclude that the tripartite leader sequence is not required for the VA RNA‐mediated stimulation of translation. Our results indicate instead that VA RNAI probably functions as a general enhancer of mRNA translation. A2‐ to 3‐fold stimulation of CAT expression was also obtained following transient expression of HeLa and CV‐1 cells. The reduced efficiency was correlated with a 10‐ to 20‐fold lower level of VA RNA expression in HeLa compared with 293 cells. Thus, it is likely that a product from region E1 indirectly enhances the translational efficiency by stimulating VA RNA transcription.

Beta‐terbium molydbate, Tb2(MoO4)3, is a coupled ferroelectric–ferroelastic crystal with Curie temperature of 436 K. Crystallizing in the orthorhombic system with space group Pba2 and four formulas per unit cell, Tb2(MoO4)3 has lattice constants at 298 K of a=10.344 43±0.00005,b=10.386 23±0.00005, and c= 10.654 85±0.00004 A˚.The integrated intensities 19 406 reflections were measured with an Enraf–Nonius CAD‐4 diffractometer, using monochromatic MoKα radiation, from a small single‐domain crystal. The crystal structure was refined by the method of least squares, using the coordinates of isomorphous β‐Gd2(MoO4)3 as the initial model, with 7505 symmetry independent Fmeas. The final agreement factor R is 0.0485, based on anisotropic thermal vibrations for all atoms. The average value of the Mo–O distance in the three independent (MoO4)2− tetrahedra is 1.759±0.005 A˚. The Tb3+ ion is seven‐coordinated with Tb‐O distances ranging from 2.256±0.006 to 2.429±0.004 A˚: The average distance is 2.336±0.016 A˚. The measured spontaneous polarization in this three‐dimensional ferroelectric crystal is 0.19×10−2 C m−2: a point‐charge model gives 0.09×10−2 C m−2. A negative charge is generated on (001) with increasing temperature. The largest atomic displacement involved in ferroelastic transformation at room temperature is 0.67 A˚ for two oxygen atoms: all other displacements are less than 0.35 A˚.

Synthesis of 2',3'-Dideoxy-3'-C-(hydroxymethyl)-α- and β-L-erythro-pentofuranosyl nucleosides of thymine, cytosine and adenine is reported.