Synthesis of a boronated naphthalimide for potential use in boron neutron capture therapy (BNCT).
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1-Naphthylamine↗
Biomedical subjects
S Sjöberg
Publications and source records attributed to S Sjöberg.
[A survey of "heavy consumers" of emergency care services in Stockholm. Six per cent of the patients accounted for a quarter of emergency consultations].
A small subgroup of patients accounts for a substantial proportion of emergency room (ER) consultations. Of the 479,956 consultations at ER facilities at Stockholm hospitals in 1996, a quarter were accounted for by six per cent of the patients, a subgroup characterised by at least four ER consultations during the year. Some 1,500 patients consulted 12-233 times. Analysis of the care-seeking habits of five extremely heavy ER-facility consumers showed them also to be heavy consumers of other health care services such as primary and tertiary facilities. Since previous studies have shown heavy ER-facility consumers to be a vulnerable subgroup both medically and socially, co-ordination and planning of their care might well be beneficial.
Adolescent↗
Comparison of the Adsorption of o-Phthalate on Boehmite (gamma-AlOOH), Aged gamma-Al2O3, and Goethite (alpha-FeOOH).
This work is concerned with the adsorption of o-phthalate (1,2-benzenedicarboxylate) at the water-metal (hydr)oxide interface. Previously published infrared spectroscopic, potentiometric, and adsorption data characterizing the boehmite (gamma-AlOOH) system are compared with new data collected for o-phthalate adsorption on aged gamma-Al2O3 and goethite (alpha-FeOOH). The study focuses on identifying bonding mechanisms, stoichiometries, and stabilities of the formed complexes, and comparing these among the three systems. Furthermore, the effects of ionic strength and composition of the ionic medium are investigated. The infrared spectroscopic data provided direct, molecular-level evidence for the existence of two dominating surface complexes on all three solids. One was shown to be a deprotonated outer-sphere species and the other was an inner-sphere surface complex. The inner-sphere complexes on the three solids were structurally related, and they were tentatively assigned to a mononuclear, chelating structure involving both carboxylate groups. The outer-sphere complexes were shown to increase in relative importance at high pH and low ionic strengths, while low pH and high ionic strengths favored the inner-sphere complexes. The information gained from the infrared spectroscopic investigations was used as qualitative input in the formulation of the surface complexation models. New models, based on the extended constant capacitance approach, were presented for the o-phthalate/aged gamma-Al2O3 and o-phthalate/goethite systems. Copyright 1998 Academic Press.
Journal Article↗
Uptake, toxicity and radiation effects of the boron compounds DAAC-1 and DAC-1 in cultured human glioma cells.
PURPOSE: To study the uptake, toxicity and radiation effects in vitro of a diol-amino acid-carborane (DAAC-1) and make comparisons with the previously studied diol-amine-carborane (DAC-1). MATERIALS AND METHODS: Toxicity and radiation effects were studied with clonogenic survival, uptake by measuring the cellular boron content and the subcellular distribution was investigated after organelle separation with centrifugation. The studied cell line was human glioma U343. RESULTS: DAAC-1 showed an accumulation of 1-1.5 times, compared with the culture medium, and was non-toxic up to 47 microg boron/ml. The accumulation of DAC-1 was about 90 times, but toxic effects were detectable already at the concentration 5 microg boron/ml. None of the compounds was localized in the cell nucleus. Following irradiation with thermal neutrons, DAC-1 was about 2.5 times more effective than DAAC-1 and about 4.9 times more effective than neutrons alone, at the survival level 0.2. The dose modifying factors, when compared with the neutron beam alone, were for both DAAC-1 and DAC-1 about 1.5 and about 5 when compared with 60Co-gamma-radiation. CONCLUSIONS: DAAC-1 was less toxic than DAC-1 but gave less accumulation of boron. Both substances gave significant boron-dependent cell inactivation when the test cells were exposed to thermal neutrons.
Boranes↗
L-thyroxine treatment and neurotransmitter levels in the cerebrospinal fluid of hypothyroid patients: a pilot study.
Monoamine precursors, neurotransmitters and their metabolites were studied in cerebrospinal fluid (CSF) obtained from nine newly diagnosed hypothyroid patients. Before treatment, the serum TSH correlated positively with the CSF concentrations of tyrosine and phenylalanine. During treatment, the levels of the precursors tryptophan, phenylalanine and tyrosine decreased significantly, as was also the case with dopamine and the noradrenaline metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG), but not with serotonin, noradrenaline and the serotonin metabolite 5-hydroxyindoleacetic acid, nor the dopamine metabolites homovanilic acid and dihydroxyphenylacetic acid. The study provided some indication that the CSF levels of phenylalanine and tyrosine are related to thyroid function. Furthermore, we have found an indication that L-thyroxine treatment affects the CSF levels of the precursors as well as dopamine and HMPG. Our results support the notion that there is an interaction between thyroid function and CSF disposition of monoamine compounds.
Adult↗
In Situ Voltammetric Determinations of Metal Ions in Goethite Suspensions: Single Metal Ion Systems.
In the present paper voltammetric techniques have been used to study the sorption of Pb(II), Cd(II), Zn(II), and Cu(II) at low concentrations ( approximately 10(-6) M) in goethite (alpha-FeOOH) suspensions with varying solid concentrations as a function of pH. Metal ion adsorption on the cell walls was minimized by using a Teflon cell. Measurements in the absence of goethite showed the applicability of the voltammetric techniques for trace analysis in a wide pH range. The analysis seems to be limited mainly by the onset of metal ion hydrolysis at high pH values, where neutral and negatively charged species are formed. The results obtained in the presence of goethite were compared with previously determined surface complexation models, evaluated from relatively high metal ion ( approximately 10(-3) M) and solid concentrations ( approximately 10 g/L). Application of these models to more dilute conditions could thus be questioned. The results obtained indicated that no "high-affinity" sites are present on the surface of alpha-FeOOH. The voltammetric measurements showed good agreement for the Zn(II) and Cu(II) goethite systems. In the case of Pb(II), deviations between calculated and experimentally determined metal ion concentrations were detected at pH >7 and a molar ratio of Pb(II) to the surface concentration of goethite of 0.17. These deviations may be explained by assuming either formation of polymeric species or surface precipitates at high total concentrations (instead of the previously suggested surface complex identical withFeOPbOH) or slow adsorption kinetics at low concentrations. Also in the Cd(II) goethite system, a corresponding weaker adsorption than predicted was found. These observations strongly emphasize the importance of evaluating surface complexation models from data within concentration ranges as wide as possible. This holds for all components including the solid concentration. Copyright 1997 Academic Press.
Journal Article↗
Is the cholesterol-lowering effect of simvastatin influenced by CYP2D6 polymorphism?
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Anticholesteremic Agents↗
Cholecystokinin peptides in cerebrospinal fluid: a study in healthy male subjects.
The clinical reliability of measuring cholecystokinin (CCK) peptides in the cerebrospinal fluid (CSF) has not been fully elucidated. Therefore, we have assayed CCK-8S and CCK-4 in CSF obtained from 14 healthy male subjects, lumbar-punctured at the L4-5 level following a strictly standardised procedure. CSF concentrations of free CCK-8S and free CCK-4 were used as dependent variables while age, height, body weight, atmospheric pressure and some other factors served as independent variables. It was shown that the CCK-8S ratio between the second (7-12 ml) and first (0-6 ml) CSF fractions, correlated significantly with the atmosphere pressure at the time of puncture. Neither CCK-8S nor CCK-4 displayed concentration gradients in CSF. The CCK-4 levels, expressed as pmol l-1 in the total amount of CSF were found to be positively correlated with the neuraxis distance in the lying position and negatively with the neuraxis distance in the sitting position. Furthermore, CCK-4, expressed as pmol l-1 per min of tapping-time (pmol l-1 min-1), showed a negative correlation with storage time, presumably mirroring a proteolytic process. CCK-8S and CCK-4 intercorrelated positively independently of whether expressed as pmol l-1 or pmol l-1 min-1. In conclusion, the results of this exploratory study indicate that the neuraxis distance (in the sitting and lying positions) and storage-time have to be accounted for when interpreting data on CSF levels of CCK-4. Attention has to be paid to the potential influence of atmospheric pressure on the concentration ratio of CCK-8S.
Adult↗
Chemistry and biology of some low molecular weight boron compounds for boron neutron capture therapy.
Boronated DNA targeting agents are especially attractive candidates for BNCT because they may deliver boron-10 to the nuclei of tumor cells. Numerous boron-containing analogs have been synthesized and some have shown promising results in initial biological tests. One of the most challenging tasks in this special field of research remains the finding of suitable targeting strategies for the selective delivery of boron rich DNA-intercalator/alkylator to tumor cells. Synthetic and biological studies of boron compounds suitable for DNA-binding are reviewed. The amino acid p-boronophenylalanine (BPA) is presently of considerable clinical interest. Other boronated amino acids might also be candidates for BNCT either per se, as part of part of tumor-seeking peptides or conjugated to targeting macromolecules. A large number of boronated L- and D-amino acids with varying liphophicility and sterical requirements are now available for evaluation. Recent synthetic and biological studies of aromatic boronoamino acids, carboranylamino acids and carboranyl amines are also reviewed.
Amino Acids↗
Cytotoxicity and subcellular localization of boronated phenanthridinium analogues.
Binding and toxicity of boronated phenanthridinium analogues were studied in vitro using cultured human malignant glioma cells. The compounds, 5-ortho- (5-o-CP), 5-para- (5-p-CP), 5-nido- (5-n-CP) and 6-nido-carboranyl phenanthridinium (6-n-CP) showed varying toxic effects. The cells were exposed to the compounds for 2 or 24 h. The span between non-toxic and toxic concentrations seemed to be very narrow. 5-p-CP was the most toxic compound, causing total cell death at a concentration of 5 micrograms/ml cell culture medium. None of the compounds showed toxic effects at a concentration of 1 microgram/ml. Viable cells incubated with the compounds at this concentration showed a > 100-fold accumulation of boron. Only approximately 1/4 of this accumulation was found in cells permeabilized and inactivated with acetone. Fluorescent images of acetone-treated cells showed clear uptake of the compounds in the cell nucleus, as for ethidium bromide, while for viable cells binding to structures other than DNA was also observed. These results were confirmed by subcellular boron determination. All tested compounds intercalate into DNA, as was demonstrated in cell-free systems with calf thymus DNA. The hypothesis is that the compounds are trapped in the cellular membranes of viable cells because of their lipophilicity, before reaching nuclear DNA.
Boron↗
Cholesterol lowering and cerebrospinal fluid neurotransmitters: increased levels of the anxiogenic cholecystokinin-tetrapeptide during simvastatin administration to healthy male volunteers.
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Adult↗
Structure and Bonding of Orthophosphate Ions at the Iron Oxide-Aqueous Interface.
The surface speciation of orthophosphate ions on goethite has been studied as a function of pH, time, total phosphate concentration, and ionic medium by means of diffuse reflectance FTIR spectroscopy. The samples were prepared in accordance with a distribution diagram of surface species as calculated from thermodynamic data. In agreement with the thermodynamic model three dominating surface complexes could be distinguished with IR spectroscopy, and the relative distribution of the species was shown to be primarily a function of pH. The IR characteristics of the individual surface complexes were indicative of molecular symmetries of the PO(4) unit of C(3v), C(2v), and C(3v), respectively. This was concluded to be incompatible with the bidentate, bridging structural model previously suggested. Instead, the IR data are in good agreement with a monodentate coordination of phosphate to the surfaces, where the three surface complexes only differ in the degree of protonation. A comparison between the adsorption behavior of phosphate on goethite and hematite was also made. Here the importance of the aqueous stability of the adsorbent on the adsorption mechanism was shown.
Journal Article↗
Sports-related groin pain: evaluation with MR imaging.
Our purpose was to assess the role of MRI in evaluating the musculoskeletal system in athletes with chronic pain laterally in the groin of unknown etiology. Magnetic resonance imaging (MRI) of the pubic ring was performed in 11 young athletes (soccer players) with long-standing groin pain. MR findings were compared with plain films and isotope examination (bone scan Tc 99M). Abnormal MRI findings included a broadened and irregular symphysis with a characteristic pattern of low signal intensity on T1W and high signal intensity on T2W images localized in the superior pubic ramus at a distance from the symphysis. Positive findings were also observed on plain films and on nuclear medicine studies. However, the imaging findings in the superior public ramus of the symphysis was located considerably more laterally on MRI. MRI is a valuable method for evaluating discrete and ambiguous pelvic pain in athletes, particularly for identifying concomitant changes in the superior ramus, which may give rise to long-standing pain localized laterally in the groin.
Adolescent↗
Stimulation of adipose tissue lipolysis following insulin-induced hypoglycaemia: evidence of increased beta-adrenoceptor-mediated lipolytic response in IDDM.
The adrenergic regulation of adipose tissue lipolysis in response to insulin-induced hypoglycaemia (intravenous infusion of soluble insulin 0.10 IU.kg body weight-1.h-1 until the arterial plasma glucose fell below 2.8 mmol/l) was investigated directly in vivo in 11 insulin-dependent diabetic (IDDM) patients and 12 control subjects, using microdialysis of the extracellular space of abdominal subcutaneous adipose tissue. The tissue glycerol level (lipolysis index) and the escape of ethanol from the perfusion medium (blood flow index) were continuously monitored. During insulin infusion the arterial glucose level was reduced in parallel and the hypoglycaemic nadir was almost identical in the two groups (diabetic patients 2.2 +/- 0.1 and control subjects 2.3 +/- 0.1 mmol/l). While the maximum response of plasma epinephrine to hypoglycaemia was 30% lower in diabetic patients than in the control subjects (p < 0.05), the glycerol levels in adipose tissue and in plasma, as well as in serum non-esterified fatty acids, increased twice as much in the former as in the latter group following hypoglycaemia (p < 0.01). Addition of the beta-adrenoceptor blocker propranolol (10(4) mol/l) to the tissue perfusate almost completely prevented the hypoglycaemia-induced increase in the adipose tissue glycerol level in both groups, whereas in situ perfusion with 10(-4) mol/l of the alpha-adrenoceptor blocker phentolamine resulted in an additional increase in the tissue glycerol levels; during alpha-blockade, the glycerol response to hypoglycaemia remained enhanced by threefold in the diabetic patients (p < 0.01). In both groups local adipose tissue blood flow increased transiently in a similar way after hypoglycaemia; the increase being inhibited by in situ beta-adrenoceptor blockade. We conclude that both alpha- and beta-adrenergic mechanisms regulate adipose tissue lipolysis in response to hypoglycaemia. In IDDM, lipolysis is markedly enhanced following hypoglycaemia, despite a reduced catecholamine secretory response, because of increased beta-adrenoceptor action in adipose tissue.
Adipose Tissue↗
Imaging in chronic achilles tendinopathy: a comparison of ultrasonography, magnetic resonance imaging and surgical findings in 27 histologically verified cases.
OBJECTIVE: To compare information gained by ultrasonography and magnetic resonance imaging (MRI) in chronic achilles tendinopathy with regard to the nature and severity of the lesion. DESIGN: Imaging of both achilles tendons with ultrasonography and MRI was performed prior to unilateral surgery. Operative findings and histological biopsies together served as a reference. PATIENTS: Twenty-seven patients (22 men, 5 women; mean age 44 years; 21 athletes) suffering from chronic achilles tendinopathy participated in the study. Eighteen patients had unilateral and 9 had bilateral symptoms. RESULTS AND CONCLUSIONS: Surgical findings included 4 partial ruptures, 21 degenerative lesions and 2 macroscopically normal cases. Microscopy revealed tendinosis (degeneration) in all tendon biopsies, including cases with a partial rupture, but only slight changes in the paratendinous tissues (paratenon). Ultrasonography was positive in 21 of 26 and MRI in 26 of 27 cases. Severe intratendinous abnormalities and a sagittal tendon diameter > 10 mm suggested a partial rupture. In tendons with a false negative result histopathological changes were mild and a tendency towards a better clinical outcome was noted in the sonographic cases. Assessment of the paratenon was unreliable with both methods. Ultrasonography and MRI give similar information and may have their greatest potential as prognostic instruments.
Achilles Tendon↗
In vitro determination of toxicity, binding, retention, subcellular distribution and biological efficacy of the boron neutron capture agent DAC-1.
In boron neutron capture therapy (BNCT), 10B is delivered selectively to the tumour cells and the nuclide then forms high-LET radiation (4He2+ and 7Li3+) upon neutron capture. Today much research is focused on development of a variety of boron compounds aimed for BNCT. The compounds must be thoroughly analysed in preclinical tests regarding basic characteristics such as binding and subcellular distribution to enable accurate estimations of dose-modifying factors. DAC-1,2-[2-(3-amino-propyl)-1,2-dicarba-closo-dodecaboran (12)-1-yl-methoxy]- 1,3-propanediol was synthesized at our laboratories and the human colon carcinoma cells LS-174T were used as an in vitro model. The boron compound showed a remarkable intracellular accumulation, 20-100 times higher than the boron content in the culture medium, in cultured cells and was not removed by extensive washes. Approximately half of the boron taken up also remained within the cells for at least 4 days. The DAC-1 compound alone was not toxic at boron concentrations below 2.5 micrograms B/g. The intracellular distribution of the boron compound was investigated by subcellular fractionation experiments and low pH treatments. It is possible that DAC-1 binds to some intracellular molecules or to membranes connected with organelles in the cytoplasm or even to the inside of the outer cell membrane. Another possibility is that the compound, due to the somewhat lipophilic properties, is embedded in the membranes. Thermal neutron irradiations were carried out at the Brookhaven Medical Research Reactor (BMRR). At a survival level of 0.1, DAC-1 + thermal neutrons were about 10.5 times more effective in cell inactivation than the thermal neutrons alone. Monte Carlo calculations gave a mean value of the 10B-dependent specific energy, the dose, of 0.22 Gy. The total physical dose during irradiation of DAC-1-containing cells with a neutron fluence of 0.18 x 10(12) n/cm2 was 0.39 Gy. The dose-modifying factor, at survival level 0.1, when comparing irradiation with thermal neutrons with and without DAC-1 was 3.4, while the dose-modifying factor when comparing neutron irradiations of cells with DAC-1 and irradiation of the cells with 60Co-gamma was 7.3. The results are encouraging and in vivo tests of tissue distributions and tumour uptake should now be carried out.
Biological Availability↗
Tolerance and efficacy of Omniscan (gadodiamide injection) in MR imaging of the central nervous system.
PURPOSE: This Swedish multicenter trial was performed on patients with known or suspected lesions of the CNS for which an MR examination using a contrast medium was indicated. A total of 8 MR centers participated in the study to establish the safety and efficacy of Omniscan (gadodiamide injection) in clinical routine using a standard dose of 0.1 mmol Gd/kg b.w. MATERIAL AND METHODS: Seven hundred adult patients who had been referred for MR investigation of suspected CNS lesions were included in the study. Since most patients were examined on an outpatient basis, it was decided to use an explicit questionnaire regarding adverse events that developed within 24 h after examination. The efficacy evaluation involved comparisons of detectability, delineation, and number of lesions before and after injection of Omniscan. RESULTS: No serious or unexpected adverse event was found. There were a total of 70 (10.2%) patients with adverse events, excluding those judged not to be contrast media-related. However, only 15 patients (2.2%) had adverse events that possibly or probably were related to the contrast medium. Usually, the symptoms were headache, dizziness, abnormal taste, and nausea. Two patients complained of itching, but only one developed urticaria. The efficacy was similar to that of other currently used Gd-based MR agents. Lesions were more often seen on T2-weighted images, but the contrast medium improved lesion delineation, contributing to higher certainty in diagnosis, and provided more confidence in excluding suspected abnormality. CONCLUSION: Omniscan was found to be a safe and clinically valuable contrast medium for MR imaging of the CNS.
Adolescent↗
Endoluminal ultrasound and low-field magnetic resonance imaging are superior to clinical examination in the preoperative staging of rectal cancer.
OBJECTIVE: To compare digital examination, endoluminal ultrasound (ELU), and plain magnetic resonance imaging (MRI), with histopathological findings in the preoperative staging of rectal cancer. DESIGN: A prospective comparative study. SETTING: University hospital, Sweden. SUBJECTS: 35 patients with rectal cancer who presented during the period February 1987 to February 1991. RESULTS: The digital examination of 19 patients could be assessed and was correct in 13 (68%). ELU was done in 34 patients; the accuracy was 88%. Extension of tumour was overestimated in two and underestimated in two. MRI was done for 35 patients with an accuracy of 66%; in 12 patients extension was underestimated. The diagnostic accuracy of the assessment of lymph node involvement was 71% with ELU, and 72% with MRI. CONCLUSION: These findings indicate that MRI seems to underestimate the extension of rectal tumours, but both ELU and MRI can be helpful in selecting patients with advanced tumours for whom preoperative adjuvant treatment is being considered. ELU is superior in staging tumours confined to the rectal wall, and could be of value in the selection of patients whose tumours were suitable for local excision. None of these techniques, however, can reliably identify the extent of lymph node involvement.
Aged↗