Biomedical subjects

S Eriksson

Publications and source records attributed to S Eriksson.

At least 199 records · Page 11Linked to original sources

PubMed1995

Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation.

The major component of the cerebral plaques in Alzheimer disease is the beta-amyloid peptide, but serine proteinase inhibitors like alpha 1-antichymotrypsin (ACT) are also present. Their role in the pathogenesis of amyloid formation is unsettled. In addition to their function as proteinase inhibitors, serine proteinase inhibitors can interact with various hydrophobic compounds, a reaction accompanied by a transition from the stressed to the relaxed conformation. We report here on the ability of ACT to regulate the formation of beta-amyloid fibrils in vitro. In a molar ratio of 1:10 (ACT to beta-amyloid) ACT inhibits beta-amyloid fibril formation. Furthermore, ACT promotes rapid disaggregation of beta-amyloid fibrils when added in the same molar ratio to preformed beta-amyloid fibrils. These processes are accompanied by increased thermostability of ACT and loss of its biological activity, consistent with a conformational transition of ACT from the stressed to the relaxed state. The influence of ACT on beta-amyloid fibril formation may be an example of a hydrophobic interaction between the beta-amyloid peptide and the hydrophobic domain C terminal to the reactive center of ACT.

Alzheimer Disease↗

PubMed1995

Randomized controlled trial of appendicectomy versus antibiotic therapy for acute appendicitis.

In a prospective controlled study the effect of antibiotics as the only treatment in acute appendicitis was evaluated. Of 40 patients admitted with a duration of abdominal pain of less than 72 h, 20 received antibiotics intravenously for 2 days followed by oral treatment for 8 days and 20 considered as controls were randomized to surgery. All patients treated conservatively were discharged within 2 days, except one who required surgery after 12 h because of peritonitis secondary to perforated appendicitis. Seven patients were readmitted within 1 year as a result of recurrent appendicitis and underwent surgery, when appendicitis was confirmed. The diagnostic accuracy within the operated group was 85 per cent. One patient had perforated appendicitis at operation. Antibiotic treatment in patients with acute appendicitis was as effective as surgery. The patients had less pain and required less analgesia, but the recurrence rate was high.

Acute Disease↗

PubMed1995

The liver in adolescents with alpha 1-antitrypsin deficiency.

Of 200,000 Swedish infants screened for alpha 1-antitrypsin deficiency (alpha 1 ATD), 184 (127 PiZ, 2 PiZ-, 54 PiSZ, and 1 PiS-) children have been followed prospectively, of whom 1 PiSZ and 5 PiZ children died in early childhood. We now report clinical and biochemical signs of liver disease in adolescence and the prognosis of neonatal liver disease up to the age of 18 years. The alpha 1 ATD subjects were offered a clinical checkup and liver tests at 16 and 18 years of age, 150 of 178 alpha 1ATD subjects undergoing checkups at age 16 and 166 at age 18. Liver tests were performed in 121 adolescents at both the 16- and 18-year checkups. None of the PiZ and PiSZ subjects checked at the age of 16 and 18 years had any clinical signs of liver disease. Abnormalities of serum alanine aminotransferase (S-ALAT) or gamma-glutamyl transferase (S-GT) were found at the 16-year checkup (all PiZ and PiSZ subjects tested included) in 17% of PiZ and 8% of PiSZ adolescents, and at the age of 18 years in 12% of PiZ and 15% of PiSZ subjects. In only two cases were both S-ALAT and S-GT concentrations abnormal at both the 16-year and 18-year follow-ups. Serum procollagen III peptide concentrations were normal in all those with abnormal liver test results. Of 127 PiZ subjects, 22 had manifested clinical signs of liver disease in infancy. Of these 22, two died early in life of cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1995

Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens.

Bone mineral density (BMD) and bone mineral content (BMC) were measured in the femoral neck area, trochanteric area and Wards triangle, and in the distal radius of the left forearm before and after 1 year of endocrine treatment in 27 patients with prostatic cancer. Eleven of the patients were treated with orchidectomy and 16 with combined oral and intramuscular estrogens. The patients were free from metastases during the entire observation period. In the orchidectomized patients, BMD and BMC of the distal radius decreased significantly following treatment, whereas no changes were observed in the estrogen-treated patients. These preliminary results demonstrate that estrogens may protect bone in male subjects also and may merit further investigations on larger groups of patients.

Aged↗

PubMed1995

Interspecies differences in the kinetic properties of deoxycytidine kinase elucidate the poor utility of a phase I pharmacologically directed dose-escalation concept for 2-chloro-2'-deoxyadenosine.

2-Chloro-2'-deoxyadenosine (CdA, Cladribine), is a purine antimetabolite currently under investigation in phase II clinical trials for the treatment of lymphoid malignancies. Significant differences in CdA toxicity between mice and humans were observed during phase I clinical evaluation. For the elucidation of interspecies differences in drug toxicity the pharmacokinetics of CdA after subcutaneous injection and the kinetic properties of the CdA-phosphorylating enzyme, deoxycytidine kinase (dCK), were compared in mice and humans. The ratio of the dose lethal to 10% of mice (LD10) to the maximum tolerated dose (MTD) in humans was 50 and the ratio of the area under the curve obtained at approximately one-half the LD10 (AUCapprox. one-half the LD10)/AUC(MTD) was 49. A significant interspecies difference was observed in the kinetic properties of dCK, the main CdA-activating enzyme. With CdA as a substrate, the Michaelis constant (Km) of dCK in crude extracts of mouse thymus was 10 times higher than that in human thymus. An approximately 9-fold interspecies difference in maximum velocity (Vmax)/Km indicated a higher efficiency of dCK for CdA in humans than in mice. The peak plasma concentration was 210 times higher and exceeded the Km in mice. Initial and terminal half-lives were approximately 7 times shorter in mice and trough levels were similar in mice and humans. Thus, the differences in AUCs at equitoxic doses are largely explained by differences in the target enzyme properties and the pharmacokinetic pattern. The observed lower tolerance for CdA in humans as compared with mice confirms the view that antimetabolites may not be good candidates for pharmacokinetically guided dose-escalation schemes unless detailed information on interspecies variability in drug bioactivation is available.

Animals↗

PubMed1995

Collagenous colitis and fecal stream diversion.

BACKGROUND & AIMS: The cause of collagenous colitis is unknown. Data on treatment are sparse, and surgical therapy has not been reported. This study reports results of surgical therapy for collagenous colitis. METHODS: Nine women with unresponsive collagenous colitis underwent surgery. An ileostomy was performed as the first procedure in 8 patients, and a sigmoidostomy using the Hartmann procedure was performed in 1 patient. RESULTS: Preoperatively, all patients had severe diarrhea, and the median thickness of the subepithelial collagenous layer was 20 microns (range, 10-40 microns). Postoperatively, diarrhea ceased in all patients, and the collagen layer was reduced to 2 microns (range, 0-10 microns). Clinical symptoms and the abnormal collagen layer recurred after restoration of intestinal continuity. After the Hartmann procedure, the collagen layer remained abnormally thickened up to 30 microns in the proximal colon but was normalized in the excluded rectosigmoid colon. One year later, the sigmoidostomy was replaced by a split ileostomy; at follow-up, the collagen layer was normal in the whole colon. CONCLUSIONS: Fecal stream diversion induced clinical and histopathologic remission in collagenous colitis. After closure of the ostomy, clinical symptoms and the abnormal collagen layer recurred. The findings strongly indicate that a noxious luminal factor is of pathogenetic importance. In older patients with medically resistant disease, a split ileostomy may be the therapeutic procedure of choice.

Adult↗

PubMed1995

Mammalian deoxyribonucleoside kinases.

The mammalian deoxyribonucleoside kinases are deoxycytidine kinase, thymidine kinase 1 and 2 and deoxyguanosine kinase. These enzymes phosphorylate deoxyribonucleosides and thereby provide an alternative to de novo synthesis of DNA precursors. Their activities are essential for the activation of several chemotherapeutically important nucleoside analogues. In recent years, these enzymes have been thoroughly characterised with regard to structure, substrate specificity and patterns of expression. In this review, these results are reviewed and furthermore, the physiologic metabolic role of the anabolic enzymes is discussed in relation to catabolic pathways. The significance of this information for the development of therapeutic protocols and choice of animal model systems is discussed. Finally, alternative pathways for nucleoside analogue phosphorylation are surveyed, such as the phosphotransfer capacity of 5'-nucleotidase.

5'-Nucleotidase↗

PubMed1995

Abnormalities in adrenal androgens, but not of glucocorticoids, in early Alzheimer's disease.

In an attempt to evaluate possible adrenal abnormalities in Alzheimer's disease (AD), prestimulus levels and ACTH-stimulated serum levels of steroid hormones, corticosteroid-binding globulin (CBG), and insulin-like growth factor I (IGF-I) were measured in 18 patients with early AD (8 men, 10 women; 74.6 +/- 6.5 years, mean +/- SD) and 19 healthy controls (10 men, 9 women; 74.2 +/- 7.6 years, mean +/- SD). Steroid hormone levels were measured before and after an intravenous bolus injection of 250 micrograms ACTH. AD per se had an independent influence on hormone levels when evaluated in MANOVA models. AD patients had significantly higher prestimulus levels of dehydroepiandrosterone and androstenedione (p = .04 and p = .003, respectively) with accentuated differences after ACTH (p = .02 and p < .001 for peak responses, respectively). Serum levels of cortisol, CBG, free cortisol, 17 alpha-hydroxyprogesterone (17 alpha-OHP), and IGF-I did not differ between groups. These abnormalities may have implications for neuronal degeneration as well as for behavioural symptoms in AD.

Adrenal Glands↗

PubMed1995

Expression of deoxycytidine kinase and phosphorylation of 2-chlorodeoxyadenosine in human normal and tumour cells and tissues.

Deoxycytidine kinase (dCK) activates several clinically important drugs, including the recently developed antileukaemic compound 2-chlorodeoxyadenosine (CdA). The distribution of dCK in cells and tissues has previously been determined by activity measurements, which may be unreliable because of the presence of other enzymes with overlapping substrate specificities. Therefore we have measured dCK polypeptide levels in extracts of normal and malignant human peripheral blood mononuclear cells, gastrointestinal tissues and sarcomas, using a specific immunoblotting technique, as well as the phosphorylation of CdA in the same extracts. High levels of dCK were found in all major subpopulations of normal mononuclear leucocytes (120 +/- 19 ng dCK/mg protein) and in B-cell chronic lymphocytic leukaemia (81 +/- 30 ng/mg, n = 23). Hairy-cell leukaemia contained lower levels (28 +/- 23 ng/mg, n = 7), as did three samples of T-cell chronic lymphocytic leukaemia (18 +/- 14 ng/mg). Phytohaemagglutinin stimulation of normal lymphocytes did not lead to any substantial increase in either dCK activity or protein expression (less than 2.5-fold). The human CEM wt T-lymphoblastoid cell line contained 56 +/- 1 ng/dCK/mg protein, while in the CEM ddC50 and AraC8D mutants that lack dCK activity, no dCK polypeptide could be detected. In colon adenocarcinomas, the dCK content was significantly higher (20 +/- 9 ng/mg, n = 20) than in normal colon mucosa (8 +/- 3.5 ng/mg, n = 19, P < 0.05). A similar pattern of dCK expression was found in gastric adenocarcinomas (21 +/- 13 ng/mg, n = 5) and normal stomach mucosa (6 +/- 5 ng/mg, n = 5, P < 0.15). One leiomyosarcoma and one extra-skeletal osteosarcoma showed dCK levels comparable with those found in normal lymphocytes (84 +/- 6 and 109 +/- 4 ng/mg, respectively), while other sarcoma samples contained lower levels, comparable to the gastrointestinal adenocarcinomas (20 +/- 7 ng/mg, n = 12). Thus, dCK is expressed constitutively and predominantly in lymphoid cells, but it is also found in solid non-lymphoid tissues, with increased levels in malignant cells. The phosphorylation of CdA in crude extracts showed a close correlation to the dCK polypeptide level.

Blotting, Western↗

PubMed1995

Local recurrence and long-term survival in patients with gastric cancer--analysis of possible impact of clinicopathological parameters.

In a retrospective study comprising 88 patients operated upon with curative intent a number of histopathological parameters of possible prognostic value regarding local recurrence and long-time survival were analysed. Local recurrence within 5 years was found in 28 patients (32%) of which 17 (61%) were diagnosed within the first 2 years. Crude survival rates at 5 and 10 years were 25% and 15%. According to Laurén's classification the results indicated better, but not significant, 5- and 10-year survival for the diffuse type (36% vs 25%). The probability of 10-year survival suggested a better (P = 0.06) prognosis for tumours in the middle third of the stomach, and for patients operated with total gastrectomy (P = 0.025). The probability of recurrence in relation to lymph node involvement suggested a more favourable prognosis (P = 0.06) for patients without lymph node metastases, and in relation to tumour fibrosis a less favourable prognosis for pronounced fibrosis (P = 0.001).

Adult↗

PubMed1995

The PiZ gene of alpha 1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis.

We have previously demonstrated that a strong correlation exists between systemic vasculitis with proteinase 3-anti-neutrophil cytoplasm antibodies (PR3-ANCA) and heterozygosity for alpha 1-antitrypsin (alpha 1-AT) deficiency, PiZ. In the present study we characterized the PiZ-positive subgroup by laboratory findings, clinical features and outcome. The series studied consisted of 18 PiZ-positive and 81 PiZ-negative PR3-ANCA patients, comparable in sex ratio, age, C-reactive protein concentrations and renal function at diagnosis, and treatment. PiZ-positive patients had a more disseminated disease as reflected by the number of affected organs (P < 0.01). We found no group differences in relapse tendency. Overall mortality was 39% (7 of 18) in the PiZ-positive and 16% (13 of 81) in the non-PiZ group (P = 0.048). When survival analysis was restricted to 66 patients included in the study at disease onset, the group difference was significant (P = 0.016). The results suggest that the subnormal response of plasma alpha 1-AT seen in PiZ-heterozygotes enhances the risk of dissemination of the vasculitic process and the risk of a fatal outcome. We consider alpha 1-AT phenotyping to be justified in cases of PR3-ANCA-positive vasculitis. Treatments decreasing plasma alpha 1-AT (such as plasmapheresis without plasma replacement) may be deleterious.

Adult↗

PubMed1995

Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism.

Azidothymidine (zidovudine, AZT) used for treatment of HIV infection blocks the viral reverse transcriptase after phosphorylation by cellular enzymes. The first step in this reaction is the formation of AZT monophosphate, primarily catalyzed by host cytoplasmatic thymidine kinase (TK1). The activity of TK1 was determined in extracts of PHA-stimulated peripheral blood mononuclear cells (PBMCs) from 20 healthy volunteers and 49 HIV-infected patients at different stages of disease. In both groups we found a large intra- and interindividual variation of TK activity. Because TK1 expression is cell cycle regulated the proportion of stimulated cells was determined in the samples and the median thymidine kinase activity calculated. It was 3.0 pmol/mg/min x % S phase in the HIV-seronegative group and 1.1 pmol/mg/min x % S phase in HIV-infected individuals. The difference in thymidine kinase activity is statistically significant (p = 0.0001). The concentration of TK1 protein in the same extracts was also determined by immunoblotting. A positive correlation (r = 0.74) was observed between TK activity and amount of TK1 protein. The reason for this downregulation of TK is still unknown but may be related to the anergy observed in lymphocytes from HIV-infected persons. The reduced capacity for intracellular phosphorylation of AZT in HIV-infected individuals may be an important factor in the emergence of clinical AZT resistance and should also be accounted for in testing AZT resistance in vitro with PBMCs from healthy blood donors.

Antiviral Agents↗

PubMed1995

The putative role of alpha-1-antitrypsin in the disaggregation of amyloid lambda fibrils.

BACKGROUND AND OBJECTIVES: Interactions between hydrophobic compounds like cholesterol and lithocholic acid and alpha-1-antitrypsin (alpha-1-AT) have previously been described. We studied the putative interaction between alpha-1-AT and the insoluble, hydrophobic, beta-pleated sheet, light-chain-derived fibrils that predominate the tissue deposits in primary immunocytic (AL) related amyloidosis. SUBJECTS AND METHODS: Amyloid fibrils were isolated from two cases with lambda and two cases with kappa AL amyloidosis. RESULTS: The lambda fibrils could be completely disaggregated (as shown by light and electron microscopy and Congo red uptake) by alpha-1-AT added in the molar ratio 1:5, whereas fibrils with predominantly kappa chains remained unaffected. The lambda-chain interaction was accompanied by characteristic changes of the physicochemical and biological properties of alpha-1-AT apparent in an increased thermal stability and loss of elastase-inhibitory activity. These findings are compatible with a transition of alpha-1-AT from a native, stressed conformation to a relaxed form. CONCLUSIONS: Disaggregation of lambda AL amyloid fibrils can be achieved by addition of alpha-1-AT. The findings may have therapeutic implications in primary amyloidosis.

Aged↗

PubMed1995

Angiotensin and the brain.

A brief account for the renal renin-angiotensin system (RAS), its inhibitors and receptors, as for the presence of an intrinsic cerebral RAS is initially provided. The review is then focused upon the circumventricular organs as cerebral targets for blood-borne angiotensin II (Ang II) and on centrally mediated Ang II effects. These concern influences upon the cardiovascular system, water balance, sodium balance, and ACTH-cortisol secretion.

Adrenocorticotropic Hormone↗

PubMed1995

Influence of forebrain lesions and isoflurane anaesthesia, respectively, on responses to the intracarotid infusion of angiotensin II in sheep.

In conscious sheep, lesions involving the anterior wall of the third cerebral ventricle extinguished the dipsogenic and cortisol releasing effects of 10 min intracarotid (i.c.) infusions of angiotensin II (Ang II) (20 pmol kg-1 min-1). The sustained hypertension obtained in response to i.c. Ang II in the intact animal was not significantly changed by the forebrain lesions. Pronounced, but short-lasting tachycardia immediately developed in response to i.c. Ang II in control animals. After a 1 min return to initial values the heart rate (HR) rose to about 20 beats min-1 above pre-infusion level during the remaining infusion period. After a brief post-infusion fall, HR retook that level. It then gradually declined but did not return to initial level until about 25 min later. During isoflurane anaesthesia in the latter animals carotid blood pressure (cBP) was reduced by approximately 30% while the HR was more than doubled. The cBP rise in response to i.c. Ang II infusion was < 50% of that seen in awake animals and the pressure returned to initial level within approximately 5 min after the end of the infusion. The infusion did not influence the HR. This study provides support for the idea that blood borne Ang II, bound at cerebral sites posterior to the hypothalamic region, continues to have cardiovascular effects for approximately 20 min after the concentration in the blood has returned to pre-infusion level.

Anesthesia↗

PubMed1995

Increased PiZ gene frequency for alpha 1 antitrypsin in patients with genetic haemochromatosis.

The putative relationship between genetic haemochromatosis and PiZ alpha 1 antitrypsin deficiency was studied using a monoclonal antibody against the PiZ variant in 67 consecutive patients with genetic haemochromatosis seen at Karolinska Hospital and Huddinge University Hospital, Stockholm over a 10 year period. Three (4.5%) of the patients with haemochromatosis were found to be PiZ homozygotes (odds ratio = 82, confidence interval = 26, 256; p < 0.0001). The prevalence of the heterozygous (PiZ) phenotype was similar to that in the general population (p = 0.937). During the ascertainment period, liver biopsy was performed in 65 (97%) of the patients; 66% (2 of 3) of the PiZ homozygotes were found to have cirrhosis compared with 10% (6/59) of the non-carriers of the PiZ variant (p = 0.039). None of the homozygous or heterozygous alpha 1 antitrypsin deficient patients had developed hepatocellular carcinoma compared with 3.4% (2 of 59) of the non-PiZ gene carriers (p = 1.0). Two of those with the homozygous phenotype had developed severe emphysema. HLA typing was performed in 18 patients, 16 (89%) of whom manifested antigens known to be linked to haemochromatosis. There were no significant differences between the PiZ gene carriers and non-carriers in mean age at onset of disease, sex distribution, or HLA type. Two of the PiZ heterozygotes had plasma alpha 1 antitrypsin concentrations below the normal range, though the group mean was lower than that of the non-PiZ carriers (p = 0.0003). The data suggest that the presence of the PiZ allele for alpha1 antitrypsin deficiency, in a double dose, is associated with genetic haemochromatosis and may contribute to the earlier onset of cirrhosis in these patients, though it does not increase the risk of hepatocellular carcinoma.

Adult↗

PubMed1995

Collagenous colitis in Orebro, Sweden, an epidemiological study 1984-1993.

The incidence and prevalence of collagenous colitis are unknown. An epidemiological study was undertaken between 1984-93. All patients living in the immediate catchment area of Orebro Medical Center Hospital with the diagnosis collagenous colitis were identified. Biopsy specimens classified as unspecific intestinal fibrosis were re-examined to identify cases not correctly diagnosed at first. Medical records were scrutinised and colorectal biopsy specimens re-evaluated. Thirty patients with collagenous colitis were diagnosed during the study period. The female:male ratio was 9:1. The median age at diagnosis was 64 (28-78) years. The prevalence at 31 December 1993, was 15.7/10(5) inhabitants (95% CI; 9.8 to 21.6/10(5)). The mean annual incidence during the period 1984-93 was 1.8/10(5) inhabitants (95% CI; 1.2 to 2.4/10(5)). A peak incidence was found in women 70-79 years old. Collagenous colitis occurs mainly in middle aged women, and the frequency is higher than earlier anticipated. The prevalence and incidence is similar to primary biliary cirrhosis. In women 70-79 years of age, the incidence for collagenous colitis approaches the incidence for ulcerative colitis.

Adult↗

PubMed1995

In vitro amyloid fibril formation from alpha 1-antitrypsin.

We have previously shown that the interaction between alpha 1-antitrypsin (AAT) and lithocholic acid (LA) results in changes of AAT properties leading to its polymerization and inactivation. To define the structural rearrangements of AAT induced by such interaction, we studied the in vitro binding between AAT and LA at molar ratio 1:5 for varying time intervals at a physiological pH. Complex formation was shown by electrophoretic techniques and autoradiography. Studies of the AAT in complex with LA by using far-UV spectra circular dichroism and fluorescence measurements indicated an increase of beta-structure of AAT and pronounced changes in surroundings of the chromophores. In addition, complexed AAT showed increase in thermal stability, compatible with that after proteolytic cleavage. Characterization of the AAT-LA complexes by Congo red binding, polarization and negative staining electron microscopy provided clear evidence that AAT, under chosen experimental conditions, can self-assemble into amyloid fibrils, compatible with accepted models of fibrillar structures. This propensity of AAT to form stable beta-structures in a hydrophobic surrounding may contribute to improved characterization of various amyloid deposits occurring in vivo and be a guide for understanding details of structure-function relationships in the intact AAT-molecule.

Amyloid↗