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Biomedical subjects

M Henriksson

Publications and source records attributed to M Henriksson.

At least 19 recordsLinked to original sources
PubMed2001

C-peptide binding to human cell membranes: importance of Glu27.

In addition to its established role in proinsulin folding, C-peptide has a function in regulation of cellular activity. The 31-residue peptide influences renal, vascular, and metabolic functions in patients with insulin-dependent diabetes mellitus. Binding to cells has been demonstrated for C-peptide, which can be displaced by its C-terminal pentapeptide. We have now used fluorescence correlation spectroscopy to investigate structural requirements on the pentapeptide part for C-peptide binding. All pentapeptide residues, E(27)GSLQ(31), were individually replaced with Ala and the capacity of the resulting peptides to displace rhodamine-labelled full-length human C-peptide from human renal tubular cell membranes was determined. This showed that Glu27 is essential for displacement, while replacement of Gly28 with Ala has little effect, and replacement of any of the three most C-terminal residues had intermediate effects. Morevover, free Glu displaces full-length C-peptide to about 50%, while free Ala, C-peptide(1-26), and the truncated pentapeptide, corresponding to the tetrapeptide G(28)SLG(31), have no displacing capacity. The peptides EVARQ (corresponding to the rat C-terminal pentapeptide) and ELGGGPGAG (corresponding to positions 11-19 of human C-peptide) do not displace human C-peptide. These results indicate that Glu27 of C-peptide is critically involved in binding to cellular targets.

Alanine↗
PubMed2001

Horizontal transfer of oncogenes by uptake of apoptotic bodies.

Tumor formation involves the accumulation of a series of genetic alterations that are required for malignant growth. In most malignancies, genetic changes can be observed at the chromosomal level as losses or gains of whole or large portions of chromosomes. Here we provide evidence that tumor DNA may be horizontally transferred by the uptake of apoptotic bodies. Phagocytosis of apoptotic bodies derived from H-ras(V12)- and human c-myc-transfected rat fibroblasts resulted in loss of contact inhibition in vitro and a tumorigenic phenotype in vivo. Fluorescence in situ hybridization analysis revealed the presence of rat chromosomes or of rat and mouse fusion chromosomes in the nuclei of the recipient murine cells. The transferred DNA was propagated, provided that the transferred DNA conferred a selective advantage to the cell and that the phagocytotic host cell was p53-negative. These results suggest that lateral transfer of DNA between eukaryotic cells may result in aneuploidy and the accumulation of genetic changes that are necessary for tumor formation.

Animals↗
PubMed2001

Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells.

Recent evidence suggests that the Myc and Mad1 proteins are implicated in the regulation of the gene encoding the human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase. We have analyzed the in vivo interaction between endogenous c-Myc and Mad1 proteins and the hTERT promoter in HL60 cells with the use of the chromatin immunoprecipitation assay. The E-boxes at the hTERT proximal promoter were occupied in vivo by c-Myc in exponentially proliferating HL60 cells but not in cells induced to differentiate by DMSO. In contrast, Mad1 protein was induced and bound to the hTERT promoter in differentiated HL60 cells. Concomitantly, the acetylation of the histones at the promoter was significantly reduced. These data suggest that the reciprocal E-box occupancy by c-Myc and Mad1 is responsible for activation and repression of the hTERT gene in proliferating and differentiated HL60 cells, respectively. Furthermore, the histone deacetylase inhibitor trichostatin A inhibited deacetylation of histones at the hTERT promoter and attenuated the repression of hTERT transcription during HL60 cell differentiation. In addition, trichostatin A treatment activated hTERT transcription in resting human lymphocytes and fibroblasts. Taken together, these results indicate that acetylation/deacetylation of histones is operative in the regulation of hTERT expression.

Acetylation↗
PubMed2001

The Schizophrenia Suicide Risk Scale (SSRS): development and initial validation.

BACKGROUND: Estimations about the lifetime risk of suicide in schizophrenia vary between 4 and 10%. At present, there does not exist a suicide risk scale developed particularly for schizophrenic patients. The aims of the present study were to: (1) develop a clinically useful semi-structured scale for the estimation of short-term suicide risk among schizophrenic patients, and (2) to carry out an initial validation of the scale. METHODS: A 25-item Schizophrenia Suicide Risk Scale (SSRS) was constructed on the base of the literature. The SSRS scores of 69 living schizophrenic patients (LS group) were compared with the scores of 69 schizophrenic suicides (SS group) whose data had been collected previously from The Finnish nationwide and representative psychological autopsy study. Internal consistency of the SSRS was evaluated with Cronbach alpha. The most important SSRS items predicting suicide were identified with a logistic regression analysis. Sensitivity, specificity, positive predictive value, and negative predictive value of the SSRS in predicting suicide with various cut-off scores were calculated. RESULTS: In the final logistic regression model, the following SSRS items significantly predicted suicide: suicide plans communicated to someone during the past 3 months; one or more previous suicide attempts; loss of professional skills demanding job; depression observed during an interview; and suicide plans communicated during an interview. With high cut-off scores the specificity of the SSRS became satisfactory, but the sensitivity dropped below 32%. Internal consistency of the anamnestic history of the SSRS was low, which suggests that anamnestic risk factors for suicide in schizophrenia are multifactorial. Internal consistency of the interview-based items was high, and present state risk factors seemed to consist of two separate factors, depression-anxiety and irritability. CONCLUSIONS: The SSRS may be clinically useful in identifying schizophrenic patients with a particularly high risk for suicide. However, the SSRS seems not to be a practical screening instrument for suicide risk in schizophrenia, and it is probably impossible to construct a suicide risk scale with both high sensitivity and high specificity in this disorder.

Adolescent↗
PubMed2001

Specific binding of proinsulin C-peptide to intact and to detergent-solubilized human skin fibroblasts.

Proinsulin C-peptide exerts physiological effects on kidney and nerve function, but the mechanisms involved remain incompletely understood. Using fluorescence correlation spectroscopy, we have studied binding of rhodamine-labelled human C-peptide to intact human skin fibroblasts and to detergent-solubilised extracts of fibroblasts, K-562, and IEC-6 cells. Specificity was shown by displacement of rhodamine-labelled human C-peptide with unlabelled human C-peptide. C-peptide was found to bind to the cell membranes of intact fibroblasts with an association constant of 3 x 10(9) M(-1), giving full saturation at about 0.9 nM, close to the physiological C-peptide plasma concentration. Treatment of all investigated cells with the zwitter-ionic detergent Chaps was found to release macromolecules that bind specifically to C-peptide. The binding in Chaps extracts of fibroblasts was sensitive to time but remained reproducible for up to 2 h at room temperature. Lysophosphatidylcholine, Triton X-100, beta-octylglucopyranoside, SDS, or cholate gave extracts with only low or nonspecific binding. It is concluded that C-peptide binding components can be solubilised from cells, and that Chaps appears to be a suitable detergent.

C-Peptide↗
PubMed2001

Differential expression of class I HDACs: roles of cell density and cell cycle.

Enzymes which affect histone acetylation status have been shown to play an important role in determining transcriptional activity in chromatin through conformational modification of its structure. Since the timely presence of such enzymes may be of critical importance, our experiments were designed to determine whether the level of expression of HDAC1 is cell cycle dependent and/or affected by a high cell density. Our results show that in mouse fibroblasts the expression of mHDAC1 is neither affected by cell cycle phases nor by cell density. In contrast, the expression of several hHDACs including hHDAC1 were affected in a cell density dependent fashion in the human prostate adenocarcinoma cell line PC3, paralleling our previously published findings in the hepatocellular carcinoma derived cell line Hep3B. Differential recruitment of HDAC mRNAs suggests that these enzymes may play unique roles in different cell types and under different environmental conditions (i.e., exposure to various cell densities and cell-cell contacts). Our study has implications for the proposed use of HDAC inhibitors in the treatment of human malignancy, highlighting issues of drug action selectivity in tissues and potential secondary effects.

Adenocarcinoma↗
PubMed2000

Frequent amplification of the telomerase reverse transcriptase gene in human tumors.

Activation of telomerase is a crucial step during cellular immortalization and malignant transformation of human cells and requires the induction of the catalytic component, human telomerase reverse transcriptase (hTERT), encoded by the hTERT gene. It is poorly understood how the hTERT gene is activated in human cancer cells. In the present study, we examined the hTERT gene copy number in human cancer cell lines and in primary tumor tissues. Amplification of the hTERT gene was observed in 8 of 26 (31%) tumor cell lines and 17 of 58 (30%) primary tumors examined (8 of 21 lung tumors, 3 of 10 cervical tumors, 5 of 19 breast carcinomas, and 1 of 8 neuroblastomas). In addition, 13 of 26 (50%) cell lines and 13 of 58 (22%) primary tumors displayed gain of hTERT gene copies with 3-4 copies/cell. The present findings imply that the hTERT locus may be a frequent target for amplification during tumorigenesis and that this genetic event probably contributes to the dysregulation of telomerase activity occurring in human tumors.

Catalytic Domain↗
PubMed2000

Inhibition of cell growth and apoptosis by inducible expression of the transcriptional repressor Mad1.

Mad1 is a Myc antagonist that heterodimerizes with Max and functions as a transcriptional repressor. We have studied the effects of Mad1 on cell growth, cell cycle distribution, and apoptosis using Mad1-inducible cell lines. Expression of Mad1 inhibited cell proliferation, S-phase entry, and colony formation, changes that were accompanied by a reduction in CDK2 activity. The inhibition of Mad1 on cell proliferation was potentiated by serum starvation and was paralleled by accumulation of cells in the G0/G1 and the G2 phases of the cell cycle. Mad1 also reduced apoptosis induced by serum withdrawal and by the cytostatic drug cisplatinum. The effects on both cell growth and apoptosis were dependent on the mSin3 interaction domain of Mad1, which is necessary for recruitment of histone deacetylases and corepressors, suggesting that transcriptional repression is mediating these functions. Taken together with the expression pattern of Mad1, these results suggest that Mad1 plays an important role during initiation of differentiation by inhibiting cell proliferation and blocking apoptosis.

3T3 Cells↗
PubMed2000

Unordered structured of proinsulin C-peptide in aqueous solution and in the presence of lipid vesicles.

Proinsulin C-peptide ameliorates renal and autonomic nerve function and increases skeletal muscle blood flow, oxygen uptake and glucose transport in patients with insulin-dependent diabetes mellitus. These effects have in part been ascribed to the stimulatory influence of C-peptide on Na+,K+-ATPase and endothelial nitric oxide synthase. To evaluate the capacity of C-peptide to insert into lipid bilayers and form ion channels, C-peptide secondary structure and membrane interactions were studied with circular dichroism spectroscopy and size exclusion chromatography. C-peptide is shown to lack a stable secondary structure, both when part of proinsulin and when free in aqueous solution, although the N-terminal third of the peptide exhibits an alpha-helical conformation in trifluoroethanol. Moreover, C-peptide remains disordered in the aqueous solvent in the presence of lipid vesicles, regardless of vesicle composition. In conclusion, C-peptide is unlikely to elicit physiological effects through stable conformation-dependent interactions with lipid membranes.

Amino Acid Sequence↗
PubMed2000

Role of C-peptide in human physiology.

The C-peptide of proinsulin is important for the biosynthesis of insulin but has for a long time been considered to be biologically inert. Data now indicate that C-peptide in the nanomolar concentration range binds specifically to cell surfaces, probably to a G protein-coupled surface receptor, with subsequent activation of Ca(2+)-dependent intracellular signaling pathways. The association rate constant, K(ass), for C-peptide binding to endothelial cells, renal tubular cells, and fibroblasts is approximately 3. 10(9) M(-1). The binding is stereospecific, and no cross-reaction is seen with insulin, proinsulin, insulin growth factors I and II, or neuropeptide Y. C-peptide stimulates Na(+)-K(+)-ATPase and endothelial nitric oxide synthase activities. Data also indicate that C-peptide administration is accompanied by augmented blood flow in skeletal muscle and skin, diminished glomerular hyperfiltration, reduced urinary albumin excretion, and improved nerve function, all in patients with type 1 diabetes who lack C-peptide, but not in healthy subjects. The possibility exists that C-peptide replacement, together with insulin administration, may prevent the development or retard the progression of long-term complications in type 1 diabetes.

Amino Acid Sequence↗
PubMed1999

Interaction of the fork head domain transcription factor MPP2 with the human papilloma virus 16 E7 protein: enhancement of transformation and transactivation.

The high risk human papillomavirus (HPV) type 16 E7 protein affects cell growth control and promotes transformation by interfering with functions of cellular proteins. A key target of E7 is the tumor suppressor protein p105RB. Although this interaction is required for E7-dependent transformation, other cellular molecules must also be involved, because some E7 mutants that have reduced transforming abilities still bind to p105RB. In order to identify additional proteins that interact with E7 and that may be responsible to mediate its transforming function, we have used the C-terminal half of E7 in a yeast two-hybrid screen. We identified the fork head domain transcription factor M phase phosphoprotein 2 (MPP2) as an interaction partner of E7. Specific interaction of the two proteins both in vitro and in vivo in mammalian cells was detected. The interaction of MPP2 with E7 is functionally relevant since MPP2 enhances the E7/Ha-Ras co-transformation of rat embryo fibroblasts. In addition HPV16 E7, but neither non-transforming mutants of HPV16 E7 nor low risk HPV6 E7, was able to stimulate MPP2-specific transcriptional activity. Thus, MPP2 is a potentially important target for E7-mediated transformation.

Animals↗
PubMed1999

Prospective study of the clinical and laboratory parameters of patients in whom ovarian hyperstimulation syndrome developed during controlled ovarian hyperstimulation for in vitro fertilization.

OBJECTIVE: To compare patient characteristics and clinical and laboratory parameters in patients in whom ovarian hyperstimulation syndrome (OHSS) develops with those in whom it does not develop. DESIGN: Prospective cohort study. SETTING: Reproductive medicine unit at a university medical center. PATIENT(S): All patients undergoing IVF (n = 428) who received controlled ovarian hyperstimulation during a 6-month period. INTERVENTION(S): Prospective data collection. MAIN OUTCOME MEASURE(S): Patient characteristics (age, body mass index, medical history, smoking habits) and clinical and laboratory data obtained during controlled ovarian hyperstimulation were evaluated in patients who had severe OHSS, any degree of OHSS, or a significant risk of OHSS and compared with the remaining populations. RESULT(S): Severe OHSS developed in 18 patients (4.2%) and mild or moderate OHSS developed in 7.3%. As a group, all the patients with OHSS were significantly younger, received lower doses of gonadotropins, had ovaries containing a higher number of total and large follicles, had a higher number of retrieved oocytes, and had a higher pregnancy rate than the patients without OHSS. The patients with severe OHSS also had an increased prevalence of allergy (56% versus 21%) and were more likely to ultimately give birth. CONCLUSION(S): The observed differences may be useful in elucidating the pathophysiology of OHSS and identifying patients who are at increased risk for OHSS.

Adult↗
PubMed1999

Treatment of mental disorders in seven physicians committing suicide.

Through psychological autopsy seven cases of physician suicide were studied. All seven victims received a diagnosis of current mood disorder, two of them bipolar disorder. Five had suffered a disabling physical condition. None of the victims had had adequate treatment with antidepressant or mood-stabilizing drugs, nor had they been in psychotherapy. Current adequate treatment for depression seems to be as rare among physician victims as among suicides with major depressive disorders in the population.

Adult↗
PubMed1998

Inadequate dosaging in general practice of tricyclic vs. other antidepressants for depression.

Several prescription database studies suggest major differences between antidepressants in the proportion of patients in general practice treated with doses likely to elicit a true drug response. However, in these studies it has been difficult to differentiate prescriptions for depression from those for other indications, or to distinguish lower starting doses from the final treatment doses. We investigated possible differences between types of antidepressant in the proportions of patients receiving adequate treatment doses for depression from the primary health care services of Helsinki. Doctors at 22 (71%) of the 31 health centres in Helsinki were surveyed with regard to their antidepressant prescriptions over a period of 2 working weeks. There were marked differences in dosaging adequacy between the various types of antidepressant prescribed for depression at final treatment doses. Overall, 71% of the prescriptions for the tricyclic antidepressants, but only 13% of those for the other antidepressants, mainly selective serotonin reuptake inhibitors, were for low doses that are generally considered to be ineffective (P<0.001). These findings endorse the emerging perception that, in general practice, tricyclic antidepressants are usually prescribed for depression in too low doses, and that a greater reliance on other antidepressants would probably improve the effectiveness of treatment in primary health care.

Adult↗
PubMed1997

Differences between urban and rural suicides.

As part of a nation-wide psychological autopsy we examined the differences in DSM-III-R mental disorders, recent life events and other characteristics between urban (n = 143) and rural (n = 85) completed suicides in a random sample of 229 cases from the National Suicide Prevention Project in Finland for the period 1987-1988. Psychoactive substance use disorders (48% vs. 34%), cluster B personality disorders (24% vs. 9%) and psychiatric comorbidity (66% vs. 42%) were found more commonly among urban than rural suicides. Urban suicides were also more often reported to be preceded by a recent separation (25% vs. 8%), whereas rural suicide victims tended to have lacked a close companion of the opposite sex (36% vs. 18%) and to have had physical disorders (56% vs. 40%). Overall, urban and rural suicides may vary with regard to the prevalence of some mental disorders, their comorbidity, and physical disorders, as well as the preceding life situation. This variation may also imply the need for differences in strategies for suicide prevention in each setting.

Adolescent↗
PubMed1997

Hopelessness, impulsiveness and intent among suicide attempters with major depression, alcohol dependence, or both.

The present study examined differences in hopelessness, impulsiveness and suicide intent between suicide attempters with either major depression or alcohol dependence, comorbid major depression and alcohol dependence, and those without these disorders. A sample of 114 patients from consecutive cases of attempted suicide referred to a general hospital in Helsinki was interviewed and diagnosed according to DSM-III-R. Suicide intent was measured by the Beck Suicide Intent Scale (SIS) and hopelessness was assessed by the Beck Hopelessness Scale (HS). Impulsiveness of the suicide attempt was measured by two items of the SIS. Suicide attempters with major depression without comorbid alcohol dependence had higher suicide intent and lower impulsiveness than attempters with non-depressive alcohol dependence. Suicide attempts may differ between subjects with major depression, alcoholism or both disorders in terms of impulsiveness and suicide intent.

Adolescent↗