Sexual abuse and violence against people with intellectual disability and physical impairments: Characteristics of police-investigated cases in a Norwegian national sample.

BACKGROUND: Although people with disabilities are more exposed to violence and sexual abuse, research on the judicial process in such cases is still lacking. This study uses crime statistics to describe this phenomenon. METHOD: A national sample from the National Criminal Investigation Service in Norway was analysed for the period October 2015 to December 2017. RESULTS: The total number of alleged victims was 175, across 74 cases. The majority of the victims (71.2%) were females, subjected to a sexual offence. Overall, 30% of all cases led to a penal sanction. CONCLUSION: The study shows a preponderance of sexual offences against females with disabilities and few cases comprise violence. Relatively, few cases involve violations against children with disabilities. This might suggest an underreporting of such criminal acts. The knowledge of potential reasons why violent crime and offences against children with disabilities are absent from the data registry needs to be strengthened.

The Role of MicroRNAs as Predictors of Response to Tamoxifen Treatment in Breast Cancer Patients.

Endocrine therapy is a key treatment strategy to control or eradicate hormone-responsive breast cancer. However, resistance to endocrine therapy leads to breast cancer relapse. The recent extension of adjuvant tamoxifen treatment up to 10 years actualizes the need for identifying biological markers that may be used to monitor predictors of treatment response. MicroRNAs are promising biomarkers that may fill the gap between preclinical knowledge and clinical observations regarding endocrine resistance. MicroRNAs regulate gene expression by posttranscriptional repression or degradation of mRNA, most often leading to gene silencing. MicroRNAs have been identified directly in the primary tumor, but also in the circulation of breast cancer patients. The few available studies investigating microRNA in patients suggest that seven microRNAs (miR-10a, miR-26, miR-30c, miR-126a, miR-210, miR-342 and miR-519a) play a role in tamoxifen resistance. Ingenuity Pathway Analysis (IPA) reveals that these seven microRNAs interact more readily with estrogen receptor (ER)-independent pathways than ER-related signaling pathways. Some of these pathways are targetable (e.g., PIK3CA), suggesting that microRNAs as biomarkers of endocrine resistance may have clinical value. Validation of the role of these candidate microRNAs in large prospective studies is warranted.

Domains and perceived benefits of treatment among patients with and without co-occurring disorders in inpatient substance use treatment.

OBJECTIVE: Persons with substance use disorders often have comorbid psychiatric problems, and treating all problem domains is important for treatment success and recovery. This study examined reported interventions provided to patients as well as patients' reports of domains of help received, perceived areas of greatest benefit, and satisfaction with substance use disorder treatment. We also compared patients with co-occurring disorders and patients with only substance use disorders to see whether there were significant differences across groups on these measures. METHODS: Patients receiving inpatient substance use treatment at clinics in Norway were recruited for the study; 85 completed a cross-sectional survey prior to discharge. Treatment personnel also completed a separate survey and gathered information from patient charts. RESULTS: The most frequently provided treatment interventions involved improving relationships with family and important others, applied relaxation, psychodynamic therapy, cognitive behavior therapy, and motivational interviewing. Patients reported receiving the most help in domains of relapse prevention, physical health, daily functioning, relationships with people, psychological health, and self-esteem. They benefited most from physical activities, support from co-patients, group therapy, counseling, and assessment/treatment of psychological health. Patients with co-occurring disorders were given more exposure therapy, motivational interviewing, and cognitive behavior therapy interventions than those without comorbidity. Patients with co-occurring disorders self-reported receiving more help with self-esteem and coping with psychiatric symptoms and benefiting more from interventions involving psychological health, acute help, and social situations. CONCLUSIONS: Patients perceived psychological and physical health as important areas for improvement. There were differences between patients with co-occurring disorders and those with substance use disorders only in several measures. It is important to acknowledge that patients with substance use disorders and co-occurring mental problems are heterogeneous groups with unique but overlapping needs.

A radioimmunoassay for guanosine-5'-diphosphate-3'-diphosphate and adenosine-5'-triphosphate-3'-diphosphate.

A radioimmunoassay for guanosine-5'-diphosphate-3'-diphosphate (ppGpp) and adenosine-5'-triphosphate-3'-diphosphate (pppApp) has been developed. The assay method is based on competition of an unlabeled highly phosphorylated nucleotide with 3H-labeled highly phosphorylated nucleotide for binding sites on a specific antibody. Antibodies to ppGpp and pppApp were obtained by immunizing rabbits with the antigen prepared by conjugating ppGpp with human serum albumin using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and with the antigen prepared by conjugating 8-(6-aminohexyl)amino-adenosine-5'-triphosphate-3'-diphosphate with human serum albumin using glutaraldehyde, respectively. Antibody-bound 3H-labeled highly phosphorylated nucleotides were separated from the free 3H-labeled highly phosphorylated nucleotides by selective adsorption on dextran-coated charcoal. Displacement plots were linear over a concentration range of 5-1,000 pmol/assay tube in a log-probit percentage plot. Application of this method to biological systems offers improved accuracy and convenience compared with the previous 32PO4-labeling technique.

Cloning and expression of aminopeptidase P gene from Escherichia coli HB101 and characterization of expressed enzyme.

The aminopeptidase P gene in Escherichia coli HB101 was cloned into the plasmid pBR322. Introduction of the hybrid plasmid, pAPP01, into the E. coli DH1 resulted in an 8-fold increase of aminopeptidase P activity as compared with that of the host. The enzyme was purified by series of chromatographies on DEAE-Sephadex, QAE-Sephadex, and hydroxyapatite. The purified enzyme was homogeneous as judged by disc-gel and SDS-gel electrophoreses. the enzyme was inhibited strongly by EDTA and slightly by p-chloromercuribenzoate, but was not affected by diisopropyl phosphorofluoridate, E-64, or iodoacetic acid. The optimum pH of the enzyme was 8.5. The enzyme was stable at pH 8 to 9. After incubation for 30 min at pH 8.0, 50% remaining activity was observed at 50 degrees C. The enzyme was activated 3-fold by the addition of 5 microM Mn2+. The molecular weight of the enzyme was estimated to be 50,000 and 200,000 by SDS-PAGE and gel filtration, respectively. The amino terminal amino acid was identified to be serine by Edman degradation, indicating that the enzyme is composed of a homo-tetramer. The enzyme hydrolyzed X-Pro bonds (X = amino acid) of peptides. These characteristics suggest that cloned aminopeptidase P is identical to APP-II reported by Yoshimoto et al. (Agric. Biol. Chem. 52(8), in press (1988].

Cloning and expression of subtilisin amylosacchariticus gene.

The gene encoding subtilisin Amylosacchariticus from Bacillus subtilis var. amylosacchariticus was isolated and the entire nucleotide sequence of the coding sequence was determined. The deduced amino acid sequence revealed an N-terminal signal peptide and pro-peptide of 106 residues followed by the mature protein comprising 275 residues. There were discrepancies in 10 amino acids between the sequence elucidated from the nucleotide sequence and the published protein sequence (Kurihara et al. (1972) J. Biol. Chem. 247, 5619-5631). The nucleotide sequence was highly homologous to that of subtilisin E gene from B. subtilis 168, with discrepancies at 12 nucleotides out of 1,426 nucleotides we sequenced. Ten of them were found in mature subtilisin coding sequence, which resulted in two amino acid changes and another one was in the putative promoter region between two genes. The productivity of subtilisin in culture broth of B. subtilis var. amylosacchariticus was much higher than that of B. subtilis 168. The enzyme gene was inserted in a shuttle vector pHY300PLK, with which B. subtilis ISW1214 was transformed. The proteolytic activity found in the culture broth of the transformed bacterium was 20- and 4-fold higher than those of the host strain and B. subtilis var. amylosacchariticus, respectively. Subtilisin Amylosacchariticus was easily purified to a crystalline form from culture filtrate of cloned B. subtilis, after a single step of chromatography on CM-cellulose.

Sequencing and high expression of aminopeptidase P gene from Escherichia coli HB101.

A plasmid pAPP1 with a 4 kbp insert at the PstI site of pBR322, encoding aminopeptidase P gene of Escherichia coli HB101 (Yoshimoto et al. (1988) J. Biochem. 104, 730-734), was subcloned into pUC18 and pUC19. The transformant of E. coli JM83 harboring pAPP4 with a 1.9 kbp fragment showed more than 50-fold higher enzyme activity than that of the host, after cultivation at 37 degrees C for 40 h in LB-medium containing ampicillin. When the gene DNA was inserted reversely in pAPP4, the enzyme productivity decreased markedly. The whole nucleotide sequence of the inserted fragment of plasmid pAPP4 was clarified by the dideoxy chain-terminating method. Within this sequence, the mature enzyme protein-encoding sequence was found to start just after an ATG codon, as judged by comparison with amino-terminal protein sequencing. Eleven bases upstream from the proposed initiation codon was an AGGAGA sequence which seemed to be a ribosome binding site. Thirty-four bases upstream from the proposed start codon was the 6-base sequence TACAAA, the so-called -10 region or Pribnow box. Further, the 6-base sequence TTTACT around 77 bases upstream from the start codon was deduced to be a putative -35 region consensus sequence. The inverted repeat at 1334 was tentatively assumed to be a terminator. The molecular weight of the enzyme was estimated to be 49,650 from the nucleotide sequence. The purified enzyme contained 0.2 gram atom of zinc per subunit. The enzyme activity was inhibited by EDTA and activated 5-fold by Mn2+.

Pharmacokinetics and disposition of 4'-O-tetrahydropyranyladriamycin in mice by HPLC analysis.

The plasma level of 4'-O-tetrahydropyranyladriamycin (THP) declined rapidly after IV injection to mice, with a t1/2(alpha) of 0.453 min. Only 1.2 micrograms/ml THP was detected 2 min after injection of 5 mg/kg. The drug was immediately transferred to various tissues, where the drug levels were much higher than the plasma concentration. In the lung and spleen, 8.26 and 13.6 micrograms/g THP was present, respectively, 2 h after administration. Major metabolites of THP were 13-dihydro-THP, ADM, 7-deoxyadriamycinone, and 7-deoxy-13-dihydro-adriamycinone. Only 1.12% of the dose had been recovered in the urine by 48 h after injection as THP and its metabolites, according to analysis by HPLC fluorospectroscopy. The observed disposition of THP was compared with that of adriamycin (ADM). The plasma disappearance and tissue transfer of THP were faster than those of ADM. THP levels in the spleen and lung were higher and those in the heart and liver were lower than the corresponding ADM levels. Drug levels declined more quickly in most tissues in the case of THP than of ADM. Tissue distributions after single bolus and multiple injections were also compared and discussed.

Sensitive enzyme immunoassay for the quantification of aclacinomycin A using beta-D-galactosidase as a label.

A sensitive enzyme immunoassay method (EIA) for an anticancer drug, aclacinomycin A (ACM), has been developed. With a double-antibody technique, ACM at a concentration as low as 100 pg/tube can be detected. An antibody to ACM was obtained by immunizing rabbits with an antigen prepared by coupling ACM with mercaptosuccinylated bovine serum albumin via N-maleoyl aminobutyric acid (MABA) as a coupling agent. Enzyme labeling of ACM was performed with beta-D-galactosidase (beta-Gal; EC 3.2.1.23) via m-maleoyl benzoic acid (MBA). The standard curve of the assay was linear on a logit-log plot over a concentration range of 30 pg to 10 ng. The antibody detected ACM and its metabolites, MA144 M1 (M1), MA144 N1 (N1), MA144 S1 (S1), and aklavin (T1) equally well, but was only minimally reactive with aklavinone (D1) and 7-deoxyaklavinone (C1), thus suggesting that this EIA can detect the total amounts of ACM and its biologically active glycosides among metabolites of ACM. This EIA is practically free from interference by any other anticancer drugs. Using this assay, serum levels of ACM equivalents can be determined accurately after administration of the drug to rats at a single dose of 10 mg/kg. Since ACM is now undergoing clinical trial, the EIA of the drug will be a valuable tool in clinical pharmacological studies.

Effects of pirarubicin, an antitumor antibiotic, on the cardiovascular system.

In the present study we examined the effects of pirarubicin [(2"R)-4'-O-tetrahydropyranyladriamycin, THP] on a cardiovascular system. An injection of THP (0.39-3.13 mg/kg, i.v.) reduced the mean blood pressure and caused an increase in the respiratory air rate in anesthetized rats. At 1.5 x 10(-6)-1.5 x 10(-5) M, THP markedly relaxed a contraction induced by 10(-7) M norepinephrine in rat aorta with endothelium but not in that without endothelium. At a dose of 0.02-0.5 mg, THP produced an increase in the contractile force and the perfusion flow of isolated perfused guinea pig hearts. At a higher concentration (4.5 x 10(-5)-1.5 x 10(-4) M), it produced a slight increase in the contractile force of the left atria in guinea pigs. This positive inotropic action of THP was inhibited by diphenhydramine (10(-6)-5 x 10(-5) M), chlorpheniramine (3 x 10(-7)-3 x 10(-5) M), and tripelennamine (3 x 10(-7)-3 x 10(-5) M) but not by propranolol (10(-6) M), cimetidine (10(-5) M), diltiazem (10(-6) M), or ryanodine (10(-8) M). THP given i.v. at 2.5 mg/kg elevated the plasma histamine level in anesthetized dogs. From these data, we conclude that THP mainly relaxed the rat aorta in the presence of endothelium and that at higher concentrations, it increased the contractile force in the cardiac muscle, probably mediated through the release of histamine.

Production of new anthracycline antibiotics by microbial 4-O-methylation using a specific daunorubicin-negative mutant.

Microbial 4-O-methylation using a specific daunorubicin-blocked, nonproducing mutant provided the new anthracycline antibiotics 4-O-methylbetaclamycin T, 4-O-methylyellamycin A and 4-O-methyl-13-hydroxyoxaunomycin, from which 4-O-methyloxaunomycin and 4-O-methyl-6-deoxyoxaunomycin were then prepared by further photochemical N-demethylation. Antitumor activities in vitro and in vivo against L1210 cells were compared with those of their 4-O-demethyl derivatives. It was found that all the 4-O-methyl derivatives had a markedly reduced cytotoxicity in vitro as compared with the 4-O-demethyl compounds. However, some of them were endowed with a significantly improved antitumor activity in vivo.

Antitumor activities of (2"R)-4'-O-tetrahydropyranyl-adriamycin (THP) and its combination with other antitumor agents on murine tumors.

(2''R)-4'-O-Tetrahydropyranyladriamycin (THP) is a new derivative of doxorubicin (adriamycin, ADM). The concentrations of THP and ADM required to inhibit by 50% the growth of a cultured L1210 cells was 0.003 microgram/ml and 0.016 microgram/ml, respectively. Various therapeutic designs of combinations of THP with other antitumor agents were investigated in vivo using the L1210 murine leukemia. The combination of THP with cytosine arabinoside (Ara-C), cyclocytidine hydrochloride (Cyclo-C), 6-mercaptopurine (6-MP) and cyclophosphamide (EX) showed a great effectiveness following daily intraperitoneal treatment from days 1 to 10. High therapeutic effects were also obtained with the combinations of THP with Ara-C, Cyclo-C, vincristine (VCR) and EX following intravenous combination therapy one day following implantation of L1210 leukemia. Schedule dependency and its therapeutic efficacy of THP were examined. THP showed almost the same antitumor activity on the solid-type sarcoma-180 or solid-type Ehrlich carcinoma as ADM by intraperitoneal or intravenous treatment. THP showed some superior activity to ADM in the advanced stage of L1210 leukemia. High antitumor activity of THP on murine leukemia L1210 has been reported by Tsuruo et al. (Cancer Res. 42: 1462-1467, 1982) and was also confirmed. THP gave many mice cures, especially in the intravenous treatment.

Synthesis of doxorubicin-cyclodextrin conjugates.

Doxorubicin-gamma-cyclodextrin conjugates have been synthesized by the coupling of 14-bromodaunomycin with mono half-ester compounds linked to a 6-hydroxyl group of gamma-cyclodextrin. Release of drug from the conjugates in saline phosphate buffer solution and in vitro antitumor activity against L1210 leukemia cells were also investigated.

Production of new anthracycline antibiotics 1-hydroxy-oxaunomycin and 6-deoxyoxaunomycin by limited biosynthetic conversion using a daunorubicin-negative mutant.

A limited biosynthetic conversion of some known anthracyclinones using a specific daunorubicin-nonproducing mutant provided four new anthracycline antibiotics: 1-Hydroxy-10-methoxycarbonyl-13-deoxocarminomycin; 1-hydroxy-13-deoxocarminomycin; 1-hydroxyoxaunomycin and 6-deoxyoxaunomycin. Their isolation and purification from bioconversion broth, structural determination and antitumor activities against leukemic L1210 cells are described.

Photochemically obtained N-demethyl derivatives of anthracyclines.

New N-monodemethyl and N-didemethyl derivatives were obtained from seven N-dimethylamino sugar (rhodosamine)-containing anthracyclines by photochemical reaction and their in vitro bioactivities against L1210 cell culture were compared with those of their N-dimethyl parent compounds. N-Demethyl derivatives obtained from betaclamycin T (7-O-rhodosaminyl-beta-rhodomycinone) were much more cytotoxic while those from the other six antibiotics were rather less active as compared with their parent compounds. The N-demethylation also gave a considerably greater decrease in the inhibitory activity on RNA synthesis as compared to DNA synthesis, so that the N-demethyl derivatives showed smaller IC50 ratios on DNA/RNA than their parent compounds.

Mer-A2026A and B, novel piericidins with vasodilating effect. II. Physico-chemical properties and chemical structures.

The structure of vasodilating active substances, Mer-A2026A and B, produced by Streptomyces pactum Me2108 were determined on the basis of their spectral and chemical properties.

Mer-A2026A and B, novel piericidins with vasodilating effect. I. Producing organism, fermentation, isolation and biological properties.

A strain of Streptomyces was found to produce new piericidins. The compounds were purified and separated into two substances named Mer-A2026A and B. These new piericidins exhibited vasodilating and depressor activities.

Pharmacological studies on carbapenem antibiotics. I. Metabolism of PS-5 in animal tissues.

After injection into mice and dogs, PS-5 showed a very rapid decrease in its blood concentration, compared with cefazolin. Using in vitro experiments with tissue homogenates and acetone powder preparations, the kidney was found to be the primary site of PS-5-inactivation, although the extent of the inactivation varied depending on the species of animals. The comparative stability data of PS-5, NS-5 (deacetylated PS-5), thienamycin and N-formimidoylthienamycin in kidney homogenates of mouse, rabbit, dog and man are presented. Bilateral nephrectomy and the injection of ethylenediaminetetraacetate seemed to prolong the survival time of PS-5 in rats and mice respectively.

A high performance liquid chromatographic method of analysis of 4'-O-tetrahydropyranyladriamycin and their metabolites in biological samples.

A method for measuring 4'-O-tetrahydropyranyladriamycin (THP) and its metabolites in biological samples are described. By reversed-phase high performance liquid chromatography using fluorescence detection, THP and its metabolites were all separated on a single chromatogram within 18 minutes. A linear calibration curve was obtained up to 2,000 ng/ml of THP in plasma. The recovery of THP in the analysis was more than 95% above 5 ng/ml and 87.1% even at 1.25 ng/ml. Thus the lower limit was 1.25 ng/ml in biological samples. Blood levels and urinary excretion in mice and dogs were satisfactory measured by this analytical method.

Microbial glycosidation of some anthracycline antibiotics by an antibiotic-negative mutant of aclarubicin producer.

Microbial conversion of anthracyclinone monosaccharides using aclarubicin-negative mutant of Streptomyces galilaeus was found to produce anthracyclinone disaccharides which had either rhodinose or 2-deoxyfucose as an additional sugar. By this conversion we obtained twelve new anthracyclines from seven anthracyclines which had rhodosamine, N-monomethyldaunosamine or daunosamine at C-7 as a glycosidic sugar. All products had a reduced cytotoxic activity in comparison with those of parent compounds. However, some of them showed a therapeutically improved antitumor effects against L1210 leukemia in vivo.