Biotransformational and neurophysiological changes in rabbits exposed to lead

Lead was administered to adult male rabbits in drinking water at a 0.1% concentration for four and five week periods. The lead contents were determined in the central and peripheral nervous tissues and in the liver, kidney, and intestinal mucosa. The conduction velocity of sciatic nerve and the activities of drug metabolizing enzymes in other tissues were determined. The lead concentration in the blood was at a steady state at four to five weeks of exposure. Lead accumulated in all tissues except the brain. The brain lead concentration was 40 to 50% of that in the blood, indicating the existence of a blood-brain barrier. However, the lead concentration in the sciatic nerve increased significantly from four to five weeks of exposure and exceeded that in the blood. This indicates the lack of a blood-nervous tissue barrier in the sciatic nerve allowing a continuous accumulation of lead. This accumulation affected the function of the sciatic nerve; motor nerve conduction velocity decreased from the control level (58.3±7.4 m/sec) to 43.8±6.3 m/sec after the four-week exposure and to 35.0 ± 1.3 m/sec at 5 weeks of exposure. After five weeks of exposure, no changes in the hepatic, intestinal, or renal drug metabolizing enzyme activites were found. These results suggest that motor nerve conduction velocity is affected by lead exposure prior to any influence on biotransformation enzymes.     

The effect of atorvastatin treatment on serum oxysterol concentrations and cytochrome P450 3A4 activity

Aims

Atorvastatin is known to both inhibit and induce the cytochrome P450 3A4 (CYP3A4) enzyme in vitro. Some clinical studies indicate that atorvastatin inhibits CYP3A4 but there are no well-controlled longer term studies that could evaluate the inducing effect of atorvastatin. We aimed to determine if atorvastatin induces or inhibits CYP3A4 activity as measured by the 4β-hydroxycholesterol to cholesterol ratio (4βHC : C).

Methods

In this randomized, double-blind, placebo-controlled 6 month study we evaluated the effects of atorvastatin 20 mg day⁻¹ (n = 15) and placebo (n = 14) on oxysterol concentrations and determined if atorvastatin induces or inhibits CYP3A4 activity as assessed by the 4βHC : C index. The respective 25-hydroxycholesterol and 5α,6α-epoxycholesterol ratios were used as negative controls.

Results

Treatment with atorvastatin decreased 4βHC and 5α,6α-epoxycholesterol concentrations by 40% and 23%, respectively. The mean 4βHC : C ratio decreased by 13% (0.214 ± 0.04 to 0.182 ± 0.04, P = 0.024, 95% confidence interval (CI) of the difference –0.0595, –0.00483) in the atorvastatin group while no significant change occurred in the placebo group. The difference in change of 4βHC : C between study arms was statistically significant (atorvastatin –0.032, placebo 0.0055, P = 0.020, 95% CI of the difference –0.069, –0.0067). The ratios of 25-hydroxycholesterol and 5α,6α-epoxycholesterol to cholesterol did not change.

Conclusions

The results establish atorvastatin as an inhibitor of CYP3A4 activity. Furthermore, 4βHC : C is a useful index of CYP3A4 activity, including the conditions with altered cholesterol concentrations.     

Effect of carboxylesterase 1 c.428G?>?A single nucleotide variation on the pharmacokinetics of quinapril and enalapril

Aim

The aim of the present study was to investigate the effects of the carboxylesterase 1 (CES1) c.428G > A (p.G143E, rs71647871) single nucleotide variation (SNV) on the pharmacokinetics of quinapril and enalapril in a prospective genotype panel study in healthy volunteers.

Methods

In a fixed-order crossover study, 10 healthy volunteers with the CES1 c.428G/A genotype and 12 with the c.428G/G genotype ingested a single 10 mg dose of quinapril and enalapril with a washout period of at least 1 week. Plasma concentrations of quinapril and quinaprilat were measured for up to 24 h and those of enalapril and enalaprilat for up to 48 h. Their excretion into the urine was measured from 0 h to 12 h.

Results

The area under the plasma concentration–time curve from 0 h to infinity (AUC_0–∞) of active enalaprilat was 20% lower in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (95% confidence interval of geometric mean ratio 0.64, 1.00; P = 0.049). The amount of enalaprilat excreted into the urine was 35% smaller in subjects with the CES1 c.428G/A genotype than in those with the c.428G/G genotype (P = 0.044). The CES1 genotype had no significant effect on the enalaprilat to enalapril AUC_0–∞ ratio or on any other pharmacokinetic or pharmacodynamic parameters of enalapril or enalaprilat. The CES1 genotype had no significant effect on the pharmacokinetic or pharmacodynamic parameters of quinapril.

Conclusions

The CES1 c.428G > A SNV decreased enalaprilat concentrations, probably by reducing the hydrolysis of enalapril, but had no observable effect on the pharmacokinetics of quinapril.     

Qualitative study of social and healthcare educators’ perceptions of their competence in education

Competent educators are needed to ensure that social and healthcare professionals are effective and highly competent. However, there is too little evidence‐based knowledge of current and required enhancements of educators' competences in this field. The aim of this study was to describe social and healthcare educators’ perceptions of their competence in education. The study had a qualitative design, based on interviews with educators and rooted in critical realism. Forty‐eight participants were recruited from seven universities of applied sciences and two vocational colleges in Finland, with the assistance of contact persons nominated by the institutions. The inclusion criterion for participation was employment by an educational institution as a part‐time or full‐time, social and/or healthcare educator. Data were collected in the period February–April 2018. The participants were interviewed in 16 focus groups with two to five participants per group. The acquired data were subjected to inductive content analysis, which yielded 506 open codes, 48 sub‐categories, nine categories and one main category. The educators’ competence was defined as a multidimensional construct, including categories of educators’ competences in practicing as an educator, subject, ethics, pedagogy, management and organisation, innovation and development, collaboration, handling cultural and linguistic diversity, and continuous professional development. Educators recognised the need for developing competence in innovation to meet rapid changes in a competitive and increasingly global sociopolitical environment. Enhancement of adaptability to rapid changes was recognised as a necessity. The findings have social value in identifying requirements to improve social and healthcare educators' competence by helping educational leadership to improve educational standards, construct a continuous education framework and create national and/or international curricula for teacher education degree programs to enhance the quality of education. We also suggest that educational leadership needs to establish, maintain and strengthen collaborative strategies to provide effective, adaptable support systems, involving educators and students, in their working practices.     

Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning

Background  

Although buprenorphine therapy has proved to be successful in opioid maintenance treatments, the drug is also widely abused in many countries by intravenous injection or sniffing (“snorting”). In Finland, buprenorphine is the most important abused opioid causing fatal poisonings.     

Occupational well-being of school staff members: a structural equation model

This study aimed to develop a theoretical basis for the promotion of school staff's occupational well-being. The 'Content Model for the Promotion of School Community Staff's Occupational Well-being' describes the four aspects of the promotion of occupational well-being ('working conditions', 'worker and work', 'working community' and 'professional competence') as well as the functionality and structure of the model. The content model was examined empirically by means of a structural equation model. The project was developed with school staff and occupational health nurses and implemented in 2001-2004. The target group consisted of the staff of 12 comprehensive schools in Eastern Finland in 2002 (n = 211) and 2004 (n = 266). The data were collected using a 'well-being at your work index' questionnaire at both times. A structural equation model for the school staff's occupational well-being, i.e. the 'Occupational Well-being of School Staff Model' (baseline OWSS Model: Study I in the year 2002), was produced. The model was tested with the 2004 data. Based on this, the model was further developed into the final OWSS Model (Study II). The theoretical Content Model for the Promotion of School Community Staff's Occupational Well-being can be used as a framework for planning, implementing and evaluating school staff's occupational well-being.     

Activation marker analysis of mononuclear cell infiltrates of oral lichen planus in situ

Monoclonal activation markers (Ia, Tac, T9, and 4F2) were used to detect the degree of activation of mononuclear cells in the inflammatory infiltrates of oral lichen planus in situ. In addition the specimens were stained with the following monoclonal antibodies: T4, T8, T11, M1, and pan-B. T-lymphocyte was the predominant cell type in the inflammatory infiltrates. According to the results of the activation marker analysis, the majority of the T-lymphocytes were resting. However, activated cytotoxic T8 and 4F2 T-cells were located close to damaged basal cells; this finding may suggest that they are responsible for the damage and supports the claim that a cell-mediated immune response participates actively in local pathogenetic mechanisms in oral lichen planus.     

Intensive chemotherapy with combinations containing anthracyclines for refractory and relapsing multiple myeloma. Finnish Leukaemia Group

94 patients with refractory multiple myeloma were treated in a multicentre trial with combinations of cytotoxic drugs including anthracyclines. All were refractory to a 5-drug combination containing 3 alkylating agents, vincristine and methylprednisolone (MOCCA). With a combination of epirubicin and iphosphamide a 50% response was achieved in 9% of 22 patients. The response rate after schedule VAP (vincristine, doxorubicin and prednisolone) was 8% of 13 patients and that after schedule VAD (vincristine, doxorubicin and dexamethasone) 20% of 59 patients. The previous chemotherapy had lasted for less than 12 months in 13 cases from among all these patients, and 5 of these (38%) responded. In contrast, there were only 10 responders (12%) among the 81 patients with longer previous chemotherapy.     

3′RNA and whole-genome sequencing of archival uterine leiomyomas reveal a tumor subtype with chromosomal rearrangements affecting either HMGA2, HMGA1, or PLAG1

Uterine leiomyomas, or fibroids, are very common smooth muscle tumors that arise from the myometrium. They can be divided into distinct molecular subtypes. We have previously shown that 3′RNA-sequencing is highly effective in classifying archival formalin-fixed paraffin-embedded (FFPE) leiomyomas according to the underlying mutation. In this study, we performed 3′RNA-sequencing with 111 FFPE leiomyomas previously classified as negative for driver alterations in mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2), and fumarate hydratase (FH) by Sanger sequencing and immunohistochemistry. This revealed 43 tumors that displayed expression features typically seen in HMGA2-positive tumors, including overexpression of PLAG1. We explored 12 such leiomyomas by whole-genome sequencing to identify their underlying genomic drivers and to evaluate the feasibility of detecting chromosomal driver alterations from FFPE material. Four tumors with significant HMGA2 overexpression at the protein-level served as controls. We identified chromosomal rearrangements targeting either HMGA2, HMGA1, or PLAG1 in all 16 tumors, demonstrating that it is possible to detect chromosomal driver alterations in archival leiomyoma specimens as old as 18 years. Furthermore, two tumors displayed biallelic loss of DEPDC5 and one tumor harbored a COL4A5–COL4A6 deletion. These observations suggest that instead of only HMGA2-positive leiomyomas, a distinct leiomyoma subtype is characterized by rearrangements targeting either HMGA2, HMGA1, or PLAG1. The results indicate that the frequency of HMGA2-positive leiomyomas may be higher than estimated in previous studies where immunohistochemistry has been used. This study also demonstrates the feasibility of detecting chromosomal driver alterations from archival FFPE material.