Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age.

Pre-existing SARS-CoV-2-reactive T cells have been identified in SARS-CoV-2-unexposed individuals, potentially modulating COVID-19 and vaccination outcomes. Here, we provide evidence that functional cross-reactive memory CD4+ T cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is established in early childhood, mirroring early seroconversion with seasonal human coronavirus OC43. Humoral and cellular immune responses against OC43 and SARS-CoV-2 were assessed in SARS-CoV-2-unexposed children (paired samples at age two and six) and adults (age 26 to 83). Pre-existing SARS-CoV-2-reactive CD4+ T cell responses targeting spike, nucleocapsid, and membrane were closely linked to the frequency of OC43-specific memory CD4+ T cells in childhood. The functional quality of the cross-reactive memory CD4+ T cell responses targeting SARS-CoV-2 spike, but not nucleocapsid, paralleled OC43-specific T cell responses. OC43-specific antibodies were prevalent already at age two. However, they did not increase further with age, contrasting with the antibody magnitudes against HKU1 (ß-coronavirus), 229E and NL63 (α-coronaviruses), rhinovirus, Epstein-Barr virus (EBV), and influenza virus, which increased after age two. The quality of the memory CD4+ T cell responses peaked at age six and subsequently declined with age, with diminished expression of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF), and CD38 in late adulthood. Age-dependent qualitative differences in the pre-existing SARS-CoV-2-reactive T cell responses may reflect the ability of the host to control coronavirus infections and respond to vaccination.

Methylphenidate for treating fatigue in palliative cancer care - effect and side effects in real-world data from a palliative care unit.

BACKGROUND: Methylphenidate can be used for the treatment of cancer-related fatigue (CRF), although randomized controlled trials have shown conflicting results. The aim of this study was to use 'real-world' data to evaluate the effect and side effects of using methylphenidate in palliative cancer care with a focus on the late palliative phase and dose-response. METHOD: A retrospective review of medical records from a palliative care unit in Sweden was performed to evaluate the effect and adverse events (AEs) of using methylphenidate to treat CRF. Univariable and multivariable regression was performed and odds ratio (OR) calculated. Adjustments were made for sex, age, cancer type, dose and starting treatment <4 weeks before death. RESULTS: Of the 2,419 screened patients, 112 had been treated with methylphenidate for CRF. The treatment was assessed as being effective in 51 patients (46%). Twenty-six patients (23%) experienced AEs that were generally mild, including anxiety, palpitations, and insomnia. Patients starting the treatment <4 weeks before death (n = 54) were less likely to have an effect from treatment compared to those starting earlier; adjusted OR 0.24 (95% CI 0.10-0.55). Doses of 20 mg and above were well-tolerated and had a higher frequency of effect in the crude data but not after adjustment for confounding factors. CONCLUSION: Methylphenidate is generally effective and well-tolerated for the treatment of CRF in palliative care. However, patients with a short life expectancy (<4 weeks) seem to benefit less from the treatment regardless of age, cancer type and dose.

Appetite and its association with mortality in patients with advanced cancer - a Post-hoc Analysis from the Palliative D-study.

BACKGROUND: Loss of appetite is a common nutrition symptom in patients with cancer. Understanding the trajectory of appetite could be of clinical use for prognostication in palliative cancer care. Our primary aim was to explore the association between self-assessed appetite and mortality in patients suffering from advanced cancer. Secondary aims included the relation between fatigue, albumin levels and CRP/albumin ratio and mortality. We also aimed to study potential sex-differences in the associations. METHODS: Post-hoc analyses were performed using data from the Palliative D-study comprising 530 patients with cancer admitted to palliative care. Appetite and fatigue were assessed with the Edmonton Symptom Assessment System (ESAS). Cox proportional hazards models were used to calculate Hazard ratios (HR) with 95% confidence intervals (CI) for exposures of appetite, fatigue, albumin and CRP/albumin ratio, and time from study inclusion to death or censoring. Analyses were also performed stratified by sex. RESULTS: The follow-up time ranged between 7 to 1420 days. Moderate and poor appetite were significantly associated with a higher mortality rate compared to reporting a good appetite; HR 1.44 (95%CI: 1.16-1.79) and HR 1.78 (95%CI: 1.39-2.29), respectively. A higher mortality rate was also seen among participants reporting severe fatigue compared to those reporting no fatigue; HR 1.84 (95%CI:1.43-2.36). Participants with low albumin levels (< 25 g/L) and those in the highest tertile of CRP/albumin ratio, had higher mortality rates, HR 5.35 (95%CI:3.75-7.63) and HR 2.66 (95%CI:212-3.35), compared to participants with high albumin levels (> 36 g/L) and those in lowest tertile of CRP/albumin ratio. These associations were more pronounced in men than in women. CONCLUSION: Poor appetite, severe fatigue, low albumin level and a high CRP/albumin ratio were associated with increased mortality rates among patients with advanced cancer. All these variables might be clinically useful for prognostication in palliative cancer care. TRIAL REGISTRATION: Clinicaltrial.gov. Identifier: NCT03038516;31, January 2017.

Variations in biomarkers of dyslipidemia and dysbiosis during the menstrual cycle: a pilot study in healthy volunteers.

BACKGROUND: Dyslipidemia in metabolic syndrome may introduce an underestimation of the risk for cardiovascular disease (CVD) using Low-Density Lipoprotein-Cholesterol (LDL-C) as a surrogate marker. Recently, non-High-Density Lipoprotein-Cholesterol (non-HDL-C), Apolipoprotein B (ApoB) and remnant-Cholesterol (remnant-C) have been suggested as better biomarkers for dyslipidemia. In addition, the microbial metabolites trimethylamine-N-oxide (TMAO), betaine and choline have been associated with CVD and suggested as markers for dysbiosis. There is a lack of knowledge on potential alterations in these biomarkers during the menstrual cycle. The aim of this single center, prospective non-interventional study, was to investigate variations in biomarkers of dyslipidemia and dysbiosis in healthy volunteers during the menstrual cycle. METHOD: Serum samples were collected from 17 healthy, regularly menstruating women during two menstrual cycles, including the follicular, ovulatory and luteal phases. Levels of lipoproteins, lipoprotein ratios and microbial metabolites were analyzed in a total of 90 samples (30 complete menstrual cycles). RESULTS: ApoB, ApoB/HDL and non-HDL-C/HDL ratios were significantly higher in the follicular phase compared to the ovulatory and luteal phases (p < 0.05). Remnant-C were higher during the luteal phase (p < 0.05). TMAO did not vary during the different phases and did not correlate with estrogen levels. CONCLUSION: Our data support that biomarkers for dyslipidemia vary during the menstrual cycle. Thus, to avoid an underestimation of cardiovascular risk, sampling during the follicular phase, when levels of pro-atherogenic lipids are higher, may be considered.

A comparative study on decision and documentation of refraining from resuscitation in two medical home care units in Sweden.

BACKGROUND: A decision to refrain from cardiopulmonary resuscitation (CPR) in the case of cardiac arrest is recommended in terminally ill patients to avoid unnecessary suffering at time of death. The aim of this study was to describe the frequency of decisions and documentation of "do not attempt cardiopulmonary resuscitation" (DNACPR) in two Medical Home Care Units in Stockholm. Unit A had written guidelines about how to document CPR-decisions in the medical records, including a requirement for a decision to be taken (CPR: yes/no) while Unit B had no such requirement. METHOD: The medical records for all patients in palliative phase of their disease at the two Units were reviewed. Data was collected on documentation of decisions about CPR (yes/no), DNACPR-decisions and documentation regarding whether the patient or next-of-kin had been informed about the DNACPR-decision. RESULTS: In the two Units, 316 and 219 patients in palliative phase were identified. In Unit A 100% of the patients had a CPR-decision (yes/no) compared to 79% in Unit B (p < 0.001). There was no statistically significant difference in DNACPR-decisions between the two Units, 43 and 37%. Documentation about informing the patient regarding the decision was significantly higher in Unit A, 53% compared to 14% at Unit B (p < 0.001). Documentation about informing the next-of-kin was also significantly higher at Unit A; 42% compared to 6% at Unit B (p < 0.001). CONCLUSION: Less than 50% of patients in palliative phase had a decision of DNACPR in two Medical Home Care Units in Stockholm. The presence of written guidelines and a requirement for a CPR-decision did not increase the frequency of DNACPR-decisions but was associated with a higher frequency of documentation of decisions and of information given to both the patients and the next-of-kin.

Vitamin D supplementation to persistent carriers of MRSA-a randomized and placebo-controlled clinical trial.

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to all beta-lactam antibiotics and can cause severe infections that are difficult to treat. Eradication strategies with conventional antibiotics are not always effective and alternative approaches are warranted. Here, we tested the hypothesis that daily supplementation with vitamin D for 12 months would reduce MRSA carriage rates among a group of persistent carriers. This was a double-blind, placebo-controlled randomized trial with n = 65 persistent MRSA carriers with 25-hydroxy vitamin D3 (25OHD) < 75 nmol/L, who were followed up with bacterial cultures at baseline and every 3 months for 1 year. The primary endpoint was the decline in MRSA positivity during the study period. The study was conducted in two MRSA outpatient clinics at the Karolinska University Hospital, Stockholm, Sweden. In total, n = 65 persistent MRSA carriers were randomized and n = 3 were lost to follow-up. Only patients deficient in vitamin D (< 75 nmol/L) were included. Vitamin D (4000 IU) or placebo/day was administered for 12 months. The decline in MRSA positivity was equal in the vitamin D and placebo group during the study period (OR, 1.00; 95% CI, 0.97-1.03; p = 0.928) and approximately 40% in both groups were MRSA-negative after 12 months. The vitamin D group produced 103 positive cultures out of 318 cultures (32.4%) from nose, throat, and perineum over the study period, whereas the placebo group produced 135/393 positive cultures (34.0%) (Fisher's exact test, p = 0.94). Vitamin D supplementation did not influence MRSA carriage. Thus, available data does not support vitamin D supplementation to persistent MRSA carriers.Trial registration: www.clinicaltrials.gov ; NCT02178488.

Vitamin D in Pain Management.

Vitamin D is a hormone synthesized in the skin in the presence of sunlight. Like other hormones, vitamin D plays a role in a wide range of processes in the body. Here we review the possible role of vitamin D in nociceptive and inflammatory pain. In observational studies, low vitamin D levels have been associated with increased pain and higher opioid doses. Recent interventional studies have shown promising effects of vitamin D supplementation on cancer pain and muscular pain-but only in patients with insufficient levels of vitamin D when starting intervention. Possible mechanisms for vitamin D in pain management are the anti-inflammatory effects mediated by reduced cytokine and prostaglandin release and effects on T-cell responses. The recent finding of vitamin D-mediated inhibition of Prostaglandin E2 (PGE2) is especially interesting and exhibits a credible mechanistic explanation. Having reviewed current literature, we suggest that patients with deficient levels defined as 25-hydroxyvitamin D (25-OHD) levels <30 nmol/L are most likely to benefit from supplementation, while individuals with 25-OHD >50 nmol/L probably have little benefit from supplementation. Our conclusion is that vitamin D may constitute a safe, simple and potentially beneficial way to reduce pain among patients with vitamin D deficiency, but that more randomized and placebo-controlled studies are needed before any firm conclusions can be drawn.

Statin treatment reduces the risk of hepatocellular carcinoma but not colon cancer-results from a nationwide case-control study in Sweden.

BACKGROUND: Several studies have indicated that statins may have anticarcinogenic effects. The aim of the present study was to investigate if statin treatment was associated with a reduced risk of hepatocellular carcinoma (HCC) or colon cancer. METHODS: A nationwide case-control study was carried out in which all cases of HCC and colon cancer in the Swedish population above 40 years of age between 1 July 2006 and 31 December 2010 were identified in the Swedish Cancer Register. For every case, five controls were selected and matched on age and sex. Data on statin use was extracted from the Swedish Prescribed Drug Register. We estimated risks using conditional logistic regression and adjusted for educational level, concomitant medications and comorbidity. RESULTS: Identified were 3994 cases of HCC and matched with 19.970 controls, and 21.143 cases of colon cancer were identified and matched with 105.715 controls. In the adjusted analysis, the odds ratio (OR) for HCC among statin users was 0.88 (95% confidence interval (CI) 0.81-0.96), and the OR for colon cancer was 1.04 (95%CI 1.00-1.08) compared with non-users. CONCLUSION: Statin use was associated with a modest decreased risk of HCC but did not influence the risk of colon cancer. Future randomized placebo-controlled trials in HCC high-risk patients are warranted to further investigate the possible prophylactic effect of statins in HCC.

Treatment with Antithrombotics in the Last Year of Life-Incidence of Bleeding and Side Effects After Deprescribing.

Background: Patients in palliative care are often treated with antithrombotics, even in the late stages of disease. Clear guidelines regarding deprescribing are lacking. Objective: The aims of this study were to investigate bleeding as a side effect of antithrombotic treatments the last year in life and map the timing of deprescribing. Methods: A retrospective cohort study was performed. All medical records were screened for deceased patients admitted to a palliative care unit in Stockholm, Sweden, over a 3-year period. Patients with antithrombotics were identified; data on bleeding, and on side effects due to deprescribing, were extracted from the medical records. Log-binomial models were used to explore factors associated with bleeding. Results: Of 1501 patients, 897 were treated with antithrombotics during the last year of life (mean age 75 years, 41% women). Of these, 56% continued treatment up until the last 3 days of life. Of the 897 patients, 144 (16%) had at least one bleeding during the treatment. The risk for bleeding was significantly higher for men with prostate cancer compared to other cancer forms, adjusted relative risk 1.9 (95% CI 1.1-3.2). No difference in risk for bleeding was found between sex, age groups, type of antithrombotics, or indication. Two patients (0.2%) developed strokes after antithrombotics were deprescribed. Conclusions: Treatment with antithrombotics during the last year of life is associated with a high risk of bleeding. In this cohort, men with prostate cancer seemed to have more side effects of bleeding than other groups. Few experienced side effects from deprescribing.

Age and co-morbidities as independent risk factors of infections leading to hospital admission in the last year of life among the elderly: A retrospective registry-based study.

Background: The immune system declines with age, but the impact of chronological age may be affected by sex, co-morbidities, and sociodemographic factors. Objective: The article aims to study infections associated with hospital admission in the elderly in their last year of life and the impact of age, sex, co-morbidities, and sociodemographic factors. Method: A retrospective study based on registry data covering all care visits in Stockholm Region, Sweden, for 7 years was conducted. All deceased subjects with at least one hospital admission with infection as the main diagnosis in the last year of life were compared with subjects with no such admission. Subjects were categorized into three different age-groups 65-79, 80-89, and 90 years and above. Co-morbidity was measured by the Charlson Comorbidity Index (CCI) and sociodemographic factors were assessed using the 'Mosaic-system'. Subjects living in nursing homes were analyzed separately. Uni- and multivariable logistic regressions were conducted. Results: Of the 55,238 subjects in the study population, 14,192 (26%) had at least one hospital admission due to infection in the last year of life. The risk of having a severe infection increased with age, adjusted odds ratio (OR): 1.30 (1.25-1.36), and 1.60 (1.52-1.69) for the age-groups 80-89 and ≥ 90 compared to the age-group 65-79. The most important factor for infection was a high co-morbidity score; adjusted OR: 1.75 (1.68-1.82). Male sex and living in a less affluent area were weaker risk factors for infections. Conclusion: Chronological age and co-morbidities are independent risk factors of infections associated with hospital admission in the last year in life while male sex and sociodemographic factors have less impact.

Five-Year Follow-Up of Health-Related Quality of Life in Differentiated Thyroid Cancer Patients Treated with Total Thyroidectomy and Radioiodine in Sweden: A Nationwide Prospective Cohort Study.

Background: Despite a good prognosis, survivors of differentiated thyroid cancer (DTC) may have reduced health-related quality of life (HRQOL) many years after treatment, and it is unclear how suppression of thyroid-stimulating hormone (TSH) may contribute to HRQOL. This study investigated changes in HRQOL in the 5 years following DTC treatment, the association between HRQOL and TSH suppression, and how HRQOL compares to the general population. Methods: In this nationwide prospective cohort study, 487 patients with DTC were identified between 2012 and 2017 from all Swedish hospitals treating patients with DTC. Patients treated with total thyroidectomy and planned for radioiodine answered the Swedish version of the Short Form-36 Health Survey (SF-36) and a study specific questionnaire at treatment and after 1, 3, and 5 years. Summary measures for physical and mental QOL were derived from the SF-36, and TSH values were collected from patient records. To study changes in HRQOL over time, linear mixed models were fitted on multiply imputed data, with all patients and measurement points included in the model. Results: In total, 351 patients consented to participate in the study. In the 5 years following DTC treatment, physical QOL did not change significantly with time, while mental QOL improved by on average 0.61 (p < 0.001) per year. TSH levels were not predictive of either physical or mental QOL, or their change over time. At 5 years, there was a significant difference in physical and mental QOL compared with the Swedish general population, but effect sizes were small (Cohen's d = 0.29 and -0.21, respectively). The SF-36 domains general health, vitality, social functioning, and mental health were lower at 5 years compared with the general population (difference 8.7-13.3), and these differences were clinically significant. Conclusions: The mental component of HRQOL improves over time following DTC treatment. HRQOL in patients with DTC is not explained by TSH suppression. Although overall differences in physical and mental HRQOL compared with the general population were small 5 years after treatment, several specific psychosocial HRQOL domains were clinically meaningfully reduced. Psychosocial health issues should be screened for during DTC follow-up.

Patient experiences of randomised placebo-controlled trial participation during end-of-life palliative cancer care.

BACKGROUND: Performing clinical trials in palliative cancer care is known to be challenging. OBJECTIVE: This study aimed to explore how patients with advanced cancer experienced their participation in a randomised, placebo-controlled trial while receiving palliative cancer care at end of life. METHOD: A descriptive design with a qualitative approach was used. 14 patients who had participated in the 'Palliative-D' study were interviewed. Data were analysed using content analysis. RESULTS: Three categories were identified understanding the study design, willingness to participate and collaboration with the research team alongside standard care. Being randomised, with the risk of receiving placebo, was perceived as non-problematic since it was understood as being important for the quality of the research. Patients showed a willingness to participate for the sake of others and also for their own sake, hoping for a cure or at least to live as long as possible. Patients felt proud of being useful and contributing to research. Consent to participate was made autonomously without discussing with others. Patients considered the study design uncomplicated and well-integrated into the standard care. CONCLUSION: Study participation in a randomised, placebo-controlled trial can be a positive and meaningful experience for patients despite advanced cancer in end of life. Participation may support patients' autonomy and give hope, and therefore, might have a positive effect on quality of life. A carefully planned and simple study design, well integrated into standard care, can facilitate the feasibility of clinical studies in specialised palliative home care.

Simvastatin inhibits the core promoter of the TXNRD1 gene and lowers cellular TrxR activity in HepG2 cells.

Thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing redox-active enzyme that is thought to be important during carcinogenesis. We have recently shown that treatment with statins, HMGCoA reductase inhibitors, reduces the levels of TrxR1 in liver of both rat and human. The reduced TrxR1 levels were correlated with inhibited hepatocarcinogenesis in a rat model. The aim of the present study was to investigate if statins affect the activity of the human TXNRD1 core promoter, which guides expression of TrxR1, and if the effects by statins on TrxR1 expression in liver could be reproduced in a cellular model system. We found that simvastatin and fluvastatin decreased cellular TrxR activity in cultured human liver-derived HepG2 cells with approximately 40% (p<0.05). Simvastatin, but not fluvastatin or atorvastatin, also reduced the TXNRD1 promoter activity in HepG2 cells by 20% (p<0.01). In line with this result, TrxR1 mRNA levels decreased with about 25% in non-transfected HepG2 cells upon treatment with simvastatin (p<0.01). Concomitant treatment with mevalonate could not reverse these effects of simvastatin, indicating that other mechanisms than HMGCoA reductase inhibition was involved. Also, simvastatin did not inhibit sulforaphane-derived stimulation of the TXNRD1 core promoter activity, suggesting that the inhibition by simvastatin was specific for basal and not Nrf2-activated TrxR1 expression. In contrast to simvastatin, the two other statins tested, atorvastatin or fluvastatin, did not influence the TrxR1 mRNA levels. Thus, our results reveal a simvastatin-specific reduction of cellular TrxR1 levels that at least in part involves direct inhibitory effects on the basal activity of the core promoter guiding TrxR1 expression.

Antagonistic effects of selenium and lipid peroxides on growth control in early hepatocellular carcinoma.

UNLABELLED: Activation of the activator protein 1 (AP-1) transcription factor as well as increased serum levels of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 predict poor prognosis of patients with hepatocellular carcinomas (HCCs). Moreover, HCC patients display reduced selenium levels, which may cause lipid peroxidation and oxidative stress because selenium is an essential component of antioxidative glutathione peroxidases (GPx). We hypothesized that selenium-lipid peroxide antagonism controls the above prognostic markers and tumor growth. (1) In human HCC cell lines (HCC-1.2, HCC-3, and SNU398) linoleic acid peroxide (LOOH) and other prooxidants enhanced the expression of VEGF and IL-8. LOOH up-regulated AP-1 activation. Selenium inhibited these effects. This inhibition was mediated by glutathione peroxidase 4 (GPx4), which preferentially degrades lipid peroxides. Selenium enhanced GPx4 expression and total GPx activity, while knock-down of GPx4 by small interfering RNA (siRNA) increased VEGF, and IL-8 expression. (2) These results were confirmed in a rat hepatocarcinogenesis model. Selenium treatment during tumor promotion increased hepatic GPx4 expression and reduced the expression of VEGF and of the AP-1 component c-fos as well as nodule growth. (3) In HCC patients, increased levels of LOOH-related antibodies (LOOH-Ab) were found, suggesting enhanced LOOH formation. LOOH-Ab correlated with serum VEGF and IL-8 and with AP-1 activation in HCC tissue. In contrast, selenium inversely correlated with VEGF, IL-8, and HCC size (the latter only for tumors smaller than 3 cm). CONCLUSION: Reduced selenium levels result in accumulation of lipid peroxides. This leads to enhanced AP-1 activation and consequently to elevated expression of VEGF and IL-8, which accelerate the growth of HCC. Selenium supplementation could be considered for investigation as a strategy for chemoprevention or additional therapy of early HCC in patients with low selenium levels.

Atorvastatin treatment induces uptake and efflux transporters in human liver.

The metabolism and disposition of statins are highly dependent on different cytochrome P450 enzymes, such as CYP3A4 and CYP2C9, as well as membrane transporters SLCO1B1, SLCO2B1, ABCB1, and ABCG2. Interindividual gene expression differences among these enzymes may explain part of the variability in tolerance and effect for statin treatment. The aim of the present study was to investigate the effect of statin treatment on these genes in human liver tissue. Levels of CYP3A4, CYP2C9, SLCO1B1, SLCO2B1, ABCB1, and ABCG2 mRNA in liver tissue from a previously performed clinical trial in 29 patients randomized to treatment with placebo, 80 mg/day of atorvastatin, or 20 mg/day of fluvastatin for 4 weeks were measured using quantitative polymerase chain reaction. Treatment with atorvastatin (n = 10), but not with fluvastatin (n = 10), resulted in 3-fold higher expression of SLCO2B1 compared with placebo-treated patients (n = 9) (P < 0.05). Atorvastatin increased the expression of both ABCB1 and ABCG2 by more than 2-fold (P < 0.05). No difference was found in CYP2C9, CYP3A4, or SLCO1B1 mRNA expression in patients administered statins or those administered placebo. Premenopausal women (n = 8) had higher expression of CYP3A4 (P < 0.05) and lower expression of CYP2C9 (P < 0.05) compared with postmenopausal women (n = 10) and men (n = 11), respectively. Here we show for the first time that atorvastatin treatment leads to increased expression of the membrane transporters SLCO2B1, ABCB1, and ABCG2 in human liver tissue, which potentially may counteract the efficacy of the treatment, and our findings may cast light on the mechanisms of clinical problems with adverse reactions and drug interactions in statin treatment.

Serum levels of 25-hydroxyvitamin D and the CYP3A biomarker 4ß-hydroxycholesterol in a high-dose vitamin D supplementation study.

The primary aim was to study the relationship between individual serum levels of 25-hydroxyvitamin D and 4ß-hydroxycholesterol, which is an endogenous biomarker of the drug-metabolizing CYP3A enzymes. In addition, the relationship between this biomarker and inflammation, measured as C-reactive protein (CRP), was investigated. Serum samples were used from a recently performed clinical trial in patients with antibody deficiency or increased susceptibility to respiratory tract infections that were randomized to either placebo or high-dose (4000 IU/day) vitamin D for 12 months. One hundred sixteen patients were included in the final analyses, and serum samples collected 6 months after study start were analyzed. At this time point, 25-hydroxyvitamin D levels were found to range between 10 and 284 nM. Individual levels of 25-hydroxyvitamin D as well as CRP were compared with 4ß-hydroxycholesterol levels. In addition, all participants were genotyped for two polymorphisms (Taq1 and Foq1) in the vitamin D receptor gene. There was no significant correlation between individual serum levels of 25-hydroxyvitamin D and 4ß-hydroxycholesterol. However, a moderate, but statistically significant, negative correlation between CRP and 4ß-hydroxycholesterol levels was observed. This study in patients with highly variable serum levels of 25-hydroxyvitamin D could not reveal any relationship between vitamin D and 4ß-hydroxycholesterol, an endogenous biomarker of CYP3A activity. However, the negative correlation between CRP and 4ß-hydroxycholesterol supports earlier experimental results that inflammation may suppress hepatic CYP3A activity, a finding of potentially high clinical relevance that warrants further exploration.

Comparison of endogenous 4ß-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin.

CYP3A4, considered the most important enzyme in drug metabolism, is often involved in drug-drug interactions. When developing new drugs, appropriate markers for detecting CYP3A4 induction are needed. Our study compared endogenously formed 4ß-hydroxycholesterol with the midazolam clearance in plasma and the 6ß-hydroxycortisol/cortisol ratio in urine as markers for CYP3A4 induction. To this end, we performed a clinical trial in which 24 healthy subjects were randomized to 10, 20, or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A4 induction. The CYP3A4 induction could be detected even at the lowest dose of rifampicin (10 mg) via the estimated midazolam clearance, the 4ß-hydroxycholesterol ratio (both P < 0.01), and the 6ß-hydroxycortisol ratio (P < 0.05). For the three dosing groups (10, 20, and 100 mg), the median fold induction from baseline was 2.0, 2.6, and 4.0 for the estimated midazolam clearance; 1.3, 1.6, and 2.5 for the 4ß-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6ß-hydroxycortisol/cortisol ratio. In conclusion, the 4ß-hydroxycholesterol ratio is comparable to midazolam clearance as a marker of CYP3A4 induction, and each may be used to evaluate CYP3A4 induction in clinical trials evaluating drug-drug interactions for new drugs.

Influence of simvastatin on the thromboxane and prostacyclin pathways, in vitro and in vivo.

3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) are believed to exert beneficial effects against cardiovascular disease beyond correction of dyslipidemia. The aim of this combined in vitro and in vivo study was to investigate the influence of the commonly used simvastatin on prostacyclin and thromboxane A2, 2 prostaglandins with different cardiovascular effects, normally in homeostatic balance in the circulatory system. Single-dose administration of simvastatin significantly decreased urinary prostacyclin excretion of healthy volunteers (P < 0.01) and increased the ratio between thromboxane A2 and prostacyclin (2-fold increase, P < 0.01), as assessed by enzyme immunoassays of the corresponding metabolites in urine. Human vascular endothelial cells, exposed to corresponding concentrations of simvastatin and assayed in the same way, reduced the release of prostacyclin about 40% (P < 0.05), altered the transcriptional expression of cyclooxygenase and prostacyclin synthase as analyzed by real-time polymerase chain reaction, and reduced the prostacyclin synthase promoter activity by 50% (P < 0.05), evaluated in a luciferase reporter system. We speculate that simvastatin shifts the balance between thromboxane A2 and prostacyclin in favor of the thromboxane pathway in vivo, and after exposure to clinically relevant concentrations in vitro. This may have pathophysiological implications by promoting a prothrombotic state in the blood vessels.

Interface management of pharmacotherapy. Joint hospital and primary care drug recommendations.

PURPOSE: In September 2012 an interactive course on the "Interface Management of Pharmacotherapy" was organized by the Stockholm Drug and Therapeutics Committee in cooperation with Department of Clinical Pharmacology at Karolinska Institutet and at Karolinska University Hospital in Stockholm, Sweden, in collaboration with the WHO. The basis for the course was the "Stockholm model" for the rational use of medicines but also contained presentations about successful models in interface management of pharmacotherapy in other European countries. METHODS: The "Stockholm model" consists of 8 components: 1) Independent Drug and Therapeutics Committee with key role for respected drug experts with policy for "interest of conflicts", 2) The "Wise List", recommendations of medicines jointly for primary and hospital care, 3) Communication strategy with continuous medical education, 4) Systematic introduction of new expensive medicines, 5) E-pharmacological support at "point of care", 6) Methods and tools for follow-up of medicines use, 7) Medicines policy strategy and 8) Operative resources. RESULTS: The course highlighted the importance of efficient and targeted communication of drug recommendations building on trust among prescribers and patients for the guidelines to achieve high adherence. Trust is achieved by independent Drug and Therapeutics Committees with a key role for respected experts and a strict policy for "conflicts of interest". Representations of GPs are also crucial for successful implementation, being the link between evidence based medicine and practice. CONCLUSION: The successful models in Scotland and in Stockholm as well as the ongoing work in Catalonia were considered as examples of multifaceted approaches to improve the quality of medicine use across primary and hospital care.