Sick leave due to mental disorders, morbidity and mortality: a prospective study of discordant twin pairs.

PURPOSE: To investigate if sick leave due to mental disorders increases the risk of morbidity measured by inpatient and specialized outpatient care, and mortality among women and men, independent of familial factors. METHODS: An open cohort study of 4979 twin pairs discordant for sick leave due to mental disorders was conducted in 2005-2013. Twins were followed up in the cause of death and national patient registries until the end of study, emigration, death, and inpatient and specialized outpatient care. Conditional Cox proportional hazard regression, adjusting for the familial factors shared by the twins, was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). In case of non-proportional hazards, time-varying covariates were used. RESULTS: Sick leave due to mental disorders increased the risk for inpatient care among men (HR: 1.90, CI 1.66-2.17) and women (HR: 1.39, CI 1.27-1.51). For men, the risk of outpatient care was higher the first 2 years (HR: 2.08, CI 1.87-2.31), after which it was attenuated (HR: 1.32, CI 1.02-1.70). For women, the HR was 1.57 (CI 1.47-1.68) for the whole study time. There was an increased risk of death among men (HR: 2.91, CI 1.70-4.99), but not among women (HR: 0.84, CI 0.53-1.35). CONCLUSIONS: Sick leave due to mental disorders was a risk factor for mortality for men only, and increased the risk of inpatient and specialized outpatient care among both women and men, but the risks were higher for men when stratifying for sex.

Comparison of filgrastim, pegfilgrastim, and lipegfilgrastim added to chemotherapy for mobilization of CD34+ cells in non-Hodgkin lymphoma patients.

BACKGROUND: Data are limited on the long-acting granulocyte-colony stimulating factors (G-CSFs) pegfilgrastim (PEG) and lipegfilgrastim (LIPEG) compared with filgrastim (FIL) regarding the mobilization efficiency of CD34+ cells, graft cellular composition, and engraftment. STUDY DESIGN AND METHODS: In this prospective nonrandomized study, 36 patients with non-Hodgkin lymphoma received FIL, 67 received PEG, and 16 patients received LIPEG as a cytokine after chemotherapy. We analyzed the mobilization and collection of CD34+ cells, cellular composition of blood grafts, and hematologic recovery after auto-SCT according to the type of G-CSF used. RESULTS: Patients in the LIPEG group had fewer apheresis sessions (1 vs. 2, p = 0.021 for FIL and p = 0.111 for PEG) as well as higher median blood CD34+ cell counts at the start of the first apheresis (LIPEG 74 × 106 /L vs. FIL 31 × 106 /L, p = 0.084 or PEG 27 × 106 /L, p = 0.021) and CD34+ yields of the first apheresis (FIL 5.1 × 106 /kg vs. FIL 2.3 × 106 /kg, p = 0.105 or PEG 1.8 × 106 /kg, p = 0.012). Also, the costs associated with G-CSF mobilization and apheresis were lower in the LIPEG group. The graft composition was comparable except for the higher infused CD34+ cell counts in the LIPEG group. The engraftment kinetics were significantly slower in the FIL group. CONCLUSION: LIPEG appears to be more efficient compared with PEG after chemotherapy to mobilize CD34+ cells for auto-SCT demonstrated as fewer sessions of aphereses needed as well as 2.8-fold CD34+ cell yields on the first apheresis day. Early hematologic recovery was more rapid in the LIPEG group. Thus further studies on LIPEG in the mobilization setting are warranted.

Preemptive plerixafor injection added to pegfilgrastim after chemotherapy in non-Hodgkin lymphoma patients mobilizing poorly.

Filgrastim is usually combined with chemotherapy to mobilize hematopoietic progenitor cells in non-Hodgkin lymphoma (NHL) patients. Limited information is available on the efficacy of a preemptive plerixafor (PLER) injection in poor mobilizers after chemotherapy and pegfilgrastim. In this prospective study, 72 patients with NHL received chemotherapy plus pegfilgrastim, and 25 hard-to-mobilize patients received also PLER. The usefulness and efficacy of our previously developed algorithm for PLER use in pegfilgrastim-containing mobilization regimen were evaluated as well as the graft cellular composition, hematological recovery, and outcome after autologous stem cell transplantation (auto-SCT) according to the PLER use. A median 3.4-fold increase in blood CD34+ cell counts was achieved after the first PLER dose. The minimum collection target was achieved in the first mobilization attempt in 66/72 patients (92%) and 68 patients (94%) proceeded to auto-SCT. An algorithm for PLER use was fulfilled in 76% of the poor mobilizers. Absolute numbers of T-lymphocytes and NK cells were significantly higher in the PLER group, whereas the number of CD34+ cells collected was significantly lower. Early neutrophil engraftment was slower in the PLER group, otherwise hematological recovery was comparable within 12 months from auto-SCT. No difference was observed in survival according to the PLER use. Chemotherapy plus pegfilgrastim combined with preemptive PLER injection is an effective and convenient approach to minimize collection failures in NHL patients intended for auto-SCT. A significant effect of PLER on the graft cellular composition was observed, but no difference in outcome after auto-SCT was detected.

Synergistic effect between back pain and common mental disorders and the risk of future disability pension: a nationwide study from Sweden.

BACKGROUND: The aim of this study was to analyse a possible synergistic effect between back pain and common mental disorders (CMDs) in relation to future disability pension (DP). METHOD: All 4,823,069 individuals aged 16-64 years, living in Sweden in December 2004, not pensioned in 2005 and without ongoing sickness absence at the turn of 2004/2005 formed the cohort of this register-based study. Hazard ratios (HRs) and 95% confidence intervals (CIs) for DP (2006-2010) were estimated. Exposure variables were back pain (M54) (sickness absence or inpatient or specialized outpatient care in 2005) and CMD (F40-F48) [sickness absence or inpatient or specialized outpatient care or antidepressants (N06a) in 2005]. RESULTS: HRs for DP were 4.03 (95% CI 3.87-4.21) and 3.86 (95% CI 3.68-4.04) in women and men with back pain. HRs for DP in women and men with CMD were 4.98 (95% CI 4.88-5.08) and 6.05 (95% CI 5.90-6.21). In women and men with both conditions, HRs for DP were 15.62 (95% CI 14.40-16.94) and 19.84 (95% CI 17.94-21.94). In women, synergy index, relative excess risk due to interaction, and attributable proportion were 1.24 (95% CI 1.13-1.36), 0.18 (95% CI 0.11-0.25), and 2.08 (95% CI 1.09-3.06). The corresponding figures for men were 1.45 (95% CI 1.29-1.62), 0.29 (95% CI 0.22-0.36), and 4.21 (95% CI 2.71-5.70). CONCLUSIONS: Co-morbidity of back pain and CMD is associated with a higher risk of DP than either individual condition, when added up, which has possible clinical implications to prevent further disability and exclusion from the labour market.

Sickness absence due to back pain or depressive episode and the risk of all-cause and diagnosis-specific disability pension: A Swedish cohort study of 4,823,069 individuals.

BACKGROUND: The aim of this study was to investigate the associations between sickness absence due to back pain or depressive episode with future all-cause and diagnosis-specific disability pension, while adjusting for comorbidity and socio-demographics, for all and stratifying for sex. METHOD: In total, 4,823,069 individuals aged 16-64 years, living in Sweden at the end of 2004, not on old-age or disability pension in 2005 and without ongoing sickness absence at the turn of 2004/2005 formed the study population. Crude and adjusted hazard ratios (HRs) for all-cause and diagnosis-specific disability pension (2006-2010) in relation to diagnosis-specific sickness absence with sickness benefits paid by the Social Insurance Agency were estimated using Cox regression. RESULTS: The HR for all-cause disability pension was 7.52 (7.25-7.52) in individuals with an incident sick-leave spell due to back pain, compared to individuals without sickness absence in 2005 in the fully adjusted (socio-demographics and comorbidity) model. The fully adjusted (multivariate) HRs for diagnosis-specific disability pension were musculoskeletal diagnoses 23.87 (22.75-25.04), mental 2.49 (2.27-2.73) or all other diagnoses, 3.44 (3.17-3.75). In individuals with an incident sick-leave spell due to a depressive episode in 2005, the multivariate adjusted HR for all-cause disability pension was 12.87 (12.42-13.35), while the multivariate HRs for disability pension due to musculoskeletal diagnoses were 4.39 (3.89-4.96), for mental diagnoses 25.32 (24.29-26.38) and for all other somatic diagnoses 3.44 (3.09-3.82). Men who were sickness absent due to a depressive episode had a higher HR for disability pension compared to women. CONCLUSION: Results indicate that sickness absence due to a depressive episode or back pain is a strong risk factor for a future disability pension due to mental, musculoskeletal or other somatic diagnoses.

Incidence of disability pension and associations with socio-demographic factors in a Swedish twin cohort.

PURPOSE: The incidence of disability pension (DP), especially due to mental diagnoses, has increased in many countries, but knowledge of socio-demographic risk factors for DP is limited. Further, the influences of genetics and early-life factors (jointly called familial factors) on these associations remain to be studied. The aims were to study incidence of DP (due to all and mental diagnoses) and associations with socio-demographic factors, and also to establish whether associations differ with DP diagnosis and sex, and are influenced by familial factors. METHODS: A prospective cohort study of all twins born in 1928-1958 (n = 52,609) in Sweden was conducted. The twins were followed from 1993 to 2008 regarding DP. Cox proportional hazard models were applied. RESULTS: The cumulative incidence of DP was 17 %. Of all the DP diagnoses 20 % were mental. Higher age (≥45 years), being a woman or unmarried, and/or living in a semi-urban area were risk factors for DP. Low education, being a blue-collar worker or being self-employed predicted either higher (all diagnoses) or lower (mental diagnoses) risk of DP. Rural areas were associated with DP due to mental diagnoses. The estimates varied for men and women. After adjustment for familial factors the associations of DP with education and marital status were attenuated and no longer significant. Similar results were apparent for DP due to mental diagnoses and socioeconomic status. CONCLUSIONS: Familial factors may select individuals into some of the established risk environments for DP. Studies investigating the causes of DP need to take such confounding into account.

The effect of microenvironmental CD40 signals on TRAIL- and drug-induced apoptosis in follicular lymphoma cells.

Follicular lymphoma (FL) cells are malignant counterparts of germinal centre (GC) B cells. Microenvironment of FL B cells has an important role in the progression of FL and might also have an impact on the treatment of FL. CD40 is an important mediator of microenvironmental survival signals in GCs. Here we studied responses of CD40 signalling on TRAIL-, dexamethasone- and doxorubicin-induced apoptosis in three human FL cell lines. In two of the FL cell lines, CD40 protected cells from apoptosis which was entirely dependent on the activation of NF-kappaB. In one of the FL cell lines, CD40 induced apoptosis itself. However, inhibition of NF-kappaB induced apoptosis in all three FL cell lines. Therefore, our results indicate that inhibitors of NF-kappaB or critical downstream anti-apoptotic targets of NF-kappaB instead of blocking CD40 antibodies in combination with TRAIL or other cytotoxic agents should be considered in the treatment of FL in order to prevent the protective effect of the microenvironment.

Feedback regulation of mitochondria by caspase-9 in the B cell receptor-mediated apoptosis.

During the germinal centre reaction (GC), B cells with non-functional or self-reactive antigen receptors are negatively selected by apoptosis to generate B cell repertoire with appropriate antigen specificities. We studied the molecular mechanism of Fas/CD95- and B cell receptor (BCR)-induced apoptosis to shed light on the signalling events involved in the negative selection of GC B cells. As an experimental model, we used human follicular lymphoma (FL) cell line HF1A3, which originates from a GC B cell, and transfected HF1A3 cell lines overexpressing Bcl-x(L), c-FLIP(long) or dominant negative (DN) caspase-9. Fas-induced apoptosis was dependent on the caspase-8 activation, since the overexpression of c-FLIP(long), a natural inhibitor of caspase-8 activation, blocked apoptosis induced by Fas. In contrast, caspase-9 activation was not involved in Fas-induced apoptosis. BCR-induced apoptosis showed the typical characteristics of mitochondria-dependent (intrinsic) apoptosis. Firstly, the activation of caspase-9 was involved in BCR-induced DNA fragmentation, while caspase-8 showed only marginal role. Secondly, overexpression of Bcl-x(L) could block all apoptotic changes induced by BCR. As a novel finding, we demonstrate that caspase-9 can enhance the cytochrome-c release and collapse of mitochondrial membrane potential (DeltaPsi(m)) during BCR-induced apoptosis. The requirement of different signalling pathways in apoptosis induced by BCR and Fas may be relevant, since Fas- and BCR-induced apoptosis can thus be regulated independently, and targeted to different subsets of GC B cells.

CD45RA and RO isoforms have distinct effects on cytokine- and B-cell-receptor-mediated signalling in human B cells.

The common leucocyte antigen, CD45, is widely expressed on the surface of lymphocytes. In T and B cells, CD45 has an important role in the early events of receptor signalling. However, the role of various CD45 isoforms in B-cell receptor (BCR)- and cytokine-induced signalling and proliferation is still unclear. In the present study, we establish two follicular lymphoma cell lines expressing either CD45RA (HF28RA) or CD45R0 (HF28R0) isoforms. It was observed that the two isoforms had distinct effects on BCR- or cytokine-induced cellular proliferation. BCR stimulation significantly increased the proliferation of HF28R0 cells, in contrast to a decreased proliferation of HF28RA cells. Moreover, proliferation of HF28R0 cells significantly increased after the addition of interleukin-2 (IL-2), IL-4, IL-6, IL-10, IL-12, IL-13, IL-15, interferon-gamma and tumour necrosis factor-alpha cytokines, whereas most of these cytokines significantly inhibited the proliferation of HF28RA cells. In addition, the cell lines had their individual cytokine mRNA expression profiles after BCR stimulation. We also analysed the effect of CD45 isoforms on intracellular signalling after BCR stimulation. It was found out that the kinetics of ERK1/2 MAP kinase phosphorylation was clearly faster in HF28R0 than in HF28RA cells. The phosphorylation of other analysed MAP kinases or PTKs was very similar in the cell lines.

Effects of oral and transdermal estradiol administration on levels of sex hormone-binding globulin in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.

SHBG, the most important transport protein for sex steroids, is produced in the liver under the control of estrogen action. In a randomized, double-blind, prospective crossover study we compared basal levels of serum SHBG and their responses to increasing doses of oral and transdermal estradiol (E2), followed by E2 plus oral progestin (medroxyprogesterone acetate [MPA]), in 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), which could affect the synthesis of SHBG. Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 plus MPA combination were assayed for SHBG and E2. Basal levels of SHBG showed no difference between the study groups. Oral but not transdermal E2 increased SHBG concentrations by 67-171% in the control group, but the response was smaller (42-121%) in the ICP group. Addition of MPA decreased SHBG levels by 14-18% in both groups during both treatments. In conclusion, a history of ICP is associated with blunted responses of SHBG to oral estrogen.

Levels of serum C-reactive protein during oral and transdermal estradiol in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.

Liver dysfunction may affect the production and release of C-reactive protein (CRP). We designed a double-blind prospective crossover study involving 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), where we compared the basal levels of CRP and their responses to increasing doses of oral and transdermal estradiol (E2), followed by addition of oral medroxyprogesterone acetate (MPA). Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 + MPA combination were assayed for CRP, estrogens, and liver enzymes. There was no difference in basal CRP between the study groups. Both regimens (oral and transdermal E2) were accompanied by significant rises in estrone and E2 concentrations; the former were 16 times higher during the oral than during the transdermal regimen. Oral E2 elevated CRP dose dependently, and this response was unaffected by a history of ICP or the use of MPA. The activities of liver transaminases varied but were in normal ranges during E2 use, in women with and without a history of ICP. In conclusion, the synthesis of CRP is not affected by a history of ICP. It is readily and dose dependently stimulated by oral but not by transdermal E2 in as soon as 2 wk.

Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy.

BACKGROUND AND AIMS: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease. PATIENTS AND METHODS: Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3. RESULTS: The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families. CONCLUSIONS: These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.

Repeatability of lifetime exercise reporting.

The purpose of the study was to determine the reliability of lifetime exercise data obtained through a structured interview. Interviews were conducted in 1992-1993 and repeated in 1997 in 150 monozygotic male twins, aged 35-69 years, from the population-based Finnish Twin Cohort. Exercise mode, frequency, duration, intensity and period of participation were solicited for each regularly performed exercise from 12 years of age to the present. Questions related to the most common exercise mode reported in the initial interview were repeated in all subjects and the entire exercise interview was repeated in a subgroup of 38 subjects. The repeatability was highest for exercise years and mean hours/ week by mode for the most commonly performed exercise (Mean ICC=0.63-0.90), and for the sum of all lifetime exercises reported (Mean ICC = 0.69-0.73). The lowest repeatability was found for exercise intensity (Mean Kappa = 0.33-0.48). Similarly poor reliability was found for whether or not exercise was performed at a competitive level (Mean Kappa = 0.25-0.63). Overall, the structured interview of lifetime exercise was most repeatable for years of exercise and mean hours/week. Thus, these exposure variables should be considered in retrospective studies of exercise effects.