Life events, mood, mental strain and cardiovascular risk factors in Swedish middle-aged men. Data from the Swedish part of the Renault/Volvo Coeur Study

The associations between life events, mood, mental strain andcardiovascular risk factors were investigated in the Renault/VolvoCoeur Study. About 1,000 men, blue-collar and white-collar workers,were asked by means of interview-administered questionnairesabout life events experienced during the year preceding thescreening, about mood and mental strain and about smoking, alcoholconsumption and exercise habits. Blood pressure, concentrationof serum lipids and blood glucose, and anthropometric measureswere determined in a screening procedure. Negative life events,especially work-related, were associated with depressed moodand mental strain but not with elevation of biological riskfactors such as elevated blood pressure and serum lipids. Depressedmood and mental strain were related to increased tobacco consumptionin blue-collar workers and increased alcohol consumption inwhite-collar workers.     

Facial Reactions to Facial Expressions

Previous research has demonstrated that different patterns of facial muscle activity are correlated with different emotional states. In the present study subjects were exposed to pictures of happy and angry facial expressions, in response to which their facial electromyographic (EMG) activities, heart rate (HR), and palmar skin conductance responses (SCRs) were recorded. It was found that happy and angry faces evoked different facial EMG response patterns, with increased zygomatic region activity to happy stimuli and increased corrugator region activity to angry stimuli. Furthermore, both happy and angry faces evoked HR decelerations and similar SCR magnitudes. The results are interpreted as suggesting that facial EMG recordings provide a method for distinguishing between response patterns to “positive” and “negative” emotional visual stimuli.     

Computerised assistance for warfarin dosage — Effects on treatment quality

BackgroundWell-managed warfarin treatment with a high time in therapeutic range (TTR) corresponds to fewer bleedings or thromboembolic complications. Many small centres manage their warfarin dosing manually, with little or no knowledge of their treatment quality as measured by TTR. AuriculA is a Swedish National web-based anticoagulation dosing system.Our hypothesis was that the web based dosing system, compared to manual dosing, would improve the TTR.MethodsRetrospective cohort study of medical records from patients with atrial fibrillation on warfarin treatment from two centres, with previously manual warfarin dosing regimens. Data for calculation of TTR was extracted manually from medical records from the time when using manual dosing and compared with the computerised regimen.ResultsIn centre 1, the mean TTR was significantly increased after the introduction of AuriculA, from 64.3% (95% CI 58.8–69.8) to 71.3% (95% CI 67.7–74.8), p = 0.03. In centre 2, a high TTR of 73.6% (95% CI 71.3–75.9) was maintained after the implementation, 74.0% (95% CI 71.6–76.3). INR tests were prescribed significantly more frequent after the introduction of AuriculA in both centres; 20% more often at centre 1 and 21% at centre 2.ConclusionComputerised dosing assistance within the Swedish national quality registry AuriculA improves or maintains a high treatment quality with warfarin as measured by TTR.     

Retinoic acid inhibits in vitro development of mast cells but has no marked effect on mature human skin tryptase- and chymase-positive mast cells

Stem cell factor plays a key role in the development of human mast cells via interaction with Kit receptor. We and other groups have previously shown that a number of cytokines can regulate the stem-cell-factor-dependent development of mast cells in vitro. In this study we investigated the effect of retinoic acid on human mast cells in vitro and in vivo. Retinoids are known to have strong modulatory effects on hematopoietic differentiation. We found that all-trans-retinoic acid, at concentrations as low as 1 nM, inhibits the stem-cell-factor-dependent differentiation of mast cells in vitro. This effect of retinoic acid was found to be on progenitor cells, whereas more mature mast cells were less affected. The use of specific agonists binding either to the RAR or the RXR nuclear receptors indicated involvement of both the RAR/RXR and RXR/RXR pathways in inhibiting mast cell differentiation. In contrast to the effects on mast cell progenitors, retinoic acid had no effect on the number of mature mast cells in skin organ cultures. Furthermore, topical treatment of normal skin with a retinoic-acid-containing cream caused an increase in the number of tryptase-positive mast cells, whereas the numbers of the major cutaneous mast cell type, tryptase- and chymase-positive mast cells, remained unaffected. Our results suggest that retinoic acid suppresses commitment of progenitor cells into the mast cell lineage and/or acts on early mast cell progenitors, whereas mature cutaneous mast cells are less susceptible to retinoic acid.     

The effect of paired stimuli on blink reflex latencies in normal subjects

Introduction: In this study we assessed the effect of paired stimuli on the latencies and amplitudes of the blink reflex. Methods: Blink reflexes were performed with single and paired (5‐ms interstimulus interval) stimuli in 47 patients. The changes in latencies between paired and single stimuli were calculated. Results: Paired stimulation produced two types of R1 waveform morphologies: single‐ and double‐peaked waveforms. Increases in R1 and contralateral R2 latencies with paired stimulation were significantly higher in those with single‐peaked R1 responses compared to those with double‐peaked R1 responses. Conclusions: Interpreting the blink reflex latencies using paired stimulation requires visualization of the R1 waveform morphology. A double‐peaked R1 response requires no change in normal latency values, but the latency of a single‐peaked R1 should be interpreted from the second shock artifact. The effect on the R2 latency is variable. Muscle Nerve, 2011     

IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells

Emerging evidence suggests the insulin-like growth factor-1 receptor (IGF-1R) to be an important mediator of tumor-cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R beta-chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 patients with MM. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G(2)/M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin, or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP down-regulated the IGF-1 RTK activity without inhibiting the insulin RTK activity. This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken together, we suggest that interfering with the IGF-1 RTK by using the cyclolignan PPP offers a novel and selective therapeutic strategy for MM.     

Effects of diabetes type 2 and metformin treatment in Swedish patients with colorectal cancer

The association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) has been thoroughly investigated and reports have demonstrated that the risk of CRC is increased in DM patients. The association between DM and the survival of patients with CRC is controversial. Evidence suggests that metformin with its anti-inflammatory effects is a protective factor against the development of CRC among DM patients and that metformin therapy is associated with a better prognosis in patients with DM. In our cohort, we did not find any associations between the presence of DM or metformin and cancer specific survival or any relation to plasma levels of a panel of 40 inflammatory factors and irisin. On the other hand, we identified that the insulin-like growth factor binding protein 7 single nucleotide polymorphism rs2041437 was associated with DM in CRC patients. The dominance of the T bearing genotypes in patients with DM was statistically significant (P = 0.038), with an odds ratio of 1.66 (95% confidence interval: 1.03-2.69).     

Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone

Circumvention of chemoresistance in the B-cell neoplasm multiple myeloma (MM) might be achieved by targeting certain intracellular signaling pathways crucial for survival of the malignant clone. The use of the macrolide rapamycin, selectively inhibiting the phosphoprotein mammalian target of rapamycin (mTOR) downstream of, for example, insulin-like growth factor-I receptor (IGF-IR), possibly represents such a molecular mode of therapy. By using a panel of MM cell lines we showed that rapamycin induced G0/G1 arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of cyclins D2 and D3. Interestingly, in primary, mainly noncycling MM cells, rapamycin, at clinically achievable concentrations, induced apoptosis. More important, rapamycin sensitized both MM cell lines and primary MM cells to dexamethasone-induced apoptosis. This effect was associated with a decreased expression of cyclin D2 and survivin. The phosphorylation of the serine/threonine kinase p70S6K at Thr389 and Thr421/Ser424 was down-regulated by rapamycin and/or dexamethasone. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the antiapoptotic effects of exogenously added IGF-I and interleukin 6 (IL-6) as well as their stimulation of p70S6K phosphorylation. The induction of apoptosis by rapamycin and dexamethasone despite the presence of survival factors was also demonstrated in primary MM cells, thus suggesting this drug combination to be active also in vivo.