Cerebrospinal fluid pro-inflammatory cytokines differentiate parkinsonian syndromes.

INTRODUCTION: Neuroinflammation has been established to be part of the neuropathological changes in Parkinson's disease (PD) and atypical parkinsonism (APD). Activated microglia play a key role in neuroinflammation by release of cytokines. Evidence of the disparity, if any, in the neuroinflammatory response between PD and APD is sparse. In this study, we investigated CSF cytokine profiles in patients with PD, multiple system atrophy (MSA), or progressive supranuclear palsy (PSP). METHODS: On a sensitive electrochemiluminescence-based platform (Quickplex, Meso Scale Discovery®), we examined a panel of C-reactive protein (CRP) and eight selected cytokines, IFN-γ, IL-10, IL-18, IL-1ß, IL-4, IL-6, TGF-ß1, and TNF-α, among patients with PD (n = 46), MSA (n = 35), and PSP (n = 39) or controls (n = 31). Additionally, CSF total tau protein levels were measured as a marker of nonspecific neurodegeneration for correlation estimates. RESULTS: CRP and the pro-inflammatory cytokines TNF-α, IL-1ß, and Il-6 were statistically significantly elevated in MSA and PSP patients compared to PD patients but not compared to control patients. No analytes differed statistically significantly between MSA and PSP patients. The best diagnostic discrimination, evaluated by ROC curve (AUC 0.77, p = 007, 95% CI 0.660-0.867), between PD and MSA patients was seen for a subset of analytes: CRP, TNF-α, IL-1ß, and IFN-γ. CONCLUSION: Among the investigated cytokines and CRP, we found a statistically significant increase of microglia-derived cytokines in MSA and PSP patients compared to PD patients.

Influence of aspirin and non-aspirin NSAID use on ovarian and endometrial cancer: Summary of epidemiologic evidence of cancer risk and prognosis.

Increasing evidence supports a role for aspirin use in reducing the incidence and mortality of several cancer types. This has spurred a new wave of interest in this widely used drug. In this review, we present and evaluate the epidemiologic evidence of the association between the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence and prognosis of ovarian and endometrial cancer. The evidence of a preventive effect of NSAID use on risk of ovarian or endometrial cancer is based primarily on results from observational studies and, consequently, is only suggestive. Overall, observational studies indicate modest reductions in risk of ovarian and endometrial cancer with aspirin use, whereas the results for non-aspirin NSAID use are equivocal. The strongest inverse associations have been reported for long-term consistent aspirin use, notably among subgroups of users (e.g., those with high body mass index). Few studies have evaluated the influence of NSAID use on the mortality of ovarian or endometrial cancer, and substantial heterogeneity of study characteristics and results preclude any conclusions. Additional studies of aspirin and non-aspirin NSAID use and ovarian or endometrial cancer risk and prognosis are warranted. In the present review, we discuss the importance of comprehensive exposure definitions (i.e., duration, timing, consistency and intensity/dose) and evaluation of potential effect modification according to user characteristics, with the aim of identifying women who may experience the largest benefit of aspirin or non-aspirin NSAID use on risk or prognosis of ovarian and endometrial cancer.

Hydrochlorothiazide use is strongly associated with risk of lip cancer.

BACKGROUND: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. OBJECTIVES: To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. METHODS: We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined potential confounders obtained from demographic, prescription and patient registries. RESULTS: Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI: 3.0-4.9) for high use (≥25 000 mg). There was a clear dose-response effect (P < 0.001), with the highest cumulative dose category of hydrochlorothiazide (≥100 000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or nondiuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. CONCLUSIONS: Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer.

Effects of nitrate supplementation in trained and untrained muscle are modest with initial high plasma nitrite levels.

Nitrate (NO3-) supplementation resulting in higher plasma nitrite (NO2-) is reported to lower resting mean arterial blood pressure (MAP) and oxygen uptake (VO2 ) during submaximal exercise in non-athletic populations, whereas effects in general are absent in endurance-trained individuals. To test whether physiologic effects of NO3- supplementation depend on local muscular training status or cardiovascular fitness, male endurance-trained cyclists (CYC, n=9, VO2 -max: 64±3 mL/min/kg; mean±SD) and recreational active subjects serving as a control group (CON, n=8, 46±3 mL/min/kg), acutely consumed nitrate-rich beetroot juice ([NO3-] ~9 mmol) (NIT) or placebo (PLA) with assessment of resting MAP and energy expenditure during moderate intensity (~50% VO2 -max) and incremental leg cycling (LEG-ex) and arm-cranking exercise (ARM-ex). NIT increased (P<.001) resting plasma NO3- by ~1200% relative to PLA. Plasma NO2- increased ~25% (P<.01) with a significant change only in CYC. LEG-ex VO2 (~2.60 L/min), ARM-ex VO2 (~1.14 L/min), and resting MAP (~87 mm Hg) remained unchanged for CYC, and similarly for CON, no changes were observed for LEG-ex VO2 (~2.03 L/min), ARM-ex VO2 (~1.06 L/min), or resting MAP (~85 mm Hg). VO2 -max was not affected by supplementation, but incremental test peak power was higher (P<.05) in LEG-ex for CYC in NIT relative to PLA (418±47 vs 407±46 W). In both CYC and CON, high initial baseline values and small increases in plasma NO2- after NIT may have lowered the effect of the intervention implying that muscular and cardiovascular training status is likely not the only factors that influence the physiologic effects of NO3- supplementation.

Pain prevalence in hospitalized children: a prospective cross-sectional survey in four Danish university hospitals.

BACKGROUND: Pain management in hospitalized children is often inadequate. The prevalence and main sources of pain in Danish university hospitals is unknown. METHODS: This prospective mixed-method cross-sectional survey took place at four university hospitals in Denmark. We enrolled 570 pediatric patients who we asked to report their pain experience and its management during the previous 24 hours. For patients identified as having moderate to severe pain, patient characteristics and analgesia regimes were reviewed. RESULTS: Two hundred and thirteen children (37%) responded that they had experienced pain in the previous 24 hours. One hundred and thirty four (24%) indicated moderate to severe pain and 43% would have preferred an intervention to alleviate the pain. In children hospitalized for more than 24 hours, the prevalence of moderate/severe pain was significantly higher compared to children admitted the same day. The single most common painful procedure named by the children was needle procedures, such as blood draw and intravenous cannulation. CONCLUSION: This study reveals high pain prevalence in children across all age groups admitted to four Danish university hospitals. The majority of children in moderate to severe pain did not have a documented pain assessment, and evidence-based pharmacological and/or integrative ('non-pharmacological') measures were not systematically administered to prevent or treat pain. Thus, practice changes are needed.

Inter-modal four-wave mixing study in a two-mode fiber.

We demonstrate efficient four-wave mixing among different spatial modes in a 1-km long two-mode fiber at telecommunication wavelengths. Two pumps excite the LP01 and LP11 modes, respectively, while the probe signal excites the LP01 mode, and the phase conjugation (PC) and Bragg scattering (BS) idlers are generated in the LP11 mode. For these processes we experimentally characterize their phase matching efficiency and bandwidth and find that they depend critically on the wavelength separation of the two pumps, in good agreement with the numerical study we carried out. We also confirm experimentally that BS has a larger bandwidth than PC for the optimum choice of the pump wavelength separation.

Interference patterns and extinction ratio of the diatom Coscinodiscus granii.

We report experimental and theoretical verification of the nature and position of multiple interference points of visible light transmitted through the valve of the centric diatom species Coscinodiscus granii. Furthermore, by coupling the transmitted light into an optical fiber and moving the diatom valve between constructive and destructive interference points, an extinction ratio of 20 dB is shown.

Peripherally applied opioids for postoperative pain: evidence of an analgesic effect? A systematic review and meta-analysis.

BACKGROUND: Opioids applied peripherally at the site of surgery may produce postoperative analgesia with few side effects. We performed this systematic review to evaluate the analgesic effect of peripherally applied opioids for acute postoperative pain. METHODS: We searched PubMed (1966 to June 2013), Embase (1980 to June 2013), and the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 6). Randomized controlled trials investigating the postoperative analgesic effect of peripherally applied opioids vs. systemic opioids or placebo, measured by pain intensity scores, consumption of supplemental analgesics and time to first analgesic were included. Trials with sample sizes of fewer than 10 patients per treatment group or trials with opioids administered intra-articularly or as peripheral nerve blocks were excluded. RESULTS: Data from 26 studies, including 1531 patients and 13 different surgical interventions were included. Clinical heterogeneity of the studies was substantial. Meta-analysis indicated statistically significant, but not clinically relevant, reductions in VAS score at 6-8 h (mean difference -4 mm, 95% CI: -6 to -2) and 12 h postoperatively (mean difference -5 mm, 95% CI: -7 to -3) for peripherally applied opioids vs. placebo and statistically significant increased time to first analgesic (mean difference 153 min, 95% CI: 41-265). When preoperative inflammation was reported (five studies), peripherally applied opioids significantly improved postoperative analgesia. CONCLUSION: Evidence of a clinically relevant analgesic effect of peripherally applied opioids for acute postoperative pain is lacking. The analgesic effect of peripherally applied opioids may depend on the presence of preoperative inflammation.

Statin use and risk for ovarian cancer: a Danish nationwide case-control study.

BACKGROUND: Limited data suggest that statin use reduces the risk for ovarian cancer. METHODS: Using Danish nationwide registries, we identified 4103 cases of epithelial ovarian cancer during 2000-2011 and age-matched them to 58,706 risk-set sampled controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for epithelial ovarian cancer overall, and for histological types, associated with statin use. RESULTS: We observed a neutral association between ever use of statins and epithelial ovarian cancer risk (OR=0.98, 95% CI=0.87-1.10), and no apparent risk variation according to duration, intensity or type of statin use. Decreased ORs associated with statin use were seen for mucinous ovarian cancer (ever statin use: OR=0.63, 95% CI=0.39-1.00). CONCLUSIONS: Statin use was not associated with overall risk for epithelial ovarian cancer. The inverse association between statin use and mucinous tumours merits further investigation.

Statin use and risk of nonmelanoma skin cancer: a nationwide study in Denmark.

BACKGROUND: Evidence is conflicting regarding statin use and risk of basal cell (BCC) and squamous cell skin cancer (SCC). METHODS: Using Danish nationwide registries, we identified all patients with incident BCC/SCC during 2005-2009 and matched them to population controls. We computed odds ratios (ORs) for BCC and SCC associated with statin use. RESULTS: We identified 38,484 cases of BCC and 3724 cases of SCC. Statin ever use was associated with ORs of 1.09 (CI: 1.06-1.13) for BCC and 1.01 (CI: 0.91-1.11) for SCC. CONCLUSIONS: Statin use was not associated with risk of SCC. Residual confounding plausibly explains the marginally increased risk of BCC.

Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis.

The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of nuclear factor (NF)κB through Gαi. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NFκB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis.

Low-dose aspirin use and the risk of ovarian cancer in Denmark.

BACKGROUND: A comprehensive body of evidence has shown that aspirin has cancer-preventive effects, particularly against gastrointestinal cancer, but its effects on the risk of ovarian cancer are less well established. This nationwide case-control study examined the association between low-dose aspirin and the risk of ovarian cancer. PATIENTS AND METHODS: We identified all patients in the Danish Cancer Registry aged 30-84 years old with a histologically verified first diagnosis of epithelial ovarian cancer during 2000-2011. Each patient was sex- and age-matched to 15 population controls using risk-set sampling. Prescription use, comorbidity, reproductive history, and demographic characteristics data were obtained from nationwide registries. The use of low-dose (75-150 mg) aspirin was defined according to the dose as well as the duration and consistency of use. Conditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between low-dose aspirin use and the risk of epithelial ovarian cancer, both overall and for specific histological types. RESULTS: For 4103 ovarian cancer cases and 58 706 population controls, the adjusted OR for epithelial ovarian cancer associated with ever use (≥2 prescriptions) of low-dose aspirin was 0.94 (95% CI 0.85-1.05). ORs for epithelial ovarian cancer were lower with the use of 150 mg aspirin tablets (OR = 0.82; 95% CI 0.68-0.99) and with long-term use (≥5 years) of low-dose aspirin (OR = 0.77; 95% CI 0.55-1.08). Continuous long-term use of low-dose aspirin, defined as close consecutive prescriptions, was associated with a further reduction in OR (0.56; 95% CI 0.32-0.97). For histological types of epithelial ovarian cancer, the strongest inverse associations with low-dose aspirin use were seen for mucinous and endometrioid tumours. CONCLUSION: This nationwide case-control study indicates that low-dose aspirin use may be associated with a reduced risk of epithelial ovarian cancer.

Matriptase promotes inflammatory cell accumulation and progression of established epidermal tumors.

Deregulation of matriptase is a consistent feature of human epithelial cancers and correlates with poor disease outcome. We have previously shown that matriptase promotes multi-stage squamous cell carcinogenesis in transgenic mice through dual activation of pro-hepatocyte growth factor-cMet-Akt-mTor proliferation/survival signaling and PAR-2-Gαi-NFκB inflammatory signaling. Matriptase was congenitally and constitutively deregulated in our prior studies, and therefore it was unclear if aberrant matriptase signaling supports only initiation of tumor formation or if it is also critical for the progression of established tumors. To determine this, we here have generated triple-transgenic mice with constitutive deregulation of matriptase and simultaneous inducible expression of the cognate matriptase inhibitor, hepatocyte growth factor inhibitor (HAI)-2. As expected, constitutive expression of HAI-2 suppressed the formation of matriptase-dependent tumors in 7,12-Dimethylbenz(a)anthracene-treated mouse skin. Interestingly, however, the induction of HAI-2 expression in already established tumors markedly impaired malignant progression and caused regression of individual tumors. Tumor regression correlated with reduced accumulation of tumor-associated inflammatory cells, likely caused by diminished expression of pro-tumorigenic inflammatory cytokines. The data suggest that matriptase-dependent signaling may be a therapeutic target for both squamous cell carcinoma chemoprevention and for the treatment of established tumors.

Concordance study and population frequencies for 16 autosomal STRs analyzed with PowerPlex® ESI 17 and AmpFℓSTR® NGM SElect™ in Somalis, Danes and Greenlanders.

A concordance study of the results of PowerPlex(®) ESI 17 and AmpFℓSTR(®) NGM SElect™ kits obtained from 591 individuals from Somalia (N=198), Denmark (N=199) and Greenland (N=194) was performed. Among 9456 STR types, seven discordant results were found with the two kits: one observed in the D19S433 system in an individual from Denmark and six in the SE33 system in six individuals from Somalia. Sequencing of SE33 in the six samples with discordant results showed G>A transition 15bp downstream of the repeat unit in three of the individuals, and G>A transition 68bp downstream of the repeat unit in the other three individuals. Population data for 16 autosomal STR systems analyzed in 989 individuals from Somalia, Denmark and Greenland are also presented. The highest mean heterozygosity was observed in Danes (82.5%). With the exception of D8S1179 in Danes, no significant deviations from Hardy-Weinberg expectations were observed. Only one pair of systems (D12S391 and D18S51) showed significant allelic association in Greenlanders (after Holm-Sidák correction). A MDS plot drawn from pairwise FST values calculated between 21 populations showed a clear displacement of the Greenlandic population versus the other ones included in the analyses. The highest combined chance of exclusion and power of discrimination was observed for Danes reaching values of 99.9999987% and 1 in 1.8×10(21), respectively.

Myasthenia and risk of cancer: a population-based case-control study.

BACKGROUND AND PURPOSE: To evaluate the association between having non-thymoma myasthenia and the risk of extra-thymic cancer in a population-based setting. METHODS: A nationwide case-control study was conducted in Denmark based on medical registries. The study included all cases with a first time diagnosis of cancer during 2000-2009. Each case was matched by birth year and gender with eight population controls using risk set sampling. Subjects with myasthenia were identified through a validated register-based algorithm. Conditional logistic regression was used to compute crude and adjusted odds ratios (ORs), with 95% confidence intervals (CIs), for cancer associated with a prior diagnosis of myasthenia. RESULTS: In all, 233 437 cases and 1 867 009 controls were identified. A total of 80 cases and 518 controls had a prior diagnosis of myasthenia. Myasthenia was not associated with an increased risk of overall cancer (OR 1.1; 95% CI 0.9-1.4). Adjusted ORs for major cancer sites were also close to unity, whereas an elevated risk of lymphomas was observed (OR 2.0; 95% CI 0.8-5.5). Early-onset myasthenia was associated with a slightly increased OR for overall cancer (1.5; 95% CI 1.0-2.3); however, this estimate was based on small numbers. CONCLUSIONS: Non-thymoma myasthenia was not associated with an increased risk of overall cancer. Larger studies are necessary to evaluate the association between myasthenia and risk of lymphoma and the potential effect modification by age of myasthenia onset in relation to cancer risk.

Risk of non-melanoma skin cancer in myasthenia patients treated with azathioprine.

BACKGROUND AND PURPOSE: The association between use of azathioprine and risk of non-melanoma skin cancer (NMSC) in patients with myasthenia was evaluated in a nationwide setting. Treatment of autoimmune myasthenia frequently involves long-term exposure to immunosuppressants, including azathioprine. Use of azathioprine increases the risk of NMSC in organ recipients and probably also in patients with other autoimmune disorders. No previous study has specifically investigated the risk of NMSC in myasthenia patients treated with azathioprine. METHODS: This is a case-control study based on Danish population-based registries. Cases were myasthenia patients with a first time diagnosis of NMSC during 2004-2009. Age- and sex-matched controls were selected amongst myasthenia patients with no history of cancer using incidence density sampling. Prior use of azathioprine in cases and controls was assessed through prescription records (1995-2009). Conditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for skin cancer associated with a high cumulative dose (≥150 g) or long-term use (≥5 years) of azathioprine, adjusted for confounders. RESULTS: Thirty NMSC cases and 360 matched controls were identified. Ever use of azathioprine was associated with a considerably increased risk of NMSC (OR 3.3, 95% CI 1.5-7.3) that was even more apparent in patients with high cumulative dose (OR 4.6, 95% CI 1.7-12.5) or long-term (OR 4.8; 95% CI 1.7-13.6) use of azathioprine. CONCLUSION: Azathioprine use in patients with myasthenia is associated with an increased risk of NMSC.

Use of azathioprine for non-thymoma myasthenia and risk of cancer: a nationwide case-control study in Denmark.

BACKGROUND AND PURPOSE: To evaluate the association between the use of azathioprine and risk of cancer in patients with non-thymoma myasthenia gravis (MG) in a nationwide setting. METHODS: Case-control study based on population-based registries. Cases were patients with MG with a first time diagnosis of cancer (except non-melanoma skin cancer) registered during 2000-2009, and controls were patients with MG with no history of cancer. Prior use of azathioprine in cases and controls was assessed through prescription records (1995-2009). We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for cancer associated with a high cumulative dose [≥ 1000 defined daily doses (DDD)] or long-term use (≥ 5 years) of azathioprine, compared with never use of the drug and adjusted for potential confounders. RESULTS: We identified 89 cases and 873 controls. The prevalence of ever use of azathioprine was similar among cases (39.3%) and controls (39.4%). We observed a slightly elevated OR for cancer overall associated with long-term use of azathioprine (1.22; 95% CI: 0.62-2.40, P = 0.56). The highest ORs were observed for use of 2000 DDD or more of azathioprine; however, these risk estimates were based on small numbers. CONCLUSIONS: Use of azathioprine in patients with non-thymoma MG may be associated with a slightly increased risk of cancer overall. Larger studies are necessary to address the risk of site-specific cancers.