Intrinsically photosensitive retinal ganglion cell function in relation to age: a pupillometric study in humans with special reference to the age-related optic properties of the lens.

BACKGROUND: The activity of melanopsin containing intrinsically photosensitive ganglion retinal cells (ipRGC) can be assessed by a means of pupil responses to bright blue (appr.480 nm) light. Due to age related factors in the eye, particularly, structural changes of the lens, less light reaches retina. The aim of this study was to examine how age and in vivo measured lens transmission of blue light might affect pupil light responses, in particular, mediated by the ipRGC. METHODS: Consensual pupil responses were explored in 44 healthy subjects aged between 26 and 68 years. A pupil response was recorded to a continuous 20 s light stimulus of 660 nm (red) or 470 nm (blue) both at 300 cd/m2 intensity (14.9 and 14.8 log photons/cm2/s, respectively). Additional recordings were performed using four 470 nm stimulus intensities of 3, 30, 100 and 300 cd/m2. The baseline pupil size was measured in darkness and results were adjusted for the baseline pupil and gender. The main outcome parameters were maximal and sustained pupil contraction amplitudes and the postillumination response assessed as area under the curve (AUC) over two time-windows: early (0-10 s after light termination) and late (10-30 s after light termination). Lens transmission was measured with an ocular fluorometer. RESULTS: The sustained pupil contraction and the early poststimulus AUC correlated positively with age (p=0.02, p=0.0014, respectively) for the blue light stimulus condition only.The maximal pupil contraction amplitude did not correlate to age either for bright blue or red light stimulus conditions.Lens transmission decreased linearly with age (p<0.0001). The pupil response was stable or increased with decreasing transmission, though only significantly for the early poststimulus AUC to 300 cd/m2 light (p=0.02). CONCLUSIONS: Age did not reduce, but rather enhance pupil responses mediated by ipRGC. The age related decrease of blue light transmission led to similar results, however, the effect of age was greater on these pupil responses than that of the lens transmission. Thus there must be other age related factors such as lens scatter and/or adaptive processes influencing the ipRGC mediated pupil response enhancement observed with advancing age.

Responsiveness to a physiological regimen of GnRH therapy and relation to genotype in women with isolated hypogonadotropic hypogonadism.

CONTEXT: Isolated hypogonadotropic hypogonadism (IHH) is caused by defective GnRH secretion or action resulting in absent or incomplete pubertal development and infertility. Most women with IHH ovulate with physiological GnRH replacement, implicating GnRH deficiency as the etiology. However, a subset does not respond normally, suggesting the presence of defects at the pituitary or ovary. OBJECTIVES: The objective of the study was to unmask pituitary or ovarian defects in IHH women using a physiological regimen of GnRH replacement, relating these responses to genes known to cause IHH. DESIGN, SETTING, AND SUBJECTS: This study is a retrospective analysis of 37 IHH women treated with iv pulsatile GnRH (75 ng/kg per bolus). MAIN OUTCOME MEASURES: Serum gonadotropin and sex steroid levels were measured, and 14 genes implicated in IHH were sequenced. RESULTS: During their first cycle of GnRH replacement, normal cycles were recreated in 60% (22 of 37) of IHH women. Thirty percent of women (12 of 37) demonstrated an attenuated gonadotropin response, indicating pituitary resistance, and 10% (3 of 37) exhibited an exaggerated FSH response, consistent with ovarian resistance. Mutations in CHD7, FGFR1, KAL1, TAC3, and TACR3 were documented in IHH women with normal cycles, whereas mutations were identified in GNRHR, PROKR2, and FGFR1 in those with pituitary resistance. Women with ovarian resistance were mutation negative. CONCLUSIONS: Although physiological replacement with GnRH recreates normal menstrual cycle dynamics in most IHH women, hypogonadotropic responses in the first week of treatment identify a subset of women with pituitary dysfunction, only some of whom have mutations in GNRHR. IHH women with hypergonadotropic responses to GnRH replacement, consistent with an additional ovarian defect, did not have mutations in genes known to cause IHH, similar to our findings in a subset of IHH men with evidence of an additional testicular defect.

Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial?.

BACKGROUND: Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI. MATERIALS AND METHODS: Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS). RESULTS: In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14). CONCLUSIONS: Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALSGOV IDENTIFIER: NCT00026273.

Blood pressure in relation to coffee and caffeine consumption.

The relationship between blood pressure (BP) and coffee is of major interest given its widespread consumption and the public health burden of high BP. Yet, there is no specific recommendation regarding coffee intake in existing hypertension guidelines. The lack of a definitive understanding of the BP-coffee relationship is partially attributable to issues that we discuss in this review, issues such as acute vs. chronic effects, genetic and smoking effect modifications, and coffee vs. caffeine effects. We also present evidence from meta-analyses of studies on the association of BP with coffee intake. The scope of this review is limited to the latest advances published with a specific focus on caffeine, acknowledging that caffeine is only one among numerous components in coffee that may influence BP. Finally, considering the state of the research, we propose a mechanism by which the CYP1A2 gene and enzyme influence BP via inhibition of the adenosine receptor differentially in smokers and non-smokers.

Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma.

Anaplastic large cell lymphoma (ALCL) is a main type of T-cell lymphomas and comprises three distinct entities: systemic anaplastic lymphoma kinase (ALK) positive, systemic ALK(-) and cutaneous ALK(-) ALCL (cALCL). Little is known about their pathogenesis and their cellular origin, and morphological and immunophenotypical overlap exists between ALK(-) ALCL and classical Hodgkin lymphoma (cHL). We conducted gene expression profiling of microdissected lymphoma cells of five ALK(+) and four ALK(-) systemic ALCL, seven cALCL and sixteen cHL, and of eight subsets of normal T and NK cells. The analysis supports a derivation of ALCL from activated T cells, but the lymphoma cells acquired a gene expression pattern hampering an assignment to a CD4(+), CD8(+) or CD30(+) T-cell origin. Indeed, ALCL display a down-modulation of many T-cell characteristic molecules. All ALCL types show significant expression of NFkappaB target genes and upregulation of genes involved in oncogenesis (e.g. EZH2). Surprisingly, few genes are differentially expressed between systemic and cALCL despite their different clinical behaviour, and between ALK(-) ALCL and cHL despite their different cellular origin. ALK(+) ALCL are characterized by expression of genes regulated by pathways constitutively activated by ALK. This study provides multiple novel insights into the molecular biology and pathogenesis of ALCL.

Relation between atherogenic dyslipidemia and the Adult Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of Metabolic Syndrome Project).

Genetic Epidemiology of Metabolic Syndrome is a multinational, family-based study to explore the genetic basis of the metabolic syndrome. Atherogenic dyslipidemia (defined as low plasma high-density lipoprotein cholesterol with elevated triglycerides (&lt;25th and &gt;75th percentile for age, gender, and country, respectively) identified affected subjects for the metabolic syndrome. This report examines the frequency at which atherogenic dyslipidemia predicts the metabolic syndrome of the National Cholesterol Education Program Adult Treatment Panel III (ATP-III). One thousand four hundred thirty-six (854 men/582 women) affected patients by our criteria were compared with 1,672 (737 men/935 women) unaffected persons. Affected patients had more hypertension, obesity, and hyperglycemia, and they met a higher number of ATP-III criteria (3.2 +/- 1.1 SD vs 1.3 +/- 1.1 SD, p &lt;0.001). Overall, 76% of affected persons also qualified for the ATP-III definition (Cohen's kappa 0.61, 95% confidence interval 0.59 to 0.64), similar to a separate group of 464 sporadic, unrelated cases (75%). Concordance increased from 41% to 82% and 88% for ages &lt; or =35, 36 to 55, and &gt; or =55 years, respectively. Affected status was also independently associated with waist circumference (p &lt;0.001) and fasting glucose (p &lt;0.001) but not systolic blood pressure (p = 0.43). Thus, the lipid-based criteria used to define affection status in this study substantially parallels the ATP-III definition of metabolic syndrome in subjects aged &gt;35 years. In subjects aged &lt;35 years, atherogenic dyslipidemia frequently occurs in the absence of other metabolic syndrome risk factors.

Bitumens in the late Variscan hydrothermal vein-type uranium deposit of Pribram, Czech Republic: Sources, radiation-induced alteration, and relation to mineralization

The late Variscan (275-278 Ma) Pribram uranium deposit is one of the largest known accumulations of uraniferous bitumens in hydrothermal veins. The deposit extends along the northwestern boundary of the Central Bohemian pluton (345-335 Ma) with low-grade metamorphosed Late Proterozoic and unmetamorphosed Cambrian rocks. From a net uranium production of 41,742 metric tons (t), more than 6,000 t were extracted from bitumen-uraninite ores during 43 years of exploration and mining. Three morphological varieties of solid bitumen are recognized: globular, asphaltlike, and cokelike. While the globular bitumen is uranium free, the other two types are uraniferous. The amount of bitumen in ore veins gradually decreases toward the contact with the plutonic body and increases with depth. Two types of bitumen microtextures are recognized using high-resolution transmission electron microscopy: amorphous and microporous, the former being less common in uraniferous samples. A lower Raman peak area ratio (1,360/1,575 cm(-1)) in mineralized bitumens (0.9) compared with uranium-free samples (2.0) indicates a lower degree of microtextural organization in the latter The H/C and O/C atomic ratios in uranium-free bitumens (0.9-1.1 and 0.09, respectively) are higher than those in mineralized samples (H/C = 0.3-0.8, O/C = 0.03-0.09). The chloroform extractable matter yield is Very low in uranium-free bitumens (0.30-0.35% of the total organic carbon,TOC) and decreases with uranium content increase. The extracted solid uraniferous bitumen infrared spectra show depletion in aliphatic CH2 and CH3 groups compared to uranium-free samples. The concentration of oxygen-bearing functional groups relative to aromatic bonds in the IR spectra of uranium-free and mineralized bitumen, however, do not differ significantly. C-13 NMR confirmed than the aromaticity of a uraniferous sample is higher (F-ar = 0.61) than in the uranium-free bitumen (F-ar = 0.51). Pyrolysates from uraniferous and nonuraniferous bitumens do not differ significantly, being predominantly cresol, alkylphenols, alkylbenzenes, and alkylnaphthalenes. The liquid pyrolysate yield decreases significantly with increasing uranium content. The delta(13)C Values of bulk uranium-free bitumens and low-grade uraniferous, asphaltlike bitumens range from -43.6 to 52.3 per mil. High-grade, cokelike, uraniferous bitumens are more C-13 depleted (54.5 to -58.4 parts per thousand). In contrast to the very light isotopic ratios of the high-grade uraniferous cokelike bitumen bulk carbon, the individual n-alkanes and isoprenoids (pristane and phytane) extracted from the same sample are significantly C-13 enriched. The isotopic composition of the C13-24 n-alkanes extracted from the high-grade uraniferous sample (delta(13)C = -28.0 to 32.6 parts per thousand) are heavier compared with the same compounds in a uranium-free sample (delta(13)C = 31.9 to 33.8 parts per thousand). It is proposed that the bitumen source was the isotopically light (delta(13)C = 35.8 to 30.2 parts per thousand) organic matter of the Upper Proterozoic host rocks that were pyrolyzed during intrusion of the Central Bohemian pluton. The C-13- depleted pyrolysates were mobilized from the innermost part of the contact-metamorphic aureole, accumulated in structural traps in less thermally influenced parts of the sedimentary complex and were later extracted by hydrothermal fluids. Bitumens at the Pribram deposit are younger than the main part of the uranium mineralization and were formed through water-washing and radiation-induced polymerization of both the gaseous and liquid pyrolysates. Direct evidence for pyrolysate reduction of uranium in the hydrothermal system is difficult to obtain as the chemical composition of the original organic fluid phase was modified during water-washing and radiolytic alteration. However, indirect evidence-e.g., higher O/C atomic ratios in uranium-free bitumens (0.1) relative to the Upper Proterozoic source rocks (0.02-0.05), isotopically very light carbon in associated whewellite (delta(13)C = 31.7 to -28.4 parts per thousand), and the striking absence of bitumens in the pre-uranium, hematite stage of the mineralization-indicates that oxidation of organic fluids may have contributed to lowering of aO(2) and uraninite precipitation.

Relation soignant-soigné quand les blogs s'en mêlent [Patient-caregiver relationship: when illness blogs step in].

The use of social media as a communication tool is rapidly growing in the community, and more specifically in patients, through illness blogs. This has been true for several years in North America, but is becoming a reality in Europe as well. We report here the first results of studies on the putative psychological benefits and risks of illness blogs for their authors. We also explore the possible impact of blogging on the patient-caregiver relationship. Social media are expected to have a growing influence in certain areas of health care. Physicians should therefore stay informed about them, take advantage of their benefits, and anticipate their risks.

Reference intervals for common carotid intima-media thickness measured with echotracking: relation with risk factors.

AIMS: Common carotid artery intima-media thickness (CCIMT) is widely used as a surrogate marker of atherosclerosis, given its predictive association with cardiovascular disease (CVD). The interpretation of CCIMT values has been hampered by the absence of reference values, however. We therefore aimed to establish reference intervals of CCIMT, obtained using the probably most accurate method at present (i.e. echotracking), to help interpretation of these measures. METHODS AND RESULTS: We combined CCIMT data obtained by echotracking on 24 871 individuals (53% men; age range 15-101 years) from 24 research centres worldwide. Individuals without CVD, cardiovascular risk factors (CV-RFs), and BP-, lipid-, and/or glucose-lowering medication constituted a healthy sub-population (n = 4234) used to establish sex-specific equations for percentiles of CCIMT across age. With these equations, we generated CCIMT Z-scores in different reference sub-populations, thereby allowing for a standardized comparison between observed and predicted ('normal') values from individuals of the same age and sex. In the sub-population without CVD and treatment (n = 14 609), and in men and women, respectively, CCIMT Z-scores were independently associated with systolic blood pressure [standardized βs 0.19 (95% CI: 0.16-0.22) and 0.18 (0.15-0.21)], smoking [0.25 (0.19-0.31) and 0.11 (0.04-0.18)], diabetes [0.19 (0.05-0.33) and 0.19 (0.02-0.36)], total-to-HDL cholesterol ratio [0.07 (0.04-0.10) and 0.05 (0.02-0.09)], and body mass index [0.14 (0.12-0.17) and 0.07 (0.04-0.10)]. CONCLUSION: We estimated age- and sex-specific percentiles of CCIMT in a healthy population and assessed the association of CV-RFs with CCIMT Z-scores, which enables comparison of IMT values for (patient) groups with different cardiovascular risk profiles, helping interpretation of such measures obtained both in research and clinical settings.

The relation of body mass index and abdominal adiposity with dyslipidemia in 27 general populations of the WHO MONICA Project.

The association between adiposity measures and dyslipidemia has seldom been assessed in a multipopulational setting. 27 populations from Europe, Australia, New Zealand and Canada (WHO MONICA project) using health surveys conducted between 1990 and 1997 in adults aged 35-64 years (n = 40,480). Dyslipidemia was defined as the total/HDL cholesterol ratio >6 (men) and >5 (women). Overall prevalence of dyslipidemia was 25% in men and 23% in women. Logistic regression showed that dyslipidemia was strongly associated with body mass index (BMI) in men and with waist circumference (WC) in women, after adjusting for region, age and smoking. Among normal-weight men and women (BMI<25 kg/m(2)), an increase in the odds for being dyslipidemic was observed between lowest and highest WC quartiles (OR = 3.6, p < 0.001). Among obese men (BMI ≥ 30), the corresponding increase was smaller (OR = 1.2, p = 0.036). A similar weakening was observed among women. Classification tree analysis was performed to assign subjects into classes of risk for dyslipidemia. BMI thresholds (25.4 and 29.2 kg/m(2)) in men and WC thresholds (81.7 and 92.6 cm) in women came out at first stages. High WC (>84.8 cm) in normal-weight men, menopause in women and regular smoking further defined subgroups at increased risk. standard categories of BMI and WC, or their combinations, do not lead to optimal risk stratification for dyslipidemia in middle-age adults. Sex-specific adaptations are necessary, in particular by taking into account abdominal obesity in normal-weight men, post-menopausal age in women and regular smoking in both sexes.

Surface deterioration of dental materials after simulated toothbrushing in relation to brushing time and load.

OBJECTIVES: (1) To evaluate the changes in surface roughness and gloss after simulated toothbrushing of 9 composite materials and 2 ceramic materials in relation to brushing time and load in vitro; (2) to assess the relationship between surface gloss and surface roughness. METHODS: Eight flat specimens of composite materials (microfilled: Adoro, Filtek Supreme, Heliomolar; microhybrid: Four Seasons, Tetric EvoCeram; hybrid: Compoglass F, Targis, Tetric Ceram; macrohybrid: Grandio), two ceramic materials (IPS d.SIGN and IPS Empress polished) were fabricated according to the manufacturer's instructions and optimally polished with up to 4000 grit SiC. The specimens were subjected to a toothbrushing (TB) simulation device (Willytec) with rotating movements, toothpaste slurry and at three different loads (100g/250g/350g). At hourly intervals from 1h to 10h TB, mean surface roughness Ra was measured with an optical sensor and the surface gloss (Gl) with a glossmeter. Statistical analysis was performed for log-transformed Ra data applying two-way ANOVA to evaluate the interaction between load and material and load and brushing time. RESULTS: There was a significant interaction between material and load as well as between load and brushing time (p<0.0001). The microhybrid and hybrid materials demonstrated more surface deterioration with higher loads, whereas with the microfilled resins Heliomolar and Adoro it was vice versa. For ceramic materials, no or little deterioration was observed over time and independent of the load. The ceramic materials and 3 of the composite materials (roughness) showed no further deterioration after 5h of toothbrushing. Mean surface gloss was the parameter which discriminated best between the materials, followed by mean surface roughness Ra. There was a strong correlation between surface gloss and surface roughness for all the materials except the ceramics. The evaluation of the deterioration curves of individual specimens revealed a more or less synchronous course suspecting hinting specific external conditions and not showing the true variability in relation to the tested material. SIGNIFICANCE: The surface roughness and gloss of dental materials changes with brushing time and load and thus results in different material rankings. Apart from Grandio, the hybrid composite resins were more prone to surface changes than microfilled composites. The deterioration potential of a composite material can be quickly assessed by measuring surface gloss. For this purpose, a brushing time of 10h (=72,000 strokes) is needed. In further comparative studies, specimens of different materials should be tested in one series to estimate the true variability.