Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity

We and others have previously demonstrated that nociception in the mouse is heritable. A genetic correlation analysis of 12 common measures of nociception among a common set of inbred strains revealed three major clusters (or 'types') of nociception in this species. In the present study, we re-evaluated the major types of nociception and their interrelatedness using ten additional assays of nociception and hypersensitivity, including: three thermal assays (tail withdrawal from 47.5 degrees C water or -15 degrees C ethanol; tail flick from radiant heat), two chemical assays of spontaneous nociception (bee venom test; capsaicin test) and their subsequent thermal hypersensitivity states (including contralateral hypersensitivity in the bee venom test), a mechanical nociceptive assay (tail-clip test), and a mechanical hypersensitivity assay (intrathecal dynorphin). Confirming our earlier findings, the results demonstrate distinct thermal and chemical nociceptive types. It is now clear that mechanical hypersensitivity and thermal hypersensitivity are genetically dissociable phenomena. Furthermore, we now see at least two distinct types of thermal hypersensitivity: afferent-dependent, featuring a preceding significant period of spontaneous nociceptive behavior associated with afferent neural activity, and non-afferent-dependent. In conclusion, our latest analysis suggests that there are at least five fundamental types of nociception and hypersensitivity: (1) baseline thermal nociception; (2) spontaneous responses to noxious chemical stimuli; (3) thermal hypersensitivity; (4) mechanical hypersensitivity; and (5) afferent input-dependent hypersensitivity.     

Colon cancer: association of histopathological parameters and patients' survival with clinical presentation

Available data correlating symptoms of colon cancer patients with the severity of the disease are very limited. In a population‐based setting, we correlated information on symptoms of colon cancer patients with several pathological tumor parameters and survival. Information on all patients diagnosed with colon cancer in Iceland in 1995–2004 for this retrospective, population‐based study was obtained from the Icelandic Cancer Registry. Information on symptoms of patients and blood hemoglobin was collected from patients' files. Pathological parameters were obtained from a previously performed standardized tumor review. A total of 768 patients entered this study; the median age was 73 years. Tumors in patients presenting at diagnosis with visible blood in stools were significantly more likely to be of lower grade, having pushing border, conspicuous peritumoral lymphocytic infiltration, and lower frequency of vessel invasion. Patients with abdominal pain and anemia were significantly more likely to have vessel invasion. Logistic regression showed that visible blood in stools was significantly associated with protecting pathological factors (OR range 0.38–0.83, p < 0.05). Tumors in patients presenting with abdominal pain were strongly associated with infiltrative margin and scarce peritumoral lymphocytic infiltration (OR = 1.95; 2.18 respectively, p < 0.05). Changes in bowel habits were strongly associated with vessel invasion (OR = 2.03, p < 0.05). Cox regression showed that blood in stools predicted survival (HR = 0.54). In conclusion, visible blood in stools correlates significantly with all the beneficial pathological parameters analyzed and with better survival of patients. Anemia, general symptoms, changes in bowel habits, acute symptoms, and abdominal pain correlate with more aggressive tumor characteristics and adverse outcome for patients.     

Aging-from molecules to populations

The mean age of the human population is steadily increasing in many areas around the globe, a phenomenon with large social, political, economic and biological/medical implications. Inevitably, this phenomenon is stimulating great interest in understanding and potentially modulating the process of human aging. To foster interactions and collaboration between diverse scientists interested in the biochemical, physiological, epidemiological and psychosocial aspects of aging, The University of Copenhagen Faculty of Health Sciences recently organized and co-sponsored a workshop entitled Aging-From Molecules to Populations. The following questions about human aging were discussed at the workshop: What is the limit of human life expectancy? What are the key indicators of human aging? What are the key drivers of human aging? Which genes have the greatest impact on human aging? How similar is aging-related cognitive decline to pathological cognitive decline associated with neurological disease? Are human progeriod diseases, characterized by premature aging, good models for "normal" human aging? Is delayed or "elite" aging informative about "normal" human aging? To what extent and by what mechanisms do early life environmental factors influence aging-associated physical and cognitive decline? To what extent and by what mechanism does the social environment influence life course outcomes? What physiological factors underlie the timing and extent of aging-associated physical and cognitive decline? How do cultural stereotypes and perceptions of aging influence the process and experience of aging? One of the primary outcomes of the workshop was a recognition that cross-disciplinary studies and "out-of-the-box" approaches, especially those that adopt an integrated life course perspective on human health status, are needed to expedite advances in aging research. This and other outcomes of the workshop are summarized and discussed in this report.     

Short stature and overweight in infants of Western Massachusetts

A cross‐sectional study of the nutritional status of 268 urban white, black and Puerto Rican infants, age 1–26 weeks, of three economic levels, was undertaken between November 1972 and March 1974. Subjects were selected at random. Mothers were interviewed and infants measured and weighed by a nutritionist during a single home visit. Crown‐heel length, weight and weight/height ratio of 254 full‐term infants are discussed. Physical characteristics of the children suggest that their diet was limited more in quality than in quantity. Limitations in linear growth and excessive weight gain were particularly noted in many boys under three months of age of all ethnic and socioeconomic groups, when compared to percentile distributions of the Child Research Council. Girls were generally less heavy for their length than boys, but girls from low income families tended to be heavier for their length than those from middle and high income families. Low income black children were longer than low income white and Puerto Rican children at the age of six months.     

Costs and efficiency of gatekeeping under varying numbers of general practitioners

We study the relationship between gatekeeping on one hand and costs as well as efficiency on the other hand. We do this with special focus on the relative amount of general practitioners in the system when compared with all practitioners. Data collected between 2002 and 2011 by The Organization for Economic Co‐operation and Development on 34 countries were analyzed. Of those, 18 countries have gatekeeping systems while 16 do not. The association between gatekeeping and health care costs was examined with regression analysis. Efficiency was assessed with data envelopment analysis. Finally, the efficiency assessments were analyzed with regression techniques to examine if gatekeeping and/or the ratio of GPs to all practitioners was associated with efficiency. Point estimates indicate that total costs tend to be lower in systems where GPs act as gatekeepers. However, efficiency is slightly lower where gatekeeping exists. Neither of these results is statistically significant at the 95% confidence level. There is also indication that the efficiency of a gatekeeping system increases with increased amount of GPs. When GPs are over 30% of practitioners, gatekeeping countries have more efficient health care systems than their counterparts. Consistent with other studies, we estimate income elasticity of health care demand to be 1.12, suggesting that those societies consider health care to be a luxury good.     

Vitamin D Intake and Status in 12-Month-Old Infants at 63–66° N

The objective was to assess the vitamin D status in healthy 12-month-old infants in relation to quantity and sources of dietary vitamin D, breastfeeding and seasons. Subjects were 76 12-month-old infants. Serum levels of 25-hydroxyvitamin D (25(OH)D) ≥ 50 nmol/L were considered indicative of vitamin D sufficiency and 25(OH)D < 27.5 nmol/L as being indicative of increased risk for rickets. Additionally, 25(OH)D > 125 nmol/L was considered possibly adversely high. Total vitamin D at 9–12 months (eight data collection days) included intake from diet and supplements. The mean ± SD of vitamin D intake was 8.8 ± 5.2 μg/day and serum 25(OH)D 98.1 ± 32.2 nmol/L (range 39.3–165.5). Ninety-two percent of infants were vitamin D sufficient and none at increased risk for rickets. The 26% infants using fortified products and supplements never/irregularly or in small amounts had lower 25(OH)D (76.8 ± 27.1 nmol/L) than the 22% using fortified products (100.0 ± 31.4 nmol/L), 18% using supplements (104.6 ± 37.0 nmol/L) and 33% using both (110.3 ± 26.6 nmol/L). Five of six infants with 25(OH)D < 50 nmol/L had no intake of supplements or fortified products from 0 to 12 months. Supplement use increased the odds of 25(OH)D > 125 nmol/L. Breastfeeding and season did not affect vitamin D status. The majority of infants were vitamin D sufficient. Our findings highlight the need for vitamin D supplements or fortified products all year round, regardless of breastfeeding.     

Virtual screening for novel openers of pancreatic K(ATP) channels

Ligand-based virtual screening approaches were applied to search for new chemotype KCOs activating Kir6.2/SUR1 KATP channels. A total of 65 208 commercially available compounds, extracted from the ZINC archive, served as database for screening. In a first step, pharmacokinetic filtering via VolSurf reduced the initial database to 1913 compounds. Afterward, six molecules were selected as templates for similarity searches: similarity scores, obtained toward these templates, were calculated with the GRIND, FLAP, and TOPP approaches, which differently encode structural information into potential pharmacophores. In this way, we obtained 32 hit candidates, 16 via GRIND and eight each via FLAP and TOPP. For biological testing of the hit candidates, their effects on membrane potentials in HEK 293 cells expressing Kir6.2/SUR1 were studied. GRIND, FLAP, and TOPP all yielded hits, but no method top-ranked all the actives. Thus, parallel application of different approaches probably improves hit detection.     

Breast cancer risk factors and age at diagnosis: an Icelandic cohort study

An increasing number of studies indicates that the strength and even direction of association between breast cancer and established risk factors differ according to the woman's age when she develops the disease. This was studied in the setting of a population based cancer registry using a databank with information on age at menarche, parity, age at first birth, oral contraceptive (OC) use, lactation, height and weight. From a cohort of 80.219 women attending population-based cervical and breast cancer screening in Iceland, 1120 cases were identified, aged 26-90 years at diagnosis and 10,537 controls, individually matched to the cases on birth year and age when attending. Information given at last visit before diagnosis was used in the analysis, applying conditional logistic regression. Odds ratios and statistical strength of relationships varied according to age at diagnosis for age at first birth, number of births, duration of lactation, height and weight. The decreased risk associated with young age at first birth and increasing duration of breast feeding became less pronounced with advancing age at diagnosis. A reduced risk associated with an increasing number of births was not detected in women diagnosed under the age of 40. An increased risk associated with giving first birth after 30 years of age was mainly detected in women who had only given 1 birth and were diagnosed under the age of 40 (OR = 7.06 95% CI = 2.16-23.01). A positive association with height and especially with weight was confined to women diagnosed after the age of 55. The results confirm that age at diagnosis should be taken into account when studying the effects of breast cancer risk factors.     

Fast and simple screening for nutritional status in hospitalized, elderly people

BACKGROUND: Undernutrition has been frequently reported among hospitalized elderly patients. The aim of this study was to evaluate the mini nutrition assessment (MNA) and a screening sheet for malnutrition (SSM) by full nutritional assessment (FNA) in elderly people, and to construct a shorter screening method by combining important questions from MNA and SSM. Having a screening tool as fast and simple as possible could increase its use in clinical routines. METHODS: FNA, MNA and SSM were carried out on 60 hospitalized patients (>65 years). Sensitivity and specificity for MNA and SSM were calculated in comparison with FNA. In order to construct a short and simple screening tool, questions from the two screening tools, which differed significantly between mal- and well-nourished patients, were used in a multivariate, stepwise linear regression. The regression model was simplified to be suitable in clinical routines. RESULTS: Malnourishment was diagnosed by FNA in 58.3% of the elderly patients, with no gender difference. Body mass index, unintended weight loss, recent surgery and loss of appetite were predictors of malnutrition in the regression model (R(2) = 60.1%). The sensitivity and specificity of the simplified regression model were 89 and 88%, respectively, which was more precise than MNA (77 and 36%) and SSM (89 and 60%). CONCLUSION: According to FNA, malnutrition is frequent in elderly hospitalized patients. Four questions are sufficient to conduct precise nutritional screening for malnutrition in elderly hospitalized patients. This new screening tool should be verified in other samples.