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Invasive techniques in the management of cancer pain.

Familiarity with potentially useful anesthetic and neurosurgical techniques is important in the management of patients who are unable to achieve a satisfactory balance between analgesia and side effects from systemic analgesic therapies. The ability to make specific recommendations is limited by the paucity of controlled data, incorporating details of pain syndromes, prior therapies, validated pain assessment, meticulous reporting of adverse effects, and longitudinal follow-up.

Analgesia, Epidural↗

Family interaction and a supportive social network as salutogenic factors in childhood atopic illness.

The role of psycho-social factors in the development of allergy was studied prospectively in 82 infants with a family history of atopy. The family participated in a standardized family test when the children were 18 months old. The ability to adjust to demands of the situation ('adaptability'), and the balance between emotional closeness and distance ('cohesion'), were assessed from videotapes by independent raters. Families rated as functional in both of these aspects were classified as 'functional', otherwise as 'dysfunctional'. The social network, life events, atopic symptoms (based on postal inquiries regarding symptoms answered by the parents, and on physical examinations), psychiatric symptoms, and socio-economic circumstances of the families were evaluated when the children were 18 months and 3 years of age. The children were classified as atopic (asthmatic symptoms or eczema) or as non-atopic. All but two children with atopic disease at 3 years of age had atopic disease before 18 months of age, while 32 of 60 children with atopic disease at 18 months of age had no problems by 3 years of age. An unbalanced family interplay at 18 months was associated with a relative risk (RR) of 1.99 for continuing atopic illness at 3 years of age (1.18 < RR < 3.37, p = 0.01). There was a weak positive confounding effect for smoking (RR reduced by 7%), eczema on three or more localizations (RR reduced by 4.5%), and the amount of cat allergen in household dust (RR reduced by 3%). Recovery from atopic illness between 18 months and 3 years of age was four times as probable in families with functional interaction and a good social supportive network when children were 18 months of age, than in dysfunctional families with a poor social network (74% versus 20% p < 0.01). Children with asthmatic symptoms showed more signs of emotional distress than did healthy children (p = 0.02). Dysfunctional family interaction patterns were more commonly observed in families of children who at 3 years of age still had atopic symptoms, than in children who had recovered. The patterns included expression of emotion and reaction to the needs of others, alternating between total disinterest and over-involvement (p = 0.02), lack of support and rejection of offered support (p = 0.01), a greater number of individual decisions without regard to the other family members (p = 0.04), and indistinct 'generational boundaries' (p = 0.04). We conclude that psychosocial factors, such as family interaction and a supportive social network, play a significant role in the course of atopic illness in early childhood and that measures which enhance family interaction and the social network could influence the course of the disease favorably.

Asthma↗

Growth, development and differentiation: a functional food science approach.

Few other aspects of food supply and metabolism are of greater biological importance than the feeding of mothers during pregnancy and lactation, and of their infants and young children. Nutritional factors during early development not only have short-term effects on growth, body composition and body functions but also exert long-term effects on health, disease and mortality risks in adulthood, as well as development of neural functions and behaviour, a phenomenon called 'metabolic programming'. The interaction of nutrients and gene expression may form the basis of many of these programming effects and needs to be investigated in more detail. The relation between availability of food ingredients and cell and tissue differentiation and its possible uses for promoting health and development requires further exploration. The course of pregnancy, childbirth and lactation as well as human milk composition and the short- and long-term outcome of the child are influenced by the intake of foods and particularly micronutrients, e.g. polyunsaturated fatty acids, Fe, Zn and I. Folic acid supplementation from before conception through the first weeks of pregnancy can markedly reduce the occurrence of severe embryonic malformations; other potential benefits of modulating nutrient supply on maternal and child health should be further evaluated. The evaluation of dietary effects on child growth requires epidemiological and field studies as well as evaluation of specific cell and tissue growth. Novel substrates, growth factors and conditionally essential nutrients (e.g. growth factors, amino acids, polyunsaturated fatty acids) may be potentially useful as ingredients in functional foods and need to be assessed carefully. Intestinal growth, maturation, and adaptation as well as long-term function may be influenced by food ingredients such as oligosaccharides, gangliosides, high-molecular-mass glycoproteins, bile salt-activated lipase, pre- and probiotics. There are indications for some beneficial effects of functional foods on the developing immune response, for example induced by antioxidant vitamins, trace elements, fatty acids, arginine, nucleotides, and altered antigen contents in infant foods. Peak bone mass at the end of adolescence can be increased by dietary means, which is expected to be of long-term importance for the prevention of osteoporosis at older ages. Future studies should be directed to the combined effects of Ca and other constituents of growing bone, such as P, Mg and Zn, as well as vitamins D and K, and the trace elements F and B. Pregnancy and the first postnatal months are critical time periods for the growth and development of the human nervous system, processes for which adequate substrate supplies are essential. Early diet seems to have long-term effects on sensory and cognitive abilities as well as behaviour. The potential beneficial effects of a balanced supply of nutrients such as I, Fe, Zn and polyunsaturated fatty acids should be further evaluated. Possible long-term effects of early exposure to tastes and flavours on later food choice preferences may have a major impact on public health and need to be further elucidated. The use of biotechnology and recombinant techniques may offer the opportunity to include various bioactive substances in special dietary products, such as human milk proteins, peptides, growth factors, which may have beneficial physiological effects, particularly in infancy and early childhood.

Adolescent↗

Associations of sensory-motor functions with poor mobility in 75- and 80-year-old people.

This study investigated the associations of sensory-motor functions with mobility in elderly people. All 75- and 80-year-old residents of the city of Jyväskylä, Finland, were invited to take part in the study. A total of 617 (93%) persons were interviewed, and 500 (75%) took part in laboratory examinations. Self-reported mobility was recorded during the interview. Basic mobility functions (maximal walking speed and stair-mounting ability) and sensory-motor functions (maximal isometric muscle strength, standing balance, reaction time and visual acuity) were measured in the laboratory. Multivariate analyses showed that poor sensory-motor functions were significantly associated with poor performance in basic mobility functions and that poor performance in basic mobility functions was associated with self-reported disability in mobility. The associations discovered were consistent with models of the disablement process. Muscle strength, balance, reaction time and vision all have individual significance for mobility, underlining the need for multifactorial approaches in prevention and rehabilitation.

Activities of Daily Living↗

Intrinsic and extrinsic regulation of T lymphocyte quiescence.

The outcome of an immune response is dependent on the interplay and complex interactions of positive (stimulatory) and negative (inhibitory) pathways and a major goal of modern immunology is to dissect these physiologic interactions in order to apply these physiologic mechanisms therapeutically. The balance of stimulatory and inhibitory signals is critical for maximizing the ability of the adoptive immune response to defend the host while maintaining immunologic tolerance and preventing autoimmunity. Cellular quiescence is a state characterized by decreased cell size and metabolic activity. The quiescent state of unstimulated T lymphocytes is thought to be due to the lack of activation signals. However, recent studies have shown that quiescence in lymphocytes is not a default state, but an actively maintained gene program. This program regulates intrinsic expression of quiescence factors in T lymphocytes. In addition to intrinsic mechanisms regulating T cell quiescence, CD4 + CD25 + regulatory T cells (Treg) naturally arising in the thymus, engage in the maintenance of immunological self-tolerance by preventing autoimmunity in vivo in a non cell-autonomous manner. Although there is still only a rudimentary knowledge of the molecular mechanisms that govern the activity of the intrinsic quiescence factors and the development of Treg, it is now clear that immune quiescence is regulated by constitutively ongoing active mechanisms.

Animals↗

Energy utilization in food-restricted female rats.

We studied changes in energy utilization in mature female rats exposed to varying degrees of food restriction. Food-restricted rats showed considerable energy conservation, exhibited primarily as a reduction in the energy required for daily maintenance. When a given body weight loss was produced by starvation (3 or 6 d), changes in body composition and energy utilization differed only slightly (and temporarily) compared with the same body weight lost by partial food restriction. All food-restricted groups demonstrated a remarkable ability to reduce maintenance energy costs and to achieve zero energy balance at food intakes 40-50% of controls. By contrasting these results with our previous work in food-restricted male rats, we identified possible gender differences in the response to food restriction. Females appear to preserve lean mass to a greater degree than male rats by utilizing relatively more fat for energy needs. This preference for fat as a fuel during negative energy balance suggests that females would lose less body weight for a given reduction in carcass energy than males, since fat is calorically denser than lean mass.

Adipose Tissue↗

An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury.

Traumatic brain injury evokes multiple axonal pathologies that contribute to the ultimate disconnection of injured axons. In severe traumatic brain injury, the axolemma is perturbed focally, presumably allowing for the influx of Ca2+ and initiation of Ca2+ -sensitive, proaxotomy processes. Mitochondria in foci of axolemmal failure may act as Ca2+ sinks that sequester Ca2+ to preserve low cytoplasmic calcium concentrations. This Ca2+ load within mitochondria, however, may cause colloid osmotic swelling and loss of function by a Ca2+ -induced opening of the permeability transition pore. Local failure of mitochondria, in turn, can decrease production of high-energy phosphates necessary to maintain membrane pumps and restore ionic balance in foci of axolemmal permeability change. The authors evaluated the ability of the permeability transition pore inhibitor cyclosporin A (CsA) to prevent mitochondrial swelling in injured axonal segments demonstrating altered axolemmal permeability after impact acceleration injury in rat. At the electron microscopic level, statistically fewer abnormal mitochondria were seen in traumatically injured axons from CsA-pretreated injured animals. Further, this mitochondrial protection translated into axonal protection in a second group of injured rats, whose brains were reacted with antibodies against amyloid precursor protein, a known marker of injured axons. Pretreatment with CsA significantly reduced the number of axons undergoing delayed axotomy, as evidenced by a decrease in the density of amyloid precursor protein-immunoreactive axons. Collectively, these studies demonstrate that CsA protects both mitochondria and the related axonal shaft, suggesting that this agent may be of therapeutic use in traumatic brain injury.

Amyloid beta-Protein Precursor↗

Oxidative damage in alcoholic liver disease.

OBJECTIVE: The metabolic effects of alcohol are due both to its direct action and to that of its first metabolite, and can also be connected with the changes in redox state. Differences in ethanol distribution, bioavailability and hepatic metabolism can provide insight into the protective and predisposing factors in alcoholism, as well as gender differences of alcohol toxicity. Oxidative stress occurs following various conditions of ethanol consumption. DESIGN: Twenty-six Caucasian patients with alcoholism and 32 healthy, abstinent controls of both sexes were investigated with special regard to reduction-oxidation status and ad hoc free-radical-antioxidant balance. METHOD: Plasma free SH-group concentration, H-donating ability, and reducing power property were measured by simple spectrophotometric methods. Total scavenger capacity was determined by a newly developed chemiluminometric method in plasma and erythrocytes. RESULTS: Alcoholics showed a decrease of free SH-group concentration, hydrogen-donating ability and an increase of reducing power property in plasma. A decreased total scavenger capacity of erythrocytes and plasma of alcoholic patients, combined with gender differences, could be detected. CONCLUSIONS: Alcoholic dependence causes gradual exhaustion of the antioxidant capacity of erythrocytes, therefore this non-invasive measurement may be useful as a follow-up of the evolution of alcoholic liver disease. The results also suggest a gender susceptibility of alcohol toxicity.

Adult↗

Should intellectual property be disseminated by "forwarding" rejected letters without permission?

Substantive scientific letter writing is a cost-effective mode of complementing observational and experimental research. The value of such philosophically uncommitted and unsponsored well-balanced scientific activity has been relegated. Critical letter writing entails the abilities to: maintain rational scepticism; refuse to conform in order to explain data; persist in keeping common sense centre-stage; exercise logic to evaluate the biological significance of mathematical figures, including statistics, and the ability to sustain the will to share insights regarding disease mechanisms on an ostensibly lower research platform. During peer review, innovative letter writing may share the occasionally unfortunate fate of innovative research. Rejected scientific letters do not automatically lose copyright. Periodicals with high letter loads will see some valuable contributions wasted, but that is the price for maintaining autonomy in scientific publication. The scientific community is an integrated whole that must respect the rights of authors at all levels. Unauthorised forwarding of rejected letters sets the dangerous precedent of justifying unjust means.

Biomedical Research↗

Differential prioritization between relevance and redundancy in correlation-based feature selection techniques for multiclass gene expression data.

BACKGROUND: Due to the large number of genes in a typical microarray dataset, feature selection looks set to play an important role in reducing noise and computational cost in gene expression-based tissue classification while improving accuracy at the same time. Surprisingly, this does not appear to be the case for all multiclass microarray datasets. The reason is that many feature selection techniques applied on microarray datasets are either rank-based and hence do not take into account correlations between genes, or are wrapper-based, which require high computational cost, and often yield difficult-to-reproduce results. In studies where correlations between genes are considered, attempts to establish the merit of the proposed techniques are hampered by evaluation procedures which are less than meticulous, resulting in overly optimistic estimates of accuracy. RESULTS: We present two realistically evaluated correlation-based feature selection techniques which incorporate, in addition to the two existing criteria involved in forming a predictor set (relevance and redundancy), a third criterion called the degree of differential prioritization (DDP). DDP functions as a parameter to strike the balance between relevance and redundancy, providing our techniques with the novel ability to differentially prioritize the optimization of relevance against redundancy (and vice versa). This ability proves useful in producing optimal classification accuracy while using reasonably small predictor set sizes for nine well-known multiclass microarray datasets. CONCLUSION: For multiclass microarray datasets, especially the GCM and NCI60 datasets, DDP enables our filter-based techniques to produce accuracies better than those reported in previous studies which employed similarly realistic evaluation procedures.

Animals↗

Production of reactive oxygen species by man-made vitreous fibres in human polymorphonuclear leukocytes.

Human polymorphonuclear leukocytes (PMNL) or erythrocytes, isolated from human blood, were exposed to graded doses of asbestos (chrysotile), quartz, or man-made vitreous fibres (MMVF), i.e. refractory ceramic fibres (RCF), glasswool, or rockwool fibres. None of the MMVF affected either the viability of PMNL, as measured by trypan blue exclusion test, or induced haemolysis, whereas the positive controls, quartz and chrysotile, dose-dependently induced haemolysis in PMNL. MMVF did not increase the release of lactate dehydrogenase (LDH) from the PMNL, whereas the positive controls, chrysotile and quartz, induced a marked and dose-dependent release of LDH. When PMNL were exposed to MMVF, some of the fibre types slightly increased the levels of free intracellular calcium ([Ca2+]i) within the cells in a manner similar to that induced by chrysotile or quartz. All MMVF induced a dose-dependent production of reactive oxygen species (ROS) in PMNL, with RCF-induced production of ROS being the most marked. Production of ROS by MMVF seemed to depend on the availability of extracellular calcium because it could be attenuated with a Ca2+ channel blocker, verapamil, or a Ca2+ chelating agent, EGTA. Production of ROS may be a common pathway through which PMNL respond to MMVF-induced cell activation, but alterations of levels of free intracellular Ca2+ do not seem to be an absolute prerequisite for this effect. Fibre length seemed not to be an important factor in affecting the ability of MMVF to induce ROS production in PMNL. However, the balance between different elements in the fibre seemed importantly to affect the biological activity of a fibre.

Adult↗

Optimising antidepressant use in clinical practice: towards criteria for antidepressant selection.

BACKGROUND: Current treatment for depression in primary care and other out-patient settings demonstrates a pattern that is incongruous with the magnitude of the burden of depression suggested by its associated disability. AIMS: To review important considerations in current depression treatment with a focus on antidepressant use. METHOD: Factors influencing the undertreatment of depression in real-world settings are examined. RESULTS: Patient and clinician behaviour as well as the incentives created by the health care system affect the likelihood of realising effective antidepressant therapy in practice. CONCLUSIONS: Given the complexities of clinical practice, selection criteria for an antidepressant should include safety, efficacy and tolerability, as well as the ability of the antidepressant to deliver real-world efficacy while balancing health care costs in the long term.

Antidepressive Agents↗

Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis.

The divalent mineral cations Ca2+ and Mg2+ play many and diverse roles both in the function of cells and in extracellular processes. The metabolism of these cations is a complex process involving the coordinated function of several organ systems and endocrine glands. A recently cloned G-protein-coupled receptor responds to extracellular calcium concentration (Ca2+0-sensing receptor, CaSR) and mediates several of the known effects of Ca2+0 on parathyroid and renal function. The CaSR, which is also expressed in a number of other tissues including thyroidal C-cells, brain and gastrointestinal tract, may function as a Ca2+0 sensor in these tissues as well. Thus, Ca2+0 is a first messenger (or hormone) which, via CaSR-mediated activation of second messenger systems (e.g. phospholipases C and A2, cyclic AMP) leads to altered function of these cells. Several mutations in the human CaSR gene have been identified and shown to cause three inherited diseases of calcium homeostasis, clearly implicating the CaSR as an important component of the homeostatic mechanism for divalent mineral ions. Ca2+ and Mg2+ losses from the body are regulated by altering the urinary excretion of these divalent cations. The localization of the CaSR transcripts and protein in the kidney not only provides a basis for a direct Ca2+0 (or Mg2+0)-mediated regulation of Ca2+ (and Mg2+) excretion but also suggests a functional link between divalent mineral and water metabolism. In the kidney, the thick ascending limb of Henle (TAL) plays crucial roles in regulating both divalent mineral reabsorption and urine concentration. Recent studies have suggested models whereby extracellular Ca2+, via the CaSR expressed in the TAL as well as in the collecting duct system, modulates both Ca2+ 0 and Mg2+ 0 as well as water reabsorbtion. When taken together, these studies suggest that the CaSR not only provides the primary mechanism for Ca2+ 0-mediated regulation of parathyroid hormone secretion from parathyroid glands but also for direct modulation of renal divalent mineral excretion and urinary concentrating ability. These latter functions may furnish a mechanism for integrating and balancing water and divalent cation losses that minimizes the risk of urinary tract stone formation. This mechanism can explain hypercalcemia-mediated polyuria (diabetes insipidus).

Animals↗

Cage allocation designs for rodent carcinogenicity experiments.

Cage allocation designs for rodent carcinogenicity experiments are discussed and presented with the goal of avoiding dosage group biases related to cage location. Considerations in selecting a cage design are first discussed in general terms. Specific designs are presented for use in experiments involving three, four, and five dose groups and with one, four, and five rodents per cage. Priorities for balancing treatment groups include horizontal position on shelf and shelf of rack, nearest neighbor balance, and male-female balance. It is proposed that these balance criteria be considered together with practical issues, such as the ability to accurately conform to a design and to determine a sensible and efficient design for each experiment.

Animals↗

Mechanism of sodium load-induced hypertension in non-insulin dependent diabetes mellitus model rats: defective dopaminergic system to inhibit Na-K-ATPase activity in renal epithelial cells.

Obesity-related non-insulin dependent diabetes mellitus (NIDDM) is frequently accompanied by hypertension. The present study was designed to clarify this mechanism. We first determined the blood pressure in male Wistar fatty rats (WFR), one of the NIDDM model rats, and in Wistar lean rats (WLR) as the control, with a normal (0.7% NaCl) or high (7% NaCl) salt diet. We observed no difference in systolic and mean blood pressures between WFR and WLR. WFR, however, became extremely hypertensive as a result of ingesting the high salt diet. We next investigated the mechanism for sodium sensitivity in WFR. Although the urinary excretion of dopamine (DA), a potent natriuretic factor, which reflects the ability for renal DA production, was preserved in WFR, the sodium balance with the high salt diet was positive. Moreover, Na-K-ATPase activity in isolated proximal convoluted tubules (PCT) from WFR with a normal salt diet was significantly (p<0.05) higher than that from WLR. A high salt load produced a significant (p<0.05) decrease in Na-K-ATPase activity in WLR but not in WFR. Similarly, Na-K-ATPase activity in WLR with a normal salt diet was significantly (p<0.05) inhibited by DA (10(-5) M), but this was not true in WFR. Furthermore, urinary excretion of norepinephrine in WFR with a high salt diet was the highest among all the groups. These results indicate that WFR tend to develop salt-sensitive hypertension that could be caused by the excessive sodium retention occurring as the results of a defective dopaminergic system in the kidney that fails to inhibit Na-K-ATPase activity. Augmentation of the renal sympathetic nervous system may play some role in this setting.

Animals↗

Plasma and urine levels of electrolytes, urea and steroid hormones involved in osmoregulation of cetaceans.

Cetaceans are well adapted to their hyperosmotic environment by properly developed osmoregulatory ability. A question here is how they regulate water and mineral balances in marine habitats. In the present study, we determined blood and urine levels of various chemicals involved in osmoregulation, compared them with those in artiodactyls, and characterized the values in the whales. Blood and urine samples obtained from baleen whales of common minke (Balaenoptera acutorostrata), sei (B. borealis), and Bryde's whales (B. brydei), and toothed whales of sperm whales (Physeter macrocephalus) were analyzed for osmolality, major electrolytes, urea, steroid hormones and glucose. The urine osmolality and Na(+) concentrations in the cetaceans were much higher than those in the cattle. Furthermore, the cetaceans had 5 to 11-fold urea in plasma than the cattle, and 2 to 4-fold urea in urine. There were no significant difference in the plasma concentrations of corticosteroids between the cetaceans and the cattle. The present results indicate that the osmoregulatory parameters seem to be not affected by the reproductive stage and sex steroid hormones. The concentrations of urea in plasma and urine of the baleen whales were higher than those of the sperm whales, indicating a possibility that their osmoregulatory mechanisms may be correlated to their feeding habits. The present results suggest that cetaceans have unique osmoregulatory mechanisms by which they excrete strongly hypertonic urine to maintain fluid homeostasis in marine habitats.

Analysis of Variance↗

Sources of variation and prospects for improvement of productive efficiency in the dairy cow: a review.

In this review, "productive efficiency" in dairy cows is defined as the yield of milk obtained in ratio to the nutritional costs associated with maintenance, milk synthesis and loss of body condition during lactation. Improvements in efficiency could occur as a result of changes in digestion and nutrient absorption, maintenance requirement, utilization of metabolizable energy for production or nutrient partitioning. Digestibility can be greatly enhanced by appropriate dietary manipulation. Likewise, it may be possible to reduce maintenance requirements and improve the efficiency with which metabolizable energy is used for milk synthesis by manipulation of the pattern of nutrients presented to tissues. However, these factors apparently do not respond to selection for increased milk yield, and little variation is observed among cows. In contrast, individual cows differ substantially in feed intake and in the partitioning of nutrients among body tissues. Techniques associated with genetic engineering and the early prediction of genetic merit have the potential to improve productive efficiency by manipulation of these processes. However, changes in nutrient partitioning and feed intake during lactation are coordinated by a complex network of controls that accommodate the nutrient requirements of each tissue while maintaining homeostatic balance. Future improvements in productive efficiency will therefore depend on our ability to understand the manner in which these controls operate.

Animal Feed↗

Eosinophil apoptosis is mediated by stimulators of cellular oxidative metabolisms and inhibited by antioxidants: involvement of a thiol-sensitive redox regulation in eosinophil cell death.

The mechanisms for induction of eosinophil apoptosis remain uncertain. The role of oxidative stress has not been investigated. The present study was undertaken to determine the role of reactive oxygen species (ROS) and selective antioxidants in eosinophil apoptosis. Eosinophils were cultured with sodium arsenite (SA) known to induce intracellular oxidative metabolites. There was a significant increase in the rate of eosinophil apoptosis with low concentrations of arsenite, whereas high concentrations showed rates of apoptosis similar to control medium. Investigating the role of intracellular oxidants by flow cytometry, we found that while inducing apoptosis, SA more than anti-Fas resulted in a significant dose-dependent production of intracellular H(2)O(2). In contrast, the extracellular release of superoxide decreased after stimulation with SA or anti-Fas as assessed by lucigenin-dependent chemiluminescence. Coincubation experiments demonstrated that arsenite-induced apoptosis can be nearly completely prevented by selective antioxidants such as glutathione (GSH) and N-acetyl-cysteine (NAC), but not dimethyl sulfoxide (DMSO) or taurine (TAUR). Moreover, GSH and NAC significantly reduced eosinophil apoptosis mediated by a monoclonal antibody directed to Fas antigen. Next it was shown that GSH and NAC, but not DMSO or TAUR, were able to significantly delay spontaneous apoptosis in unstimulated eosinophils. Taken together, these data point to an important role of oxygen-dependent mechanisms in the regulation of eosinophil survival and apoptosis. We propose that eosinophil apoptosis may be related to the ability of the cell to maintain an appropriate oxidant-antioxidant balance.

Acetylcysteine↗