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Immunonutrition: problematic or problem solving?

The addition of immune-modulating nutrients to enteral formulas has been examined in clinical trials and meta-analyses. Enhancing immunity through diet is generally done by adding n-3 fatty acids, arginine, and nucleotides to an otherwise nutritionally complete formula. Despite flaws in many studies, a consistent trend to reduced infectious complications has been seen with immunonutrition, especially in patients undergoing surgery for upper gastrointestinal cancer or trauma. In critical care populations, however, the results have been mixed. In this review, we analyze these studies and focus on select clinical points that may explain the variation. One common flaw has been a failure to deliver an adequate nutrition volume. Few patients, especially in the earliest studies, received even close to goal feeding. A minimum quantity of immunonutrition may be required for effective reduction in infections. When feeding volumes are low, immunonutrition is usually not better than an isonitrogenous control. In more recent studies, practitioners have been increasingly aggressive with enteral feeding, and this has been reflected in improved outcomes from immunonutrition. Early delivery of immunonutrition (preoperatively in surgical patients with cancer) might be particularly beneficial. Another consideration is illness severity: we discuss evidence that the use of immunonutrition in moderate illness is more likely to be helpful, whereas severe sepsis is probably beyond the reach of any nutritional intervention, and mild illness is more likely to improve irrespective of feeding. If future trials can consider these vital points, level 1 recommendations in favor of immunonutrition might be justified, although presently such evidence is lacking for most clinical indications.

Adjuvants, Immunologic↗

Geographic variation in the prevalence of common mental disorders in Britain: a multilevel investigation.

It is still not known whether the places that people live affect their mental health. The principal aim of this 1991 study was to quantify simultaneously variance in the prevalence of the most common mental disorders, anxiety and depression, in Britain at the individual, household, and electoral ward levels. Data from a cross-sectional, nationally representative survey of 8,979 adults aged 16-74 years living in private households nested within 642 electoral wards in England, Wales, and Scotland were analyzed by using multilevel logistic and linear regression. Common mental disorders were assessed by using the General Health Questionnaire. Less than 1% of the total variance in General Health Questionnaire scores occurred at the ward level. This variance was further reduced and was no longer statistically significant after adjustment for characteristics of persons. By contrast, the proportion of total variance at the household level (14.4%, 95% confidence interval: 11.4, 17.5 in the null model) (p < 0.001) was statistically significant and remained so after adjustment for individual- and household-level exposures. While these findings suggest that future interventions should target persons and households rather than places, further research is first required to establish whether other (particularly smaller) areas lead to similar results.

Adolescent↗

Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin Lymphoma Study.

Recent findings suggest that genetic polymorphisms in TNF and IL10 are associated with an increased risk of non-Hodgkin lymphoma (NHL), particularly for diffuse large B-cell lymphoma (DLBCL). To further investigate the contribution of common genetic variation in key cytokine and innate immunity genes to the etiology of NHL, we genotyped participants in a case-control study of NHL conducted in Australia (545 cases, 498 controls). We investigated 36 single nucleotide polymorphisms in IL10, TNF and 21 other immune function genes. We observed an elevated risk of DLBCL with the IL10 -3575T>A polymorphism [TA genotype: odds ratio (OR)=1.32, 95% confidence interval (CI)=0.86-2.02; AA, OR=1.84, 95% CI=1.10-3.08; trend test, P=0.02]. Our most noteworthy TNF finding was an association between -857C>T and a decreased risk of NHL (CT or TT, OR=0.59, 95% CI=0.42-0.84, P=0.003) and particularly follicular lymphoma (OR=0.40, 95% CI=0.23-0.68, P=0.0009). Additionally, TNF -863C>A was associated with an elevated risk of DLBCL (CA, OR=1.45, 95% CI=0.95-2.21; AA, OR=2.06, 95% CI=0.88-4.83; trend test, P=0.02). Our findings offer further evidence that variation in the IL10 and TNF loci influences NHL risk. Additional studies are needed to clarify the genetic and biologic basis for these relationships.

Adult↗

Translocation within the acceptor helix of a major tRNA identity determinant.

The genetic code is defined by the specific aminoacylations of tRNAs by aminoacyl-tRNA synthetases. Although the synthetases are widely conserved through evolution, aminoacylation of a given tRNA is often system specific-a synthetase from one source will not acylate its cognate tRNA from another. This system specificity is due commonly to variations in the sequence of a critical tRNA identity element. In bacteria and the cytoplasm of eukaryotes, an acceptor stem G3:U70 base pair marks a tRNA for aminoacylation with alanine. In contrast, Drosophila melanogaster (Dm) mitochondrial (mt) tRNA(Ala) has a G2:U71 but not a G3:U70 pair. Here we show that this translocated G:U and the adjacent G3:C70 are major determinants for recognition by Dm mt alanyl-tRNA synthetase (AlaRS). Additionally, G:U at the 3:70 position serves as an anti-determinant for Dm mt AlaRS. Consequently, the mitochondrial enzyme cannot charge cytoplasmic tRNA(Ala). All insect mitochondrial AlaRSs appear to have split apart recognition of mitochondrial from cytoplasmic tRNA(Ala) by translocation of G:U. This split may be essential for preventing introduction of ambiguous states into the genetic code.

Alanine-tRNA Ligase↗

The adaptability of the health promoting schools concept: a case study from Australia.

The adoption of the concept of the health promoting school internationally indicates that it is a timely and flexible concept that can be utilized by different countries to accommodate their particular contexts. Political, economic and socio-cultural factors are powerful forces that shape the construction of health promoting schools globally. How some of these factors operate will be exemplified through a description of the health promoting school movement in Australia with commonalities and variations with activities in member countries of the European Network of Health Promoting Schools highlighted. The unique role globally of the Australian Health Promoting Schools Association, as a non-government organization specifically established to promote the concept of the health promoting school, is described. Its contribution is as a neutral body representing diverse interests that can advocate in different settings and at all levels of influence. Additionally it provides a mechanism for networking, awareness raising and information exchange. The structure of the health and education sectors in Australia has shaped the conceptualization of a health promoting school, one that accommodates the country's specific context. Barriers, facilitating factors and challenges that exist for future work in the area are described.

Australia↗

Physiological significance of apolipoprotein mutants.

The major plasma lipids, cholesterol, and triglycerides are transported in the blood by different classes of lipoprotein, which can be differentiated from each other by their apoprotein and lipid constituents. Defects in the genes coding for the apolipoprotein components, besides those coding for lipolytic enzymes and cellular receptors, can cause an imbalance in the plasma lipid homeostasis. The physiological significance on lipid metabolism of genetic defects, both rare inborn errors or common genetic variation at these gene loci, are the topics of this review.

Apolipoproteins↗

Q fever pneumonia.

PURPOSE OF REVIEW: In this era of emerging infectious diseases and bioterrorism it is important to be up to date with the diagnosis and management of Q fever pneumonia. RECENT FINDINGS: A considerable amount of new information has emerged regarding the pathogenesis of Coxiella burnetii infection. The complete genome of this microorganism has now been sequenced and there are several unique features. The spectrum of manifestations of infection due to C. burnetii continues to expand. Some of the more recently described findings are acalculous cholecystitis, rhabdomyolysis, long-term persistence of Coxiella, post Q fever fatigue syndrome, and hemolytic uremic syndrome. Pneumonia as a manifestation of acute Q fever shows tremendous geographic variation, being common in one area of a country such as Spain but not in another area. SUMMARY: Pneumonia continues to be an important manifestation of infection with C. burnetii. It responds to treatment with doxycycline, quinolones or macrolides.

Anti-Bacterial Agents↗

Variations in patient compliance with common long-term drugs.

An indirect measure of adherence to drug regimens was developed from pharmacy records of prescription refills. This measure was validated by demonstrations of significant relationships between compliance with hydrochlorothiazide and propranolol and expected physiologic effects of these drugs (decreased blood pressures and decreased pulse rates, respectively). The measure was used to survey compliance with 20 common drugs prescribed to 419 outpatients for long-term administration on regular schedules. Eight of the study drugs showed very low levels of compliance, suggesting "take-as-needed" (PRN) use, in spite of medical record, pharmacy record, and label instructions for regular administration. For the whole survey population, 12 truly "non-PRN" drugs showed showed a considerable gradient in mean compliance rates, ranging from digoxin (76.6 per cent) to hydralazine (50.4 per cent). Within-patient differences in mean compliance with different drugs were shown (e.g., hydrochlorothiazide 61.2 per cent versus potassium chloride 41.2 per cent mean compliance, p < 0.001). Correlations between compliance rates with different drugs in a single regimen were sometimes strikingly low. We conclude that 1) chart and prescription directions for regular administration are not sufficient to identify "non-PRN" drugs in compliance studies; 2) when compliance is an outcome measure in health care trials, drug mix is an important confounding variable; 3)in outpatient clinical settings, it may be appropriate to be inherently more suspicious of noncompliance with some drugs than others; and 4) patients may comply at different rates with individual drug components of a single regimen.

Angina Pectoris↗

Intragenic polymorphisms of the vitamin D receptor gene associated with intervertebral disc degeneration.

STUDY DESIGN: A study in genetic epidemiology of disc degeneration, based on lifetime exposure data, findings on magnetic resonance imaging, and genotyping of intragenic markers. OBJECTIVES: To pursue the potential correlation between common allelic variations in the vitamin D receptor locus and degeneration of the intervertebral disc. SUMMARY OF BACKGROUND DATA: Familial aggregation has been observed in intervertebral disc degeneration, but the relative significance of the genetic component and shared environmental influences is unknown. The identification of relevant candidate genes associated with disc degeneration would specify a genetic component and increase our understanding of the etiopathogenesis of disc degeneration. METHODS: From the population-based Finnish Twin cohort, 85 pairs of male monozygotic twins were selected based on exposure to suspected risk factors for disc degeneration. Interview data were gathered on relevant lifetime exposures, and thoracic and lumbar disc degeneration was determined through quantitative and qualitative assessments of signal intensity on magnetic resonance imaging, and qualitative assessments of disc bulging and disc height narrowing. Possible associations were examined between disc degeneration measures and two polymorphisms of the coding region of the vitamin D receptor locus. RESULTS: Two intragenic polymorphisms of the vitamin D receptor gene revealed an association with disc degeneration. Quantitatively assessed signal intensities of thoracic and lumbar (T6-S1) discs were 12.9% worse in men with the Taql tt genotype and 4.5% worse in men with the Tt genotype, compared with signal intensity in men with the TT genotype (age adjusted P = 0.003). A similar pattern was found between disc signal intensity and Fokl genotypes; men with the ff and Ff genotypes had mean signal intensities that were 9.3% and 4.3% lower, respectively, than those in men with FF genotypes (age-adjusted P = 0.006). The summary scores of qualitatively assessed signal intensity, bulging, and disc height were 4.0% and 6.9% worse in men with Ff and ff genotypes, respectively, when compared with those in men with the FF genotype (age-adjusted P = 0.029). CONCLUSION: Specific vitamin D receptor alleles were associated with intervertebral disc degeneration as measured by T2-weighted signal intensity, demonstrating for the first time, the existence of genetic susceptibility to this progressive, age-related degenerative process.

Adult↗

Control charts 101: a guide to health care applications.

A control chart can be an effective way to display process data over time. It can differentiate common cause variation from special cause variation through the application of several probability-based interpretation rules. In addition, a control chart can be helpful in evaluating the effectiveness of a change. There are numerous types of control charts, and this tutorial was developed to guide the user through the selection process.

Data Collection↗

Urolithiasis in patients with spinal cord injuries: risk factors, management, and outcomes.

PURPOSE OF REVIEW: Despite major advances in the urological care of spinal cord injury patients, the incidence of urolithiasis has not changed. Although the incidence of kidneys lost to staghorn calculus disease has decreased considerably, stone disease is still a significant cause of morbidity and concern. The purpose of this review is to summarize the risk factors for the development of stone diseases in the spinal cord injury patient population and present the outcomes of current endourologic treatment modalities. RECENT FINDINGS: Recurrent urinary tract infections, indwelling catheters, vesicoureteral reflux, and immobilization hypercalcuria are a few of the major risk factors for the development of urolithiasis among spinal cord injury patients. Retrograde endourologic techniques are often not possible to address stone disease due to lower extremity contractures, spinal curvature, and pelvic tilt. Extracorporeal shockwave lithotripsy success rates vary from 50 to 90%, but clearance rates are often delayed. Success rates for percutaneous nephrolithotomy match those quoted in the general population ( > 90%), but at the expense of a higher rate of complications (6-20%). Meticulous planning with regard to appropriate prophylactic antibiotics and body position will maximize efficacious outcomes. SUMMARY: Early identification and treatment of urolithiasis in spinal cord injury patients will aid in preserving renal function and minimizing associated complications. Despite variation in common urological practices between spinal cord injury units and the lack of clear cut guidelines for follow-up, the increased incidence of risks associated with urolithiasis lends support for routine genitourinary imaging in order to identify and treat those individuals at highest risk.

Humans↗

From genotype to phenotype: understanding the genetic basis of autism.

PURPOSE OF REVIEW: This paper covers some of the key findings on the topic of genetic influences in autism over the last 12-18&#x200a;months, which consist of significant conceptual shifts and new insights from recent technological advances. RECENT FINDINGS: Autism is a highly heritable condition, with significant heterogeneity of the genes that influence the development of this condition. The heterogeneity of autism, and multiple pathways contributing to the development of an autistic phenotype, create challenges in our understanding, diagnosis, and management of this condition.Recent studies of common genetic variation and polygenic risk scores have focussed on resolving phenotypic heterogeneity and identifying meaningful autism subtypes. Rare-variant discovery has expanded across ancestries, the X chromosome, noncoding loci, structural variants, and tandem repeats, aided by long-read and pangenome-informed sequencing. Single-cell multiomics, spatial perturbation methods and human organoid models have connected genetic variation to cell-type-specific and developmental phenotypes, while also revealing substantial mutation-specific effects and methodological sensitivity. Genetic testing increasingly provides aetiological diagnoses and informs medical surveillance. Recent developments also illustrate the therapeutic potential of gene-first approaches for selected monogenic neurodevelopmental disorders. SUMMARY: Recent developments have expanded our understanding of the way the genetic basis of autism manifests phenotypically.

autism↗

Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene.

The difficulty of fine localizing the polymorphisms responsible for genotype-phenotype correlations is emerging as an important constraint in the implementation and interpretation of genetic association studies, and calls for the definition of protocols for the follow-up of associated variants. One recent example is the 3435C>T polymorphism in the multidrug transporter gene ABCB1, associated with protein expression and activity, and with several clinical conditions. Available data suggest that 3435C>T may not directly cause altered transport activity, but may be associated with one or more causal variants in the poorly characterized stretch of linkage disequilibrium (LD) surrounding it. Here we describe a strategy for the follow-up of reported associations, including a Bayesian formalization of the associated interval concept previously described by Goldstein. We focus on the region of high LD around 3435C>T to compile an exhaustive list of variants by (1) using a relatively coarse set of marker typings to assess the pattern of LD, and (2) resequencing derived and ancestral chromosomes at 3435C>T through the associated interval. We identified three intronic sites that are strongly associated with the 3435C>T polymorphism. One of them is associated with multidrug resistance in patients with epilepsy (chi2 = 3.78, P = 0.052), and sits within a stretch of significant evolutionary conservation. We argue that these variants represent additional candidates for influencing multidrug resistance due to P-glycoprotein activity, with the IVS 26+80 T>C being the best candidate among the three intronic sites. Finally, we describe a set of six haplotype tagging single-nucleotide polymorphisms that represent common ABCB1 variation surrounding 3435C>T in Europeans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

The portability of tagSNPs across populations: a worldwide survey.

In the search for common genetic variants that contribute to prevalent human diseases, patterns of linkage disequilibrium (LD) among linked markers should be considered when selecting SNPs. Genotyping efficiency can be increased by choosing tagging SNPs (tagSNPs) in LD with other SNPs. However, it remains to be seen whether tagSNPs defined in one population efficiently capture LD in other populations; that is, how portable tagSNPs are. Indeed, tagSNP portability is a challenge for the applicability of HapMap results. We analyzed 144 SNPs in a 1-Mb region of chromosome 22 in 1055 individuals from 38 worldwide populations, classified into seven continental groups. We measured tagSNP portability by choosing three reference populations (to approximate the three HapMap populations), defining tagSNPs, and applying them to other populations independently on the availability of information on the tagSNPs in the compared population. We found that tagSNPs are highly informative in other populations within each continental group. Moreover, tagSNPs defined in Europeans are often efficient for Middle Eastern and Central/South Asian populations. TagSNPs defined in the three reference populations are also efficient for more distant and differentiated populations (Oceania, Americas), in which the impact of their special demographic history on the genetic structure does not interfere with successfully detecting the most common haplotype variation. This high degree of portability lends promise to the search for disease association in different populations, once tagSNPs are defined in a few reference populations like those analyzed in the HapMap initiative.

Chromosomes, Human, Pair 22↗

Modeling the impact of imperfections in high-index-contrast photonic waveguides.

By formulating Maxwell's equations in perturbation-matched curvilinear coordinates, we have derived rigorous perturbation theory (PT) and coupled-mode theory expansions that are applicable in the case of generic nonuniform dielectric profile perturbations in high-index-contrast waveguides, including photonic band gap fibers, and two-dimensional (2D) and 3D waveguides. PT is particularly useful in the optimization stage of a component design process where fast evaluation of an optimized property with changing controlling variables is crucial. We demonstrate our method by studying radiation scattering due to common geometric variations in planar 2D photonic crystals waveguides.

Journal Article↗

Resolution of the frozen-charge paradox in stopping of channeled heavy ions.

The long-standing problem of the lacking signature of a Barkas effect in the stopping of swift heavy ions under channeling conditions has been analyzed theoretically. The stopping model provides explicit dependences on impact parameter and allows for projectile screening and higher-order Z(1) corrections. The analysis differentiates between principal target shells. A distinct Barkas correction is found in accordance with standard theory. It is less pronounced for channeled than for random stopping because of the dominance of outer target shells. Varying contributions from different target shells to the stopping force may give rise to an inversion of the commonly observed variation with ion energy and charge state of the Barkas correction.

Journal Article↗

Melanocytic dysplasia and melanoma.

A review of a series of 226 melanomas, representing 95% of the melanomas presenting in one year, has shown that 34% are associated with atypical melanocytic proliferation or melanocytic dysplasia in the adjacent skin. The dysplasia may be lentiginous, predominantly spindle-celled or non-lentiginous in pattern. These variants appear to correspond to the previously reported lesions, lentiginous and epithelioid melanocytic dysplasia and atypical melanocytic hyperplasia respectively. Some of these are referred to as dysplastic naevi. All these variants were seen in a review of 325 cases of melanocytic dysplasia. The variations are commonly seen within the same lesion and it is argued that they are variants of a single premalignant process which might best be termed melanocytic dysplasia. Melanocytic dysplasia is seen in white races, on non-exposed and exposed skin. They may be solitary as well as multiple and the majority are non-familial. Although melanocytic dysplasia may be a precursor of a large proportion of malignant melanomas it is suggested that most lesions mature into a benign intradermal melanonaevus. The behaviour of the lesions in any single patient appears to be proportional to the number and cellularity of the lesions and the strength of the family history. A diffuse mottled pattern of melanocytic dysplasia appears to have a particularly unfavourable prognosis.

Female↗