Leptin, a neuroendocrine mediator of immune responses, inflammation, and sickness behaviors

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Effective immune responses are coordinated by interactions among the nervous, endocrine, and immune systems. Mounting immune, inflammatory, and sickness responses requires substantial energetic investments, and as such, an organism may need to balance energy allocation to these processes with the energetic demands of other competing physiological systems. The metabolic hormone leptin appears to be mediating trade-offs between the immune system and other physiological systems through its actions on immune cells and the brain. Here we review the evidence in both mammalian and non-mammalian vertebrates that suggests leptin is involved in regulating immune responses, inflammation, and sickness behaviors. Leptin has also been implicated in the regulation of seasonal immune responses, including sickness; however, the precise physiological mechanisms remain unclear. Thus, we discuss recent data in support of leptin as a mediator of seasonal sickness responses and provide a theoretical model that outlines how seasonal cues, leptin, and proinflammatory cytokines may interact to coordinate seasonal immune and sickness responses.     

Organisational downsizing,sickness absence,and mortality: 10-town prospective cohort study

Objective To examine whether downsizing, the reduction of personnel in organisations, is a predictor of increased sickness absence and mortality among employees.Design Prospective cohort study over 7.5 years of employees grouped into categories on the basis of reductions of personnel in their occupation and workplace: no downsizing (< 8% reduction), minor downsizing (8-18%), and major downsizing (> 18%).Setting Four towns in Finland.Participants 5909 male and 16 521 female municipal employees, aged 19-62 years, who kept their jobs.Main outcome measures Annual sickness absence rate based on employers'' records before and after downsizing by employment contract; all cause and cause specific mortality obtained from the national mortality register.Results Major downsizing was associated with an increase in sickness absence (P for trend < 0.001) in permanent employees but not in temporary employees. The extent of downsizing was also associated with cardiovascular deaths (P for trend < 0.01) but not with deaths from other causes. Cardiovascular mortality was 2.0 (95% confidence interval 1.0 to 3.9) times higher after major downsizing than after no downsizing. Splitting the follow up period into two halves showed a 5.1 (1.4 to 19.3) times increase in cardiovascular mortality for major downsizing during the first four years after downsizing. The corresponding hazard ratio was 1.4 (0.6 to 3.1) during the second half of follow up.Conclusion Organisational downsizing may increase sickness absence and the risk of death from cardiovascular disease in employees who keep their jobs.     

Sickness absence as a global measure of health: evidence from mortality in the Whitehall II prospective cohort study

Objective To examine the association between sickness absence and mortality compared with associations between established health indicators and mortality.Design Prospective cohort study. Medical examination and questionnaire survey conducted in 1985-8; sickness absence records covered the period 1985-98.Setting 20 civil service departments in London.Participants 6895 male and 3413 female civil servants aged 35-55 years.Main outcome measure All cause mortality until the end of 1999.Results After adjustment for age and grade, men and women who had more than five medically certified absences (spells > 7 days) per 10 years had a mortality 4.8 (95% confidence interval 3.3 to 6.9) and 2.7 (1.5 to 4.9) times greater than those with no such absence. Poor self rated health, presence of longstanding illness, and a measure of common clinical conditions comprising diabetes, diagnosed heart disease, abnormalities on electrocardiogram, hypertension, and respiratory illness were all associated with mortality—relative rates between 1.3 and 1.9. In a multivariate model including all the above health indicators and additional health risk factors, medically certified sickness absence remained a significant predictor of mortality. No linear association existed between self certified absence (spells 1-7 days) and mortality, but the findings suggest that a small amount of self certified absence is protective.Conclusion Evidence linking sickness absence to mortality indicates that routinely collected sickness absence data could be used as a global measure of health differentials between employees. However, such approaches should focus on medically certified (or long term) absences rather than self certified absences.     

Cloning, heterologous expression, and distinct substrate specificity of protein farnesyltransferase from Trypanosoma brucei

Protein prenylation occurs in the protozoan that causes African sleeping sickness (Trypanosoma brucei), and the protein farnesyltransferase appears to be a good target for developing drugs. We have cloned the alpha- and beta-subunits of T. brucei protein farnesyltransferase (TB-PFT) using nucleic acid probes designed from partial amino acid sequences obtained from the enzyme purified from insect stage parasites. TB-PFT is expressed in both bloodstream and insect stage parasites. Enzymatically active TB-PFT was produced by heterologous expression in Escherichia coli. Compared with mammalian protein farnesyltransferases, TB-PFT contains a number of inserts of >25 residues in both subunits that reside on the surface of the enzyme in turns linking adjacent alpha-helices. Substrate specificity studies with a series of 20 peptides SSCALX (where X indicates a naturally occurring amino acid) show that the recombinant enzyme behaves identically to the native enzyme and displays distinct specificity compared with mammalian protein farnesyltransferase. TB-PFT prefers Gln and Met at the X position but not Ser, Thr, or Cys, which are good substrates for mammalian protein farnesyltransferase. A structural homology model of the active site of TB-PFT provides a basis for understanding structure-activity relations among substrates and CAAX mimetic inhibitors.     

Optimal Cutoff Values of WHO-HPQ Presenteeism Scores by ROC Analysis for Preventing Mental Sickness Absence in Japanese Prospective Cohort

Objectives

Sickness absence due to mental disease in the workplace has become a global public health problem. Previous studies report that sickness presenteeism is associated with sickness absence. We aimed to determine optimal cutoff scores for presenteeism in the screening of the future absences due to mental disease.

Methods

A prospective study of 2195 Japanese employees from all areas of Japan was conducted. Presenteeism and depression were measured by the validated Japanese version of the World Health Organization Health and Work Performance Questionnaire (WHO-HPQ) and K6 scale, respectively. Absence due to mental disease across a 2-year follow-up was surveyed using medical certificates obtained for work absence. Socioeconomic status was measured via a self-administered questionnaire. Receiver operating curve (ROC) analysis was used to determine optimal cutoff scores for absolute and relative presenteeism in relation to the area under the curve (AUC), sensitivity, and specificity.

Results

The AUC values for absolute and relative presenteeism were 0.708 (95% CI, 0.618–0.797) and 0.646 (95% CI, 0.546–0.746), respectively. Optimal cutoff scores of absolute and relative presenteeism were 40 and 0.8, respectively. With multivariate adjustment, cohort participants with our proposal cutoff scores for absolute and relative presenteeism were significantly more likely to be absent due to mental disease (OR = 4.85, 95% CI: 2.20–10.73 and OR = 5.37, 95% CI: 2.42–11.93, respectively). The inclusion or exclusion of depressive symptoms (K6≥13) at baseline in the multivariate adjustment did not influence the results.

Conclusions

Our proposed optimal cutoff scores of absolute and relative presenteeism are 40 and 0.8, respectively. Participants who scored worse than the cutoff scores for presenteeism were significantly more likely to be absent in future because of mental disease. Our findings suggest that the utility of presenteeism in the screening of sickness absence due to mental disease would help prevent such an absence.     

Genomic and epigenomic instability, fragile sites, schizophrenia and autism

Increasing evidence links genomic and epigenomic instability, including multiple fragile sites regions to neuropsychiatric diseases including schizophrenia and autism. Cancer is the only other disease associated with multiple fragile site regions, and genome and epigenomic instability is a characteristic of cancer. Research on cancer is far more advanced than research on neuropsychiatric disease; hence, insight into neuropsychiatric disease may be derived from cancer research results. Towards this end, this article will review the evidence linking schizophrenia and other neuropsychiatric diseases (especially autism) to genomic and epigenomic instability, and fragile sites. The results of studies on genetic, epigenetic and environmental components of schizophrenia and autism point to the importance of the folate-methionine-transulfuration metabolic hub that is diseases also perturbed in cancer. The idea that the folate-methionine-transulfuration hub is important in neuropsychiatric is exciting because this hub present novel targets for drug development, suggests some drugs used in cancer may be useful in neuropsychiatric disease, and raises the possibility that nutrition interventions may influence the severity, presentation, or dynamics of disease.     

Sex, glia, and development: Interactions in health and disease

This article is part of a Special Issue "Neuroendocrine-Immune Axis in Health and Disease." Microglia and astrocytes are the primary immune cells within the central nervous system. Microglia influence processes including neural development, synaptic plasticity and cognition; while their activation and production of immune molecules can induce stereotyped sickness behaviors or pathologies including cognitive dysfunction. Given their role in health and disease, we propose that glia may also be a critical link in understanding the etiology of many neuropsychiatric disorders that present with a strong sex-bias in their symptoms or prevalence. Specifically, males are more likely to be diagnosed with disorders that have distinct developmental origins such as autism or schizophrenia. In contrast, females are more likely to be diagnosed with disorders that present later in life, after the onset of adolescence, such as depression and anxiety disorders. In this review we will summarize the evidence suggesting that sex differences in the colonization and function of glia within the normal developing brain may contribute to distinct windows of vulnerability between males and females. We will also highlight the current gaps in our knowledge as well as the future directions and considerations of research aimed at understanding the link between neuroimmune function and sex differences in mental health disorders.     

Trypanosoma brucei rhodesiense: characterisation of stocks from Zambia, Kenya, and Uganda using repetitive DNA probes

We have previously described a system for characterising the relationships between trypanosome stocks of the T.brucei group based on Southern blotting with repetitive DNA probes followed by cluster analysis of resultant banding patterns (G. Hide et al. Molec. Bioch. Parasitol. 39, 213-226, 1990). In this study, we extend this analysis to examine the relationships between trypanosome stocks isolated from major sleeping sickness foci in Zambia, Kenya, and Uganda. We show that the trypanosome strains responsible for disease in Zambia are quite distinct from those sampled from the Kenya/Uganda foci. Furthermore, the human serum resistant stocks isolated from the Kenya/Uganda foci which were isolated from man (or from animals) were found to form a tight group in the cluster analysis, while stocks isolated from nonhuman sources in the same area or stocks from elsewhere were found in separate groups. Thus, the human infective trypanosome strains found in these foci may have common origins and have, perhaps, arisen by clonal selection from a common source.     

Leishmania amastigotes as targets for drug screening

Human African trypanosomiasis is a threat to millions of people living in sub-Saharan countries and is fatal unless treated. At present, the serological and parasitological tests used in the field for diagnosis of sleeping sickness have low specificity and sensitivity. There is clearly an urgent need for accurate tools for both diagnosis and staging of the disease. The Foundation for Innovative New Diagnostics and the World Health Organization have announced that they will collaborate to develop and evaluate new diagnostic tests for human African trypanosomiasis.     

Trypanosomatid comparative genomics: Contributions to the study of parasite biology and different parasitic diseases

In 2005, draft sequences of the genomes of Trypanosoma brucei, Trypanosoma cruzi and Leishmania major, also known as the Tri-Tryp genomes, were published. These protozoan parasites are the causative agents of three distinct insect-borne diseases, namely sleeping sickness, Chagas disease and leishmaniasis, all with a worldwide distribution. Despite the large estimated evolutionary distance among them, a conserved core of ~6,200 trypanosomatid genes was found among the Tri-Tryp genomes. Extensive analysis of these genomic sequences has greatly increased our understanding of the biology of these parasites and their host-parasite interactions. In this article, we review the recent advances in the comparative genomics of these three species. This analysis also includes data on additional sequences derived from other trypanosmatid species, as well as recent data on gene expression and functional genomics. In addition to facilitating the identification of key parasite molecules that may provide a better understanding of these complex diseases, genome studies offer a rich source of new information that can be used to define potential new drug targets and vaccine candidates for controlling these parasitic infections.     

Preventing deaths from malaria.

To reduce the number of avoidable deaths from malaria in Britain the following five points are recommended. Parliament should pass a Malaria Prevention Act that compels travel agents and airlines to give written and verbal advice on prevention and diagnosis of malaria to people travelling to countries where the disease occurs. To improve diagnostic and therapeutic efficiency for all diseases the Department of Health and Social Security should prepare a procedure manual for the NHS that gives guidance for doctors and other medical staff. Avoidable deaths from all diseases should be the subject of open inquiries at district medical committees, with recorded evidence. Failure to perform diagnostic tests such as blood films for malaria in cases of sickness in people returning from the tropics should automatically be considered negligent. Compensation should be offered by the State to the next of kin of people who have died because of medical negligence from malaria or other diseases.     

ROC graphs for assessing the ability of a diagnostic marker to detect three disease classes with an umbrella ordering

Receiver operating characteristic (ROC) curves and the area under these curves are commonly used to assess the ability of a continuous diagnostic marker (e.g., DNA methylation markers) to correctly classify subjects as having a particular disease or not (e.g., cancer). These approaches, however, are not applicable to settings where the gold standard yields more than two disease states or classes. ROC surfaces and the volume under the surfaces have been proposed for settings with more than two disease classes. These approaches, however, do not allow one to assess the ability of a marker to differentiate two disease classes from a third disease class without requiring a monotone order for the three disease classes under study. That is, existing approaches do not accommodate an umbrella ordering of disease classes. This article proposes the construction of an ROC graph that is applicable for an umbrella ordering. Furthermore, this article proposes that a summary measure for this umbrella ROC graph can be used to summarize the classification accuracy, and corresponding variance estimates can be obtained using U-statistics theory or bootstrap methods. The proposed methods are illustrated using data from a study assessing the ability of a DNA methylation marker to correctly classify lung specimens into three histologic classes: squamous cell carcinoma, large cell carcinoma, and nontumor lung.     

Physical map of the Streptomyces lividans 66 genome and comparison with that of the related strain Streptomyces coelicolor A3(2).

A physical map of the chromosome of Streptomyces lividans 66 ZX7 was constructed by ordering the macrorestriction fragments generated from the genomic DNA with the restriction enzymes AseI and DraI. AseI and DraI linking cosmids (i.e., recombinant cosmids including either AseI or DraI sites) were isolated from a gene bank and used as hybridization probes against Southern transfers of pulsed-field gel electrophoresis (PFGE) restriction patterns. The DraI sites were precisely mapped by PFGE analyses of AseI-DraI double digests and hybridization with the AseI junctions. The 16 AseI and 7 DraI fragments were aligned as a single chromosome of about 8,000 kb. The data supported the interpretation that the chromosome is a linear structure. The related strain Streptomyces coelicolor A3(2) M145, recently mapped by H. Kieser, T. Kieser, and D. A. Hopwood (J. Bacteriol. 174:5496-5507, 1992), was compared with S. lividans at the level of the genomic structure by hybridizing the linking cosmids to Southern transfers of PFGE patterns. In spite of little apparent similarity in their restriction patterns, the comparison of the physical maps revealed a common structure with an identical ordering of the cosmid sequences. This conservation of the map order was further confirmed by assigning genetic markers (i.e., cloned genes and DNA elements relevant to the unstable region) to the AseI fragments.     

Clinical Profiles,Disease Outcome and Co-Morbidities among T. b. rhodesiense Sleeping Sickness Patients in Uganda

BackgroundThe acute form of Human African Trypanosomiasis (HAT, also known as Sleeping sickness) caused by Trypanosoma brucei rhodesiense has been shown to have a wide spectrum of focus specific clinical presentation and severity in East and Southern Africa. Indeed HAT occurs in regions endemic for other tropical diseases, however data on how these co-morbidities might complicate the clinical picture and affect disease outcome remains largely scanty. We here describe the clinical presentation, presence of co-infections, and how the latter impact on HAT prognosis.ConclusionsWe show a wide spectrum of sleeping sickness clinical presentation and disease outcome that was apparently not significantly influenced by concurrent infections. It would thus be interesting to determine the host and/or parasite factors that might be responsible for the observed diverse clinical presentation.     

An optimal algorithm for perfect phylogeny haplotyping.

Inferring haplotype data from genotype data is a crucial step in linking SNPs to human diseases. Given n genotypes over m SNP sites, the haplotype inference (HI) problem deals with finding a set of haplotypes so that each given genotype can be formed by a combining a pair of haplotypes from the set. The perfect phylogeny haplotyping (PPH) problem is one of the many computational approaches to the HI problem. Though it was conjectured that the complexity of the PPH problem was O(nm), the complexity of all the solutions presented until recently was O(nm (2)). In this paper, we make complete use of the column-ordering that was presented earlier and show that there must be some interdependencies among the pairwise relationships between SNP sites in order for the given genotypes to allow a perfect phylogeny. Based on these interdependencies, we introduce the FlexTree (flexible tree) data structure that represents all the pairwise relationships in O(m) space. The FlexTree data structure provides a compact representation of all the perfect phylogenies for the given set of genotypes. We also introduce an ordering of the genotypes that allows the genotypes to be added to the FlexTree sequentially. The column ordering, the FlexTree data structure, and the row ordering we introduce make the O(nm) OPPH algorithm possible. We present some results on simulated data which demonstrate that the OPPH algorithm performs quiet impressively when compared to the previous algorithms. The OPPH algorithm is one of the first O(nm) algorithms presented for the PPH problem.     

Equal opportunities and positive action in the British National Health Service: some lessons from the recruitment of minority ethnic groups to nursing and midwifery

The National Health Service [NHS] remains one of the most significant employers of minority ethnic groups. However, evidence suggests that members of such groups are significantly disadvantaged in NHS employment. In this article we present research evidence about the recruitment of minority ethnic groups into nursing and midwifery. In case studies of nurse education centres we identified few positive action provisions which were part of a systematic strategy for improving recruitment from minority ethnic communities. The arguments for positive action were neither widely understood nor embraced, and the problem was compounded by the fragmented organizational structure of the NHS. We conclude that what is required is an effective national strategy to build on the NHS's underlying principle of equitable and effective health care for all. This entails linking the moral imperatives of service delivery to a diverse patient community to a business case for equality of opportunity and positive action.     

Topology-based cancer classification and related pathway mining using microarray data

Cancer classification is the critical basis for patient-tailored therapy, while pathway analysis is a promising method to discover the underlying molecular mechanisms related to cancer development by using microarray data. However, linking the molecular classification and pathway analysis with gene network approach has not been discussed yet. In this study, we developed a novel framework based on cancer class-specific gene networks for classification and pathway analysis. This framework involves a novel gene network construction, named ordering network, which exhibits the power-law node-degree distribution as seen in correlation networks. The results obtained from five public cancer datasets showed that the gene networks with ordering relationship are better than those with correlation relationship in terms of accuracy and stability of the classification performance. Furthermore, we integrated the ordering networks, classification information and pathway database to develop the topology-based pathway analysis for identifying cancer class-specific pathways, which might be essential in the biological significance of cancer. Our results suggest that the topology-based classification technology can precisely distinguish cancer subclasses and the topology-based pathway analysis can characterize the correspondent biochemical pathways even if there are subtle, but consistent, changes in gene expression, which may provide new insights into the underlying molecular mechanisms of tumorigenesis.     

The 1901 uganda sleeping sickness epidemic revisited: a case of mistaken identity?

The great sleeping sickness epidemic that occurred in Busoga at the turn of the century was caused by a trypanosome identified by Bruce as Trypanosoma gambiense. A study of trypanosomes from the recent epidemic in southeast Uganda has shed new light on the origins of the disease in Busoga. Thorsten Koerner, Peter de Raadt and Ian Maudlin suggest that the epidemic of the turn of the century was of T. p. rhodesiense sleeping sickness, brought about then, as now by social upheaval.     

Linking elements in German Origin, Change, Functionalization

Contemporary German is known for its complex system of linking elements. They not only show different degrees of productivity (between unproductive -es- and very productive -s-), but also exhibit functional diversity, with some of them even allowing plural interpretation, e.g. -er- in Völk+er+kunde ‘ethnology’ vs. Volk+s+kunde ‘folklore’. In this paper, we argue that this is due to the complex historical development from two different sources. The first layer of linking elements, which arose out of Germanic primary suffixes, was reduced to one member, the “older” linking -e-, already in Old High German (e.g. in NHG Tag+e+werk ‘daily task’). The current functional diversity of the linking elements is primarily due to the later evolution out of inflectional endings. The dissociation from the second source has included a gradual change of the assignment rules from lexical (gender, declension class) to prosodic (formal) level. Thus, the current distribution of the most developed linking -s- is the most formalized one, as it can be directly deduced from the prosodic form of the first constituent. The development of the second layer of linking elements resembles the process of grammaticalization. However, linking elements form part of word formation and therefore are not the typical result of grammaticalization.