Anti-tuberculosis activity and structure-activity relationships of oxygenated tricyclic carbazole alkaloids and synthetic derivatives.

A series of 49 oxygenated tricyclic carbazole derivatives has been tested for inhibition of the growth of Mycobacterium tuberculosis and a mammalian cell line (vero cells). From this series, twelve carbazoles showed a significant anti-TB activity. The four most active compounds were the naturally occurring carbazole alkaloids clauszoline-M (45), murrayaline-C (41), carbalexin-C (27), and the synthetic carbazole derivative 22 with MIC90 values ranging from 1.5 to 3.7µM. The active compounds were virtually nontoxic for the mammalian cell line in the concentration range up to 50µM.

How the oxygen tolerance of a [NiFe]-hydrogenase depends on quaternary structure.

'Oxygen-tolerant' [NiFe]-hydrogenases can catalyze H2 oxidation under aerobic conditions, avoiding oxygenation and destruction of the active site. In one mechanism accounting for this special property, membrane-bound [NiFe]-hydrogenases accommodate a pool of electrons that allows an O2 molecule attacking the active site to be converted rapidly to harmless water. An important advantage may stem from having a dimeric or higher-order quaternary structure in which the electron-transfer relay chain of one partner is electronically coupled to that in the other. Hydrogenase-1 from E. coli has a dimeric structure in which the distal [4Fe-4S] clusters in each monomer are located approximately 12 Å apart, a distance conducive to fast electron tunneling. Such an arrangement can ensure that electrons from H2 oxidation released at the active site of one partner are immediately transferred to its counterpart when an O2 molecule attacks. This paper addresses the role of long-range, inter-domain electron transfer in the mechanism of O2-tolerance by comparing the properties of monomeric and dimeric forms of Hydrogenase-1. The results reveal a further interesting advantage that quaternary structure affords to proteins.

Coordination of Synthesis and Assembly of a Modular Membrane-Associated [NiFe]-Hydrogenase Is Determined by Cleavage of the C-Terminal Peptide.

UNLABELLED: During biosynthesis of [NiFe]-hydrogenase 2 (Hyd-2) of Escherichia coli, a 15-amino-acid C-terminal peptide is cleaved from the catalytic large subunit precursor, pro-HybC. This peptide is removed only after NiFe(CN)2CO cofactor insertion by the Hyp accessory protein machinery has been completed, suggesting that it has a regulatory function during enzyme maturation. We show here that in hyp mutants that fail to synthesize and insert the NiFe cofactor, and therefore retain the peptide, the Tat (twin-arginine translocon) signal peptide on the small subunit HybO is not removed and the subunit is degraded. In a mutant lacking the large subunit, the Tat signal peptide was also not removed from pre-HybO, indicating that the mature large subunit must actively engage the small subunit to elicit Tat transport. We validated the proposed regulatory role of the C-terminal peptide in controlling enzyme assembly by genetically removing it from the precursor of HybC, which allowed assembly and Tat-dependent membrane association of a HybC-HybO heterodimer lacking the NiFe(CN)2CO cofactor. Finally, genetic transfer of the C-terminal peptide from pro-HyaB, the large subunit of Hyd-1, onto HybC did not influence its dependence on the accessory protein HybG, a HypC paralog, or the specific protease HybD. This indicates that the C-terminal peptide per se is not required for interaction with the Hyp machinery but rather suggests a role of the peptide in maintaining a conformation of the protein suitable for cofactor insertion. Together, our results demonstrate that the C-terminal peptide on the catalytic subunit controls biosynthesis, assembly, and membrane association of Hyd-2. IMPORTANCE: [NiFe]-hydrogenases are multisubunit enzymes with a catalytic subunit containing a NiFe(CN)2CO cofactor. Results of previous studies suggested that after synthesis and insertion of the cofactor by the Hyp accessory proteins, this large subunit changes conformation upon proteolytic removal of a short peptide from its C terminus. We show that removal of this peptide is necessary to allow the cleavage of the Tat signal peptide from the small subunit with concomitant membrane association of the heterodimer to occur. Genetic removal of the C-terminal peptide from the large subunit allowed productive interaction with the small subunit and Tat-dependent membrane insertion of a NiFe cofactor-free enzyme. Results based on swapping of C-terminal peptides between hydrogenases suggest that this peptide governs enzyme assembly via a conformational switch.

Heterologous complementation studies in Escherichia coli with the Hyp accessory protein machinery from Chloroflexi provide insight into [NiFe]-hydrogenase large subunit recognition by the HypC protein family.

Six Hyp maturation proteins (HypABCDEF) are conserved in micro-organisms that synthesize [NiFe]-hydrogenases (Hyd). Of these, the HypC chaperones interact directly with the apo-form of the catalytically active large subunit of Hyd enzymes and are believed to transfer the Fe(CN)2CO moiety of the bimetallic cofactor from the Hyp machinery to this large subunit. In E. coli, HypC is specifically required for maturation of Hyd-3 while its paralogue, HybG, is specifically required for Hyd-2 maturation; either HypC or HybG can mature Hyd-1. In this study, we demonstrate that the products of the hypABFCDE operon from the deeply branching hydrogen-dependent and obligate organohalide-respiring bacterium Dehalococcoides mccartyi strain CBDB1 were capable of maturing and assembling active Hyd-1, Hyd-2 and Hyd-3 in an E. coli hyp mutant. Maturation of Hyd-1 was less efficient, presumably because HypB of E. coli was necessary to restore optimal enzyme activity. In a reciprocal maturation study, the highly O2-sensitive H2-uptake HupLS [NiFe]-hydrogenase from D. mccartyi CBDB1 was also synthesized in an active form in E. coli. Together, these findings indicated that HypC from D. mccartyi CBDB1 exhibits promiscuity in its large subunit interaction in E. coli. Based on these findings, we generated amino acid variants of E. coli HybG capable of partial recovery of Hyd-3-dependent H2 production in a hypC hybG double null mutant. Together, these findings identify amino acid regions in HypC accessory proteins that specify interaction with the large subunits of hydrogenase and demonstrate functional compatibility of Hyp accessory protein machineries.

[NiFe]-hydrogenase maturation in vitro: analysis of the roles of the HybG and HypD accessory proteins1.

[NiFe]-hydrogenases (Hyd) bind a nickel-iron-based cofactor. The Fe ion of the cofactor is bound by two cyanide ligands and a single carbon monoxide ligand. Minimally six accessory proteins (HypA-HypF) are necessary for NiFe(CN)2CO cofactor biosynthesis in Escherichia coli. It has been shown that the anaerobically purified HypC-HypD-HypE scaffold complex carries the Fe(CN)2CO moiety of this cofactor. In the present study, we have purified the HybG-HypDE complex and used it to successfully reconstitute in vitro active Hyd from E. coli. HybG is a homologue of HypC that is specifically required for the maturation of Hyd-2 and also functions in the maturation of Hyd-1 of E. coli. Maturation of active Hyd-1 and Hyd-2 could be demonstrated in extracts derived from HybG- and HypD-deficient E. coli strains by adding anaerobically purified HybG-HypDE complex. In vitro maturation was dependent on ATP, carbamoylphosphate, nickel and reducing conditions. Hydrogenase maturation was prevented when the purified HybG-HypDE complex used in the maturation assay lacked a bound Fe(CN)2CO moiety. These findings demonstrate that it is possible to isolate incompletely processed intermediates on the maturation pathway and to use these to activate apo-forms of [NiFe]-hydrogenase large subunits.

Regioselective prenylation of bromocarbazoles by palladium(0)-catalysed cross coupling--synthesis of O-methylsiamenol, O-methylmicromeline and carquinostatin A.

We describe the regioselective prenylation of 3-bromocarbazole by palladium(0)-catalysed cross coupling with a prenylstannane or a prenylboronate. The procedure is applied to the synthesis of precursors for biologically active carbazole alkaloids.

Association between younger age when first overweight and increased risk for CKD.

There is little information on how the duration of overweight or obesity during life affects the risk for CKD. To investigate whether prolonged exposure to overweight during adult life increases the risk of later CKD in a cumulative manner, we analyzed data from the Medical Research Council National Survey of Health and Development, a socially stratified sample of 5362 singleton children born in 1 week in March 1946 in England, Scotland, and Wales. Multiple imputation expanded the analysis sample from the initial 1794 participants with complete data to 4584. This study collected self-reported body mass index (BMI) at ages 20 and 26 years and measured BMI at ages 36, 43, 53, and 60-64 years. The outcome of interest was CKD at age 60-64 years, suggested by estimated GFR (eGFR) <60 ml/min per 1.73 m(2) and/or urine albumin-to-creatinine ratio (UACR) ≥ 3.5 mg/mmol. In analyses adjusted for childhood and adulthood social class, first becoming overweight at younger ages was associated with higher odds of developing CKD by age 60-64 years. Compared with those who first became overweight at age 60-64 years or never became overweight, those first overweight at age 26 or 36 years had approximately double the odds of developing CKD. The strength of this association decreased with increasing age when first overweight (P for trend <0.001). These associations were consistent for creatinine-based eGFR, cystatin C-based eGFR, and UACR. Taken together, these results suggest that preventing overweight in early adulthood may have a considerable effect on the prevalence of CKD in the population.

Early-life overweight trajectory and CKD in the 1946 British birth cohort study.

BACKGROUND: Few studies have examined the impact of childhood obesity on later kidney disease, and consequently, our understanding is very limited. STUDY DESIGN: Longitudinal population-based cohort. SETTING & PARTICIPANTS: The Medical Research Council National Survey of Health and Development, a socially stratified sample of 5,362 singletons born in 1 week in March 1946 in England, Scotland, and Wales, of which 4,340 were analyzed. PREDICTOR: Early-life overweight latent classes (never, prepubertal only, pubertal onset, or always), derived from repeated measurements of body mass index between ages 2 and 20 years. OUTCOMES & MEASUREMENTS: The primary outcome was chronic kidney disease (CKD), defined as creatinine- or cystatin C-based estimated glomerular filtration rate (eGFRcr and eGFRcys, respectively) <60 mL/min/1.73 m² or urine albumin-creatinine ratio (UACR) ≥3.5 mg/mmol measured at age 60-64 years. Associations were explored through regression analysis, with adjustment for socioeconomic position, smoking, physical activity level, diabetes, hypertension, and overweight at ages 36 and 53 years. RESULTS: 2.3% of study participants had eGFRcr <60 mL/min/1.73 m², 1.7% had eGFRcys <60 mL/min/1.73 m², and 2.9% had UACR ≥3.5 mg/mmol. Relative to being in the never-overweight latent class, being in the pubertal-onset- or always-overweight latent classes was associated with eGFRcys-defined CKD (OR, 2.04; 95% CI, 1.09-3.82). Associations with CKD defined by eGFRcr (OR, 1.27; 95% CI, 0.71-2.29) and UACR (OR, 1.33; 95% CI, 0.70-2.54) were less marked, but in the same direction. Adjustment for lifestyle and health factors had little impact on effect estimates. LIMITATIONS: A low prevalence of CKD resulted in low statistical power. No documentation of chronicity for outcomes. All-white study population restricts generalizability. CONCLUSIONS: Being overweight in early life was found to be associated with eGFRcys-defined CKD in later life. The associations with CKD defined by eGFRcr and UACR were less marked, but in the same direction. Reducing or preventing overweight in the early years of life may significantly reduce the burden of CKD in the population.

Childhood psychosocial adversity and adult cortisol patterns.

BACKGROUND: Cortisol levels may be altered in childhood in association with maltreatment (neglect, abuse and witnessing abuse) and other adversities, yet little is known about whether effects on cortisol persist into later life. AIMS: To establish whether childhood psychosocial adversities predict cortisol levels in mid-adulthood. METHOD: Childhood psychosocial adversities were ascertained in the 1958 British birth cohort and cortisol was measured in two saliva samples, one 45 min after awaking (T(1)) and the other 3 h later the same day (T(2)), from 6524 participants aged 45 years. RESULTS: No association was seen for abuse or household dysfunction in childhood and adult cortisol levels. In women but not men, T(1) cortisol was lowered by 7.9% per unit increase in childhood neglect score (range 0-3); T(1) to T(2) cortisol decline was less steep. High levels of maltreatment (abuse, neglect, witnessed abuse) were associated with >25% lower T(1) cortisol in both men and women, and 24% higher T(2) cortisol for men after adjustment for concurrent depressive/anxiety symptoms. CONCLUSIONS: In a non-clinical population, cumulative maltreatments in childhood were associated with flattened morning cortisol secretion in mid-adult life.

Diagnostic Criteria for the Painful Swollen Pediatric Knee: Distinguishing Septic Arthritis From Aseptic Effusion in a Non-Lyme Endemic Area.

Purpose: The child with a painful swollen knee must be worked-up for possible septic arthritis; the classic clinical prediction algorithms for septic arthritis of the hip may not be the best models to apply to the knee. Materials and methods: This was a retrospective case-control study of 17 years of children presenting to one hospital with a chief complaint of a painful swollen knee, to evaluate the appropriateness of applying a previously described clinical practice algorithm for the hip in differentiating between the septic and aseptic causes of the painful knee effusions. The diagnoses of true septic arthritis, presumed septic arthritis, and aseptic effusion were established, based upon the cultures of synovial fluid, blood cultures, synovial cell counts, and clinical course. Using a logistic regression model, the disease status was regressed on both the demographic and clinical variables. Results: In the study, 122 patients were included: 51 with true septic arthritis, 37 with presumed septic arthritis, and 34 with aseptic knee effusion. After applying a backward elimination, age <5 years and C-reactive protein (CRP) >2.0 mg/dl remained in the model, and predicted probabilities of having septic knee arthritis ranged from 15% for the lowest risk to 95% for the highest risk. Adding a knee aspiration including percent polymorphonucleocytes (%PMN) substantially improved the overall model performance, lowering the lowest risk to 11% while raising the highest risk to 96%. Conclusions: This predictive model suggests that the likelihood of pediatric septic arthritis of the knee is >90% when both "age <5 years" and "CRP > 2.0 mg/dl" are present in a child with a painful swollen knee, though, in the absence of these factors, the risk of septic arthritis remains over 15%. Aspiration of the knee for those patients would be the best next step.

Shift work and risk factors for cardiovascular disease: a study at age 45 years in the 1958 British birth cohort.

This study examined associations between exposure to shift-work and risk factors for cardiovascular disease (CVD) and whether the associations are explained by socio-economic circumstances, occupational factors or health behaviours. Biological risk factors for CVD were measured in 7,839 participants of the 1958 British birth cohort at age 45 years who were in paid employment. Regular (>or=1/week) shift-workers included 46% working evenings (1800-2200), 28% weekends, 13% nights (2200-0400) and 14% early mornings (0400-0700). Adverse levels of several CVD risk factors were found in association with increasing participation in any shift-work. Men regularly working all four shift-work types had increased CVD risk factors of approximately 0.1-0.2 standard deviations (e.g. 0.8 kg/m(2) for body mass index; 1.2 cm for waist circumference) than those not regularly working shifts; for women, there was a positive linear trend for triglyceride levels, but a negative trend for diastolic blood pressure. Separate analyses of shift-work types showed associations primarily for night/morning working rather than evening/weekend working. Men had adverse levels of all CVD risk factors except blood pressure and total-cholesterol in association with night or early morning work and women had adverse triglyceride levels. Adjustment for socioeconomic, occupational factors and health behaviours explained most associations except for adiposity and C-reactive protein. Our results highlight night and early morning working associations with an adverse profile of CVD risk factors, which are partly explained by socioeconomic, other occupational factors and health behaviours.

Delimiting the Function of the C-Terminal Extension of the Escherichia coli [NiFe]-Hydrogenase 2 Large Subunit Precursor.

The active site of all [NiFe]-hydrogenases (Hyd) has a bimetallic NiFe(CN)2CO cofactor that requires the combined action of several maturation proteins for its biosynthesis and insertion into the precursor form of the large subunit of the enzyme. Cofactor insertion is an intricately controlled process, and the large subunit of almost all Hyd enzymes has a C-terminal oligopeptide extension that is endoproteolytically removed as the final maturation step. This extension might serve either as one of the recognition motifs for the endoprotease, as well as an interaction platform for the maturation proteins, or it could have a structural role to ensure the active site cavity remains open until the cofactor is inserted. To distinguish between these alternatives, we exchanged the complete C-terminal extension of the precursor of Escherichia coli hydrogenase 2 (Hyd-2) for the C-terminal extension of the Hyd-1 enzyme. Using in-gel activity staining, we demonstrate clearly that this large subunit precursor retains its specificity for the HybG maturation chaperone, as well as for the pro-HybC-specific endoprotease HybD, despite the C-terminal exchange. Bacterial two-hybrid studies confirmed interaction between HybD and the pro-HybC variant carrying the exchanged C-terminus. Limited proteolysis studies of purified precursor and mature HybC protein revealed that, in contrast to the precursor, the mature protein was protected against trypsin attack, signifying a major conformational change in the protein. Together, our results support a model whereby the function of the C-terminal extension during subunit maturation is structural.

Chronified Pain Following Operative Procedures.

BACKGROUND: Over 18 million operative procedures are performed each year in Germany alone. Approximately 10% of surgical patients develop moderate to severe chronic post-surgical pain (CPSP), which can severely impair their quality of life. The pain must persist for at least three months to be called chronic; pain that arises after a symptom-free interval is not excluded. The perioperative use of local anesthetic agents may lessen the incidence of CPSP. METHODS: We selectively reviewed the pertinent literature, including two current Cochrane Reviews. Local and regional anesthetic techniques are discussed, as is the intravenous administration of lidocaine. RESULTS: The main risk factors for CPSP are pre-existing (preoperative) chronic pain, opioid intake, a pain-related catastrophizing tendency, intraoperative nerve injury, and severe acute postoperative pain. CPSP is reported to be especially common after thoracic surgery, breast surgery, amputations, and orthopedic procedures. Local and regional anesthetic techniques have been shown to significantly lower the incidence of CPSP after thoracotomy (number needed to treat for an additional beneficial outcome [NNTB] = 7), breast cancer surgery (NNTB = 7), and cesarean section (NNTB = 19). Intravenous lidocaine also lowers the incidence of CPSP after various types of procedures. CONCLUSION: Local and regional anesthetic techniques and intravenous lidocaine lower the incidence of CPSP after certain types of operative procedures. The intravenous administration of lidocaine to prevent CPSP is off label and requires the patient's informed consent. The evidence for the measures presented here is of low to medium quality.

In vivo near-infrared fluorescence imaging of carcinoembryonic antigen-expressing tumor cells in mice.

PURPOSE: To prospectively depict carcinoembryonic antigen (CEA)-expressing tumors in mice with a high-affinity probe consisting of a near-infrared (NIR) fluorochrome and the clinically used anti-CEA antibody fragment arcitumomab. MATERIALS AND METHODS: This study was approved by the regional animal committee. By coupling a NIR fluorescent (NIRF) cyanine dye (DY-676) to a specific antibody fragment directed against CEA (arcitumomab) and a nonspecific IgG Fab fragment, a bio-optical high-affinity fluorescent probe (anti-CEA-DY-676) and a low-affinity fluorescent probe (FabIgG-DY-676) were designed. The dye-to-protein ratios were determined, and both probes were tested for NIRF imaging in vitro on CEA-expressing LS-174T human colonic adenocarcinoma cells and CEA-nonexpressing A-375 human melanoma cells by using a bio-optical NIR small-animal imager. In vivo data of xenografted LS-174T and A-375 tumors in mice (n = 10) were recorded and statistically analyzed (Student t test). RESULTS: The dye-to-protein ratios were determined as 3.0-3.5 for both probes. In vitro experiments revealed the specific binding of the anti-CEA-DY-676 probe on CEA-expressing cells as compared with CEA-nonexpressing cells; the FabIgG-DY-676 probe showed a markedly lower binding affinity to cells. In vivo LS-174T tumors xenografted in all mice could be significantly distinguished from A-375 tumors with application of the anti-CEA-DY-676 but not with that of the FabIgG-DY-676 at different times (2-24 hours, P < .005) after intravenous injection of the probes. Semiquantitative analysis revealed maximal fluorescence signals of anti-CEA-DY-676 to CEA-expressing tumors about 8 hours after injection. CONCLUSION: Findings of this study indicate the potential use of the high-affinity probe anti-CEA-DY-676 for specific NIRF imaging in in vivo tumor diagnosis.

The Extended C-Terminal α-Helix of the HypC Chaperone Restricts Recognition of Large Subunit Precursors by the Hyp-Scaffold Machinery during [NiFe]-Hydrogenase Maturation in Escherichia coli.

Members of the HypC protein family are chaperone-like proteins that play a central role in the maturation of [NiFe]-hydrogenases (Hyd). Escherichia coli has a second copy of HypC, called HybG, and, as a component of the HypDEF maturation scaffold, these proteins help synthesize the NiFe-cofactor and guide the scaffold to its designated hydrogenase large subunit precursor. HypC is required to synthesize active Hyd-1 and Hyd-3, while HybG facilitates Hyd-2 and Hyd-1 synthesis. To identify determinants on HypC that allow it to discriminate against Hyd-2, we made amino acid exchanges in 3 variable regions, termed VR1, VR2, and VR3, of HypC, that make it more similar to HybG. Region VR3 includes a HypC-specific C-terminal α-helical extension, and this proved particularly important in preventing the maturation of Hyd-2 by HypC. Truncation of this extension on HypC increased Hyd-2 activity in the absence of HybG, while retaining maturation of Hyd-3 and Hyd-1. Combining this truncation with amino acid exchanges in VR1 and VR2 of HypC negatively affected the synthesis of active Hyd-1. The C-terminus of E. coli HypC is thus a key determinant in hindering Hyd-2 maturation, while VR1 and VR2 appear more important for Hyd-1 matu-ration.

Psychological distress after employment transitions: the role of subjective financial position as a mediator.

OBJECTIVE: To explore the extent to which the mental health effects of transitions into unemployment, or other forms of non-employment, and vice versa, are mediated by financial changes. METHODS: Longitudinal analysis of the British Household Panel Survey from 1991 to 2000. There were 89,264 person-years of observation from 14,686 individuals aged > or =16 years. Main outcome measure was psychological distress measured by the 12-item General Health Questionnaire. RESULTS: Transitions to unemployment were associated with increased risk of psychological distress for men (adjusted odds ratio (OR) 3.15 (95% confidence interval (CI) 2.50 to 3.98)) and for women (OR 2.60 (95% CI 1.97 to 3.43)). Women who left work to look after the family were also more likely to experience psychological distress (OR 1.72 (95% CI 1.45 to 2.05)). A reduced risk of psychological distress was seen for transitions from unemployment to paid employment for men (OR 0.52 (95% CI 0.41 to 0.68)) and for women (OR 0.68 (95% CI 0.69 to 1.40)). Financial difficulty partially mediated these relationships: men who became unemployed and were worse off financially were more likely to experience psychological distress (OR 4.19 (95% CI 3.20 to 5.50)) than men who were not (OR 1.48 (95% CI 0.95 to 2.33)). Conversely, the beneficial health effect for people who left unemployment and became employed was confined to those who were better off financially (OR 0.34 (0.25 to 0.48) for men). CONCLUSIONS: Changes in employment status have both direct and indirect effects, through changes in financial circumstances, on subsequent psychological distress. The results support the view that the direction of causation runs from employment transitions to financial difficulties and psychological distress.

Type 2 diabetes mellitus in midlife estimated from the Cambridge Risk Score and body mass index.

BACKGROUND: The Cambridge Risk Score (CRS) was developed to screen for type 2 diabetes mellitus risk. We assessed the ability of the CRS to predict glycosylated hemoglobin (HbA(1c)) levels and determined whether the CRS was better than body mass index (BMI) at predicting HbA(1c) levels in midlife. METHODS: We included 7452 participants without known diabetes in a biomedical survey of the 1958 British Birth Cohort at 45 years of age. Receiver operator characteristic curves were used to compare the ability of the CRS and BMI to identify individuals with elevated HbA(1c) levels using thresholds of 7.0% or more, 6.0% or more, and 5.5% or more. RESULTS: Of the total sample, 0.9% (95% confidence interval [CI], 0.7%-1.1%) had HbA(1c) levels of 7.0% or more; 3.8% (95% CI, 3.2%-4.5%), 6.0% or more; and 24.4% (95% CI, 23.1%-25.9%), 5.5% or more. The CRS detected individuals with elevated HbA(1c) levels with reasonable accuracy (area under the curve, 0.84 for HbA(1c) level >or=7.0%; 0.76 for HbA(1c) level >or=6.0%). Similar area under the curve values were obtained using BMI alone (0.84 for HbA(1c) level >or=7.0%; 0.79 for HbA(1c) level >or=6.0%). When tested using the lower HbA(1c) threshold of 5.5% or more, the CRS and BMI did not perform well (areas under the curve, 0.65 and 0.63 for CRS and BMI, respectively). Both measures indicated that approximately 20% of the cohort were at increased risk of diabetes. Owing to the low prevalence of diabetes at 45 years of age, only 2% to 3% of those considered at risk had elevated HbA(1c) levels. CONCLUSIONS: For a population in mid-adult life, the CRS identified individuals with elevated HbA(1c) levels reasonably well. However, the CRS had no advantage compared with BMI alone in identifying diabetes risk.

Life Course Socioeconomic Position: Associations with Cardiac Structure and Function at Age 60-64 Years in the 1946 British Birth Cohort.

Although it is recognized that risks of cardiovascular diseases associated with heart failure develop over the life course, no studies have reported whether life course socioeconomic inequalities exist for heart failure risk. The Medical Research Council's National Survey of Health and Development was used to investigate associations between occupational socioeconomic position during childhood, early adulthood and middle age and measures of cardiac structure [left ventricular (LV) mass index and relative wall thickness (RWT)] and function [systolic: ejection fraction (EF) and midwall fractional shortening (mFS); diastolic: left atrial (LA) volume, E/A ratio and E/e' ratio)]. Different life course models were compared with a saturated model to ascertain the nature of the relationship between socioeconomic position across the life course and each cardiac marker. Findings showed that models where socioeconomic position accumulated over multiple time points in life provided the best fit for 3 of the 7 cardiac markers: childhood and early adulthood periods for the E/A ratio and E/e' ratio, and all three life periods for LV mass index. These associations were attenuated by adjustment for adiposity, but were little affected by adjustment for other established or novel cardio-metabolic risk factors. There was no evidence of a relationship between socioeconomic position at any time point and RWT, EF, mFS or LA volume index. In conclusion, socioeconomic position across multiple points of the lifecourse, particularly earlier in life, is an important determinant of some measures of LV structure and function. BMI may be an important mediator of these associations.

Mussel-Inspired Polymer Carpets: Direct Photografting of Polymer Brushes on Polydopamine Nanosheets for Controlled Cell Adhesion.

2D mussel-inspired polydopamine (PDA) nanosheets are prepared and exploited as a functional surface for grafting various polymer brushes. The PDA nanosheet and its polymer-brush derivatives show lateral integrity and are robust; therefore, they can be detached from their substrates. Cell-adhesion tests show that the PDA nanosheet promotes cell growth and attachment, while a PDA-based poly(3-sulfopropyl methacrylate) carpet exhibits nonfouling behavior.

Employment transitions and mental health: an analysis from the British household panel survey.

STUDY OBJECTIVE: To describe the impact of changes between employment and various forms of non-employment, and vice versa, on the psychological wellbeing of men and of women. DESIGN: Separate multivariate models for men and for women were constructed to study the association between employment transitions and episodes of psychological distress (general health questionnaire). PARTICIPANTS: 13,359 employment transitions from 5092 people aged 16-74 years in the British household panel survey from 1991 to 1998. MAIN RESULTS: Transitions from paid employment to either unemployment or long term sick leave were associated with increased psychological distress for both men and women. Starting maternity leave or staying home to look after the family were also associated with psychological distress for women. Transitions from these roles to formal employment resulted in an improvement in mental health. There was some evidence that the effects were felt most strongly within six months of the transition. CONCLUSIONS: This paper provides further evidence that movements between paid employment and various forms of non-employment, in addition to unemployment, have an impact on mental health. The emphasis on transitions between a full range of employment states for both men and women from a large population based longitudinal study and a comparison of the relative magnitude of effects are unique features of this analysis. Interventions are suggested to minimise the psychological distress associated with transitions.