Environmental drivers of increased ecosystem respiration in a warming tundra.

Arctic and alpine tundra ecosystems are large reservoirs of organic carbon1,2. Climate warming may stimulate ecosystem respiration and release carbon into the atmosphere3,4. The magnitude and persistency of this stimulation and the environmental mechanisms that drive its variation remain uncertain5-7. This hampers the accuracy of global land carbon-climate feedback projections7,8. Here we synthesize 136 datasets from 56 open-top chamber in situ warming experiments located at 28 arctic and alpine tundra sites which have been running for less than 1 year up to 25 years. We show that a mean rise of 1.4 °C [confidence interval (CI) 0.9-2.0 °C] in air and 0.4 °C [CI 0.2-0.7 °C] in soil temperature results in an increase in growing season ecosystem respiration by 30% [CI 22-38%] (n = 136). Our findings indicate that the stimulation of ecosystem respiration was due to increases in both plant-related and microbial respiration (n = 9) and continued for at least 25 years (n = 136). The magnitude of the warming effects on respiration was driven by variation in warming-induced changes in local soil conditions, that is, changes in total nitrogen concentration and pH and by context-dependent spatial variation in these conditions, in particular total nitrogen concentration and the carbon:nitrogen ratio. Tundra sites with stronger nitrogen limitations and sites in which warming had stimulated plant and microbial nutrient turnover seemed particularly sensitive in their respiration response to warming. The results highlight the importance of local soil conditions and warming-induced changes therein for future climatic impacts on respiration.

Effects of adding early cooperation and a work-place dialogue meeting to primary care management for sick-listed patients with stress-related disorders: CO-WORK-CARE-Stress - a pragmatic cluster randomised controlled trial.

OBJECTIVES: To investigate whether intensified cooperation between general practitioner (GP), care manager and rehabilitation coordinator (RC) for patients sick-listed for stress-related mental disorder, combined with a person-centred dialogue meeting with employer, could reduce sick-leave days compared with usual care manager contact. DESIGN: Pragmatic cluster-randomised controlled trial, randomisation at primary care centre (PCC) level. SETTING: PCCs in Region Västra Götaland, Sweden, with care manager organisation. PARTICIPANTS: Of 30 invited PCCs, 28 (93%) accepted the invitation and recruited 258 patients newly sick-listed due to stress-related mental disorder (n = 142 intervention, n = 116 control PCCs). INTERVENTION: Cooperation between GP, care manager and rehabilitation coordinator from start of illness notification plus a person-centred dialogue meeting between patient and employer within 3 months. Regular contact with care manager was continued at the control PCCs. MAIN OUTCOME MEASURES: 12-months net and gross number of sick-leave days. Secondary outcomes: Symptoms of stress, depression, anxiety; work ability and health related quality of life (EQ-5D) over 12 months. RESULTS: There were no significant differences between intervention and control groups after 12 months: days on sick-leave (12-months net sick-leave days, intervention, mean = 110.7 days (95% confidence interval (CI) 82.6 - 138.8); control, mean = 99.1 days (95% CI 73.9 - 124.3)), stress, depression, or anxiety symptoms, work ability or EQ-5D. There were no significant differences between intervention and control groups concerning proportion on sick-leave after 3, 6, 12 months. At 3 months 64.8% were on sick-leave in intervention group vs 54.3% in control group; 6 months 38% vs 32.8%, and12 months 16.9% vs 15.5%. CONCLUSION: Increased cooperation at the PCC between GP, care manager and RC for stress-related mental disorder coupled with an early workplace contact in the form of a person-centred dialogue meeting does not reduce days of sick-leave or speed up rehabilitation.Trial registration: ClinicalTrials.gov Identifier: NCT03250026 https://clinicaltrials.gov/study/NCT03250026?tab=results#publicationsCO-WORK-CAREFirst Posted: August 15, 2017. Recruitment of PCCs: September 2017. Inclusion of patients from December 2017.

Methodological approach for measuring the effects of organisational-level interventions on employee withdrawal behaviour.

BACKGROUND: Theoretical frameworks have recommended organisational-level interventions to decrease employee withdrawal behaviours such as sickness absence and employee turnover. However, evaluation of such interventions has produced inconclusive results. The aim of this study was to investigate if mixed-effects models in combination with time series analysis, process evaluation, and reference group comparisons could be used for evaluating the effects of an organisational-level intervention on employee withdrawal behaviour. METHODS: Monthly data on employee withdrawal behaviours (sickness absence, employee turnover, employment rate, and unpaid leave) were collected for 58 consecutive months (before and after the intervention) for intervention and reference groups. In total, eight intervention groups with a total of 1600 employees participated in the intervention. Process evaluation data were collected by process facilitators from the intervention team. Overall intervention effects were assessed using mixed-effects models with an AR (1) covariance structure for the repeated measurements and time as fixed effect. Intervention effects for each intervention group were assessed using time series analysis. Finally, results were compared descriptively with data from process evaluation and reference groups to disentangle the organisational-level intervention effects from other simultaneous effects. RESULTS: All measures of employee withdrawal behaviour indicated statistically significant time trends and seasonal variability. Applying these methods to an organisational-level intervention resulted in an overall decrease in employee withdrawal behaviour. Meanwhile, the intervention effects varied greatly between intervention groups, highlighting the need to perform analyses at multiple levels to obtain a full understanding. Results also indicated that possible delayed intervention effects must be considered and that data from process evaluation and reference group comparisons were vital for disentangling the intervention effects from other simultaneous effects. CONCLUSIONS: When analysing the effects of an intervention, time trends, seasonal variability, and other changes in the work environment must be considered. The use of mixed-effects models in combination with time series analysis, process evaluation, and reference groups is a promising way to improve the evaluation of organisational-level interventions that can easily be adopted by others.

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

The "Saltin-Grimby Physical Activity Level Scale" and its application to health research.

The use of a four-level questionnaire to assess leisure time physical activity (PA) and its validation is reviewed in this paper. This questionnaire was first published in 1968 and has then been used by more than 600,000 subjects, especially in different population studies in the Nordic countries. A number of modifications to the questionnaire have been published. These are mostly minor changes, such as adding practical examples of activities to illustrate the levels of PA. Some authors have also added duration requirements that were not included for all levels of PA in the original version. The concurrent validity, with respect to aerobic capacity and movement analysis using objective measurements has been shown to be good, as has the predictive validity with respect to various risk factors for health conditions and for morbidity and mortality.

Increased insulin secretion and decreased glucose concentrations, but not allostatic load, are associated with stress-related exhaustion in a clinical patient population.

Allostatic load (AL) has been shown to be a useful marker of physiological strain during chronic stress and burnout in non-clinical working populations. The usability of the AL index for a clinical population with severe stress-related exhaustion was tested in this study. Thirteen biomarkers assembled as an AL index were analysed using blood samples from 90 patients with stress-related exhaustion (43 men and 47 women, age 31-61 years) and 90 healthy controls (46 men and 44 women, age 25-56 years). The AL scores did not differ between patients and controls. For men, some indication of higher cardiovascular risk was seen in the patient group: male patients had higher body mass index and waist-hip ratio and a poorer blood lipid status than male controls. We found lower plasma glucose concentrations in both female and male patients than those in controls. The male patients also showed increased fasting serum insulin concentrations. Further analysis using homeostasis model assessment for insulin resistance and ß-cell function showed indications of insulin resistance in the patient group, particularly in the males, and an increased insulin secretion in both male and female patients. In conclusion, AL index does not seem to capture plausible physiological strain in patients diagnosed with stress-related exhaustion. The finding of lower plasma glucose concentrations, probably due to higher insulin secretion, in patients with severe stress-related exhaustion, needs to be further investigated, including mechanisms and the clinical relevance.

Cognitive impairment in patients with stress-related exhaustion.

Patients who seek medical care for stress-related mental health problems frequently report cognitive impairments as the most pronounced symptom. The purpose of the present study was to compare cognitive function in patients with stress-related exhaustion with that in healthy controls, using a comprehensive battery of cognitive tests. We also explored whether neuropsychological findings were related to severity of illness measured using the Shirom-Melamed burnout questionnaire and hospital anxiety and depression scale. Thirty-three patients (15 males) and 37 healthy controls (11 males), mean age 46 years [standard deviation (SD) 3.9] and 47 years (SD 4.3), respectively, were included in the final analysis. Five cognitive domains were assessed: (1) speed, attention and working memory, (2) learning and episodic memory, (3) executive functions, (4) visuospatial functions and (5) language. The most pronounced difference between patients and controls was seen on executive function, when tested with a multidimensional test, including aspects of speed, control and working memory. The patients also performed poorer on Digit span, measuring attention span and working memory as well as on learning and episodic memory, when measured as delayed recall and the difference between immediate and delayed recall. Delayed recall was the only test that was significantly related to severity of burnout symptoms among the patients. This could reflect poor cognitive sustainability in the patients with the highest burnout scores, as this particular test was the last one performed during the test session. This study clearly shows that cognitive impairment should be considered when evaluating and treating patients who seek medical care for stress-related exhaustion.

Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study.

OBJECTIVES: The genetic aetiology of osteoarthritis has not yet been elucidated. To enable a well-powered genome-wide association study (GWAS) for osteoarthritis, the authors have formed the arcOGEN Consortium, a UK-wide collaborative effort aiming to scan genome-wide over 7500 osteoarthritis cases in a two-stage genome-wide association scan. Here the authors report the findings of the stage 1 interim analysis. METHODS: The authors have performed a genome-wide association scan for knee and hip osteoarthritis in 3177 cases and 4894 population-based controls from the UK. Replication of promising signals was carried out in silico in five further scans (44,449 individuals), and de novo in 14 534 independent samples, all of European descent. RESULTS: None of the association signals the authors identified reach genome-wide levels of statistical significance, therefore stressing the need for corroboration in sample sets of a larger size. Application of analytical approaches to examine the allelic architecture of disease to the stage 1 genome-wide association scan data suggests that osteoarthritis is a highly polygenic disease with multiple risk variants conferring small effects. CONCLUSIONS: Identifying loci conferring susceptibility to osteoarthritis will require large-scale sample sizes and well-defined phenotypes to minimise heterogeneity.

Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium.

OBJECTIVE: To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes. METHODS: Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. We investigated whether different OA definitions result in different association results by creating various hip OA definitions in one large population based cohort (the Rotterdam Study I (RSI)) and testing those for association with gender, age and body mass index using one-way ANOVA. For ROA, we standardized the hip-, knee- and hand ROA definitions and calculated prevalence's of ROA before and after standardization in nine cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment. RESULTS: In this consortium, all studies with SOA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee-, hip- and hand ROA five, four and seven different definitions were used, respectively. Different hip ROA definitions do lead to different association results. For example, we showed in the RSI that hip OA defined as "at least definite joint space narrowing (JSN) and one definite osteophyte" was not associated with gender (P =0.22), but defined as "at least one definite osteophyte" was significantly associated with gender (P=3×10(-9)). Therefore, a standardization process was undertaken for ROA definitions. Before standardization a wide range of ROA prevalence's was observed in the nine cohorts studied. After standardization the range in prevalence of knee- and hip ROA was small. CONCLUSION: Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.

Self-reported exhaustion: a possible indicator of reduced work ability and increased risk of sickness absence among human service workers.

OBJECTIVE: The aim of this study was to assess the construct and predictive validity of a new instrument for self-rating of stress-related Exhaustion Disorder (s-ED). METHODS: Public healthcare workers and social insurance officers, 85% females, were included (N = 2,683) in a longitudinal study. The s-ED instrument, based on clinical criteria for Exhaustion Disorder, was used at baseline to classify participants into three categories: non-s-ED, light/moderate s-ED and pronounced s-ED. Other assessments include burnout, anxiety, depression and work ability. Sick leave at follow-up after 2 years was defined as 14 days of ongoing sick leave (SA14) or a period of 60 days of sick leave during the last 12 months (SA60). Associations at baseline were expressed as prevalence ratios, and adjusted relative risks (RR) were calculated using Cox regression. RESULTS: At baseline, 16% reported s-ED. Scores of depression, anxiety and burnout and the rate of poor work ability increased with increasing severity of s-ED. Self-reported exhaustion at baseline increased the risk of reporting sickness absence at follow-up; pronounced s-ED RR 2.7; CI 1.8-4.0 for SA14 and RR 3.4; CI 2.3-5.2 for SA60. CONCLUSIONS: Self-rated ED corresponded well to established scales for mental health, indicating sufficient construct validity. Individuals reporting s-ED at baseline were more likely to report sickness absence at follow-up, confirming its predictive properties. The s-ED instrument may be a useful tool for occupational health services in identifying human service workers at risk of having or developing a potentially disabling stress-related mental illness.

IC31, a two-component novel adjuvant mixed with a conjugate vaccine enhances protective immunity against pneumococcal disease in neonatal mice.

IC31 is a novel adjuvant which combines the immunostimulatory effects of an 11-mer antibacterial peptide (KLKL(5)KLK) and a synthetic oligodeoxynucleotide (ODN1a) which is a Toll-like receptor 9 agonist without containing cytosine phosphate guanine (CpG) motifs. The effects of IC31 on neonatal immune response to vaccination have not been reported. Neonatal mice were immunized once or twice with a Streptococcus pneumoniae serotype 1 polysaccharide conjugate containing Tetanus Toxoid (Pnc1-TT) carrier protein, with or without IC31 or CpG-ODN. IC31 significantly enhanced IgG1, IgG2a and IgG2b antibodies (Ab) to the serotype 1 polysaccharide. One dose of Pnc1-TT and low dose IC31 elicited high Ab levels that protected the neonatal mice completely from bacteraemia and significantly reduced lung infection following i.n. challenge with serotype 1 pneumococcal strain. One-sixth of an adult murine dose of IC31 was sufficient and optimal for induction of protective immunity in neonatal mice. Two doses of Pnc1-TT with or without adjuvants protected the neonatal mice completely, but more rapid Ab response was observed when IC31 was given with the Pnc1-TT. IC31 is a promising new adjuvant for neonatal vaccinations, rapidly enhancing protective humoral responses when combined with Pnc1-TT.

Adjuvants LT-K63 and CpG enhance the activation of dendritic cells in neonatal mice.

Dendritic cells (DC) play a major role in the priming of T cells and initiating specific immune responses. We assessed the effects of the adjuvants LT-K63 and CpG on neonatal DC in vivo and in vitro. Cytokine levels (IL-10, IL-12p70 and IL-12p40/IL-23p40) were measured and the expression of the activation markers CD86, CD40 and MHCII on CD11c+ DC was analysed by using FACS. The proportion of MHCII high CD11c+ DC was higher in neonatal mice immunized with a pneumococcal conjugate (PncTT) and LT-K63 or CpG compared with that when PncTT was alone. In vitro stimulation with LT-K63 enhanced the expression of CD86 more on CD11c+ DC from spleens of mice immunized as neonates than those immunized as adults, whereas in vitro stimulation with CpG enhanced the expression of CD86 and CD40 on CD11c+ DC similarly in both age groups. CpG stimulation in vitro enhanced IL-10 and IL-12(p70) production in mice immunized as neonates with PncTT and either adjuvant, but not PncTT alone. The adjuvants LT-K63 and CpG enhance the activation of CD11c+ DC in mice immunized as neonates and can thereby overcome one of the limiting factors in the initiation of the immune response to conjugate vaccines in early life. The fact that neonatal DC are more susceptible to stimulation with either adjuvant, LT-K63 or CpG, could imply that neonatal CD11c+ DC are more easily activated than adult CD11c+ DC, and /or be a consequence of the predominance of different DC subsets in neonatal and adult mice.

Maturation of mucosal immune responses and influence of maternal antibodies.

The mucosae represent the primary point of contact between the major respiratory and enteric pathogens and the innate and adaptive immune response. The microanatomy and function of the mucosal immune system is now well-characterized, in particular the major effector mechanism that involves the production and translocation of secretory immunoglobulin A (IgA). Mucosal delivery of antigen has the potential to induce potent local and systemic immunity, although such responses may differ between neonatal, infant and adult mice. In younger animals mucosal immune responses are Th2 biased, whereas in adults there is a broader Th1 and Th2 responsiveness. There is much interest in the development of mucosally delivered vaccines which can be tailored to enhance Th1 immunity or to avoid potential interference from maternally derived antibodies (MDA). Accordingly, a range of mucosal adjuvants (particularly those derived from bacteria) has been tested, and live recombinant vectored vaccines may also be effectively delivered by this route.

Associations between systemic pro-inflammatory markers, cognitive function and cognitive complaints in a population-based sample of working adults.

BACKGROUND: The knowledge is limited regarding the relation between systemic inflammatory biomarkers and subjective and objective cognitive functioning in population-based samples of healthy adults across the adult age-span. Thus, the aim of this study was to study a selection of four pro-inflammatory biomarkers (IL-6, MCP-1, TNF-α, CRP) in relation to executive cognitive functioning, episodic memory and subjective cognitive complaints (SCC) in a population-based sample of 215 working adults (age 25-67). RESULTS: Higher levels of MCP-1 were associated with poorer executive cognitive functioning, even after adjustments for demographical factors, health status/conditions, SCC and depressive symptoms. IL-6 and CRP were associated with poorer executive cognitive functioning, but these associations covaried with age especially and were not present after adjustment for demographical factors. MCP-1 was associated with poorer episodic memory, but this association also covaried with age especially and was not present after adjustment for demographical factors, and CRP was associated with episodic memory only among participants without reported health conditions. Higher MCP-1 levels were also associated with more SCC and this association covaried with depressive symptoms, while higher levels of TNF-α were associated with less SCC. CONCLUSION: Low grade inflammatory processes in terms of higher systemic levels of pro-inflammatory biomarkers (MCP-1, IL-6 & CRP) were associated with poorer executive functioning in this sample of working adults, and MCP-1 was so after extensive adjustments. Support for associations between these biomarkers and episodic memory and SCC were more limited. Future research should address the causality of associations between low grade inflammatory processes and cognitive functioning.

Effect of exercise on ovarian morphology and expression of nerve growth factor and alpha(1)- and beta(2)-adrenergic receptors in rats with steroid-induced polycystic ovaries.

Oestadiol valerate (EV)-induced polycystic ovaries (PCO) in rats cause anovulation and cystic ovarian morphology. Denervation of ovarian sympathetic nerves restores ovulatory disruption. In the present study, we determined whether 5 weeks of voluntary exercise influence ovarian morphology and the expression of sympathetic markers in the EV-induced PCO rat model. The effect of exercise on (i) ovarian morphology; (ii) mRNA and protein expression of nerve growth factor (NGF); and (iii) mRNA and number of ovarian-expressing cells for the NGF receptor (p75 neurotrophin receptor) and the alpha(1a)-, alpha(1b)-, alpha(1d)- and beta(2)-adrenergic receptors (ARs) in rats with EV-induced PCO was evaluated. PCO was induced by a single i.m. injection of EV, and controls were injected with oil alone in adult cycling rats. The rats were divided into four groups: (i) control (oil); (ii) exercise group (oil + exercise); (iii) a PCO group (EV); and (iv) a PCO exercise group (EV + exercise). The exercise and PCO exercise groups ran voluntarily for 5 weeks in computer-monitored wheels placed in the cages where they were housed. The results obtained indicated that ovarian morphology was almost normalised in the PCO exercise group; NGF mRNA and protein concentrations were normalised in the PCO exercise group; high numbers of NGF receptor expressing cells in PCO ovaries were lowered by exercise; and the number of immunopositive cells of the different AR subtypes were all reduced after exercise in the PCO group, except for the alpha(1b)- and beta(2)-AR whereas the mRNA levels were unaffected, indicating transcriptional regulation. In conclusion, our data indicate a beneficial effect of regular exercise, as a modulator of ovarian sympathetic innervation, in the prevention and treatment of human PCOS.

Comparative study of pituitary and bacteria-derived human growth hormone by monoclonal antibodies.

We have established hybridoma lines which secrete mouse monoclonal antibodies (Mabs) to human pituitary growth hormone, hGH. Using indirect competitive ELISA and indirect passive hemagglutination inhibition twelve different Mabs were characterized with regard to cross-reactivity with the hGH-related hormones, human chorionic somatomammotropin, hCS, and human prolactin, hPRL. The reactivity of these Mabs with pituitary hGH was compared to that with either bacterially-produced methionyl-hGH or to that of reduced and S-carboxymethylated hGH, which has an altered conformation. None of the Mabs reacted with hPRL. Four did not react with hCS whereas the others showed varying degree of cross-reactivity with hCS. All Mabs reacted more weakly with reduced and S-carboxymethylated hGH than with the native form of the hormone, which was not seen with conventional rabbit antisera to hGH. Thus in the case of hGH the Mabs are superior to conventional antisera in revealing small conformational differences. However the pituitary and bacterially-derived methionyl-hGH were indistinguishable as determined by the 12 Mabs.

Immunochemical characterization of charge isomers of bacteria-derived human growth hormone with monoclonal antibodies.

Monoclonal antibodies were used to study the immunochemical nature of charge isomers of bacterially produced methionyl human growth hormone. After isoelectric focusing of the hormone the 12 monoclonal antibodies reacted similarly in immunoblotting experiments and none of them could discriminate between the two isolated charge isomers in ELISA. This indicates that the generation of charge isomers of met-hGH does not result in loss of the determinants recognized by the monoclonal antibodies and that the conformation of the two main charge isomers is identical within these determinants.

Monoclonal antibodies recognize conformational alterations leading to decreased bioactivity of human growth hormone.

By means of monoclonal antibodies to five different antigenic determinants on human growth hormone (hGH) and polyclonal antisera from mice and rabbits, the immunoactivity of native hGH was compared with that of reduced and S-carboxymethylated hGH, which has an unstable conformation. Native and reduced and S-carboxymethylated hGH were also tested in a radioreceptor assay which reflects the bioactivity of the hormone. The IM-9 cell line was used as a receptor source in this assay. All five monoclonal antibodies were superior in discriminating between the native active form of hGH and its reduced and S-carboxymethylated form, which has a markedly reduced receptor binding activity.

Purification of pituitary and biosynthetic human growth hormone using monoclonal antibody immunoadsorbent.

This report describes the purification of human growth hormone from crude pituitary extract and lysate of recombinant E. coli by an immunoadsorbent purification with monoclonal antibody coupled to solid phase. By a single-immunoaffinity chromatography step pure hGH can be obtained from either origin as revealed by SDS-PAGE followed by silver staining or immunoblotting. An additional ion-exchange chromatography step results in homogeneous 22 kDa hGH preparations. Furthermore, this method may be used for isolation of a pituitary hGH variant which has higher binding affinity for this monoclonal antibody than the major 22 kDa form. This study clearly illustrates the potential of monoclonal antibody immunoadsorbents for purification of different molecular forms of hGH.

Immune responses of infants vaccinated with serotype 6B pneumococcal polysaccharide conjugated with tetanus toxoid.

BACKGROUND: Streptococcus pneumoniae is a major cause of meningitis, bacteremia, pneumonia and otitis media. Pneumococcal polysaccharides are not immunogenic in infants, but improved immunogenicity of polysaccharide-protein conjugates has been demonstrated. Antibiotic-resistant pneumococci have increased the need for an effective vaccine. OBJECTIVE: To study the safety and immunogenicity of a pneumococcal type 6B polysaccharidetetanus toxoid conjugate (Pn6B-TT) in infants and to assess the function of antibodies. METHODS: Healthy infants were injected, Group A at 3, 4 and 6 months (n = 21) and Group B at 7 and 9 months (n = 19). Booster injection was given at 18 months. Antibodies were measured by enzyme-linked immunosorbent assay and radioimmunoassay, and functional activity was measured by opsonization of radiolabeled pneumococci. Nasopharyngeal cultures were obtained. RESULTS: No significant adverse reactions were observed. Pn6B-IgG (enzyme-linked immunosorbent assay) increased to a geometric mean of 0.62 microgram/ml (P = 0.367, compared with prevaccination titers) in Group A at 7 months and 1.22 micrograms/ml (P < 0.001) in Group B at 10 months. Total Pn6B antibodies (radioimmunoassay) were 44 ng of antibody N/ml (P < 0.053) in Group A and 211 ng of antibody N/ml (P < 0.001) in Group B. A smaller increase in IgM and IgA anti-Pn6B was observed. Reinjection at 18 months elicited booster responses in total and IgG anti-Pn6B; 62% of those in Group A and 79% of those in Group B had > 300 ng of antibody N/ml. Opsonic activity, after initial and booster vaccinations, correlated with Pn6B-antibody titers. Three infants with nasopharyngeal cultures repeatedly positive for serogroup 6 had poor serum IgG responses. CONCLUSION: Our results demonstrate that Pn6B-TT is safe, elicits functional antibodies and memory responses in infants.