Seasonal patterns of sickness absence due to diagnosed mental disorders: a nationwide 12-year register linkage study.

AIMS: Although seasonality has been documented for mental disorders, it is unknown whether similar patterns can be observed in employee sickness absence from work due to a wide range of mental disorders with different severity level, and to what extent the rate of change in light exposure plays a role. To address these limitations, we used daily based sickness absence records to examine seasonal patterns in employee sickness absence due to mental disorders. METHODS: We used nationwide diagnosis-specific psychiatric sickness absence claims data from 2006 to 2017 for adult individuals aged 16-67 (n = 636,543 sickness absence episodes) in Finland, a high-latitude country with a profound variation in daylength. The smoothed time-series of the ratio of observed and expected (O/E) daily counts of episodes were estimated, adjusted for variation in all-cause sickness absence rates during the year. RESULTS: Unipolar depressive disorders peaked in October-November and dipped in July, with similar associations in all forms of depression. Also, anxiety and non-organic sleep disorders peaked in October-November. Anxiety disorders dipped in January-February and in July-August, while non-organic sleep disorders dipped in April-August. Manic episodes reached a peak from March to July and dipped in September-November and in January-February. Seasonality was not dependent on the severity of the depressive disorder. CONCLUSIONS: These results suggest a seasonal variation in sickness absence due to common mental disorders and bipolar disorder, with high peaks in depressive, anxiety and sleep disorders towards the end of the year and a peak in manic episodes starting in spring. Rapid changes in light exposure may contribute to sickness absence due to bipolar disorder. The findings can help clinicians and workplaces prepare for seasonal variations in healthcare needs.

Assessing Cut-off Points of Eosinophils, Nasal Polyp, and Lund-Mackay Scores to Predict Surgery in Nasal Polyposis: A Real-World Study.

BACKGROUND: Developing tools to identify chronic rhinosinusitis with nasal polyps (CRSwNP) patients requiring surgical treatment would help clinicians treat patients more effectively. The aim of this retrospective cross-sectional study was to identify cut-off values ​​for eosinophil percentage, nasal polyps (NP), and Lund-Mackay (LM) scores that may predict the need for surgical treatment in Finnish CRSwNP patients. METHODS: Data of CRSwNP patients (N = 378) undergoing consultation for ESS in 2001-19 were used. Data was collected from patient records and Lund-Mackay scores were determined from sinus computed tomography scans. The percentage of eosinophils was microscopically evaluated from the polyp samples available (n = 81). Associations were analyzed by Mann Whitney U test, and cut-off values by the area under the receiver operating characteristic curve (AUROC). RESULTS: ESS was performed to 293 (77.5%) of patients. Polyp eosinophilia was associated significantly with ESS (p = 0.001), whereas peripheral blood eosinophil count, LM- score and endoscopic NP- score were not (p > 0.05). AUROC values (95% CI) for detecting those needing ESS were for polyp eosinophilia 0.71 (0.60-0.83), p = 0.001, for LM score 0.59 (0.50-0.67), p = 0.054; for NP score 0.56 (0.48-0.64), p = 0.17, and for blood eosinophil count 0.68 (0.46-0.90), p = 0.08. With the threshold value of polyp eosinophilia (>25%), the sensitivity and specificity were optimal for detecting the group needing ESS from the group not undergoing ESS. The cut-off value of blood eosinophil count (>0.26 × 109/L) had relatively good, yet statistically insignificant (underpowered), predictive potential. Moderate cut-off values were found for endoscopic LM score (≥14/24) and NP score (≥4/8). CONCLUSIONS: Polyp eosinophilia (>25%) predicted ESS among Finnish hospital-level CRSwNP patients. A future challenge would be to find less invasive and cost-effective clinical factors predicting uncontrolled CRSwNP.

Diagnostic Accuracy of Symptoms, Endoscopy, and Imaging Signs of Chronic Rhinosinusitis Without Nasal Polyps Compared to Allergic Rhinitis.

Objectives The diagnosis of chronic rhinosinusitis without nasal polyps (CRSsNP) and distinguishing it from allergic rhinitis is difficult. Yet, early detection of CRSsNP is important to prevent progressive and severe chronic rhinosinusitis. Our aim was to compare diagnostic accuracy of symptoms, endoscopy, and imaging signs of CRSsNP and allergic rhinitis -only phenotypes. Setting Prospective controlled follow-up study. Participants Forty-two nonsmoking patients visiting tertiary care due to CRSsNP and 19 nonsmoking volunteer controls with allergic rhinitis filled a symptoms questionnaire and underwent nasal endoscopy off-seasonally. All CRSsNP patients underwent computed tomography scans of paranasal sinuses. All the allergic rhinitis control subjects and 14 of the CRSsNP patients underwent sinus magnetic resonance imaging. Results Radiologic Lund-Mackay score, duration of symptoms, visual analogue scale scores of symptoms, and Sinonasal Outcome Test 22 were significantly higher in the CRSsNP group compared to allergic rhinitis control group. These factors also correlated in part with each other. Endoscopic score did not correlate with other factors, nor did it differ between CRSsNP and allergic rhinitis groups. The highest area under curve value was demonstrated for visual analogue scale score of facial pain/pressure (0.93) and score ≥4/10 showed 60% sensitivity and 95% specificity for detecting CRSsNP group ( P < .001). Radiologic sign of obstructed osteomeatal complex showed 100% specificity and 38% sensitivity for detecting CRSsNP group ( P < .001). Conclusions CRSsNP phenotype could be primarily distinguished from allergic rhinitis by higher facial pain/pressure score and secondarily by radiologic sings of obstructed ostiomeatal complex and higher Lund-Mackay score. Endoscopic score has limited value in distinguishing CRSsNP from allergic rhinitis.

Distribution of exogenous complement factor H in mice in vivo.

Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self-surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full-length mFH, mFH1-5 and mFH18-20 fragments were radiolabelled, and their distribution was examined in WT, FH-/- and FH-/- C3-/- mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full-length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1-5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18-20 to kidneys was slower, and at tissue level, mFH18-20 was localized at the proximal tubuli in WT and FH-/- C3-/- mice. No C3-independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.

Job strain as a risk factor for clinical depression: systematic review and meta-analysis with additional individual participant data.

BACKGROUND: Adverse psychosocial working environments characterized by job strain (the combination of high demands and low control at work) are associated with an increased risk of depressive symptoms among employees, but evidence on clinically diagnosed depression is scarce. We examined job strain as a risk factor for clinical depression. METHOD: We identified published cohort studies from a systematic literature search in PubMed and PsycNET and obtained 14 cohort studies with unpublished individual-level data from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium. Summary estimates of the association were obtained using random-effects models. Individual-level data analyses were based on a pre-published study protocol. RESULTS: We included six published studies with a total of 27 461 individuals and 914 incident cases of clinical depression. From unpublished datasets we included 120 221 individuals and 982 first episodes of hospital-treated clinical depression. Job strain was associated with an increased risk of clinical depression in both published [relative risk (RR) = 1.77, 95% confidence interval (CI) 1.47-2.13] and unpublished datasets (RR = 1.27, 95% CI 1.04-1.55). Further individual participant analyses showed a similar association across sociodemographic subgroups and after excluding individuals with baseline somatic disease. The association was unchanged when excluding individuals with baseline depressive symptoms (RR = 1.25, 95% CI 0.94-1.65), but attenuated on adjustment for a continuous depressive symptoms score (RR = 1.03, 95% CI 0.81-1.32). CONCLUSIONS: Job strain may precipitate clinical depression among employees. Future intervention studies should test whether job strain is a modifiable risk factor for depression.

Maternal diabetes induces changes in the umbilical cord gene expression.

INTRODUCTION: Since maternal diabetes may affect fetal development and the umbilical cord provides an extension of the fetal vasculature, we decided to investigate cords' biological responses to maternal diabetic milieu. METHODS: Using microarray analysis, we determined the gene expression profiles in the umbilical cords of six neonates born to type 1 diabetic mothers and in six control cords. Umbilical cord tissue was collected immediately after elective cesarean section. Expression data were confirmed by real-time polymerase chain reaction (11 genes). Additionally, the same umbilical cords were analyzed histologically. RESULTS: Two hundred eighty six genes were differentially expressed in the umbilical cords from diabetic pregnancies compared to the controls (fold change ±1.5 and P < 0.01). Maternal diabetes had a major effect on the expression of genes involved in vascular development (Bone morphogenetic protein 4, Delta-like 1, and Notch homolog 4), vessel wall integrity (Collagen type VIII alpha 1, Myocyte enhancer factor 2C, and Matrix metalloproteinase 2), and vascular function (Natriuretic peptide precursor B, Endothelin 1, Endothelin receptor B, Cyclooxygenase 1, and Phosphodiesterase 5A). Maternal diabetes was associated with thicker umbilical vein intima-media layers and larger umbilical vein and artery intima-media areas compared to the controls. DISCUSSION: Maternal diabetic environment seems to alter umbilical cord expression of genes involved in the regulation of vascular development and function with simultaneous umbilical vessel muscle layer thickening. These alterations suggest vascular phenotypic modifications, which in turn may lead to long-term vascular consequences in various tissues in infants of diabetic mothers.

Resistin as a factor in osteoarthritis: synovial fluid resistin concentrations correlate positively with interleukin 6 and matrix metalloproteinases MMP-1 and MMP-3.

OBJECTIVES: Resistin is an adipocytokine that has been related to inflammation and insulin resistance. Following knee injury, elevated levels of resistin have been found in synovial fluid (SF) while very little is known about the role of resistin in osteoarthritis (OA). The aim of the present study was to investigate resistin levels in OA joints and to determine if it is associated with inflammatory and catabolic factors in the joints. METHOD: SF, plasma, and cartilage samples were collected from 88 OA patients undergoing knee replacement surgery. Resistin levels were measured by enzyme-linked immunosorbent assay (ELISA) in SF, plasma, and cartilage culture media. RESULTS: Significant levels of resistin [0.75 (0.67) ng/mL; median (IQR)] were found in SF from OA patients. Resistin correlated positively with interleukin (IL)-6 (r = 0.39, p < 0.001) and with matrix metalloproteinases MMP-1 (r = 0.31, p = 0.004) and MMP-3 (r = 0.24, p = 0.024) in SF. Resistin was also released from cultured OA cartilage and it correlated with resistin levels in SF (r = 0.39, p < 0.001). In addition, resistin levels in plasma correlated positively with those in SF (r = 0.44, p < 0.001). There were no differences in SF or plasma resistin concentrations between females and males or between non-diabetic and diabetic patients, and resistin did not correlate with body mass index (BMI). CONCLUSIONS: Resistin is present in OA joints and is released from OA cartilage. Levels of resistin in SF are associated with inflammatory and catabolic factors, suggesting that resistin has a role to play in the pathogenesis of, and as a possible drug target in, OA.

Job strain and the risk of severe asthma exacerbations: a meta-analysis of individual-participant data from 100 000 European men and women.

BACKGROUND: Many patients and healthcare professionals believe that work-related psychosocial stress, such as job strain, can make asthma worse, but this is not corroborated by empirical evidence. We investigated the associations between job strain and the incidence of severe asthma exacerbations in working-age European men and women. METHODS: We analysed individual-level data, collected between 1985 and 2010, from 102 175 working-age men and women in 11 prospective European studies. Job strain (a combination of high demands and low control at work) was self-reported at baseline. Incident severe asthma exacerbations were ascertained from national hospitalization and death registries. Associations between job strain and asthma exacerbations were modelled using Cox regression and the study-specific findings combined using random-effects meta-analyses. RESULTS: During a median follow-up of 10 years, 1 109 individuals experienced a severe asthma exacerbation (430 with asthma as the primary diagnostic code). In the age- and sex-adjusted analyses, job strain was associated with an increased risk of severe asthma exacerbations defined using the primary diagnostic code (hazard ratio, HR: 1.27, 95% confidence interval, CI: 1.00, 1.61). This association attenuated towards the null after adjustment for potential confounders (HR: 1.22, 95% CI: 0.96, 1.55). No association was observed in the analyses with asthma defined using any diagnostic code (HR: 1.01, 95% CI: 0.86, 1.19). CONCLUSIONS: Our findings suggest that job strain is probably not an important risk factor for severe asthma exacerbations leading to hospitalization or death.

Sensitization to Malassezia in children with atopic dermatitis combined with food allergy.

BACKGROUND: The yeast Malassezia belongs to our normal cutaneous flora, but is capable of sensitizing individuals with atopic dermatitis (AD). Our objective was to investigate the prevalence of sensitization to Malassezia with a 10-yr follow-up among children suffering from AD combined with food allergy (FA) in relation to the extent of AD in infancy. METHODS: One hundred and eighty seven infants diagnosed with AD and milk/wheat allergy before 1 yr of age were included in the study. The area of AD was estimated from patient records of the first visit and measured with SCORAD at the 10-yr follow-up. Specific IgE against Malassezia was determined with ImmunoCAP™ at 11 yr of age. RESULTS: In infancy, 24 children (13%) were allergic to milk, 71 (38%) to wheat, and 92 (49%) to both milk and wheat, and 94 (50%) children had mild, 57 (30%) moderate and 36 (19%) severe AD. At the 10-yr follow-up visit, 19 (10%) of the children had ongoing milk and/or wheat allergy; 147 children (79%) had mild AD and 30 (16%) had SCORAD index of 0. Specific IgE against Malassezia mix was positive (≥0.35 kU/l) in 27% and specific IgE against M. sympodialis in 20% of the 187 children. The area of AD in infancy was associated with a greater risk of having allergen-specific IgE to Malassezia at the 10-yr follow-up. The risk ratio for FA was 3.11 (95% CI: 2.05-4.72; p < 0.001) if specific IgE to Malassezia was positive. CONCLUSIONS: Infants with severe AD and FA seem to have a greater risk of becoming sensitized to Malassezia during a 10-yr follow-up.

Complement activation during liver transplantation-special emphasis on patients with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy often caused by mutations in complement factor H (CFH), the main regulator of alternative complement pathway. Because CFH is produced mainly by the liver, combined liver-kidney transplantation is a reasonable option in treatment of patients with severe aHUS. We studied complement activation by monitoring activation markers during liver transplantation in two aHUS patients treated extensively with plasma exchange and nine other liver transplantation patients. After the reperfusion, a clear increase in all the activation markers except C4d was observed indicating that the activation occurs mainly through the alternative pathway. Concentration of SC5b-9 was higher in the hepatic than the portal vein indicating complement activation in the graft. Preoperatively and early during the operation, the aHUS patients showed highest C3d concentrations but otherwise their activation markers were similar to the other patients. In the other patients, correlation was found between perioperative SC5b-9 concentration and postoperative alanine aminotransferase and histological changes. This study explains why supply of normal CFH by extensive plasma exchange is beneficial before combined liver-kidney transplantation of aHUS patients. Also the results suggest that perioperative inhibition of the terminal complement cascade might be beneficial if enhanced complement activation is expected.

Occupational burnout and chronic work disability: an eight-year cohort study on pensioning among Finnish forest industry workers.

BACKGROUND: The objective was to explore if burnout, a syndrome from chronic work stress, predicts work disability during eight years among industrial employees. We investigated whether burnout would predict disability in initially healthy employees and all subgroups by the most common causes for disability. METHODS: Of the participants in a company-wide survey (n=9705, 63%) performed in 1996, 8371 employees were identified and 7810 provided full information. The impact of burnout and its sub-dimensions, assessed with the Maslach Burnout Inventory-General Survey, on being granted register-based new disability pension till 2004 was analysed with Cox hazard regression and multinomial regression. The analyses were adjusted for socio-demographic factors, registered medication use, and self-reported chronic illness at baseline. RESULTS: The hazard ratio (HR) for new disability pension was 3.8 (95% confidence interval CI 2.7-5.4) with severe burnout. The risk of severe burnout and severe exhaustion for work disability attenuated but remained significant after adjustments. The association between severe burnout and work disability was significant also in the subpopulation of employees without registered medication at baseline but not among employees healthy by self-report. Crude associations between burnout and all categories of cause-specific disability were significant. The exhaustion dimension predicted work disability due to mental and miscellaneous disorders after adjustments. LIMITATIONS: A non-random one-branch sample was used. The final sample covered 50% of eligible employees. CONCLUSIONS: In industrial work, burnout-related chronic work disability is general in nature. Burnout predicts work disability among healthy employees when health is assessed with registered use of medication but not when it is determined by self-report.

Job strain as a predictor of disability pension: the Finnish Public Sector Study.

OBJECTIVE: To examine whether high job strain (a combination of high job demands and low job control) is a risk factor for disability pension. SETTING: Ten municipalities and 21 hospitals in Finland. DESIGN AND PARTICIPANTS: A prospective cohort study of 20 386 female and 4 764 male Finnish public sector employees aged 19-50 using data from two surveys (baseline in 2000-2 and follow-up in 2005) and employers' registers. In addition to self-reported job strain, we computed work unit-aggregated job strain for each participant (the average of scores of all workers of participant's work unit except the participant him/herself). MAIN RESULTS: 93 employees (0.4%) retired because of disability during the follow-up. In multilevel logistic regression analysis adjusted for demographic characteristics and health risk behaviour, odds for disability pension was 2.60 (95% CI 1.26 to 5.34) times higher for employees with high self-assessed job strain than for those with low self-assessed job strain at baseline. The corresponding OR for passive job versus low job strain was 2.82 (95% CI 1.34 to 5.96). Analysis of work unit-aggregated scores replicated the association for high job strain, OR 2.25 (95% CI 1.17 to 4.35), but not that for passive job. The association between work unit job strain and disability pension remained significant after further adjustment for prevalent diseases, psychological distress and perceived health status. CONCLUSIONS: Job strain is associated with risk of subsequent disability pension. If causal, this association suggests that organisational interventions to reduce job strain may also reduce early exit from work.

Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H.

A 12-month-old boy and his 16-year-old aunt became acutely ill 6 months apart and were diagnosed to have atypical hemolytic uremic syndrome (aHUS). Genetic analysis revealed heterozygous R1215Q mutation in complement factor H (CFH) in both patients. The same mutation was found in five healthy adult relatives indicating incomplete penetrance of the disease. The patients developed terminal renal failure and experienced reversible neurological symptoms in spite of plasma exchange (PE) therapy. In both cases, liver-kidney transplantation was successfully performed 6 months after the onset of the disease. To minimize complement activation and prevent thrombotic microangiopathy or overt thrombotic events due to the malfunctioning CFH, extensive PE with fresh frozen plasma was performed pre- and perioperatively and anticoagulation was started a few hours after the operation. No circulatory complications appeared and all four grafts started to function immediately. Also, no recurrence or other major clinical setbacks have appeared during the postoperative follow-up (15 and 9 months) and the grafts show excellent function. While more experience is needed, it seems that liver-kidney transplantation combined with pre- and perioperative PE is a rational option in the management of patients with aHUS caused by CFH mutation.

Effects of homeopathic treatment on salivary flow rate and subjective symptoms in patients with oral dryness: a randomized trial.

Twenty-eight patients with xerostomia participated in a blind, placebo-controlled longitudinal study of the possible effects of homeopathic medicines on oral discomfort. All patients were first divided in two groups according to their medication. After that the two groups were randomly assigned according to a coin-toss to the experimental or control group. Most patients had systemic diseases, such as rheumatoid arthritis and/or Sjögren's syndrome, and frequent daily medications. The randomly selected experimental group (n=15) got an individually prescribed homeopathic medicine and the control group (n=13) a placebo substance (sugar granules), both for 6 weeks. Neither group knew of the nature of the medicine. Oral dryness was evaluated by measurement of unstimulated and wax-stimulated salivary flow rates and visual analogue scale. With only two exceptions, the experimental group experienced a significant relief of xerostomia whereas no such effect was found in the placebo group. Stimulated salivary flow rate was slightly higher with homeopathy than placebo but no consistent changes occurred in salivary immunoglobulin (IgA, IgG) levels. In an open follow-up period those receiving homeopathic medicine continued treatment and the placebo group patients were treated with individually prescribed homeopathic medicines. The symptoms of xerostomia improved in both groups. Our results suggest that individually prescribed homeopathic medicine could be a valuable adjunct to the treatment of oral discomfort and xerostomic symptoms.

Estradiol and cognition during androgen deprivation in men with prostate carcinoma.

BACKGROUND: The adverse effects of hormonal manipulation in prostate carcinoma need to be established in view of its increasing use as an adjuvant treatment. This prospective study investigated the association of androgen deprivation-induced estradiol decline with cognition in prostate carcinoma. METHODS: Cognitive testing of prostate carcinoma patients was carried out at baseline and at 6 and 12 months on androgen deprivation (AD). Cognitive performances were evaluated with standardized measures of information processing, including working memory and attention, visual and verbal skills, and memory performances in 31 tests. Testosterone and estradiol changes during AD were measured with the DELFIA (PerkinElmer, Inc., Wellesley, MA) system. Associations between changes in cognitive performances and estradiol decline were studied. RESULTS: Cognitive performances, which were significantly associated with decline in estradiol, included visual memory of figures (r = -0.52; P = 0.022) and recognition speed of numbers, which were impaired, (r = -0.57; P = 0.030) at 6 months, and improvement in verbal fluency (r = -0.52; P = 0.019) at 12 months. Other cognitive domains appeared unaffected by estradiol decline. The character of change (impairment or improvement) depended on the magnitude of estradiol decline. CONCLUSIONS: The cognitive domains of verbal fluency, visual recognition, and visual memory were associated with decline in estradiol during androgen deprivation. The results suggest selective associations among testosterone decline, estradiol, and cognitive performance. Documentation of these associations has implications for informed patient support in hormonally treated prostate carcinoma.

Effect of adjuvant androgen deprivation on thyroid function tests in prostate cancer patients.

Androgen deprivation (AD) used in the treatment of prostate cancer is known to alter concentrations of sex hormones and their binding globulins. Less is known as to its effect on thyroid hormones. In this prospective study the effects of AD on thyroid function were clarified. Levels of serum thyroid stimulating hormone (TSH), free thyroxine (FT4) and thyroid binding globulin concentrations were measured in prostate cancer patients treated with either radical radiotherapy and androgen deprivation for 12 months (AD) or radical radiotherapy alone (RT). Measurements were made at baseline, and at 3, 6 and 12 months. At baseline and at 3 months the results of thyroid function tests did not differ significantly between groups. A significant decline in serum testosterone in the AD group was accompanied by a significant decline in FT4 at 6 and 12 months, while no significant changes in thyroid function were observed in the RT group. The decline in FT4 among AD patients did not evoke a normal TSH response. Prolonged use of AD hampers the interpretation of thyroid test results. This finding has substantial implications for the follow-up of patients in hormonally treated prostate cancer.

Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma.

BACKGROUND: Interleukin-13 is believed to be important in asthmatic inflammation and airway hyper-reactivity. OBJECTIVE: To investigate the role of IL-13 in chronic asthma, using an improved experimental model of asthma that reproduces most of the morphological features of the human disease. METHODS: BALB/c mice or gene-targeted mice deficient in their ability to produce IL-13 or the IL-4 receptor alpha-chain (IL-4Ralpha) were sensitized to ovalbumin and exposed to aerosolized antigen for 30 min/day on 3 days/week for 6 weeks. Intraepithelial eosinophils, accumulation of chronic inflammatory cells in the airway wall, subepithelial fibrosis, epithelial hypertrophy and numbers of mucous cells were quantified histomorphometrically. Airway hyper-reactivity (AHR) to a cholinergic agonist was assessed by barometric plethysmography. RESULTS: Compared with wild-type animals, IL-13 -/- mice exhibited diminished accumulation of eosinophils and chronic inflammatory cells, as well as reduced subepithelial fibrosis, epithelial hypertrophy and mucous cell hyperplasia (P < 0.01 for all comparisons). In contrast, AHR was still demonstrable in IL -13 -/- mice. In IL-4Ralpha -/- mice the inflammatory response, subepithelial fibrosis and AHR were similar to wild-type mice, although the receptor-deficient mice had significantly less epithelial hypertrophy and mucous cell hyperplasia. CONCLUSION: These results imply a critical role for IL-13 in accumulation of intraepithelial eosinophils in chronic asthma, as well as in epithelial and subepithelial remodelling. In addition, they suggest that in chronic asthma, IL-13 may be capable of signalling via a pathway that does not involve IL-4Ralpha.

Synthesis of Fmoc-protected trans-4-methylproline.

Fmoc-protected trans-4-methylproline was synthesized starting from D-serine. The chiral scaffold of serine in the form of olefinated Garner's aldehyde 3 was used to control the diastereoselective formation of the new stereocenter on the hydrogenation of allylic alcohol 4. The diastereoselectivity (syn/anti ratio) of the process was 86:14, attained with Raney nickel. Hydrogen migration seems not to be the sole factor lowering the diastereoselectivity, as nickel is known not to promote double-bond migration. Instead, the moderate stereocontrol is attributed to the mobility of the side chain of 4, which allows the attack of hydrogen on both faces of the olefin (open transition state). A series of transformations led to ring precursor 8, which after recrystallization afforded the syn diastereoisomer in dr = 95:5. Protected trans-4-methylproline 11 was obtained from 8 in a straightforward fashion.

Integrated signals between IL-13, IL-4, and IL-5 regulate airways hyperreactivity.

In this investigation, we have examined the integrated relationship between IL-13, IL-4, and IL-5 for the development of airways hyperreactivity (AHR) in a model of asthma in BALB/c mice. Sensitization and aeroallergen challenge of both wild-type (WT) and IL-13 gene-targeted (IL-13-/-) mice induced allergic disease that was characterized by pulmonary eosinophilia and AHR to beta-methacholine. Although these responses in IL-13-/- mice were heightened compared with WT, they could be reduced to the level in nonallergic mice by the concomitant neutralization of IL-4. Mice in which both IL-4 and IL-13 were depleted displayed a marked reduction in tissue eosinophils, despite the development of a blood eosinophilia. Similar neutralization of IL-4 in WT mice only partially reduced AHR with no effect on tissue eosinophilia. In addition, neutralization of IL-5 in IL-13-/- mice, but not in WT mice, inhibited AHR, suggesting that tissue eosinophilia is linked to the mechanism underlying AHR only in the absence of IL-13. Additionally, mucus hypersecretion was attenuated in IL-13-/- mice, despite the persistence of AHR. Taken together, our data suggest both a modulatory role for IL-13 during sensitization and a proinflammatory role during aeroallergen challenge. The latter process appears redundant with respect to IL-4.