Sensor based time budgets in commercial Dutch dairy herds vary over lactation cycles and within 24 hours.

Cows from 8 commercial Dutch dairy farms were equipped with 2 sensors to study their complete time budgets of eating, rumination, lying, standing and walking times as derived from a neck and a leg sensor. Daily sensor data of 1074 cows with 3201 lactations was used from 1 month prepartum until 10 months postpartum. Farms provided data over a 5 year period. The final models (lactational time budget and 24h time budget) showed significant effects of parity, farm and calving season. When primiparous cows were introduced in the lactational herd, they showed a decrease in lying time of 215 min (95% CI: 187-242) and an increase in standing time of 159 min (95% CI: 138-179), walking time of 23 min (95% CI: 20-26) and rumination time of 69 min (95% CI: 57-82). Eating time in primiparous cows increased from 1 month prepartum until 9 months in lactation with 88 min (95% CI: 76-101) and then remained stable until the end of lactation. Parity 2 and parity 3+ cows decreased in eating time by 30 min (95% CI: 20-40) and 26 min (95% CI: 18-33), respectively, from 1 month before to 1 month after calving. Until month 6, eating time increased 11 min (95% CI: 1-22) for parity 2, and 24 min (95% CI: 16-32) for parity 3+. From 1 month before calving to 1 month after calving, they showed an increase in ruminating of 17 min (95% CI: 6-28) and 28 min (95% CI: 21-35), an increase in standing time of 117 min (95% CI: 100-135) and 133 min (95% CI: 121-146), while lying time decreased with 113 min (95% CI: 91-136) and 130 min (95% CI: 114-146), for parity 2 and 3+, respectively. After month 1 in milk to the end of lactation, lying time increased 67 min (95% CI: 49-85) for parity 2, and 77 min (95% CI: 53-100) for parity 3+. Lactational time budget patterns are comparable between all 8 farms, but cows on conventional milking system (CMS) farms with pasture access appear to show higher standing and walking time, and spent less time lying compared to cows on automatic milking system (AMS) farms without pasture access. Every behavioral parameter presented a 24h pattern. Cows eat, stand and walk during the day and lie down and ruminate during the night. Daily patterns in time budgets on all farms are comparable except for walking time. During the day, cows on CMS farms with pasture access spent more time walking than cows on AMS farms without pasture access. The average 24h pattern between parities is comparable, but primiparous cows spent more time walking during daytime compared to older cows. These results indicate a specific behavioral pattern per parameter from the last month prepartum until 10 months postpartum with different patterns between parities but comparable patterns across farms. Furthermore, cows appear to have a circadian rhythm with varying time budgets in the transition period and during lactation.

Global parental leave in surgical careers: differences according to gender, geographical regions and surgical career stages.

BACKGROUND: There is a lack of information regarding the provision of parental leave for surgical careers. This survey study aims to evaluate the experience of maternity/paternity leave and views on work-life balance globally. METHODS: A 55-item online survey in 24 languages was distributed via social media as per CHERRIES guideline from February to March 2020. It explored parental leave entitlements, attitude towards leave taking, financial impact, time spent with children and compatibility of parenthood with surgical career. RESULTS: Of the 1393 (male : female, 514 : 829) respondents from 65 countries, there were 479 medical students, 349 surgical trainees and 513 consultants. Consultants had less than the recommended duration of maternity leave (43.8 versus 29.1 per cent), no paid maternity (8.3 versus 3.2 per cent) or paternity leave (19.3 versus 11.0 per cent) compared with trainees. Females were less likely to have children than males (36.8 versus 45.6 per cent, P = 0.010) and were more often told surgery is incompatible with parenthood (80.2 versus 59.5 per cent, P < 0.001). Males spent less than 20 per cent of their salary on childcare and fewer than 30 hours/week with their children. More than half (59.2 per cent) of medical students did not believe a surgical career allowed work-life balance. CONCLUSION: Surgeons across the globe had inadequate parental leave. Significant gender disparity was seen in multiple aspects.

Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections.

INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.

[Fosfomycin, an old antibiotic with new possibilities]. / Fosfomycine, een oud antibioticum met nieuwe mogelijkheden.

- Fosfomycin is a broad-spectrum antibiotic agent used orally for uncomplicated cystitis. The intravenous form of administration has recently been authorised in the Netherlands.- Thanks to its broad spectrum and extensive tissue penetration, fosfomycin offers possibilities for the treatment of infections in different organs.- Infections with multidrug-resistant bacteria pose a significant threat to public health. Many of these multidrug-resistant bacteria are sensitive to fosfomycin, which means fosfomycin may be an option for the treatment of infections with multidrug-resistant bacteria. - There is a lack of knowledge about the pharmacological properties of fosfomycin to establish a good dosing schedule. Knowledge is also lacking about the safety of fosfomycin and the extent of its tolerability in the treatment of different infections. - More research is needed before fosfomycin can be used in the battle against multidrug-resistant bacteria.

Chronobiology of mood disorders.

OBJECTIVE: As part of a series of papers examining chronobiology ['Getting depression clinical guidelines right: time for change?' Kuiper et al. Acta Psychiatr Scand 2013;128(Suppl. 444):24-30; and 'Manipulating melatonin in managing mood' Boyce & Hopwood. ActaPsychiatrScand 2013;128(Suppl. 444):16-23], in this article, we review and synthesise the extant literature pertaining to the chronobiology of depression and provide a preliminary model for understanding the neural systems involved. METHOD: A selective literature search was conducted using search engines such as MEDLINE/PubMed, combining terms associated with chronobiology and mood disorders. RESULTS: We propose that understanding of sleep-wake function and mood can be enhanced by simultaneously considering the circadian system, the sleep homoeostat and the core stress system, all of which are likely to be simultaneously disrupted in major mood disorders. This integrative approach is likely to allow flexible modelling of a much broader range of mood disorder presentations and phenomenology. CONCLUSION: A preliminary multifaceted model is presented, which will require further development and testing. Future depression research should aim to examine multiple systems concurrently in order to derive a more sophisticated understanding of the underlying neurobiology.

Getting depression clinical practice guidelines right: time for change?

OBJECTIVE: As part of a series of papers ['Chronobiology of mood disorders' Malhi & Kuiper. Acta Psychiatr Scand 2013;128(Suppl. 444):2-15; and 'It's time we managed depression: The emerging role of chronobiology' Malhi et al. Acta Psychiatr Scand 2013;128(Suppl. 444):1] examining chronobiology in the context of depression, this article examines recent western clinical practice guidelines (CPGs) for the treatment of depression with respect to the recommendations they make, in particular as regards chronobiological treatments, and briefly considers the implications of their methodology and approach. METHOD: Five international treatment guidelines, which had been published in the past 5 years, were identified, representing North American and European views. Chosen guidelines were reviewed by the authors, and the relevant recommendations were distributed for discussion and subsequent synthesis. RESULTS: Most current guidelines do not address chronobiology in detail. Chronotherapeutic recommendations are tentative, although agomelatine is considered as an option for major depression and bright light therapy for seasonal affective disorder. Sleep deprivation is not routinely recommended. CONCLUSION: Recommendations are limited by the lack of reliable therapeutic markers for chronotherapeutics. Current evidence supports use of light therapy in seasonal depression, but in non-seasonal depression there is insufficient evidence to support reliance on chronotherapeutics over existing treatment modalities.

Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder due to deficiency of alpha-Galactosidase A, causing accumulation of globotriaosylceramide and elevated plasma globotriaosylsphingosine (lysoGb3). The diagnostic value and clinical relevance of plasma lysoGb3 concentration was investigated. All male and adult female patients with classical Fabry disease could be discerned by an elevated plasma lysoGb3. In young pre-symptomatic Fabry heterozygotes, lysoGb3 levels can be normal. Individuals carrying the R112H and P60L mutations, without classical Fabry symptoms, showed no elevated plasma lysoGb3. Multiple regression analysis showed that there is no correlation of plasma lysoGb3 concentration with total disease severity score in Fabry males. However, plasma lysoGb3 concentration did correlate with white matter lesions (odds ratio: 6.1 per 100 nM lysoGb3 increase (95% CI: 1.4-25.9, p=0.015). In females, plasma lysoGb3 concentration correlated with overall disease severity. Furthermore, plasma lysoGb3 level was related to left ventricular mass (19.5+/-5.5 g increase per 10 nM lysoGb3 increase; p=0.001). In addition, it was assessed whether lifetime exposure to lysoGb3 correlates with disease manifestations. Male Fabry patients with a high lysoGb3 exposure (>10,000 U), were moderately or severely affected, only one mildly. Female patients with a low exposure (<1000 U) were asymptomatic or mildly affected. A large proportion of the females with an exposure >1000 U showed disease complications. Plasma lysoGb3 is useful for the diagnosis of Fabry disease. LysoGb3 is an independent risk factor for development of cerebrovascular white matter lesions in male patients and left ventricular hypertrophy in females. Disease severity correlates with exposure to plasma lysoGb3.

Active Damping of a Piezoelectric Tube Scanner using Self-Sensing Piezo Actuation.

In most Atomic Force Microscopes (AFM), a piezoelectric tube scanner is used to position the sample underneath the measurement probe. Oscillations stemming from the weakly damped resonances of the tube scanner are a major source of image distortion, putting a limitation on the achievable imaging speed. This paper demonstrates active damping of these oscillations in multiple scanning axes without the need for additional position sensors. By connecting the tube scanner in a capacitive bridge circuit the scanner oscillations can be measured in both scanning axes, using the same piezo material as an actuator and sensor simultaneously. In order to compensate for circuit imbalance caused by hysteresis in the piezo element, an adaptive balancing circuit is used. The obtained measurement signal is used for feedback control, reducing the resonance peaks in both scanning axes by 18 dB and the cross-coupling at those frequencies by 30 dB. Experimental results demonstrate a significant reduction in scanner oscillations when applying the typical triangular scanning signals, as well as a strong reduction in coupling induced oscillations. Recorded AFM images show a considerable reduction in image distortion due to the proposed control method, enabling artifact free AFM imaging at a speed of 122 lines per second with a standard piezoelectric tube scanner.

Plasma glucosylceramide and ceramide in type 1 Gaucher disease patients: correlations with disease severity and response to therapeutic intervention.

The concentrations of plasma glucosylceramide (GlcCer) and ceramide (Cer) were determined in a cohort of type 1 Gaucher disease patients. In plasma of untreated patients, GlcCer concentrations were on average 3-fold increased (median Gaucher: 17.5 nmol/ml, range: 6.5-45.5 (n=27); median control: 5.9 nmol/ml, range 4.0-8.6 (n=15)). Although plasma Cer concentrations were not significantly different between the two groups (median Gaucher: 7.2 nmol/ml, range: 4.2-10.9 (n=27); median control: 7.8 nmol/ml, range 5.7-11.9 (n=15)) in individual patients plasma GlcCer/Cer ratio yields slightly better discrimination between Gaucher disease patients and normal individuals than the GlcCer levels. Positive correlations were detected between plasma GlcCer concentration and GlcCer/Cer ratio and severity of disease, plasma chitotriosidase and CCL18, surrogate markers of storage cells. Gaucher disease is treated by enzyme replacement and substrate reduction therapy. Both therapies were found to result in decreases in plasma GlcCer already within 6 months, without causing abnormal plasma GlcCer or Cer concentrations. The corrections in plasma GlcCer were most robust in patients with a pronounced clinical response. In conclusion, plasma GlcCer concentration and GlcCer/Cer ratio is of value to monitor Gaucher disease manifestation and response to therapeutic intervention.

Association between first-degree familial predisposition of asthma and atopy (total IgE) in newborns.

BACKGROUND: It is generally thought that infants with a first-degree familial predisposition of asthma are at higher risk of developing asthma than infants without predisposition. OBJECTIVE: To investigate whether there is an association between being at high risk for developing asthma and increased level of total IgE in newborns and whether total IgE is influenced by gender, family size, birth season, maternal smoking, birth weight, gestational age, and maternal diet. METHODS: Two hundred and twenty-one high risk and 308 low-risk infants were prenatally selected in a 5-year-period. Three to 5 days after birth, the total IgE was measured in capillary heel blood. RESULTS: Data on total IgE and first-degree familial predisposition were available for 170 high-risk and 300 low-risk infants. There was a statistically significant relationship between being at high-risk (maternal asthma) and increased levels of total IgE in newborns (total IgE cut-off levels: 0.6-0.9 IU/mL (odds ratio (OR)=2.1, 95% confidence interval (CI): 1.2-3.7 to 3.0, 95% CI: 1.5-5.9)), between being born in autumn and increased levels of total IgE in newborns [total IgE cut-off levels: 0.5-0.6 IU/mL (OR=2.5, 95% CI: 1.2-5.1 to 2.5, 95% CI: 1.2-5.4)] and between maternal vitamin supplements intake and decreased levels of total IgE in newborns (total IgE cut-off level: 0.9 IU/mL (OR=0.5, 95% CI:0.3-1.0)). There was no interaction between the effects of maternal asthma and birth season on total IgE, as well as between the effects of maternal asthma and maternal vitamin supplements intake. Gender, family size, maternal smoking, birth weight, and gestational age did not influence the associations. CONCLUSION; Being at high-risk of asthma (maternal asthma) and birth season are positively associated with the presence of increased levels of total IgE at birth, whereas maternal vitamin supplements intake is negatively associated with the presence of total IgE at birth.

Prenatal exposure to mite and pet allergens and total serum IgE at birth in high-risk children.

To examine the relationship between prenatal exposure to mite, cat and dog allergens and total serum IgE at birth in newborns at high risk of asthma. In the homes of 221 newborns with at least one first-degree relative with asthma, concentrations (ng/g dust) of allergens of house dust mite (mite), cat and dog were measured at the fourth to sixth month of pregnancy in dust samples from the maternal mattress and living room. At day 3-5 after birth, total IgE was measured in capillary heel blood. A total number of 174 blood samples were available (11 mothers refused newborn's blood sampling, and in 36 cases the blood sample was too small for analysis). In 24% of the newborns, total IgE was elevated (cut-off value 0.5 IU/ml). A significant dose response relationship was found between increasing mite allergen levels [divided in quartiles ng/g dust (qrt)] and the percentage of elevated IgE: first qrt (0-85 ng/g) 13%; second qrt (86-381) 19%; third qrt (382-2371) 26%; fourth qrt (> or =2372) 42%, respectively, p=0.01. This relationship remained significant after adjusting for passive smoking, maternal and paternal mite allergy, socio-demographic factors, birth characteristics and (breast) feeding practice in the first week of life. In high-risk newborns, prenatal exposure to mite allergens, but not to cat and dog allergens from dust of the living room and of the maternal mattress was associated with total serum IgE at birth.

Human apolipoprotein E4 accelerates beta-amyloid deposition in APPsw transgenic mouse brain.

The human apolipoprotein E4 (ApoE4) isoform is associated with genetic risk for Alzheimer's disease. To assess the effects of different ApoE isoforms on amyloid plaque formation, human ApoE3 and ApoE4 were expressed in the brains of transgenic mice under the control of the human transferrin promoter. Mice were crossed with transgenic mice expressing human amyloid precursor protein containing the Swedish mutation (APPsw), which facilitates amyloid beta peptide (A beta) production. The following progeny were selected for characterization: APPsw+/- x ApoE3+/- and APPsw+/-, APPsw+/- x ApoE4+/- and APPsw+/- littermates. All mice analyzed were wild type for the endogenous mouse APP and ApoE genes. Mice expressing ApoE4 in combination with APPsw have accelerated A beta deposition in the brain as assessed by enzyme immunoassay for A beta40 and A beta42 extractable in 70% formic acid, by assessment of amyloid plaque formation using thioflavin-S staining, and by immunohistochemical staining with antibodies specific for A beta40 or A beta42 and the 4G8 monoclonal or 162 polyclonal antibody. No difference in the rate of A beta deposition in the brain was seen in mice expressing ApoE3 in combination with APPsw. Thus, our data are consistent with the observation in Alzheimer's disease that ApoE4 is associated with increased accumulation of A beta in the brain relative to ApoE3.

Assessment of short-term physical loading of the back: is serum keratin sulfate an appropriate biomarker?

STUDY DESIGN: A prospective experimental study. OBJECTIVES: To investigate the potential of serum keratan sulfate (KS) as an indicator of biochemical changes in intervertebral discs induced by physical loading of the back. BACKGROUND: By providing objective information on exposure and effects at the tissue level, biomarkers may enable us to improve our understanding of the intermediate steps between exposure to physical loading and the occurrence of back disorders. Serum KS has been proposed as a potential biomarker of the molecular changes in intervertebral discs that occur because of physical loading and are a potential cause of back disorders. METHODS AND MEASURES: Thirty-two nonimpaired men volunteers with a mean age of 22.5+/-2.3 years participated in the experimental condition, a manual lifting task, as well as in the control condition, lying on the back. Serum KS levels were measured immediately before and after both conditions, as well as 24 hours and 1 week later. RESULTS: No significant changes in serum KS levels were found after exposure to physical loading (mean SD serum KS before, 287.4+/-83.9 ng/mL; immediately after, 279.5+/-65.5 ng/mL; 24 hours after, 266.6+/-71.9 ng/mL; and 1 week after, 268.9+/-79.3 ng/mL), and no significant changes were found after lying on the back for 8 hours (mean+/-SD serum KS before, 273.0+/-94.3 ng/mL; immediately after, 261.6+/-68.9 ng/mL; 24 hours after, 277.3+/-68.9 ng/mL; and 1 week after, 274.5+/-68.5 ng/mL). CONCLUSIONS: These results indicate that the serum KS level is not suitable as a biomarker of the effects of short-term physical loading of the back induced by a manual lifting task.

Influence of sex, age, and menopausal state on the course of early rheumatoid arthritis.

OBJECTIVE: To investigate the influences of the menopausal state, sex, and age on the course and outcome of rheumatoid arthritis (RA). METHODS: A cohort of patients with early RA (209 female, 123 male) was studied. Sex, age, and menopausal state at baseline, and disease activity, radiographic joint destruction, and physical disability during 6 years of followup were assessed. RESULTS: The Disease Activity Score (DAS) was significantly higher in female compared to male patients at any time point except at the time of inclusion. This was mainly due to postmenopausal patients. Radiographic joint destruction (RJD) was significantly worse in female patients compared to males at the time of inclusion. Postmenopausal patients had significantly higher RJD than premenopausal patients at the time of inclusion and 3 years thereafter. Older male patients showed worse RJD than younger male patients at all time points measured. Physical disability was significantly worse in female compared to male patients, as well as in postmenopausal compared to premenopausal patients, and older male compared to younger male patients. Stepwise regression analysis revealed that at 3 years higher age and female sex were the best predictors for a worse DAS. Higher age and the interaction term between menopausal state and age best predicted higher RJD. Higher age and the interaction term between menopausal state and age best predicted Health Assessment Questionnaire (HAQ) score. CONCLUSION: Higher age at presentation of RA leads to a more severe disease course in terms of DAS, RJD, and HAQ. Although female sex has a deteriorating effect on the DAS, the menopausal state is responsible for the major part of the differences in outcome between men and women. Postmenopausal state in early RA influences future disability and damage, especially in older patients.

Osseous anatomy of the scapula.

Detailed anatomy and morphometry of the scapula were obtained to provide information for surgical procedures such as hardware fixation, drill hole placement, arthroscopic portal placement, and prosthetic positioning. Twenty-six measurements were made in 15 pairs of scapulas from cadavers. The average length of the scapulas from the superior to the inferior angle was 155 +/- 16 mm (mean +/- standard deviation). The thickness of the medial border 1 cm from the edge was 4 +/- 1 mm. The superior border was sharp and thin, and the suprascapular notch was present as a foramen in two scapulas. The distance from the base of the suprascapular notch to the superior rim of the glenoid was 32 +/- 3 mm. The length of the spine from the medial edge of the scapula to the lateral edge of the acromion was 134 +/- 12 mm. The anteroposterior width of the spine at 1 and 4 cm from the medial edge was 7 +/- 1 and 18 +/- 3 mm, respectively; the width at the lateral edge (spinoglenoid notch) was 46 +/- 6 mm. The acromion measured 48 +/- 5 mm x 22 +/- 4 mm and was 9 +/- 1 mm thick. The acromial shape was flat in 23%, curved in 63%, and hooked in 14% of scapulas. The distance from the glenoid to the acromion was 16 +/- 2 mm. The glenoid dimensions were 29 +/- 3 mm (anteroposterior) x 36 +/- 4 mm (superoinferior) and faced posterior by 8 +/- 4 degrees. Anteroposterior thickness of the head of the scapula 1 cm from the surface was 22 +/- 4 mm. The thickness of the coracoid was 11 +/- 1 mm. The average length of the coracoacromial ligament was 27 +/- 5 mm. Scapulas from male cadavers were significantly larger than scapulas from female cadavers in 19 measurements.

Different roles of tumour necrosis factor alpha and interleukin 1 in murine streptococcal cell wall arthritis.

In this study two different aspects of tumour necrosis factor alpha (TNF-alpha) and interleukin 1 (IL-1) in locally induced murine streptococcal cell wall arthritis (SCW) were investigated. First, the kinetics and interdependence of TNF-alpha and IL-1 release; and second; their involvement in inflammation and cartilage destruction. Kinetic studies showed that the TNF-alpha peak level preceded the IL-1 peak level. However, in vivo neutralization of TNF-alpha did not result in decreased IL-1 bioactivity or immunoreactivity, suggesting that there is no dominant TNF-alpha-dependent IL-1 release in this model. Inflammation was studied by measuring knee joint swelling and inflammatory cell influx. Impact on cartilage was studied by measuring chondrocyte proteoglycan synthesis and cartilage proteoglycan depletion. The role of TNF-alpha in these phenomena was investigated using anti-TNF-alpha antibodies and tumour necrosis factor binding protein (TNFbp). Similarly, the role of IL-1 was studied using anti-IL-1 antibodies or IL-1 receptor antagonist (IL-1Ra). Anti-TNF-alpha treatment significantly reduced joint swelling, whereas this effect was not found by using anti-IL-1 or IL-1Ra. In contrast, neutralization of IL-1, but not TNF-alpha, resulted in a significant decrease of chondrocyte proteoglycan synthesis inhibition. Moreover, histology revealed that anti-IL-1 treatment reduced cartilage proteoglycan depletion and inflammatory cell influx. Combined anti-TNF-alpha/anti-IL-1 treatment significantly suppressed both inflammation and cartilage damage. However, the impact on these separate parameters did not exceed the effects of either anti-TNF-alpha or anti-TNF-1. It can be concluded that both TNF-alpha and IL-1 exert specific activities in SCW arthritis. The involvement of TNF-alpha in this model is limited to joint swelling, whereas IL-1 plays a dominant role in cartilage destruction and inflammatory cell influx.

Remodeling of the HDL in NIDDM: a fundamental role for cholesteryl ester transfer protein.

When the Ay gene is expressed in KK mice, the yellow offspring (KKAy mice) become obese, insulin resistant, hyperglycemic, and severely hypertriglyceridemic, yet they maintain extraordinarily high plasma high-density lipoprotein (HDL) levels. Mice lack the ability to redistribute neutral lipids among circulating lipoproteins, a process catalyzed in humans by cholesteryl ester transfer protein (CETP). To test the hypothesis that it is the absence of CETP that allows these hypertriglyceridemic mice to maintain high plasma HDL levels, simian CETP was expressed in the KKAy mouse. The KKAy-CETP mice retained the principal characteristics of KKAy mice except that their plasma HDL levels were reduced (from 159 +/- 25 to 25 +/- 6 mg/dl) and their free apolipoprotein A-I concentrations increased (from 7 +/- 3 to 22 +/- 6 mg/dl). These changes appeared to result from a CETP-induced enrichment of the HDL with triglyceride (from 6 +/- 2 to 60 +/- 18 mol of triglyceride/mol of HDL), an alteration that renders HDL susceptible to destruction by lipases. These data support the premise that CETP-mediated remodeling of the HDL is responsible for the low levels of that lipoprotein that accompany hypertriglyceridemic non-insulin-dependent diabetes mellitus.

Interleukin-6 reduces cartilage destruction during experimental arthritis. A study in interleukin-6-deficient mice.

Using interleukin (IL)-6-deficient (IL-6(0/0) mice or wild-type mice, we investigated the controversial role of IL-6 in joint inflammation and cartilage pathology during zymosan-induced arthritis (ZIA). Monoarticular arthritis was elicited by injection of zymosan into the right knee joint cavity. Production of IL-1, tumor necrosis factor (TNF), IL-6, and nitric oxide by the inflamed knee was assessed in washouts of joint capsule specimens. Plasma corticosterone was measured using a radioimmunoassay. Proteoglycan synthesis was assessed using [35S]sulfate incorporation into patellas ex vivo. Joint swelling was quantified by joint uptake of circulating 99mTechnetium pertechnetate. Histology was taken to evaluate cellular infiltration and cartilage damage. Zymosan caused a rapid increase in articular IL-1, IL-6, TNF, and NO levels. Except for IL-6, the released amounts and time course of these mediators were comparable in the IL-6-deficient mice and the wild-type mice. Elevated plasma corticosterone levels were measured during the first day of arthritis in both strains. At day 2 of ZIA, joint inflammation (joint swelling and cell exudate) in IL-6-deficient mice was comparable with that in the wild-type mice. The marked suppression of chondrocyte proteoglycan synthesis and proteoglycan degradation were on the average higher in the IL-6-deficient mice. Together this resulted in a more pronounced proteoglycan depletion in the IL-6-deficient mice as compared with the wild-type mice during the first week of arthritis. Injection of recombinant IL-6 into the joint cavity corrected the IL-6 deficiency and significantly reduced cartilage destruction. Inflammation was more chronic in the wild-type mice, and these mice also showed a higher prevalence for osteophyte formation. In ZIA, IL-6 plays a dual role in connective tissue pathology, reducing proteoglycan loss in the acute phase and enhancing osteophyte formation in the chronic phase. The latter could be related to the more severe joint inflammation as seen in the normal (IL-6-producing) animals during the chronic phase of arthritis.

Coating in vitro of erythrocytes with Tamm Horsfall-protein.

A method is described to coat isolated peripheral blood erythrocytes in vitro with Tamm-Horsfall Protein (THP, uromodulin). Coating of erythrocytes with THP was accomplished by incubation of the cells in the presence of THP, made monomeric by incubation in a high urea concentration. THP-coating of erythrocytes was dependent on the THP-concentration, maximal coating being obtained at a protein concentration > or = 250 mg/ml. The best coating results were obtained if, during the co-incubation of erythrocytes with THP, urea was removed while the sodium chloride concentration was increased up to a physiologic concentration by means of dialysis. This alteration in chemical conditions promotes THP-polymerisation. Erythrocytes coated in this way could be preserved for at least 5 weeks in preserving solution, making them an interesting source of testing and control material. Coating of erythrocytes with THP could also be accomplished under conditions in which THP was preserved in a monomeric form, which suggests that peripheral blood erythrocytes having binding-sites for THP.