Comparisons of recycled manure solids and wood shavings/sawdust as bedding material -implications for animal welfare, herd health, milk quality and bedding costs in Swedish dairy herds.

Increasing shortages and costs of common bedding materials have led dairy farmers in Sweden to consider using recycled manure solids (RMS), which are readily available and low-cost, as an alternative bedding material. The main risks are effects on udder health and milk quality, but RMS could also affect animal welfare and claw health. The advantages and disadvantages of using RMS bedding have not been fully investigated, and findings in other countries cannot be directly applied to Swedish conditions and climate. This observational cross-sectional study investigated the use of RMS as bedding regarding associations with certain aspects of animal welfare, herd health, milk quality, and bedding costs in Swedish dairy herds. Thirty-four dairy farms using RMS or wood shavings/sawdust (each n = 17) were compared. Each farm was visited 2 times during the housing period 2020-2021, once in October-December and once in March-May. Dairy barns were observed, animal welfare was assessed, and free-stall dimensions were measured. Farm owners were interviewed about housing system characteristics, herd performance, and herd management. Data on milk production and herd health were obtained from the Swedish official milk recording scheme for the indoor period October-March. The prevalence of claw disorders and abnormal claw conformation were collected from the national claw health database for the period, October-May. On each farm visit, composite samples of unused bedding outside the barn and used bedding material from the free stalls, respectively, were taken for total bacterial count and dry matter analysis. Samples of bulk tank milk for determination of total bacterial count were taken in connection to the visits. In addition, samples of unused and used bedding material and manure from alleys for analysis of 3 Treponema species associated with digital dermatitis (DD) were gathered and analyzed. Total bacterial count was significantly higher in unused (8.50 log10 cfu/g) and used RMS bedding (9.75 log10 cfu/g) than in wood shavings/sawdust (used 4.74; unused 8.63 log10 cfu/g), but there were no significant differences in bulk milk total bacterial count (median 4.07 versus 3.89 log10 cfu/mL) or somatic cell count (median 243,800 versus 229,200 cells /mL). The aspects of animal welfare that were assessed did not differ significantly between the 2 bedding systems, while the prevalence of total claw disorders (25.9 versus 38.0% of trimmed cows), dermatitis (6.9 versus 16.2% of trimmed cows) and sole ulcers (2.0 versus 4.0% of trimmed cows) were significantly lower in the RMS herds. Treponema spp. were not detected in unused RMS material, but all RMS herds had presence of DD recorded at foot trimming. An economic assessment based on the interview results and price level from winter 2021 revealed that the costs of RMS bedding varied with amount of RMS produced. Thus, RMS is a potential alternative bedding material for dairy cows in Sweden and can be a profitable option for large dairy herds. However, the high level of total bacteria in the material requires attention to bedding and milking routines as well as regular monitoring of herd health.

Ventricular-arterial coupling (VAC) in a population-based cohort of middle-aged individuals: The STANISLAS cohort.

BACKGROUND AND AIMS: Data exploring normal values of different ventricular-arterial coupling (VAC) parameters and their association with anthropometric and cardiovascular (CV) factors are scarce. We aim to report values of two different methods of VAC assessment according to age and sex and explore their association with CV factors within a large population-based cohort of middle-aged individuals. METHODS: For 1333 (mean age 48 ± 14) individuals participating in the 4th visit of the STANISLAS cohort, VAC was assessed by two methods [1]: arterial elastance (Ea)/end-systolic elastance (Ees) and [2] Pulse wave velocity (PWV)/Global longitudinal strain (GLS). RESULTS: The mean values of Ea/Ees and PWV/GLS were 1.06 ± 0.20 and 0.42 ± 0.12, respectively. The two methods of VAC assessment were poorly correlated (Pearson's correlation coefficient r = 0.14 (0.08; 0.19)). Increased PWV/GLS was associated with older age and a higher degree of cardiovascular risk factors (i.e., BMI, blood pressure, LDL, diabetes, hypertension) in the whole population as well as in the parent generation. In contrast, higher Ea/Ees were associated with decreasing age, and lower prevalence of risk factors in the whole cohort but neutrally associated with risk factors in the parent generation. CONCLUSIONS: Higher PWV/GLS is significantly associated with CV factors regardless of age. In contrast, worse Ea/Ees is associated with a better CV risk profile when considering individuals aged 30 to 70 but neutrally associated with CV factors when considering only older patients. These results may suggest that PWV/GLS should preferably be used to explore VAC. In addition, age-individualized threshold of Ea/Ees should be used.

Proteomic and Metabolomic Characterization of Metabolically Healthy Obesity: A Descriptive Study from a Swedish Cohort.

Method: Associations between different biomarkers (proteomics, lipidomics, and metabolomics) coupled to either MHO or metabolically unhealthy obese (MUO) individuals were analyzed through principal component analysis (PCA). Subjects were identified from a subsample of 416 obese individuals, selected from the Malmö Diet and Cancer study-Cardiovascular arm (MDCS-CV, n = 3,443). They were further divided into MHO (n = 143) and MUO (n = 273) defined by a history of hospitalization, or not, at baseline inclusion, and nonobese subjects (NOC, n = 3,027). Two distinctive principle components (PL2, PP5) were discovered with a significant difference and thus further investigated through their main loadings. Results: MHO individuals had a more metabolically favorable lipid and glucose profile than MUO subjects, that is, lower levels of traditional blood glucose and triglycerides, as well as a trend of lower metabolically unfavorable lipid biomarkers. PL2 (lipidomics, p=0.02) showed stronger associations of triacylglycerides with MUO, whereas phospholipids correlated with MHO. PP5 (proteomics, p=0.01) included interleukin-1 receptor antagonist (IL-1ra) and leptin with positive relations to MUO and galanin that correlated positively to MHO. The group differences in metabolite profiles were to a large extent explained by factors included in the metabolic syndrome. Conclusion: Compared to MUO individuals, corresponding MHO individuals present with a more favorable lipid metabolic profile, accompanied by a downregulation of potentially harmful proteomic biomarkers. This unique and extensive biomarker profiling presents novel data on potentially differentiating traits between these two obese phenotypes.

Antibodies against phosphorylcholine in hospitalized versus non-hospitalized obese subjects.

Obesity associates with reduced life expectancy, type 2 diabetes, hypertension and cardiovascular disease, and is characterized by chronic inflammation. Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein, dead cells and some microorganisms. Antibodies against PC (anti-PC) have anti-inflammatory properties. Here, we explored the role of anti-PC in hospitalized versus non-hospitalized obese. One-hundred-and-twenty-eight obese (BMI ≥ 30 kg/m2) individuals (59.8 (± 5.5) years, 53.9% women) from the Malmö Diet and Cancer Cardiovascular Cohort were examined and IgM, IgG1 and IgG2 anti-PC were analyzed by ELISA. Individuals with at least one recorded history of hospitalization prior to study baseline were considered hospitalized obese (HO). Associations between IgM, IgG1 and IgG2 anti-PC and HO (n = 32)/non-hospitalized obese (NHO) (n = 96), but also with metabolic syndrome and diabetes were analysed using logistic regressions. Both IgM and IgG1 anti-PC were inversely associated with HO, also after controlling for age and sex. When further adjusted for waist circumference, systolic blood pressure, glucose levels and smoking status, only IgG1 anti-PC remained significantly associated with HO. In multivariate models, each 1 standard deviation of increment in anti-PC IgG1 levels was inversely associated with prevalence of HO (odds ratio 0.57; CI 95% 0.33-0.98; p = 0.044). IgG2 anti-PC did not show any associations with HO. Low levels of IgM and IgG1 anti-PC are associated with higher risk of being a HO individual independent of sex and age, IgG1 anti-PC also independently of diabetes and metabolic syndrome. The anti-inflammatory properties of these antibodies may be related to inflammation in obesity and its complications.

Comparison of quality of urinary bladder filling in CT urography with different doses of furosemide in the work-up of patients with macroscopic hematuria.

INTRODUCTION: The protocol for preparation of computed tomography urography (CTU) examinations at our hospital was changed in 2013 to improve the quality of urinary bladder filling in the excretory phase. The aim of this study was to evaluate the quality of urinary bladder filling on CTU after different doses of furosemide were administered to patients with macroscopic hematuria. METHODS: The cohort was 215 patients who underwent elective CTU due to macroscopic hematuria between 2014 and 2018. 5 mg furosemide were administrated to 100 patients, 2.5 mg to 100 patients and 0 mg to 15 patients. Contrast medium layered bladders were excluded, leaving 193 patients: 92, 89 and 12 in each group. Urinary bladder volume was calculated in corticomedullary (CMP) and excretory phase (EP). Bladder distension was classified as satisfactory or not. Attenuation of bladder content in EP was noted. RESULTS: Average volume in EP was 370 ± 224 ml (28-1052) after 5 mg furosemide, 274 ± 120 ml (43-628) after 2.5 mg and 180 ± 104 ml (53-351) after 0 mg. 85% of the bladders were satisfactory distended after 5 mg, 80% after 2.5 mg and 58% after 0 mg. Average attenuation was 266 ± 89 HU (103-524) after 5 mg, 362 ± 156 HU (118-948) after 2.5 mg and 761 ± 331 HU (347-1206) after 0 mg. The differences in volume and attenuation were significant. CONCLUSION: 5 mg furosemide is preferred rather than 2.5 mg in preparation for CTU examinations of patients with macroscopic hematuria. There was no difference between the doses concerning rate of satisfactory bladder distension, but the higher dose resulted in larger bladder volume and more suitable attenuation of bladder content. IMPLICATIONS FOR PRACTICE: Development of CTU-image quality could improve bladder cancer diagnostics.

High circulating levels of midregional proenkephalin A predict vascular dementia: a population-based prospective study.

Midregional Pro-enkephalin A (MR-PENK A) and N-terminal Protachykinin A (NT-PTA) have been associated with vascular dementia. However, the longitudinal relationship between these biomarkers and incident dementia has not been fully investigated. In the population-based Malmö Preventive Project, circulating levels of MR-PENK A and NT-PTA were determined in a random sample of 5,323 study participants (mean age: 69 ± 6 years) who were followed-up over a period of 4.6 ± 1.6 years. The study sample included 369 patients (7%) who were diagnosed in the same period with dementia. We analyzed relationship of MR-PENK A and NT-PTA with the risk of developing dementia by using multivariable-adjusted Cox regression models adjusted for traditional risk factors. Increased plasma levels of MR-PENK A were associated with higher risk of incident vascular dementia whereas no associations were found with all-cause or Alzheimer dementia. The risk of vascular dementia was mainly conferred by the highest quartile of MR-PENK as compared with lower quartiles. Elevated levels of NT-PTA yielded significant association with all-cause dementia or dementia subtypes. Elevated plasma concentration of MR-PENK A independently predicts vascular dementia in the general population. MR-PENK A may be used as an additional tool for identifying vascular subtype in ambiguous dementia cases.

Beta-blocker therapy and risk of vascular dementia: A population-based prospective study.

There are a few studies that report cognitive impairment as a complication of treatment with beta- blockers. We aimed to evaluate the longitudinal association between use of beta-blockers, as a class, and incident risk of all-cause dementia, vascular dementia, Alzheimer's and mixed dementia in the prospective population-based Malmö Preventive Project. We included 18,063 individuals (mean age 68.2, males 63.4%) followed up for 84,506 person-years. Dementia cases were retrieved from the Swedish National Patient Register and validated by review of medical records and neuroimaging data. We performed propensity score matching analysis, resulting in 3720 matched pairs of beta-blocker users and non-users at baseline, and multivariable Cox proportional-hazards regression. Overall, 122 study participants (1.6%) were diagnosed with dementia during the follow-up. Beta-blocker therapy was independently associated with increased risk of developing vascular dementia, regardless of confounding factors (HR: 1.72, 95%CI 1.01-3.78; p = .048). Conversely, treatment with beta-blockers was not associated with increased risk of all-cause, Alzheimer's and mixed dementia (HR:1.15; 95%CI 0.80-1.66; p = .44; HR:0.85; 95%CI 0.48-1.54; P = .59 and HR:1.35; 95%CI 0.56-3.27; p = .50, respectively). We observed that use of beta-blockers, as a class, is associated with increased longitudinal risk of vascular dementia in the general elderly population, regardless of cardiovascular risk factors, prevalent or incident history of atrial fibrillation, stroke, coronary events and heart failure. Further studies are needed to confirm our findings in the general population and to explore the mechanisms underlying the relationship between use of beta- blockers and increased risk of vascular dementia.

Investigation of self-reported dizziness in the elderly when lying down or turning over in bed, and possible benign paroxysmal positional vertigo.

OBJECTIVES: This study aimed to investigate the rate of dizziness and occurrence of benign paroxysmal positional vertigo in the elderly by physical examination in those reporting dizziness symptoms when lying down or turning over in bed. METHODS: A total of 498 people, aged 70-85 years, were asked to complete a questionnaire regarding dizziness symptoms. Subjects answering that they became dizzy in bed were asked to participate in a physical examination and diagnostic manoeuvres investigating benign paroxysmal positional vertigo. RESULTS: A total of 324 participants (65 per cent) completed the questionnaire. More than one-quarter (29 per cent) reported dizziness and 32 (10 per cent) reported dizziness when turning in bed. Of these 32 persons, 22 (69 per cent) underwent a physical examination. Six participants tested positive for benign paroxysmal positional vertigo. CONCLUSION: Ten per cent of the elderly participants reported positional symptoms, and 6 out of 22 fulfilled diagnostic criteria for benign paroxysmal positional vertigo. Furthermore, benign paroxysmal positional vertigo was established despite a delay between questionnaire completion and investigation, emphasising that this type of dizziness may not be a self-limiting disorder.

T-pattern detection and analysis for the discovery of hidden features of behaviour.

BACKGROUND: The behaviour of all living beings consists of hidden patterns in time; consequently, its nature and its underlying dynamics are intrinsically difficult to be perceived and detected by the unaided observer. METHOD: Such a scientific challenge calls for improved means of detection, data handling and analysis. By using a powerful and versatile technique known as T-pattern detection and analysis (TPA) it is possible to unveil hidden relationships among the behavioural events in time. RESULTS: TPA is demonstrated to be a solid and versatile tool to study the deep structure of behaviour in different experimental contexts, both in human and non human subjects. CONCLUSION: This review deepens and extends contents recently published by adding new concepts and examples concerning the applications of TPA in the study of behaviour both in human and non-human subjects.

GaAs Nanowire pn-Junctions Produced by Low-Cost and High-Throughput Aerotaxy.

Semiconductor nanowires could significantly boost the functionality and performance of future electronics, light-emitting diodes, and solar cells. However, realizing this potential requires growth methods that enable high-throughput and low-cost production of nanowires with controlled doping. Aerotaxy is an aerosol-based method with extremely high growth rate that does not require a growth substrate, allowing mass-production of high-quality nanowires at a low cost. So far, pn-junctions, a crucial element of solar cells and light-emitting diodes, have not been realized by Aerotaxy growth. Here we report a further development of the Aerotaxy method and demonstrate the growth of GaAs nanowire pn-junctions. Our Aerotaxy system uses an aerosol generator for producing the catalytic seed particles, together with a growth reactor with multiple consecutive chambers for growth of material with different dopants. We show that the produced nanowire pn-junctions have excellent diode characteristics with a rectification ratio of >105, an ideality factor around 2, and very promising photoresponse. Using electron beam induced current and hyperspectral cathodoluminescence, we determined the location of the pn-junction and show that the grown nanowires have high doping levels, as well as electrical properties and diffusion lengths comparable to nanowires grown using metal organic vapor phase epitaxy. Our findings demonstrate that high-quality GaAs nanowire pn-junctions can be produced using a low-cost technique suitable for mass-production, paving the way for industrial-scale production of nanowire-based solar cells.

High-dose vitamin D3 supplementation decreases the number of colonic CD103+ dendritic cells in healthy subjects.

PURPOSE: Vitamin D may induce tolerance in the intestinal immune system and has been shown to regulate the phenotype of tolerogenic intestinal dendritic cells (DCs) in vitro. It is unknown whether vitamin D supplementation affects human intestinal DCs in vivo, and we aimed to investigate the tolerability and effect on intestinal CD103+DCs of high-dose vitamin D3 treatment in healthy subjects. METHODS: Ten healthy subjects received a total of 480,000 IU oral vitamin D3 over 15 days and colonic biopsies were obtained before and after intervention by endoscopy. Lamina propria mononuclear cells (LPMCs) were isolated from the biopsies, stained with DC surface markers and analysed with flow cytometry. Snap-frozen biopsies were analysed with qPCR for DC and regulatory T cell-related genes. RESULTS: No hypercalcemia or other adverse events occurred in the test subjects. Vitamin D decreased the number of CD103+ DCs among LPMCs (p = 0.006). Furthermore, vitamin D induced mRNA expression of TGF-ß (p = 0.048), TNF-α (p = 0.006) and PD-L1 (p = 0.02) and tended to induce IL-10 expression (p = 0.06). Multivariate factor analysis discriminated between pre- and post-vitamin D supplementation with a combined increased qPCR expression of PD1, PD-L1, TGF-ß, IL-10, CD80, CD86, FOXP3, NFATc2 and cathelicidin. CONCLUSION: High-dose vitamin D supplementation is well tolerated by healthy subjects and has a direct effect on the CD103+ DCs, local cytokine and surface marker mRNA expression in the colonic mucosa, suggestive of a shift towards a more tolerogenic milieu.

Monitoring of cerebral oximetry during head-up tilt test in adults with history of syncope and orthostatic intolerance.

Aims: We applied near-infrared-spectroscopy (NIRS) to measure absolute frontal cerebral tissue oxygen saturation (SctO2) during head-up tilt test (HUT) in patients investigated for unexplained syncope. Methods and results: Synchronized non-invasive beat-to-beat haemodynamic monitoring, ECG, SctO2 (NIRS; normal range: 60-80%), and peripheral oxygen saturation (left hand, SpO2) were applied during HUT in a random sample of patients with unexplained syncope. Tracings of 54 patients (mean-age: 55 ± 19 years, 39% male) with negative HUT, vasovagal syncope (VVS), or orthostatic hypotension (OH) were analysed. In 44 patients HUT was diagnostic, in 10 HUT was negative. Thirty-one experienced VVS. Of these, 6 had spontaneous and 25 nitroglycerin-induced syncope. Thirteen patients had orthostatic hypotension (OH). Although there was no significant change in mean-arterial pressure from baseline to 1 min before syncope or end of passive HUT phase (-1.4 ± 13.9 mmHg; P = 0.45), there was a significant fall in SctO2 during the same period (-3.2 ± 3.2%; P ≤ 0.001). Among patients who experienced syncope, a decrease in SctO2 from 71 ± 5% at baseline to 53 ± 9% (P < 0.001) at syncope was observed. During HUT, there was a significant difference in delta SctO2 between spontaneous VVS (-4.5 ± 3.0%) and negative HUT (-1.3 ± 1.9%; P = 0.021), but not between spontaneous VVS and OH (-5.4 ± 4.2%; P = 0.65). In spontaneous VVS, progressive decrease of SctO2 was independent of mean arterial pressure decrease (P = 0.22). Conclusions: Progressive decrease in cerebral tissue oxygenation independent of mean-arterial pressure may precede spontaneous vasovagal reflex during tilt. Patients experience syncope when SctO2 falls below 60%. These data confirm clinical utility of absolute cerebral oximetry monitoring for syncope investigation. We applied NIRS to measure frontal cerebral tissue oxygen saturation (SctO2) during head-up tilt test (HUT) in patients with unexplained syncope. In 44 of 54 patients, HUT was diagnostic. In patients with syncope, a significant SctO2-decrease was observed. Different patterns of SctO2 can be detected.

[Diagnostic criteria for Menière's disease according to the Classification Committee of the Bárány Society]. / M. Menière: Diagnostische Kriterien des Internationalen Klassifikationskomitees der Bárány-Gesellschaft.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12 h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24 h.

Gait of dairy cows on floors with different slipperiness.

This study assessed the slip resistance of different types of solid flooring in cattle housing using a range of technical tests and gait analysis. Dynamic and static coefficient of friction, skid resistance, and abrasiveness were tested on concrete flooring with a smooth finish, a grooved pattern, or a tamped pattern, acid-resistant mastic asphalt, soft rubber mats, and a worn slatted concrete floor. Coefficients of friction and skid resistance were tested under clean and slurry-soiled conditions. Linear kinematic variables were assessed in 40 cows with trackway measurements after the cows passed over the floors in a straight walk. All gait variables were assessed as deviations from those obtained on the slatted concrete floor, which was used as a baseline. The coefficient of friction tests divided the floors into 3 categories: concrete flooring, which had a low coefficient of friction (0.29-0.41); mastic asphalt flooring, which had medium values (0.38-0.45); and rubber mats, which had high values (0.49-0.57). The highest abrasion (g/10 m) was on the asphalt flooring (4.48), and the concrete flooring with a tamped pattern had significantly higher abrasiveness (2.77) than the other concrete floors (1.26-1.60). Lowest values on the skid-resistance tests (dry/wet) were for smooth concrete (79/35) and mastic asphalt (65/47), especially with a slurry layer on the surface. Gait analysis mainly differentiated floors with higher friction and abrasion by longer strides and better tracking. Step asymmetry was lower on floors with high skid-resistance values. The most secure cow gait, in almost every aspect, was observed on soft rubber mats. Relationships between gait variables and physical floor characteristics ranged from average to weak (partial correlations 0.54-0.16). Thus, none of the physical characteristics alone was informative enough to characterize slip resistance. With reference to gait analysis, the abrasiveness of the hard surfaces was more informative than the coefficient of friction, but the effect of pattern was better detected by skid-resistance measurements. Consequently, several physical characteristics are needed to objectively describe the slip resistance of cattle floors. Soft rubber mats gave better tracking than hard, solid floors, even with a grooved surface or a tamped pattern.

Discovery of recurring behavioural sequences in Wistar rat social activity: Possible support to studies on Autism Spectrum Disorders.

This study was undertaken to investigate whether, in rat interactive activities, recurring sequences of behavioural events might be identified and how and to what extent each component of the pair is involved. To this aim, the multivariate temporal-pattern (t-pattern) analysis was applied to the social interactions of 9 pairs of male Wistar rats tested in open field. Interactive activities were classified into intra- and inter-subjects. Quantitative evaluations showed that intra-subject behavioural elements represented 62.37% and inter-subject ones 37.63% of the comprehensive behaviour. T-pattern analysis revealed the presence of 221 different t-patterns organized in four different categories: containing exclusively inter-subject elements; containing both inter- and intra-subject elements; consisting of rat 1 and rat 2 intra-subject elements and, finally, consisting of intra-subject elements carried out by one of the two subjects. Results show that the activity of two interacting Wistar rats is structured on the basis of several recurring temporal sequences. Moreover, social interactions appear to be expressed also by t-patterns where the behavioural elements are carried out by animals seemingly not interacting. A support of t-pattern analysis to studies on Autism Spectrum Disorders is proposed.

Biomarkers of microvascular endothelial dysfunction predict incident dementia: a population-based prospective study.

BACKGROUND: Cerebral endothelial dysfunction occurs in a spectrum of neurodegenerative diseases. Whether biomarkers of microvascular endothelial dysfunction can predict dementia is largely unknown. We explored the longitudinal association of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal endothelin-1 (CT-proET-1) and midregional proadrenomedullin (MR-proADM) with dementia and subtypes amongst community-dwelling older adults. METHODS: A population-based cohort of 5347 individuals (men, 70%; age, 69 ± 6 years) without prevalent dementia provided plasma for determination of MR-proANP, CT-proET-1 and MR-proADM. Three-hundred-and-seventy-three patients (7%) were diagnosed with dementia (120 Alzheimer's disease, 83 vascular, 102 mixed, and 68 other aetiology) over a period of 4.6 ± 1.3 years. Relations between baseline biomarker plasma concentrations and incident dementia were assessed using multivariable Cox regression analysis. RESULTS: Higher levels of MR-proANP were significantly associated with increased risk of all-cause and vascular dementia (hazard ratio [HR] per 1 SD: 1.20, 95% confidence interval [CI], 1.07-1.36; P = 0.002, and 1.52; 1.21-1.89; P < 0.001, respectively). Risk of all-cause dementia increased across the quartiles of MR-proANP (p for linear trend = 0.004; Q4, 145-1681 pmol L-1 vs. Q1, 22-77 pmol L-1 : HR: 1.83; 95%CI: 1.23-2.71) and was most pronounced for vascular type (p for linear trend = 0.005: HR: 2.71; 95%CI: 1.14-6.46). Moreover, the two highest quartiles of CT-proET-1 predicted vascular dementia with a cut-off value at 68 pmol L-1 (Q3-Q4, 68-432 pmol L-1 vs. Q1-Q2,4-68 pmol L-1 ; HR: 1.94; 95%CI: 1.12-3.36). Elevated levels of MR-proADM indicated no increased risk of developing dementia after adjustment for traditional risk factors. CONCLUSIONS: Elevated plasma concentration of MR-proANP is an independent predictor of all-cause and vascular dementia. Pronounced increase in CT-proET-1 indicates higher risk of vascular dementia.

Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse.

Essentials Stimulating endogenous fibrinolysis could be a novel antithrombotic strategy. The effect of valproic acid on endothelial tissue plasminogen activator in mice was investigated. Valproic acid increased tissue plasminogen activator expression in vascular endothelium. Valproic acid reduced fibrin deposition and thrombus formation after vascular injury. SUMMARY: Background The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue-type plasminogen activator (t-PA) production is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown. Objectives To determine whether the HDAC inhibitor valproic acid (VPA) stimulates production of t-PA in the vasculature of mice, and whether VPA pretreatment affects fibrin deposition and clot formation after mechanical vessel injury. Methods Mice were injected with VPA twice daily for up to 5 days. t-PA mRNA, and antigen expression in the mouse aorta and the circulating levels of t-PA were determined. Fibrin and thrombus dynamics after mechanical vessel injury were monitored with intravital confocal microscopy. Potential effects of VPA on platelets and coagulation were investigated. Results and Conclusions We found that VPA treatment increased vascular t-PA production in vivo and, importantly, that VPA administration was associated with reduced fibrin accumulation and smaller thrombi in response to vascular injury, but still was not associated with an increased risk of bleeding. Furthermore, we observed that higher concentrations of VPA were required to stimulate t-PA production in the brain than in the vasculature. Thus, this study shows that VPA can be dosed to selectively manipulate the fibrinolytic system in the vascular compartment and reduce thrombus formation in vivo.

The conundrum of cervicogenic dizziness.

Cervicogenic or cervical dizziness is debated as an entity. However, there exists both a physiologic basis and a multitude of clinical data to make such a disease concept at least possible and worth considering. In addition, the interaction of proprioceptive and vestibular mechanisms may amplify dizziness of other origin. Cervical pain and dizziness are both common symptoms and may coincide, and neck pain or obvious dysfunction does not necessarily cause dizziness or balance disturbances. So far, there is also the lack of a proper diagnostic test for cervicogenic dizziness. On the other hand, there is growing evidence that cervical proprioceptive input is important for balance and postural control not only in animals but also in humans, and that intervention in disorders affecting the human cervical segment may relieve dizziness in some patients. It is advocated that the diagnosis should be used with care and that there is a need for better diagnostic tests. In the absence of such a test, one has to rely on preliminary criteria and a diagnosis ex juvantibus. A possible approach would require patients to present with neck pain before or in close temporal relation with dizziness; that other causes should be made at least unlikely; and that treatment of a cervical dysfunction reduces also dizziness or balance disturbance.

No widening socioeconomic gap within a general decline in Swedish breastfeeding.

AIM: To study potential socioeconomic differences within the general decline in breastfeeding over time. METHODS: Data was collected for 51 415 infants born 2004-2010 from the databases of statistics of the Preventive Child Health Care Services in Uppsala and Orebro counties in Sweden and socioeconomic indicators from Swedish national registers. Breastfeeding data (breastfed/not breastfed) from 1 week, 4 months and 6 months of age were used as the main outcome variables. Educational level of the mother was defined as the highest level on a three-grade scale, low, medium and high. Family type was defined as whether the mother was single or married/cohabiting. Family disposable income was divided into quartiles where quartile 1 included the 25% children in families with the lowest incomes. Analyses were conducted by logistic regression models using the methodology of generalized estimating equations (GEE). An exchangeable correlation structure was used to control for the dependence among infants with the same mother. RESULTS: Breastfeeding rate in Sweden has declined gradually since the late 1990s. The results indicated that overall breastfeeding rates over the study period were influenced by socioeconomic status in a gradient manner but no widening socioeconomic gap was detected. Rather the interaction analyses showed a narrowing socioeconomic gap over the study period between high and low educational level and single versus cohabiting mothers at 4 months. The narrowing socioeconomic gap between the educational level categories was also detectable at 6 months. CONCLUSION: No increase in socioeconomic gap was detected within the general decline in Swedish breastfeeding. However, there are reasons to maintain and strengthen the overall breastfeeding supportive measures including extended support for vulnerable groups.

HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.

The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492(HER2)) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492(HER2) (D492(HER2/EGFR)) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492(HER2/EGFR) xenografts grow slower than the D492(HER2) tumors, while overexpression of EGFR alone (D492(EGFR)) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492(HER2) xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492 cells, EGFR can behave as a tumor suppressor, by pushing the cells towards epithelial differentiation.