Parous women perform less moderate to vigorous physical activity than their nulliparous peers: a population-based study in Denmark.

OBJECTIVES: The World Health Organization (WHO) highlights parous women as a key population for monitoring trends of physical activity (PA). We aimed to estimate the proportion of Danish women non-adhering to WHO PA guidelines in parous women compared with nulliparous women and to describe leisure-time PA intensity in each of these groups. STUDY DESIGN: Cross-sectional study. METHODS: This population-based study builds on a sample of 27,668 women aged 16-40 years from the Danish National Health Survey 2021. These data were linked with childbirth data from the Danish National Birth Registry. The primary outcome was self-reported weekly hours of moderate to vigorous leisure-time PA (MVPA) dichotomized into: (i) adhering to WHO guidelines for MVPA or (ii) not adhering to WHO guidelines for MVPA. Binomial regression analysis was used to calculate prevalence proportions (PP) and prevalence proportion ratios (PPR). RESULTS: Of the 27,668 women, a total of 20,022 were included; 9338 (46.6%) parous women and 10,684 (53.4%) nulliparous women. The PP of women non-adhering to WHO PA guidelines was 63.8% (95% CI 62.9-64.8) for parous and 51.3% (95% CI 50.4-52.3) for nulliparous women, corresponding to a PPR of 1.24 (95% CI 1.21; 1.27). CONCLUSIONS: The proportion of parous women who did not adhere to WHO PA guidelines for MVPA was 24% higher than that of nulliparous women. This highlights parous women as a subgroup of the adult population at increased risk of non-adherence to WHO PA guidelines. These findings call for future research to inform new strategies aiming to promote PA in parous women.

Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice.

Disruptions in circadian rhythms and dopaminergic activity are involved in the pathophysiology of bipolar disorder, though their interaction remains unclear. Moreover, a lack of animal models that display spontaneous cycling between mood states has hindered our mechanistic understanding of mood switching. Here, we find that mice with a mutation in the circadian Clock gene (ClockΔ19) exhibit rapid mood-cycling, with a profound manic-like phenotype emerging during the day following a period of euthymia at night. Mood-cycling coincides with abnormal daytime spikes in ventral tegmental area (VTA) dopaminergic activity, tyrosine hydroxylase (TH) levels and dopamine synthesis. To determine the significance of daytime increases in VTA dopamine activity to manic behaviors, we developed a novel optogenetic stimulation paradigm that produces a sustained increase in dopamine neuronal activity and find that this induces a manic-like behavioral state. Time-dependent dampening of TH activity during the day reverses manic-related behaviors in ClockΔ19 mice. Finally, we show that CLOCK acts as a negative regulator of TH transcription, revealing a novel molecular mechanism underlying cyclic changes in mood-related behavior. Taken together, these studies have identified a mechanistic connection between circadian gene disruption and the precipitation of manic episodes in bipolar disorder.

Reproducibility and responsiveness of a Danish Pedi-IKDC subjective knee form for children with knee disorders.

The modified International Knee Documentation Committee Subjective Knee Form (Pedi-IKDC) is a widely used patient-reported tool ranging on a scale from 0 to 100. We aimed to translate Pedi-IKDC into Danish and assess its reproducibility and responsiveness in children with knee disorders. The translation complied with the international guidelines. Reproducibility was assessed in 53 children (15 years) responding Pedi-IKDC at baseline and after 3-14 days. For analysis of responsiveness, 94 children (15 years) responded Pedi-IKDC again after 3 months. Test-retest reliability was excellent. Intraclass correlation coefficient was 0.9, standard error of measurement was 4.1 points, and smallest detectable change (SDC) was 11.3 points. Evaluating responsiveness as a large effect was found in children reporting improvement compared with children reporting deterioration. The change score was correlated to the external anchor Global Rating Scale consisting of 15 answers from -7 "A very great deal worse" to +7 "A very great deal better," with a Spearmen's rho of 0.45 (P > 0.001). The minimal clinically important changes was 12.0. In conclusion, excellent test-retest reproducibility was found at group level, but at individual level the SDC was high. The Pedi-IKDC showed adequate responsiveness and is suitable for assessing improvement or deterioration in children with knee disorders.

Effect of a local anesthetic lozenge in relief of symptoms in burning mouth syndrome.

OBJECTIVE: Patients with burning mouth syndrome (BMS) often represent a clinical challenge as available agents for symptomatic treatment are few and often ineffective. The aim was to evaluate the effect of a bupivacaine lozenge on oral mucosal pain, xerostomia, and taste alterations in patients with BMS. METHODS: Eighteen patients (4 men and 14 women) aged 39-71 years with BMS were included in this randomized, double-blinded, placebo-controlled, crossover trial. Lozenges (containing bupivacaine or placebo) were administrated three times a day for 2 weeks for two separate treatment periods. Assessment of oral mucosal pain, xerostomia, and taste alterations was performed in a patient diary on a visual analog scale (ranging from 0 to 100 mm) before and after the lozenge was dissolved. RESULTS: The bupivacaine lozenge significantly reduced the burning oral pain (P < 0.001), increased the sense of taste disturbances (P < 0.001), and had no impact on xerostomia, when adjusted for the treatment period. CONCLUSIONS: Our results indicate that the bupivacaine lozenge offers a novel therapeutic modality to patients with BMS, although without alleviating effect on the associated symptoms, taste alterations, and xerostomia.

Conducted vasoreactivity: the dynamical point of view.

Conducted vasodilation is part of the physiological response to increasing metabolic demand of the tissue. Similar responses can be elicited by focal electrical or chemical stimulation. Some evidence suggests an endothelial pathway for nondecremental transmission of hyperpolarizing pulses. However, the underlying mechanisms are debated. Here, we focus on dynamical aspects of the problem hypothesizing the existence of a bistability-powered mechanism for regenerative pulse transmission along the endothelium. Bistability implies that the cell can have two different stable resting potentials and can switch between those states following an appropriate stimulus. Bistability is possible if the current-voltage curve is N shaped instead of monotonically increasing. Specifically, the presence of an inwardly rectifying potassium current may provide the endothelial cell with such properties. We provide a theoretical analysis as well as numerical simulations of both single- and multiunit bistable systems mimicking endothelial cells to investigate the self-consistence and stability of the proposed mechanism. We find that the individual cell may switch readily between two stable potentials. An array of coupled cells, however, as found in the vascular wall, requires a certain adaptation of the membrane currents after a switch, in order to switch back. Although the formulation is generic, we suggest a combination of specific membrane currents that could underlie the phenomenon.

Otolith shape: a population marker for Atlantic herring Clupea harengus.

Otolith shape variation of seven Atlantic herring Clupea harengus populations from Canada, the Faroe Islands, Iceland, Ireland, Norway and Scotland, U.K., covering a large area of the species' distribution, was studied in order to see if otolith shape can be used to discriminate between populations. The otolith shape was obtained using quantitative shape analysis, transformed with Wavelet and analysed with multivariate methods. Significant differences were detected among the seven populations, which could be traced to three morphological structures in the otoliths. The differentiation in otolith shape between populations was not only correlated with their spawning time, indicating a strong environmental effect, but could also be due to differing life-history strategies. A model based on the shape differences discriminates with 94% accuracy between Icelandic summer spawners and Norwegian spring spawners, which are known to mix at feeding grounds. This study shows that otolith shape could become an accurate marker for C. harengus population discrimination.

Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice.

Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.

Exact exponents for the spin quantum Hall transition in the presence of multiple edge channels.

Critical properties of quantum Hall systems are affected by the presence of extra edge channels-those that are present, in particular, at higher plateau transitions. We study this phenomenon for the case of the spin quantum Hall transition. Using supersymmetry, we map the corresponding network model to a classical loop model, whose boundary critical behavior was recently determined exactly. We verify predictions of the exact solution by extensive numerical simulations.

Eccentric hip abductor weakness in patients with symptomatic external snapping hip.

Symptomatic external snapping hip can be a long-standing condition affecting physical function in younger people between 15-40 years. Gluteal weakness has been suggested to be associated with the condition. The aim of this study was to investigate whether eccentric hip abduction strength is decreased in patients with external snapping hip compared with healthy matched controls, and to examine isometric hip abduction, adduction, extension, flexion, internal rotation, and external rotation in patients with external snapping hip and matched controls. Thirteen patients with external snapping hip were compared with 13 healthy matched controls in a cross-sectional study design. The mean age of the patients was 25.5 ± 3.4 years and the mean age of the controls was 25.6 ± 2.6 years. Eccentric and isometric strength were assessed with a handheld dynamometer, using reliable test procedures. Eccentric hip abduction strength was 16% lower in patients with external snapping hip compared with healthy matched controls (1.50 ± 0.47 Nm/kg versus 1.82 ± 0.48 Nm/kg, P = 0.01). No other strength differences were measured between patients and controls (P > 0.05). Eccentric hip abductor weakness was present in patients with symptomatic external snapping hip compared with healthy matched controls.

Investigating the effect of graphene oxide in chitosan/alginate-based foams on the release and antifungal activity of clotrimazole in vitro.

Polyelectrolyte complexes (PECs) have been used as the matrix of solid foams for drug delivery. This study aimed at investigating the effect of graphene oxide (GO) and the composition of excipients in chitosan/alginate-based buccal foams on the clotrimazole release and antifungal activities. The investigation has been focused on the interactions of the drug with excipients in the foams, and the changes of ionization degree upon exposure to various media are discussed. The solid foams were prepared by mixing the excipients and clotrimazole via probe sonication, followed by a freeze-drying method. The pH values of the formulations were measured during the foam preparation process to estimate the ionization degree of clotrimazole and the other excipients. The foam matrix was the PECs between the cationic chitosan and anionic alginate. The mechanical strength of clotrimazole-loaded foams was lower than that of drug-free foams due to the positively charged clotrimazole interacting with the anionic alginate and interfering the PECs between chitosan and alginate. Addition of GO in the clotrimazole-loaded matrix made the foams mechanically stronger and contributed to a faster release of clotrimazole from the buccal foams by disrupting the electrostatic interactions between alginate and clotrimazole. However, addition of 1 wt% GO in the formulations didn't affect the antifungal activity of clotrimazole-loaded foams significantly. A lower amount GO in the formulation may be required for enhancing the antifungal effect, which should be further investigated in future.

Structural correlates of antibodies associated with acute reversal of amyloid beta-related behavioral deficits in a mouse model of Alzheimer disease.

Immunotherapy targeting of amyloid beta (Abeta) peptide in transgenic mouse models of Alzheimer disease (AD) has been widely demonstrated to resolve amyloid deposition as well as associated neuronal, glial, and inflammatory pathologies. These successes have provided the basis for ongoing clinical trials of immunotherapy for treatment of AD in humans. Acute as well as chronic Abeta-targeted immunotherapy has also been demonstrated to reverse Abeta-related behavioral deficits assessing memory in AD transgenic mouse models. We observe that three antibodies targeting the same linear epitope of Abeta, Abeta(3-7), differ in their ability to reverse contextual fear deficits in Tg2576 mice in an acute testing paradigm. Reversal of contextual fear deficit by the antibodies does not correlate with in vitro recognition of Abeta in a consistent or correlative manner. To better define differences in antigen recognition at the atomic level, we determined crystal structures of Fab fragments in complex with Abeta. The conformation of the Abeta peptide recognized by all three antibodies was highly related and is also remarkably similar to that observed in independently reported Abeta:antibody crystal structures. Sequence and structural differences between the antibodies, particularly in CDR3 of the heavy chain variable region, are proposed to account for differing in vivo properties of the antibodies under study. These findings provide a structural basis for immunotherapeutic strategies targeting Abeta species postulated to underlie cognitive deficits in AD.

Intravenous bisphosphonate therapy and atrial fibrillation/flutter risk in cancer patients: a nationwide cohort study.

BACKGROUND: There is conflicting evidence regarding bisphosphonates and atrial fibrillation (AF) risk in osteoporosis patients. However, bisphosphonates are used in much higher doses in treatment of bone metastasis and hypercalcemia, but little is known about the AF risk in cancer patients. METHODS: We conducted a nationwide population-based cohort study using Danish databases. All cancer patients exposed to intravenous bisphosphonates during 2000-2008 were matched with two non-exposed cancer patients by cancer type, distant metastasis presence at diagnosis, age, and gender. We used Cox proportional hazard regression to estimate hazards ratios (HRs) of AF/flutter adjusting for important confounding factors. RESULTS: Of the 3981 cancer patients exposed to intravenous bisphosponates, 128 (3.2%) developed AF/flutter. This condition occurred in 192 (2.4%) of the 7906 non-exposed cancer patients, corresponding to an adjusted HR of 1.7 (95% CI: 1.2-2.4). CONCLUSION: Intravenous bisphosphonates may increase AF/flutter risk in cancer patients.

Improvement of diabetes care in a small but geographically widely spread population in Greenland. Effects of a national diabetes care programme.

AIMS: To estimate the prevalence of diagnosed Type 2 diabetes mellitus in Greenland and to evaluate the quality of the diabetes care before and after implementation of a new diabetes programme. METHODS: In this observational and cross-sectional study, data from the medical records were collected in Greenland in 2008 and 2010. Information about age, gender, most recently measured HbA(1c) , blood pressure and serum cholesterol and from the examination of eyes, feet and urine was obtained. The prevalence was estimated using the whole adult population in Greenland as background population. The quality of the diabetes care was monitored by six process, three biological and three treatment indicators. A diabetes concept based on national guidelines, systematized recording in an electronic medical record and feedback to the clinics were used to improve diabetes care. RESULTS: Four hundred and sixty-five patients were included in the 2008 sample and 691 in the 2010 sample. The total prevalence increased from 2.3 (95% CI 2.1-2.5) % in 2008 to 2.7 (95%CI 2.5-3.0) among Greenlanders aged 40 years old or above, corresponding to an increase of 19% (P = 0.006). All process indicators improved significantly between the two observations. CONCLUSIONS: Along with an increasing prevalence of diagnosed Type 2 diabetes, all six process quality indicators increased. It is strongly recommended that focus on the quality of diabetes care in Greenland should be maintained in order to benefit from the programme in the longer term.

Functional modeling of the shift in cellular calcium dynamics at the onset of synchronization in smooth muscle cells.

In the present paper we address the nature of synchronization properties found in populations of mesenteric artery smooth muscle cells. We present a minimal model of the onset of synchronization in the individual smooth muscle cell that is manifested as a transition from calcium waves to whole-cell calcium oscillations. We discuss how different types of ion currents may influence both amplitude and frequency in the regime of whole-cell oscillations. The model may also explain the occurrence of mixed-mode oscillations and chaotic oscillations frequently observed in the experimental system.

Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade.

The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between Abeta production and clearance. Enzymes responsible for the degradation of Abeta are not well understood, and, thus far, it has not been possible to enhance Abeta catabolism by pharmacological manipulation. We provide evidence that Abeta catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain Abeta levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades Abeta oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain Abeta. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain Abeta levels, restore long-term potentiation deficits in hippocampal slices from transgenic Abeta-producing mice, and reverse cognitive deficits in these mice.

Contaminating DNA in human saliva alters the detection of variants from whole genome sequencing.

Cells obtained from human saliva are commonly used as an alternative DNA source when blood is difficult or less convenient to collect. Although DNA extracted from saliva is considered to be of comparable quality to that derived from blood, recent studies have shown that non-human contaminating DNA derived from saliva can confound whole genome sequencing results. The most concerning complication is that non-human reads align to the human reference genome using standard methodology, which can critically affect the resulting variant genotypes identified in a genome. We identified clusters of anomalous variants in saliva DNA derived reads which aligned in an atypical manner. These reads had only short regions of identity to the human reference sequence, flanked by soft clipped sequence. Sequence comparisons of atypically aligning reads from eight human saliva-derived samples to RefSeq genomes revealed the majority to be of bacterial origin (63.46%). To partition the non-human reads during the alignment step, a decoy of the most prevalent bacterial genome sequences was designed and utilised. This reduced the number of atypically aligning reads when trialled on the eight saliva-derived samples by 44% and most importantly prevented the associated anomalous genotype calls. Saliva derived DNA is often contaminated by DNA from other species. This can lead to non-human reads aligning to the human reference genome using current alignment best-practices, impacting variant identification. This problem can be diminished by using a bacterial decoy in the alignment process.

Graphene oxide as a functional excipient in buccal films for delivery of clotrimazole: Effect of molecular interactions on drug release and antifungal activity in vitro.

Graphene oxide (GO) is an amphiphilic, high surface area material with great potential as a functional excipient in drug delivery. The present study aimed at incorporating GO in buccal polyelectrolyte films for delivery of antifungal drugs and investigating the effect of GO on the film properties and drug release profiles, as well as antifungal activities. Mucoadhesive excipients chitosan and alginate were selected to form polyelectrolyte films with the antifungal drug clotrimazole. The buccal formulations were prepared by mixing the excipients and clotrimazole via probe sonication, followed by film casting and drying. Inclusion of GO in the formulations increased clotrimazole release from the films in vitro (pH 6.8), possibly due to GO altering the electrostatic interactions between chitosan and alginate. An increase of in vitro activity against Candida albicans was observed when 0.04 wt% GO was added in the formulation containing clotrimazole. However, when the GO amount increased to 0.09 wt%, the films had similar antifungal ability to the films with 0.04 wt% GO, suggesting that the electrostatic and hydrophobic interactions between GO and clotrimazole also affects the antifungal effect of clotrimazole. In summary, GO has a great potential as a functional excipient for delivery of antifungal drugs.

Penetrating Traumatic Brain Injury Triggers Dysregulation of Cathepsin B Protein Levels Independent of Cysteine Protease Activity in Brain and Cerebral Spinal Fluid.

Cathepsin B (CatB), a lysosomal cysteine protease, is important to brain function and may have dual utility as a peripheral biomarker of moderate-severe traumatic brain injury (TBI). The present study determined levels of pro- and mature (mat) CatB protein as well as cysteine protease activity within the frontal cortex (FC; proximal injury site), hippocampus (HC; distal injury site), and cerebral spinal fluid (CSF) collected 1-7 days after craniotomy and penetrating ballistic-like brain injury (PBBI) in rats. Values were compared with naïve controls. Further, the utility of CatB protein as a translational biomarker was determined in CSF derived from patients with severe TBI. Craniotomy increased matCatB levels in the FC and HC, and led to elevation of HC activity at day 7. PBBI caused an even greater elevation in matCatB within the FC and HC within 3-7 days. After PBBI, cysteine protease activity peaked at 3 days in the FC and was elevated at 1 day and 7 days, but not 3 days, in the HC. In rat CSF, proCatB, matCatB, and cysteine protease activity peaked at 3 days after craniotomy and PBBI. Addition of CA-074, a CatB-specific inhibitor, confirmed that protease activity was due to active matCatB in rat brain tissues and CSF at all time-points. In patients, CatB protein was detectable from 6 h through 10 days after TBI. Notably, CatB levels were significantly higher in CSF collected within 3 days after TBI compared with non-TBI controls. Collectively, this work indicates that CatB and its cysteine protease activity may serve as collective molecular signatures of TBI progression that differentially vary within both proximal and distal brain regions. CatB and its protease activity may have utility as a surrogate, translational biomarker of acute-subacute TBI.

Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.

Inheritance of the apoE4 allele (epsilon4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of epsilon4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of epsilon2/2, epsilon3/3, and epsilon4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; epsilon2/2 >epsilon3/3 >epsilon4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the epsilon3/4 mouse brains. ApoE4 represented 30-40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between epsilon3/3 and epsilon3/4 mice, implying that the reduced levels of total apoE in epsilon3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from epsilon3/4 human astrocytoma or epsilon3/3, epsilon4/4 and epsilon3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from epsilon4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by epsilon4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or Abeta clearance.