Role of aquaporin-4 polarization in extracellular solute clearance.

Waste from the brain has been shown to be cleared via the perivascular spaces through the so-called glymphatic system. According to this model the cerebrospinal fluid (CSF) enters the brain in perivascular spaces of arteries, crosses the astrocyte endfoot layer, flows through the parenchyma collecting waste that is subsequently drained along veins. Glymphatic clearance is dependent on astrocytic aquaporin-4 (AQP4) water channels that are highly enriched in the endfeet. Even though the polarized expression of AQP4 in endfeet is thought to be of crucial importance for glymphatic CSF influx, its role in extracellular solute clearance has only been evaluated using non-quantitative fluorescence measurements. Here we have quantitatively evaluated clearance of intrastriatally infused small and large radioactively labeled solutes in mice lacking AQP4 (Aqp4-/-) or lacking the endfoot pool of AQP4 (Snta1-/-). We confirm that Aqp4-/- mice show reduced clearance of both small and large extracellular solutes. Moreover, we find that the Snta1-/- mice have reduced clearance only for the 500 kDa [3H]dextran, but not 0.18 kDa [3H]mannitol suggesting that polarization of AQP4 to the endfeet is primarily important for clearance of large, but not small molecules. Lastly, we observed that clearance of 500 kDa [3H]dextran increased with age in adult mice. Based on our quantitative measurements, we confirm that presence of AQP4 is important for clearance of extracellular solutes, while the perivascular AQP4 localization seems to have a greater impact on clearance of large versus small molecules.

MAIN POINTS: Solute clearance is reduced in mice lacking AQP4 Polarization of AQP4 to the endfeet may have a greater impact on clearance of large versus small molecules Clearance of large but not small solutes is correlated with age within adult age.

Effectiveness of a Digital Health Application for the Treatment of Diabetes Type II-A Pilot Study.

(1) Background: This study aimed at providing preliminary evidence for mebix, an app-based treatment program for patients with diabetes mellitus type II. The main target was to show a positive healthcare impact as defined by improved blood glucose control, i.e., reduced HbA1c values. (2) Methods: For this, a 3-month, prospective, open-label trial with an intraindividual control group was conducted. Participants received the mebix intervention for 3 months. HbA1c values were observed every 3 months: retrospectively, at baseline, and 3 months after the start of using the app. Additionally, weight and patients' reported outcomes (well-being, diabetes-related distress, and self-management) were assessed. Data generated within the app were summarized and analyzed (steps, physical activity, fulfilled tasks, and food logs). (3) Results: After the usage of mebix for 3 months, participants significantly reduced their HbA1c levels (-1.0 ± 0.8%). Moreover, improvements in weight, well-being, and self-management as well as a reduction in diabetes-related distress were observed. App-generated data mainly supported the other main finding, that higher baseline HbA1c values lead to higher reductions. Overall, the study provided preliminary evidence that mebix can help patients improve metabolic and psychological health outcomes.

A randomized-controlled trial to evaluate the app-based multimodal weight loss program zanadio for patients with obesity.

OBJECTIVE: This study aimed to evaluate the effectiveness of the app-based, multimodal weight loss program zanadio. METHODS: A randomized-controlled trial was conducted from January 2021 to March 2022. A total of 150 adults with obesity were randomized into an intervention group and used zanadio for 1 year or into a wait list control group. The primary end point, weight change, and the secondary end points, quality of life, well-being, and waist to height ratio, were assessed every 3 months for up to 1 year via telephone interviews and online questionnaires. RESULTS: After 12 months, participants of the intervention group lost, on average, -7.75% (95% CI: -9.66% to -5.84%) of their initial weight, achieving a clinically relevant and statistically stronger weight reduction than the control group (mean = 0.00% [95% CI: -1.98% to 1.99%]). All secondary end points improved significantly in the intervention group, with significantly greater improvements in well-being and waist to height ratio than in the control group. CONCLUSIONS: This study showed that adults with obesity who have used zanadio achieved a significant and clinically relevant weight loss within 12 months and improved further obesity-related health variables compared with a control group. Because of its effectiveness and flexible applicability, the app-based multimodal treatment zanadio might alleviate the present care gap for patients with obesity in Germany.

Introducing zanadio-A Digitalized, Multimodal Program to Treat Obesity.

While the prevalence of overweight and obesity has been increasing annually, the accessibility of on-site treatment programs is not rising correspondingly. Digital, evidence-based obesity treatment programs could potentially alleviate this situation. The application zanadio has been developed to enable patients with obesity (BMI 30-45 kg/m2) to participate in a digital, multimodal weight reduction program based on current treatment guidelines. This article is divided into two parts: (I) it introduces zanadio, its aims and therapeutic concept, and (II) provides a first impression and demographic data on more than 11,000 patients from across the country who have used zanadio within the last 16 months, which demonstrates the demand for a digital obesity treatment. zanadio has the potential to partially close the current gap in obesity care. Future work should focus on identifying predictors of successful weight loss to further individualize digital obesity treatment, and an important next step would be to prevent obesity, i.e., to start the treatment at lower BMI levels, and to invent digital treatment programs for children and adolescents.

Wheeze and cough measurements at night in children with respiratory symptoms.

BACKGROUND: Nocturnal cough and wheeze are important symptoms when diagnosing any respiratory disease in a child, but objective measurements of these symptoms are not performed. METHODS: The aim of our study was to analyze the use of an automated detection system to assess breath sounds objectively in comparison to cough and wheeze questionnaires and to evaluate its feasibility in clinical practice. RESULTS: Forty-nine recordings of thirty-nine children were processed (asthma n = 13; cystic fibrosis n = 2; pneumonia n = 5; suspicion of habit cough n = 7; prolonged, recurrent or chronic cough n = 13), and cough and asthma scores were compared to the objective nocturnal recordings. Time for audio-validation of recordings took between 2 and 40 min (mean: 14.22 min, (SD): 10.72). Accuracy of the automated measurement was higher for cough than for wheezing sounds. Nocturnal cough readings but not wheeze readings correlated with some of the corresponding scores. CONCLUSION: To our knowledge this is the first study using a new device to assess nocturnal cough and obstructive breath sounds objectively in children with a wide variety of respiratory diseases. The assessment proved user friendly. We obtained additional information on nighttime symptoms, which would otherwise have remained obscure. Further studies to assess possible diagnostic and therapeutic benefits of this device are needed.

[Influence of Sociodemographic Factors on Type of and Stage at Diagnosis in Breast Cancer]. / Zum Einfluss soziodemografischer Faktoren auf die Art der Verdachtsdiagnosestellung und das Tumorstadium bei Erstdiagnose von Brustkrebs.

This study examines the influence of sociodemographic factors on the type of and stage at diagnosis in breast cancer in Germany. METHOD: As part of the certification of the breast cancer centers by the German Cancer Society (DGK), the Institute of Medical Sociology, Health Services and Rehabilitation Science (IMVR) conducted nationwide post-stationary postal patient surveys (n=852). The influence of sociodemographic factors on the type of diagnosis and on the stage at diagnosis were each analyzed using a multinomial logistic regression. RESULTS: 45.5% palpated the tumor by themselves, 33.4% were diagnosed by mammography screening and 16.6% by gynecological check-up. Being diagnosed by screening was associated with an early stage cancer. Furthermore, breast cancer patients without private health insurance or with a low educational level were less likely to be diagnosed by a gynecological check-up. Patients within screening age (50-69) had higher odds for an early stage breast cancer. Patients with a low educational level had lower odds for an early stage breast cancer. CONCLUSION: Fifty percent of the breast cancer patients were not diagnosed by screening. Mammography screening appears to be more sensitive in detecting early stage cancer, since we found an association between diagnosis by screening and an early stage cancer. Age outside of the screening range and a low educational level might be risk factors for an advanced stage breast cancer. High screening rates, especially for these risk groups, seem to be important for early detection of breast cancer.

Deciphering the Contributions of CRH Receptors in the Brain and Pituitary to Stress-Induced Inhibition of the Reproductive Axis.

Based on pharmacological studies, corticotropin-releasing hormone (CRH) and its receptors play a leading role in the inhibition of the hypothalamic-pituitary-gonadal (HPG) axis during acute stress. To further study the effects of CRH receptor signaling on the HPG axis, we generated and/or employed male mice lacking CRH receptor type 1 (CRHR1) or type 2 (CRHR2) in gonadotropin-releasing hormone neurons, GABAergic neurons, or in all central neurons and glia. The deletion of CRHRs revealed a preserved decrease of plasma luteinizing hormone (LH) in response to either psychophysical or immunological stress. However, under basal conditions, central infusion of CRH into mice lacking CRHR1 in all central neurons and glia, or application of CRH to pituitary cultures from mice lacking CRHR2, failed to suppress LH release, unlike in controls. Our results, taken together with those of the earlier pharmacological studies, suggest that inhibition of the male HPG axis during acute stress is mediated by other factors along with CRH, and that CRH suppresses the HPG axis at the central and pituitary levels via CRHR1 and CRHR2, respectively.

Electrotonic Coupling in the Pituitary Supports the Hypothalamic-Pituitary-Gonadal Axis in a Sex Specific Manner.

Gap junctions are present in many cell types throughout the animal kingdom and allow fast intercellular electrical and chemical communication between neighboring cells. Connexin-36 (Cx36), the major neuronal gap junction protein, synchronizes cellular activity in the brain, but also in other organs. Here we identify a sex-specific role for Cx36 within the hypothalamic-pituitary-gonadal (HPG) axis at the level of the anterior pituitary gland (AP). We show that Cx36 is expressed in gonadotropes of the AP sustaining their synchronous activity. Cx36 ablation affects the entire downstream HPG axis in females, but not in males. We demonstrate that Cx36-mediated coupling between gonadotropes in the AP supports gonadotropin-releasing hormone-induced secretion of luteinizing hormone. Furthermore, we provide evidence for negative feedback regulation of Cx36 expression in the AP by estradiol. We thus, conclude that hormonally-controlled plasticity of gap junction communication at the level of the AP constitutes an additional mechanism affecting female reproduction.

A New Population of Parvocellular Oxytocin Neurons Controlling Magnocellular Neuron Activity and Inflammatory Pain Processing.

Oxytocin (OT) is a neuropeptide elaborated by the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei. Magnocellular OT neurons of these nuclei innervate numerous forebrain regions and release OT into the blood from the posterior pituitary. The PVN also harbors parvocellular OT cells that project to the brainstem and spinal cord, but their function has not been directly assessed. Here, we identified a subset of approximately 30 parvocellular OT neurons, with collateral projections onto magnocellular OT neurons and neurons of deep layers of the spinal cord. Evoked OT release from these OT neurons suppresses nociception and promotes analgesia in an animal model of inflammatory pain. Our findings identify a new population of OT neurons that modulates nociception in a two tier process: (1) directly by release of OT from axons onto sensory spinal cord neurons and inhibiting their activity and (2) indirectly by stimulating OT release from SON neurons into the periphery.

Hypothalamic miR-103 protects from hyperphagic obesity in mice.

The role of neuronal noncoding RNAs in energy control of the body is not fully understood. The arcuate nucleus (ARC) of the hypothalamus comprises neurons regulating food intake and body weight. Here we show that Dicer-dependent loss of microRNAs in these neurons of adult (DicerCKO) mice causes chronic overactivation of the signaling pathways involving phosphatidylinositol-3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) and an imbalance in the levels of neuropeptides, resulting in severe hyperphagic obesity. Similarly, the activation of PI3K-Akt-mTOR pathway due to Pten deletion in the adult forebrain leads to comparable weight increase. Conversely, the mTORC1 inhibitor rapamycin normalizes obesity in mice with an inactivated Dicer1 or Pten gene. Importantly, the continuous delivery of oligonucleotides mimicking microRNAs, which are predicted to target PI3K-Akt-mTOR pathway components, to the hypothalamus attenuates adiposity in DicerCKO mice. Furthermore, loss of miR-103 causes strong upregulation of the PI3K-Akt-mTOR pathway in vitro and its application into the ARC of the Dicer-deficient mice both reverses upregulation of Pik3cg, the mRNA encoding the catalytic subunit p110γ of the PI3K complex, and attenuates the hyperphagic obesity. Our data demonstrate in vivo the crucial role of neuronal microRNAs in the control of energy homeostasis.