Navigating the multifaceted intricacies of the Na+-Cl- cotransporter, a highly regulated key effector in the control of hydromineral homeostasis.

The Na+-Cl- cotransporter (NCC; SLC12A3) is a highly regulated integral membrane protein that is known to exist as three splice variants in primates. Its primary role in the kidney is to mediate the cosymport of Na+ and Cl- across the apical membrane of the distal convoluted tubule. Through this role and the involvement of other ion transport systems, NCC allows the systemic circulation to reclaim a fraction of the ultrafiltered Na+, K+, Cl-, and Mg+ loads in exchange for Ca2+ and [Formula: see text]. The physiological relevance of the Na+-Cl- cotransport mechanism in humans is illustrated by several abnormalities that result from NCC inactivation through the administration of thiazides or in the setting of hereditary disorders. The purpose of the present review is to discuss the molecular mechanisms and overall roles of Na+-Cl- cotransport as the main topics of interest. On reading the narrative proposed, one will realize that the knowledge gained in regard to these themes will continue to progress unrelentingly no matter how refined it has now become.

Persisting chemosensory dysfunction in COVID-19 - a cross-sectional population-based survey.

BACKGROUND: Chemosensory dysfunction (CD) has been reported as a common symptom of SARS-CoV-2 infection, but it is not well understood whether and for how long changes of smell, taste and chemesthesis persist in infected individuals. METHODOLOGY: Unselected adult residents of the German federal state of Schleswig-Holstein with Polymerase Chain Reaction (PCR)-test-confirmed SARS-CoV-2 infection were invited to participate in this large cross-sectional study. Data on the medical history and subjective chemosensory function of participants were obtained through questionnaires and visual analogue scales (VAS). Olfactory function (OF) was objectified with the Sniffin Sticks test (SST), including threshold (T), discrimination (D) and identification (I) test as well as summarized TDI score, and compared to that in healthy controls. Gustatory function (GF) was evaluated with the suprathreshold taste strips (TS) test, and trigeminal function was tested with an ampoule containing ammonia. RESULTS: Between November 2020 and June 2021, 667 infected individuals (mean age: 48.2 years) were examined 9.1 months, on average, after positive PCR testing. Of these, 45.6% had persisting subjective olfactory dysfunction (OD), 36.2% had subjective gustatory dysfunction (GD). Tested OD, tested GD and impaired trigeminal function were observed in 34.6%, 7.3% and 1.8% of participants, respectively. The mean TDI score of participants was significantly lower compared to healthy subjects. Significant associations were observed between subjective OD and GD, and between tested OD and GD. CONCLUSION: Nine months after SARS-CoV-2 infection, OD prevalence is significantly increased among infected members of the general population. Therefore, OD should be included in the list of symptoms collectively defining Long-COVID.

Pulsatility Index in the Basal Ganglia Arteries Increases with Age in Elderly with and without Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Cerebral small vessel disease contributes to stroke and cognitive impairment and interacts with Alzheimer disease pathology. Because of the small dimensions of the affected vessels, in vivo characterization of blood flow properties is challenging but important to unravel the underlying mechanisms of the disease. MATERIALS AND METHODS: A 2D phase-contrast sequence at 7T MR imaging was used to assess blood flow velocity and the pulsatility index of the perforating basal ganglia arteries. We included patients with cerebral amyloid angiopathy (n = 8; identified through the modified Boston criteria), hypertensive arteriopathy (n = 12; identified through the presence of strictly deep or mixed cerebral microbleeds), and age- and sex-matched controls (n = 28; no cerebral microbleeds). RESULTS: Older age was related to a greater pulsatility index, irrespective of cerebral small vessel disease. In hypertensive arteriopathy, there was an association between lower blood flow velocity of the basal ganglia and the presence of peri-basal ganglia WM hyperintensities. CONCLUSIONS: Our results suggest that age might be the driving factor for altered cerebral small vessel hemodynamics. Furthermore, this study puts cerebral small vessel disease downstream pathologies in the basal ganglia region in relation to blood flow characteristics of the basal ganglia microvasculature.

Recovery time of a plasma-wakefield accelerator.

The interaction of intense particle bunches with plasma can give rise to plasma wakes1,2 capable of sustaining gigavolt-per-metre electric fields3,4, which are orders of magnitude higher than provided by state-of-the-art radio-frequency technology5. Plasma wakefields can, therefore, strongly accelerate charged particles and offer the opportunity to reach higher particle energies with smaller and hence more widely available accelerator facilities. However, the luminosity and brilliance demands of high-energy physics and photon science require particle bunches to be accelerated at repetition rates of thousands or even millions per second, which are orders of magnitude higher than demonstrated with plasma-wakefield technology6,7. Here we investigate the upper limit on repetition rates of beam-driven plasma accelerators by measuring the time it takes for the plasma to recover to its initial state after perturbation by a wakefield. The many-nanosecond-level recovery time measured establishes the in-principle attainability of megahertz rates of acceleration in plasmas. The experimental signatures of the perturbation are well described by simulations of a temporally evolving parabolic ion channel, transferring energy from the collapsing wake to the surrounding media. This result establishes that plasma-wakefield modules could be developed as feasible high-repetition-rate energy boosters at current and future particle-physics and photon-science facilities.

Long-term health sequelae and quality of life at least 6 months after infection with SARS-CoV-2: design and rationale of the COVIDOM-study as part of the NAPKON population-based cohort platform (POP).

PURPOSE: Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany. METHODS: The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, Würzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained. RESULTS: As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36% wished to participate and 1295 have already been examined at least once. CONCLUSION: NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity. TRIAL REGISTRATION: Registered at the German registry for clinical studies (DRKS00023742).

Subclinical Pulmonary Involvement in Active IBD Responds to Biologic Therapy.

OBJECTIVE: Increased mortality from respiratory diseases was observed in epidemiological studies of patients with ulcerative colitis [UC] as a potentially underestimated extraintestinal manifestation. We therefore investigated the presence of pulmonary manifestations of inflammatory bowel disease [IBD] and the potential effect of tumour necrosis factor alpha [TNF-α] inhibitors on pulmonary function tests [PFT] in a prospective, longitudinal study. METHODS: In all, 92 consecutive patients with IBD (49 Crohn´s disease [CD], 43 UC) and 20 healthy controls were recruited. Fifty patients with IBD were in remission, and 42 had active disease with 22 of these being examined before and 6 weeks after initiating anti-TNF therapy. Pulmonary function tests [PFT] were evaluated using the Medical Research Council [MRC] dyspnoea index and a standardized body plethysmography. IBD activity was assessed using Harvey-Bradshaw index for CD and partial Mayo score for UC. Data are presented as mean ± standard error of the mean [SEM]. RESULTS: Patients with active IBD showed significant reduction of PFT. Forced expiration [Tiffeneau index] values [FEV1%] were significantly reduced in IBD patients with active disease [78.8 ± 1.1] compared with remission [86.1 ± 0.9; p = 0.0002] and with controls [87.3 ± 1.3; p = 0.001]. Treatment with anti-TNF induced a significant relief in obstruction [p = 0.003 for FEV1% in comparison with baseline levels]. The level of pulmonary obstruction significantly correlated with clinical inflammation scores [HBI or Mayo]. CONCLUSIONS: PATIENTS: with active IBD present with significant obstructive abnormalities in their PFTs. Obstruction is related to inflammatory activity, with anti-TNF improving PFTs. Pulmonary obstruction and possibly chronic bronchopulmonary inflammation is an overlooked problem in active IBD that is probably obscured by intestinal symptoms.

Experimental demonstration of novel beam characterization using a polarizable X-band transverse deflection structure.

The PolariX TDS (Polarizable X-Band Transverse Deflection Structure) is an innovative TDS-design operating in the X-band frequency-range. The design gives full control of the streaking plane, which can be tuned in order to characterize the projections of the beam distribution onto arbitrary transverse axes. This novel feature opens up new opportunities for detailed characterization of the electron beam. In this paper we present first measurements of the Polarix TDS at the FLASHForward beamline at DESY, including three-dimensional reconstruction of the charge-density distribution of the bunch and slice emittance measurements in both transverse directions. The experimental results open the path toward novel and more extensive beam characterization in the direction of multi-dimensional-beam-phase-space reconstruction.

Optic nerve sheath diameter sonography during the acute stage of intracerebral hemorrhage: a potential role in monitoring neurocritical patients.

BACKGROUND: Optic nerve sheath diameter (ONSD) sonography has been proposed as a reliable bedside tool for the detection of increased intracranial pressure (ICP). ONSD reacts almost simultaneously to oscillations in ICP. The aim of this study was to investigate the ONSD dynamics in the acute stage of intracerebral hemorrhage (ICH) and to compare ONSD dynamics to the clinical outcome. METHODS: We enrolled 35 acute ICH patients and 20 healthy volunteers in this prospective study. At the admission, all patients underwent brain CT scan and ONSD sonography. We repeated the ONSD on the second and the third day in all patients while CT scan was repeated if a patient condition deteriorated. The changes in serial ONSD measurements were termed as stable or unstable ONSD trend. ONSD trend was considered as unstable if variations of average ONSD were above 5%. The outcome of the patient was assessed with the Modified Rankin Scale (mRS) and Glasgow Outcome Scale (GOS). RESULTS: In healthy volunteers serial ONSD recordings for 3 days revealed a stable trend in 100%. However, in the study group, 23 patients had unstable and 12 had stable ONSD trend during the acute stage of ICH. The patients with unstable ONSD trend were more likely to have worse outcomes (p value 0.003). CONCLUSION: In patients with ICH, the acute-phase ONSD dynamics can help in predicting the clinical outcome.

Anticoagulation treatment of cancer patients with deep or superficial leg vein thrombosis - a retrospective observational study of German statutory health insurance claims data (the CERTIFICAT initiative).

Background: Thrombosis is a common complication of cancer with a negative impact on quality of life and overall prognosis. Guidelines recommend low-molecular-weight heparin (LMWH) as initial and prolonged anticoagulation treatment. Little is known about current treatment patterns of these patients in ambulatory care. Patients and methods: The current retrospective observational study interrogates a large German statutory health insurance claims database in order to understand which kind of data can be extracted and analysed. An age- and sex-adjusted sample of about 4.1 million insured people from 2011 to 2016 could be used. Cancer patients with incident deep and superficial leg vein thrombosis were identified. Patients with preexisting cancer were allocated to a normal risk group; those who suffered from simultaneously diagnosed cancer and thrombosis were classified as high-risk group. Results: We identified 322,600 patients with inpatient or outpatient documented cancer diagnosis in at least two different quarters within one year. 87,755 patients were identified with an incident deep or superficial vein thrombosis. 8,201 patients suffered from both cancer and incident thrombosis. 56.9% of the patients received an anticoagulation regimen with predominant LMWH prescription, 24.2% vitamin K antagonists, 17.2% direct oral anticoagulants; in 1.7% of patients, no predominant anticoagulant drug/regime could be identified. On average, patients were prescribed anticoagulants for 4.5 months. An estimate of clinically relevant gastrointestinal bleeding could be derived (1.8% of patients). Conclusions: The dataset allows assigning detailed information of anticoagulant prescriptions in ambulatory care to well-defined groups of cancer patients. A first analysis suggests that in Germany current medical care of patients with cancer-related deep or superficial vein thrombosis does not entirely comply with guideline recommendations regarding type and duration of anticoagulation.

Invited Review: The spectrum of age-related small vessel diseases: potential overlap and interactions of amyloid and nonamyloid vasculopathies.

Deep perforator arteriopathy (DPA) and cerebral amyloid angiopathy (CAA) are the commonest known cerebral small vessel diseases (CSVD), which cause ischaemic stroke, intracebral haemorrhage (ICH) and vascular cognitive impairment (VCI). While thus far mainly considered as separate entities, we here propose that DPA and CAA share similarities, overlap and interact, so that 'pure' DPA or CAA are extremes along a continuum of age-related small vessel pathologies. We suggest blood-brain barrier (BBB) breakdown, endothelial damage and impaired perivascular ß-amyloid (Aß) drainage are hallmark common mechanisms connecting DPA and CAA. We also suggest a need for new biomarkers (e.g. high-resolution imaging) to deepen understanding of the complex relationships between DPA and CAA.

Trazodone and mirtazapine: A possible opioid involvement in their use (at low dose) for sleep?

The efficacy of each antidepressant available has been found equal to that of amitriptyline in double-blind studies. However, a few of them are being prescribed (at under-therapeutic doses) for sleep, in non-depressed persons, when there are relative contraindications for sedative-hypnotics. Following previous studies regarding the antinociceptive mechanisms of various antidepressants, we suggest that the involvement of the opioid system in some of the antidepressants' mechanism of action may contribute to these medications' use for the induction and maintenance of sleep. The mostly prescribed antidepressants for sleep are trazodone (a weak, but specific inhibitor of the synaptosomal uptake of serotonin, that also binds to alpha-1 and alpha-2 adrenoreceptor sites) and mirtazapine (a postsynaptic drug which enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission via antagonism of central alpha-2-auto- and hetero-adrenoreceptors). In our previous studies when ICR mice were tested with a hotplate analgesia meter, both trazodone and mirtazapine induced, a naloxone-reversible antinociceptive effect following i.p administration. Summing up the various interactions of trazodone and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of trazodone is influenced by the opioid receptor subtypes mu and delta (and a clear 5-HT mechanism of antinociception), while the antinociceptive effect of mirtazapine is mainly influenced by kappa and mu opioid receptor subtype (combined with both serotonergic and noradrenergic receptors). This opioid profile of the two drugs may be one of the explanations to their efficacy in the treatment of insomnia, when sedatives (either benzodiazepines or the non-benzodiazepine "Z-compounds") cannot be prescribed.

Social information drives ecological outcomes among competing species.

Through its behavior, an organism intentionally or unintentionally produces information. Use of this "social information" by surrounding conspecifics or heterospecifics is a ubiquitous phenomenon that can drive strong correlations in fitness-associated behaviors, such as predator avoidance, enhancing survival within and among competing species. By eliciting indirect positive interactions between competing individuals or species, social information might alter overall competitive outcomes. To test this potential, we present new theory that quantifies the effect of social information, modeled as predator avoidance signals/cues, on the outcomes from intraspecific and interspecific competition. Our analytical and numerical results reveal that social information can rescue populations from extinction and can shift the long-term outcome of competitive interactions from mutual exclusion to coexistence, or vice versa, depending on the relative strengths of intraspecific and interspecific social information and competition. Our findings highlight the importance of social information in determining ecological outcomes.

Dyspnea in amyotrophic lateral sclerosis: The Dyspnea-ALS-Scale (DALS-15) essentially contributes to the diagnosis of respiratory impairment.

BACKGROUND: Dyspnea is a cardinal but often underestimated symptom in amyotrophic lateral sclerosis (ALS). The newly developed Dyspnea-ALS-Scale (DALS-15) is highly relevant for therapeutic decisions because dyspnea is a separate criterion to consider noninvasive ventilation (NIV) in ALS. In comparison to the limited effects of neuroprotective compounds, NIV has the greatest impact on survival and improves quality of life. OBJECTIVE: To investigate whether dyspnea corresponds to parameters of respiratory status mainly used in clinical neurological practice. We also investigated if the DALS-15 could help identify patients for consideration of NIV in whom neither spirometry nor blood gas parameters indicate the need for NIV (forced vital capacity (FVC) < 50% or probable <75%, pCO2 ≥45  mmHg). METHODS: Seventy ALS patients with dyspnea according to the DALS-15 obtained blood gas analysis and spirometry (FVC in sitting and supine positions). The supine decline in FVC was calculated. RESULTS: There was no linear relationship between dyspnea and spirometry as well as blood gases. 83% of our patients had an upright FVC still greater than 50% and no daytime hypercapnia. CONCLUSIONS: Our study clearly shows that dyspnea can occur independently of objective indicators of respiratory impairment like spirometry or blood gases. Hence, the DALS-15 covers another aspect of respiratory impairment than these tests and refers to the subjective component of respiratory impairment. It detects dyspnea in a considerable proportion of patients in whom NIV should thus be considered although their spirometric and blood gas results do not point towards NIV. The DALS-15 therefore may help to improve the stratification of patients with respiratory impairment for more efficient symptom management and timely coordination of care.

Cannabis use during pregnancy: Are we at the verge of defining a "fetal cannabis spectrum disorder"?

Cannabis is probably the drug most commonly used globally since ancient times. Following the trend of legalization of access to cannabis in several Western countries, its use has increased in North America over the past few years. In spite of warnings of the potential hazards associated with in-utero exposure to cannabis, approximately 10% of pregnant women in an American study reported using cannabis in recent years, and most of them on a daily basis. Significant effects of prenatal cannabis exposure have been found on children's sleep, cognitive functions (memory and scholastic skills), as well as on executive (frontal lobe) functions (reasoning, attention, impulsivity, and motivation), and affective (depression) and anxiety symptoms throughout the stages of development. Following the presentation of two case vignettes, we integrate the published information on outcomes of maternal use of cannabis during pregnancy on the developing fetus and the "soft" neurological deficits and neuro-behavioral disturbances manifested by them from early childhood and evolving to peaks in adolescence. Taken together, these data serve to define what we call a heretofore unspecified "fetal cannabis spectrum disorder".

Safety of apnea testing for the diagnosis of brain death: a comprehensive study on neuromonitoring data and blood gas analysis.

BACKGROUND AND PURPOSE: Here, we studied the safety of apnea testing (AT) for the determination of brain death with regard to intracranial pressure (ICP), cerebral perfusion and arterial blood gas parameters. We hypothesized that ICP only increases when cerebral perfusion pressure (CPP) remains positive during AT. METHODS: A total of 34 patients who fulfilled brain death criteria were identified by chart review (2009-2017). We analysed ICP, CPP and mean arterial pressure (MAP) prior to AT, during AT and after AT, as well as arterial pH, paCO2 , paO2 and arterial O2 saturation at the start and end of AT. RESULTS: Intracranial pressure was 87.9 ± 17.7 mmHg (mean ± SD) prior to AT, 89.9 ± 17.2 mmHg during AT and 86.4 ± 15.2 mmHg after AT (P = 0.9). CPP was -6.9 ± 12.8 mmHg prior to AT, -7.1 ± 13.7 mmHg during AT and -8.6 ± 13.0 mmHg after AT (P = 0.98), respectively. MAP was 82.9 ± 14.6 mmHg prior to AT, 84.7 ± 13.9 mmHg during AT and 79.7 ± 9.6 mmHg after AT (P = 0.57), respectively. A total of 10 patients had positive CPP (8.6 ± 4.3 mmHg), but ICP did not increase during AT. Arterial pH decreased from 7.43 ± 0.06 to 7.22 ± 0.06 (P < 0.05), paCO2 increased from 38.6 ± 4.2 to 69.6 ± 8.0 mmHg (P < 0.05), paO2 decreased from 416.3 ± 113.4 to 289.2 ± 146.5 mmHg (P < 0.05), and O2 saturation was stable at 99.8 ± 0.4% and 98.2 ± 3.2% (P = 0.39). CONCLUSIONS: Apnea testing had no detrimental effect on ICP, CPP, MAP or oxygenation, regardless of the presence of an initially positive CPP. The lack of further ICP elevations is presumably explained by critical closing pressures above individual CPP levels during AT.

Surface and aggregation properties of a plant-oil derived biosurfactant.

The plant-oil derived biosurfactant HeBra® shows a high surface activity combined with a versatile aggregation behavior. The hydrophilic protein head groups provide an excellent water solubility that still enables micelle formation due to the hydrophobic interactions of the fatty acid chains. The observed low CMC of 1 g L-1 allows an efficient utilization in different application fields already at very low concentrations. The mixture of low and high molecular weight components provides highly dynamic behavior during foam formation or dispersion processes combined with the formation of large and stable structures in solutions and at surfaces.