Can non-renal clearance and/or bioavailability of drugs be assessed reliably in renal impairment studies with oral drug administration?

OBJECTIVE: The causes for the variable susceptibility of renal clearance (CLr) and bioavailability (F) of drugs in renal impairment are still unknown. We investigated whether the impact of chronic kidney disease (CKD) on non-renal clearance (CLnr) or F can be appraised when drug administration is by the oral route only in dedicated renal impairment studies (DRIS), as is routinely done when developing drugs intended for oral use. MATERIALS AND METHODS: A literature search on DRIS administering drugs orally only or orally and intravenously was conducted. Seven drugs administered orally only with notable CLnr and 2 drugs administered by the oral and intravenous routes with negligible CLnr were identified. Regressions of oral clearance (CL/F), normalized by absolute bioavailability in healthy subjects (F1), on CLr were performed for the drugs with notable non-renal elimination to determine the impact of CKD on CLnr. Regressions of CL/F and CL on CLr were conducted for the drugs with negligible CLnr to determine F. RESULTS: Excessive variability in CL/F and CLr precluded evaluation of CLnr for 1 drug with notable CLnr and F1 < 0.01. A categorization based on the susceptibility of CLnr to CKD appeared possible for the 6 drugs with notable non-renal elimination if the parameters of the F1 normalized regressions of CL/F on CLr are taken at face value, i.e., if equality of F and F1 is assumed. However, the true relationship between F and F1 in subjects with varying renal function is unknowable for drugs with significant CLnr when administered orally only. F of drugs with significant CLnr may be altered by a reduced activity of uptake-transporters and/or enzymes so that in renal impaired subjects both absorption and first pass metabolism of intact drug may be reduced relative to healthy subjects, making it impossible to predict whether F in the former or latter population is greater. Bioavailability of drugs with negligible CLnr may depend primarily on the integrity of uptake-transporters so that F in healthy subjects is expected to be greater than in renal impaired subjects. Apparently accurate estimates of F for drugs with negligible CLnr may be obtained from DRIS with oral administration by using the reciprocal of the slope of the regressions. CONCLUSION: A reliable assessment of the impact of CKD on CLnr for drugs with significant non-renal elimination requires information after oral and intravenous administration in the same DRIS study. However, apparently accurate estimates of F for drugs with negligible non-renal elimination may be obtained in DRIS with oral drug administration only, but validation of the proposed method with other drugs exhibiting negligible non-renal elimination and variable F1 is required.

Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis.

TDP-43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects. TDP-43 gain-of-function effects in these mice reveal a novel category of splicing events controlled by TDP-43, referred to as "skiptic" exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain-of-function mutation in endogenous Tardbp causes an adult-onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain-of-function and skiptic exons in ALS patient-derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP-43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages.

Mechanosensory Signaling in Astrocytes.

Mechanosensitivity is a well-known feature of astrocytes, however, its underlying mechanisms and functional significance remain unclear. There is evidence that astrocytes are acutely sensitive to decreases in cerebral perfusion pressure and may function as intracranial baroreceptors, tuned to monitor brain blood flow. This study investigated the mechanosensory signaling in brainstem astrocytes, as these cells reside alongside the cardiovascular control circuits and mediate increases in blood pressure and heart rate induced by falls in brain perfusion. It was found that mechanical stimulation-evoked Ca2+ responses in astrocytes of the rat brainstem were blocked by (1) antagonists of connexin channels, connexin 43 (Cx43) blocking peptide Gap26, or Cx43 gene knock-down; (2) antagonists of TRPV4 channels; (3) antagonist of P2Y1 receptors for ATP; and (4) inhibitors of phospholipase C or IP3 receptors. Proximity ligation assay demonstrated interaction between TRPV4 and Cx43 channels in astrocytes. Dye loading experiments showed that mechanical stimulation increased open probability of carboxyfluorescein-permeable membrane channels. These data suggest that mechanosensory Ca2+ responses in astrocytes are mediated by interaction between TRPV4 and Cx43 channels, leading to Cx43-mediated release of ATP which propagates/amplifies Ca2+ signals via P2Y1 receptors and Ca2+ recruitment from the intracellular stores. In astrocyte-specific Cx43 knock-out mice the magnitude of heart rate responses to acute increases in intracranial pressure was not affected by Cx43 deficiency. However, these animals displayed lower heart rates at different levels of cerebral perfusion, supporting the hypothesis of connexin hemichannel-mediated release of signaling molecules by astrocytes having an excitatory action on the CNS sympathetic control circuits.SIGNIFICANCE STATEMENT There is evidence suggesting that astrocytes may function as intracranial baroreceptors that play an important role in the control of systemic and cerebral circulation. To function as intracranial baroreceptors, astrocytes must possess a specialized membrane mechanism that makes them exquisitely sensitive to mechanical stimuli. This study shows that opening of connexin 43 (Cx43) hemichannels leading to the release of ATP is the key central event underlying mechanosensory Ca2+ responses in astrocytes. This astroglial mechanism plays an important role in the autonomic control of heart rate. These data add to the growing body of evidence suggesting that astrocytes function as versatile surveyors of the CNS metabolic milieu, tuned to detect conditions of potential metabolic threat, such as hypoxia, hypercapnia, and reduced perfusion.

Assembly of a Rovibrational Ground State Molecule in an Optical Tweezer.

We demonstrate the coherent creation of a single NaCs molecule in its rotational, vibrational, and electronic (rovibronic) ground state in an optical tweezer. Starting with a weakly bound Feshbach molecule, we locate a two-photon transition via the |c^{3}Σ_{1},v^{'}=26⟩ excited state and drive coherent Rabi oscillations between the Feshbach state and a single hyperfine level of the NaCs rovibronic ground state |X^{1}Σ,v^{''}=0,N^{''}=0⟩ with a binding energy of D_{0}=h×147044.63(11) GHz. We measure a lifetime of 3.4±1.6 s for the rovibronic ground state molecule, which possesses a large molecule-frame dipole moment of 4.6D and occupies predominantly the motional ground state. These long-lived, fully quantum-state-controlled individual dipolar molecules provide a key resource for molecule-based quantum simulation and information processing.

Attitude is everything: keep probe pitch neutral during side-fire prostate biopsy. A simulator study.

OBJECTIVES: To develop and validate on a simulator a learnable technique to decrease deviation of biopsied cores from the template schema during freehand, side-fire systematic prostate biopsy (sPBx) with the goal of reducing prostate biopsy (PBx) false-negatives, thereby facilitating earlier sampling, diagnosis and treatment of clinically significant prostate cancer. PARTICIPANTS AND METHODS: Using a PBx simulator with real-time three-dimensional visualization, we devised a freehand, pitch-neutral (0°, horizontal plane), side-fire, transrectal ultrasonography (TRUS)-guided sPBx technique in the left lateral decubitus position. Thirty-four trainees on four Canadian and US urology programmes learned the technique on the same simulator, which recorded deviation from the intended template location in a double-sextant template as well as the TRUS probe pitch at the time of sampling. We defined deviation as the shortest distance in millimeters between a core centre and its intended template location, template deviation as the mean of all deviations in a template, and mastery as achieving a template deviation ≤5.0 mm. RESULTS: All results are reported as mean ± sd. The mean absolute pitch and template deviation before learning the technique (baseline) were 8.2 ± 4.1° and 8.0 ± 2.7 mm, respectively, and after mastering the technique decreased to 4.5 ± 2.7° (P = 0.001) and 4.5 ± 0.6 mm (P < 0.001). Template deviation was related to mean absolute pitch (P < 0.001) and increased by 0.5 mm on average with each 1° increase in mean absolute pitch. Participants achieved mastery after practising 3.9 ± 2.9 double-sextant sets. There was no difference in time to perform a double-sextant set at baseline (277 ± 102 s) and mastery (283 ± 101 s; P = 0.39). CONCLUSION: A pitch-neutral side-fire technique reduced template deviation during simulated freehand TRUS-guided sPBx, suggesting it may also reduce PBx false-negatives in patients in a future clinical trial. This pitch-neutral technique can be taught and learned; the University of Florida has been teaching it to all Urology residents for the last 2 years.

Forming a Single Molecule by Magnetoassociation in an Optical Tweezer.

We demonstrate the formation of a single NaCs molecule in an optical tweezer by magnetoassociation through an s-wave Feshbach resonance at 864.11(5) G. Starting from single atoms cooled to their motional ground states, we achieve conversion efficiencies of 47(1)%, and measure a molecular lifetime of 4.7(7) ms. By construction, the single molecules are predominantly [77(5)%] in the center-of-mass motional ground state of the tweezer. Furthermore, we produce a single p-wave molecule near 807 G by first preparing one of the atoms with one quantum of motional excitation. Our creation of a single weakly bound molecule in a designated internal state in the motional ground state of an optical tweezer is a crucial step towards coherent control of single molecules in optical tweezer arrays.

Development of apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent and its preliminary evaluation in an orthotopic patient-derived xenograft (PDX) model.

Despite the significant progress in the field of cancer therapeutics, the incidence of pancreatic cancer (PC) has continuously increased. One possible mechanism for this increasing burden is impaired drug delivery and drug resistance resulting from a unique tumor microenvironment and genetic mutations. Apratoxins are potent anticancer agents and cotranslational translocation inhibitors with potential therapeutic applications to treat cancers with active secretory pathways. Here, we developed apratoxin S10 (Apra S10) as an anti-pancreatic cancer agent which potently inhibited the growth of both established and patient-derived primary pancreatic cancer cells. We validated its mechanism of action on pancreatic cancer cells by demonstrating the downregulation of multiple receptor tyrosine kinases and inhibition of growth factor and cytokine secretion. Apra S10 also inhibited a number of cytokines secreted by stromal cells, suggesting that Apra S10 not only inhibited pancreatic cancer cell secretion, but also reduced the level of factors secreted by other cell types active within the tumor microenvironment. As Apra S10 tissue distribution indicated its high enrichment in pancreas tissue, an orthotopic pancreatic patient-derived xenograft mouse model that closely mimics the human pancreatic tumor microenvironment was for the first time used in apratoxin studies. Apra S10 showed promising antitumor effect in this pancreatic cancer model and this effect was mediated through anti-proliferation properties.

Impact of dosage timing on the bioavailability of oral anticancer medications: Is pre-prandial dosing equivalent to post-prandial dosing.

Many oral anticancer agents are recommended to be given either at least 1 h before or 2 h after a meal, according to the prescribing information. However, the effect of dosage timing of an oral anticancer agent with reference to food intake on anticancer treatment remains unclear. As shown by the literature survey and labeling analysis for oral anticancer drugs approved by the US Food and Drug Administration from 2010 to 2016, labeling information regarding dosage timing for several anticancer drugs appeared not be optimum, leading to suboptimal bioavailability and plasma drug concentrations. This supports a call to regularly recalibrate the labeling information for dosage timing of oral anticancer medications to minimize the risks of compromised efficacy or unintended toxicities.

Inhibition of IL-8 secretion on BxPC-3 and MIA PaCa-2 cells and induction of cytotoxicity in pancreatic cancer cells with marine natural products.

Pancreatic cancer presents one of the most negative prognosis of all cancers as it has usually metastasized by the time a patient is diagnosed. The American Cancer Society estimates that 93% of patients will die within 5 years of diagnosis, highlighting the need for new drugs to treat this disease. Interleukin 8 (IL-8) mediates the angiogenesis of tumors arising from Ras mutations, which are present in about 90% of pancreatic adenocarcinomas. Overexpression of IL-8 in pancreatic tumors is believed to promote tumor angiogenesis and to activate survival signaling pathways. A 96-well cell-based enzyme-linked immunosorbent assay was set up to screen the Harbor Branch Oceanographic Institute library of marine natural products to identify those with the ability to inhibit IL-8 production by BxPC-3 pancreatic cancer cells. Over 1000 fractions were screened, resulting in the identification of 10 known marine natural products with this ability. These compounds fall into four classes of compounds including the pyrroloiminoquinone alkaloids secobatzelline A and isobatzelline C; mycalamide A and B, onnamide A, discalamide A, and theopederin K from the mycalamide class of polyketides; the lipopeptide microcolin A; and the cyclic depsipeptides didemnin B and nordidemnin B. In addition, didemnin B, nordidemnin B, and theopederin K induce potent cytotoxicity against four pancreatic cancer cell lines tested. Many of these compounds have been previously reported to inhibit protein synthesis and the decrease in IL-8 production may be nonspecific. Nevertheless, this is a new activity for these compounds and inhibition of IL-8 secretion by pancreatic cancer cells can now be added to the previously reported antiangiogenic activities of the didemnins.

Effects of 8 weeks parent-accompanied swimming on physical capacity and intelligence in preschool children.

This study aimed to explore the potential effects of 8-week parents-accompanied swimming on the physical capacity and intelligence of preschool children in China. Thirty-six boys (mean age 3.56 ± 0.27 years) were divided into three groups: the traditional physical exercise group (TP, n = 12), the accompanied swimming group (AS, n = 12) and the independent swimming group (IS, n = 12). Participants' physical capacity was assessed before and after the intervention using the following indicators: height, weight, distance of tennis ball throw, standing long jump distance, time for the 10-meter shuttle run, time for a two-legged continuous jump, sit-and-reach distance, and time on the walking balance beam. Intelligence was assessed at three points: pre-test, mid-test after 4 weeks, and post-test. Data were analyzed using a two-way repeated measures ANOVA, Bonferroni test (p < 0.05) and effect size. The time of the AS and IS groups to walk the balance beam was significantly lower than the TP group, with a difference of 1.81 s (p < 0.01, [95% CI -3.22 to -0.40], ES = 1.53) and 1.25 s (p < 0.05, [95% CI -2.66 to 0.16], ES = 0.81). At the mid-test, the IQ scores of the TP group were lower than the AS group (p < 0.05, [95% CI -12.45 to -0.96], ES = 0.89). Additionally, at post-test, the IQ scores of the TP group were significantly lower than those of both AS (p < 0.01, [95% CI -14.12 to -2.74], ES = 1.15) and IS groups (p < 0.01, [95% CI -12.53 to -3.31], ES = 1.21). Swimming enhances children's balance and IQ scores more than traditional physical exercises. Involving parents in swimming leads to a more significant increase in IQ scores within 4 weeks of initial swimming exercise.

Dose-response relationship between weekly physical activity level and the frequency of colds in Chinese middle-aged and elderly individuals.

Background: Engaging in appropriate physical activity can significantly lower the risk of various diseases among middle-aged and older adults. Investigating optimal levels of physical activity (PA) is crucial for enhancing the health of this demographic. This study aims to explore the dose-response relationship between weekly PA levels and the frequency of colds among Chinese middle-aged and elderly individuals, identifying the necessary PA level to effectively diminish the risk of colds. Methods: We conducted a cross-sectional study using a web-based survey targeting individuals aged 40 and older (n = 1, 683) in China. The survey collected information on PA and the frequency of colds. Data was analyzed using Kruskal-Wallis test and the χ2 test. We explored the dose-response relationship between weekly PA and cold frequency over the past year through an ordered multivariate logistic regression model and a restricted cubic spline model. Results: (1) Brisk walking emerged as the preferred physical exercise for those over 40. The findings suggest that engaging in moderate (odds ratio (OR) = 0.64, P < 0.001, 95% confidence interval (CI) [0.50-0.81]) and high (OR = 0.64, P < 0.001, 95% CI [0.51-0.79]) levels of PA weekly significantly reduces the risk of catching a cold. Individuals with one (OR = 1.47, P < 0.001, 95% CI [1.20-1.80]) or multiple chronic diseases (OR = 1.56, P < 0.001, 95% CI [1.21-2.00]) were at increased risk. Those residing in central (OR = 1.64, P < 0.001, 95% CI [1.33-02.01]) and western China (OR = 1.49, P = 0.008, 95% CI [1.11-02.00]) faced a higher risk compared to their counterparts in eastern China. (2) According to the restricted cubic spline model, adults who experienced one cold in the past year had a weekly PA level of 537.29 metabolic equivalent-minutes per week (MET-min/wk) with an OR value of 1. For those reporting two or more colds, the PA level was 537.76 MET-min/wk with an OR of 1. Conclusions: (1) Brisk walking is the most favored exercise among the Chinese middle-aged and elderly, with the prevalence of colds being affected by the number of chronic diseases and the geographic location. (2) Regular, moderate exercise is linked to a lower risk of colds. To effectively reduce cold frequency, it is recommended that middle-aged and elderly Chinese individuals engage in a minimum of 538 MET-min/wk of exercise.

Brisk walking improves motor function and lower limb muscle strength in Chinese women aged 80 years and older.

This study investigates the effects of a 12-week brisk walking exercise regimen on motor function improvements in elderly women. Twenty-six elderly women, aged 84.2 ± 3.2 years, participated in a 12-week brisk walking exercise program. Fitness assessments and blood biomarker analyses (including CHO, HDLC, LDLC, TC) were conducted pre- and post-intervention. Additionally, targeted metabolomics was employed to measure short-chain fatty acids, amino acids, and vitamin metabolites. The intervention led to significant enhancements in participants' flexibility (p < 0.05), lower limb muscle strength (p < 0.01), and cardiorespiratory endurance (p < 0.01), while muscle mass showed no significant changes. Fifteen significant differential metabolites were identified (VIP > 1.0, FC > 1.2 or < 0.8, and p < 0.05), with arginine, ornithine, aspartic acid, glutamine, phenylalanine, tyrosine, and pantothenic acid playing key roles across seven metabolic pathways. A 12-week brisk walking exercise program significantly enhanced flexibility, lower limb muscle strength, and cardiorespiratory endurance among elderly women. These improvements did not extend to muscle mass or upper limb muscle strength. The observed enhancement in exercise capacity may be attributed to improved regulation of neurotransmitters.

Changes in cardiac-driven perivascular fluid movement around the MCA in a pharmacological model of acute hypertension detected with non-invasive MRI.

Perivascular spaces mediate a complex interaction between cerebrospinal fluid and brain tissue that may be an important pathway for solute waste clearance. Their structural or functional derangement may contribute to the development of age-related neurogenerative conditions. Here, we employed a non-invasive low b-value diffusion-weighted ECG-gated MRI method to capture perivascular fluid movement around the middle cerebral artery of the anaesthetised rat brain. Using this method, we show that such MRI estimates of perivascular fluid movement directionality are highly sensitive to the cardiac cycle. We then show that these measures of fluid movement directionality are decreased in the angiotensin-II pharmacological model of acute hypertension, with an associated dampening of vessel pulsatility. This translational MRI method may, therefore, be useful to monitor derangement of perivascular fluid movement associated with cardiovascular pathologies, such as hypertension, in order to further our understanding of perivascular function in neurology.

Dosing Cefazolin for Surgical Site Infection Prophylaxis in Adolescent Idiopathic Scoliosis Surgery: Intermittent Bolus or Continuous Infusion?-A Pilot Study.

Background: Cefazolin may minimize the risk of surgical site infection (SSI) following posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). Cefazolin dosing recommendations vary and there is limited evidence for achieved tissue concentrations. Methods: We performed a randomized, controlled, prospective pharmacokinetic pilot study of 12 patients given cefazolin by either intermittent bolus (30 mg/kg every 3 h) or continuous infusion (30 mg/kg bolus followed by 10/mg/kg per hour) during PSF for AIS. Results: Patients were well matched for demographic and perioperative variables. While total drug exposure, measured as area-under-the-curve (AUC), was similar in plasma for bolus and infusion dosing, infusion dosing achieved greater cefazolin exposure in subcutaneous and muscle tissue. Using the pharmacodynamic metric of time spent above minimal inhibitory concentration (MIC), both bolus and infusion dosing performed well. However, when targeting a bactericidal concentration of 32 µg/mL, patients in the bolus group spent a median of 1/5 and 1/3 of the typical 6 h operative time below target in subcutaneous and muscle tissue, respectively. Conclusions: We conclude that intraoperative determination of cefazolin tissue concentrations is feasible and both bolus and infusion dosing of cefazolin achieve concentrations in excess of typical MICs. Infusion dosing appears to more consistently achieve bactericidal concentrations in subcutaneous and muscle tissues.

Human mutations in SLITRK3 implicated in GABAergic synapse development in mice.

This study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients' SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.

Relationship between methods of monitoring training load and physiological indicators changes during 4 weeks cross-country skiing altitude training.

This study aimed to: (i) analyze the load characteristics of 4 weeks cross-country skiing altitude training; (ii) analyze the relationships between methods of monitoring training load and physiological indicators changes of elite male Chinese cross-country skiers during this period. Practitioners collected load data during 4 weeks of altitude training camp. Participants performed maximal oxygen uptake, lactate threshold, body composition, and skierg power test before and after the training camp to investigate the changes in physiological performance. Edwards TRIMP, Lucia TRIMP, and session rating of perceived exertion were collected as internal load. Training distance, time recorded by the Catapult module were collected as external load. The result revealed a " pyramid " pattern in the load characteristics during the altitude training camp. The correlation between luTRIMP and percent change in physiological indicators was highest. Percentage changes in lactate threshold velocity (r = .78 [95% CI -.01 to .98]), percentage changes in lactate threshold HR (r = .71 [95% CI .14- .99]), percentage changes in maximum HR (r = .83 [95% CI .19-1.00]), percentage changes in skierg power-to-weight ratio (r = .75 [95% CI -.28 to .98]) had very large relationships with luTRIMP. In cross-country skiing altitude training, training loads should be reasonably controlled to ensure that athletes do not become overly fatigued. Methods of training load monitoring that combine with athletes' physiological characteristics and program characteristics have the highest dose-response relationships, it is an important aspect of cross-country ski training load monitoring. The luTRIMP could be a good monitoring tool in cross-country skiing altitude training.

Monitoring Physiological Performance over 4 Weeks Moderate Altitude Training in Elite Chinese Cross-Country Skiers: An Observational Study.

The current observational study aimed to monitor the physiological performance over 4 weeks of living and training at a moderate altitude in elite Chinese cross-country skiers (8 males, mean age 20.83 ± 1.08 years). Lactate threshold, maximal oxygen uptake, blood, and body composition tests were performed at different time points to investigate the changes in physiological performance. The data were analysed by a one-way repeated measures ANOVA and a paired sample T-test between the test results. During the training camp, systematic load monitoring was carried out. Lactate threshold velocity, lactate threshold heart rate, and upper body muscle mass increased significantly (p < 0.01) after moderate altitude training. Maximum oxygen uptake was reduced compared to pre-tests (p < 0.05). Aerobic capacity parameters (maximal oxygen uptake, haemoglobin, red blood cell count) did not significantly increase after athletes returned to sea level (p > 0.05). These findings suggest that 4 weeks of moderate altitude training can significantly improve athletes' lactate threshold and upper body muscle mass; no significant improvement in other aerobic capacity was seen. Exposure time, training load, and nutritional strategies should be thoroughly planned for optimal training of skiers at moderate altitudes.

Image-Guided Magnetic Thermoseed Navigation and Tumor Ablation Using a Magnetic Resonance Imaging System.

Medical therapies achieve their control at expense to the patient in the form of a range of toxicities, which incur costs and diminish quality of life. Magnetic resonance navigation is an emergent technique that enables image-guided remote-control of magnetically labeled therapies and devices in the body, using a magnetic resonance imaging (MRI) system. Minimally INvasive IMage-guided Ablation (MINIMA), a novel, minimally invasive, MRI-guided ablation technique, which has the potential to avoid traditional toxicities, is presented. It comprises a thermoseed navigated to a target site using magnetic propulsion gradients generated by an MRI scanner, before inducing localized cell death using an MR-compatible thermoablative device. The authors demonstrate precise thermoseed imaging and navigation through brain tissue using an MRI system (0.3 mm), and they perform thermoablation in vitro and in vivo within subcutaneous tumors, with the focal ablation volume finely controlled by heating duration. MINIMA is a novel theranostic platform, combining imaging, navigation, and heating to deliver diagnosis and therapy in a single device.

Remote and Selective Control of Astrocytes by Magnetomechanical Stimulation.

Astrocytes play crucial and diverse roles in brain health and disease. The ability to selectively control astrocytes provides a valuable tool for understanding their function and has the therapeutic potential to correct dysfunction. Existing technologies such as optogenetics and chemogenetics require the introduction of foreign proteins, which adds a layer of complication and hinders their clinical translation. A novel technique, magnetomechanical stimulation (MMS), that enables remote and selective control of astrocytes without genetic modification is described here. MMS exploits the mechanosensitivity of astrocytes and triggers mechanogated Ca2+ and adenosine triphosphate (ATP) signaling by applying a magnetic field to antibody-functionalized magnetic particles that are targeted to astrocytes. Using purpose-built magnetic devices, the mechanosensory threshold of astrocytes is determined, a sub-micrometer particle for effective MMS is identified, the in vivo fate of the particles is established, and cardiovascular responses are induced in rats after particles are delivered to specific brainstem astrocytes. By eliminating the need for device implantation and genetic modification, MMS is a method for controlling astroglial activity with an improved prospect for clinical application than existing technologies.