Chiral Pyclen-Based Heptadentate Chelates as Highly Stable MRI Contrast Agents.

In recent years, pyclen-based complexes have attracted a great deal of interest as magnetic resonance imaging (MRI) contrast agents (CAs) and luminescent materials, as well as radiopharmaceuticals. Remarkably, gadopiclenol, a Gd(III) bishydrated complex featuring a pyclen-based heptadentate ligand, received approval as a novel contrast agent for clinical MRI application in 2022. To maximize stability and efficiency, two novel chiral pyclen-based chelators and their complexes were developed in this study. Gd-X-PCTA-2 showed significant enhancements in both thermodynamic and kinetic stabilities compared to those of the achiral parent derivative Gd-PCTA. 1H NMRD profiles reveal that both chiral gadolinium complexes (Gd-X-PCTA-1 and Gd-X-PCTA-2) have a higher relaxivity than Gd-PCTA, while variable-temperature 17O NMR studies show that the two inner-sphere water molecules have distinct residence times τMa and τMb. Furthermore, in vivo imaging demonstrates that Gd-X-PCTA-2 enhances the signal in the heart and kidneys of the mice, and the chiral Gd complexes exhibit the ability to distinguish between tumors and normal tissues in a 4T1 mouse model more efficiently than that of the clinical agent gadobutrol. Biodistribution studies show that Gd-PCTA and Gd-X-PCTA-2 are primarily cleared by a renal pathway, with 24 h residues of Gd-X-PCTA-2 in the liver and kidney being lower than those of Gd-PCTA.

Systematic review of leadless pacemaker.

Conventional pacing systems consist of a pacemaker and one or more leads threaded from the device pocket through veins into the heart conducting the pacing therapy to the desired pacing site. Although these devices are effective, approximately one in eight patients treated with these traditional pacing systems experiences a complication attributed to the pacemaker pocket or leads. With the technological advances in electronics, leadless pacemakers that small enough to implant within the heart were introduced. Leadless pacemakers have been developed to overcome many of the challenges of transvenous pacing including complications related to leads or pacemaker pockets. This review aims to provide an overview of advantages of leadless pacemaker, complications and limitations of leadless pacemaker, leadless pacemaker candidate, and future directions of this promising technology.

Chiral Gd-DOTA as a Versatile Platform for Hepatobiliary and Tumor Targeting MRI Contrast Agents.

The leakage of gadolinium ions (Gd3+) from commercial Gd3+-based contrast agents (GBCAs) in patients is currently the major safety concern in clinical magnetic resonance imaging (MRI) scans, and the lack of task-specific GBCAs limits its usage in the early detection of disease and imaging of specific biological regions. Herein, ultrastable GBCAs were constructed via decorating chiral Gd-DOTA with a phenylic analogue to one of the pendent arms, and the stability constant was determined as high as 27.08, accompanied by negligible decomplexation in 1 M of HCl over 2 years. A hepatic-specific chiral Gd-DOTA was screened out as a potential alternative to commercial Gd-EOB-DTPA, while combination with functional molecules favored chiral Gd-DOTA as tumor targeting probes. Therefore, the novel chiral Gd-DOTA is believed to be an ideal platform for designing the next generation of GBCAs for various clinical purposes due to its outstanding inert nature.

A novel Gd3+ DTPA-bisamide complex with high relaxivity as an MRI contrast agent.

A novel Gd(III) complex-based magnetic resonance imaging (MRI) contrast agent GdL has been designed and synthesized, which exhibited a much higher relaxivity (7.8 mM-1 s-1) than the commercially used Magnevist® (3.5 mM-1 s-1), good water solubility (>100 mg mL-1), excellent thermodynamic stability (log KGdL = 17.21 ± 0.27), high biosafety and biocompatibility. In particular, the relaxivity of GdL increased to 26.7 mM-1 s-1 in a 4.5% bovine serum albumin (BSA) solution at 1.5 T, which was not significant in other commercial MRI contrast agents. The interaction sites and interaction types of GdL and BSA were further demonstrated by molecular docking simulations. Furthermore, the in vivo MRI behaviour was evaluated by using a 4T1 tumour-bearing mouse model. These results suggested that GdL is an excellent T1-weighted MRI contrast agent and has the potential to be applied in clinical diagnosis.

Rational Design of Gd-DOTA-Type Contrast Agents for Hepatobiliary Magnetic Resonance Imaging.

The safety risks of gadolinium (Gd3+)-based contrast agents (GBCAs) arise from their inevitable leakage of Gd3+, and the pursuit of more stable GBCAs for magnetic resonance imaging (MRI) has drawn increasing attention. Yet, Gd-EOB-DTPA and Gd-BOPTA are the only two authorized GBCAs for liver diagnosis in spite of their weak stability. In this study, one of the pendent arms of the most inert commercial Gd-DOTA was decorated with phenyl moieties, in which obvious enhancements of both kinetic and thermodynamic stability were achieved. Gd-L4 with a para-substituted OBn group was observed with ready hepatocellular uptake, with significant contrast provided in diagnosing orthotopic hepatocellular carcinoma, and its hepatobiliary secretion accounted for more than 50% of the injection dose in mice. In this study, Gd-L4 was found with comparable performance in liver MRI diagnosis to that of commercial Gd-EOB-DTPA and was thus deemed as an ideal candidate for further clinical applications.

A Survey of Anxiety and Depressive Symptoms in Pulmonary Tuberculosis Patients With and Without Tracheobronchial Tuberculosis.

Background and Objective: Anxiety/depression and tuberculosis are global public health problems. The incidence of psychiatric morbidities is high among tuberculosis patients. However, little is known about the prevalence of anxiety and depression among Chinese pulmonary tuberculosis (PTB) patients, especially those with tracheobronchial tuberculosis (TBTB). The goal of the present study was to explore the prevalence of and associated factors of anxiety and depressive symptoms among PTB patients with and without TBTB. Methods: A cross-sectional survey of PTB patients from three hospitals in Liaoning, China, was conducted using a structured questionnaire. Depression and anxiety were evaluated by using the Hospital Anxiety and Depression Scale (HADS) and the Patient Health Questionnaire-9 (PHQ-9). Results: According to HADS and PHQ-9, 17.73 and 18.13% of 1252 PTB patients, respectively, had significant depressive symptoms and based on HADS scale, 18.37% had significant anxiety symptoms. Approximately 70% of patients with probable depression also had significant anxiety symptoms, and vice versa, and 69.6% patients with anxiety symptoms were also diagnosed with probable depression in our study population. Dyspnea and TBTB were significantly associated with depressive symptoms. Other depressive symptoms-related factors included age, divorce, abnormal body mass index (BMI), and low income. Patients with lower incomes, symptoms of dyspnea, or a combination of ≥3 clinical symptoms had an increased risk of anxiety symptoms, while patients with occasional or frequent alcohol consumption had a reduced risk of anxiety symptoms. Conclusion: Depressive and anxiety symptoms are common among PTB patients, especially those with TBTB. Screening for depression and anxiety is essential for identifying patients who require further psychosocial assessment and support.

Effects of zoledronic acid and ibandronate in the treatment of cancer pain in rats with lung cancer combined with bone metastases.

The aim of the study was to investigate the efficiency and safety of zoledronic acid and ibandronate in the treatment of rats with lung cancer combined with bone metastases. A total of 124 rats with lung cancer bone metastasis were established. Rats were randomly divided into A, B and C groups (n=30). Rats in group A were treated with ibandronate combined with zoledronic acid, rats in group B were treated with zoledronic acid monotherapy, and rats in group C were treated with ibandronate monotherapy. Rats in group A were injected subcutaneously with zoledronic acid 0.1 mg/kg and ibandronate 10 µg/kg, once per week for 12 weeks; rats in group B were injected subcutaneously with zoledronic acid, and rats in group C were injected subcutaneously with ibandronate, the same method as the treatment group. The remaining 34 SD rats were not treated to serve as the control group. Treatment efficacy and physical improvement in 8 weeks were observed, and improvement of pain behavior in rats was evaluated to reflect the effect of drug treatment. Of the 30 rats in group A, 25 showed different degrees of remission, 5 rats showed no improvement and the effective rate was 83.3%. Of the 30 rats in group B, 21 showed different degrees of remission, 9 rats showed no improvement and the effective rate was 70%. Of the 30 rats in group C, 20 showed different degrees of remission, 10 rats showed no improvement and the effective rate was 66.7%. Statistically significant differences in total effective rate were found among three groups, and the combined method showed the highest effective rate (P<0.05). Ibandronate combined with zoledronic acid has a good therapeutic effect on cancer pain caused by bone metastases from lung cancer.

The Adverse Events Rate of Endothelial Progenitor Cell Capturing Stent in the Treatment of CAD Patients.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) have regenerative capacities and play an important role in vessel wall homeostasis. When attracted to the site of vessel wall injury, EPCs rapidly differentiate into a functional layer as part of the healing process. The Genous TM endothelial progenitor cell (EPC) capturing stent is coated with anti-human CD34+ antibodies which combine with circulating EPCs from the peripheral blood to the stent surface. OBJECTIVE: This meta-analysis aims to explore the Genous TM endothelial progenitor cell capturing stent in coronary artery disease (CAD) adverse event rate after one-year follow-up. METHODS: PubMed, EMBASE and, Google Scholar databases were searched for eligible studies. CAD survival data and clinicopathological features were analyzed by expected shortfall (ES) and 95% CI. Fixed-effect model and random-effect model are used for summary statistics. RESULTS: 12 studies, including 15985 coronary artery disease (CAD) patients who received PCI treatment were included in this study. After 1-year follow-up, the rate of adverse event showed that the target vessel failure (TVF) was 8.5% (7.6%-17.4%), target vessel revascularization was 4.1% (TVR, 0-15.6%), target lesion revascularization was 4.2% (TLR, 3.7%-22%), myocardial infarction was 2.0% (MI, 1.8%-5.2%), major adverse cardiac events was 8.7% (MACE, 6.4%-28%), and the all-cause death was 4.0% (0-9.2). CONCLUSION: After one-year follow-up, the incidence rate of Genous stent adverse events was stable in CAD patients. The study showed a better evaluation of Genous stent, and it provides a better reference for CAD clinical treatment.

Batch affinity adsorption of His-tagged proteins with EDTA-based chitosan.

Affinity adsorption purification of hexahistidine-tagged (His-tagged) proteins using EDTA-chitosan-based adsorption was designed and carried out. Chitosan was elaborated with ethylenediaminetetraacetic acid (EDTA), and the resulting polymer was characterized by FTIR, TGA, and TEM. Different metals including Ni(2+), Cu(2+), and Zn(2+) were immobilized with EDTA-chitosan, and their capability to the specific adsorption of His-tagged proteins were then investigated. The results showed that Ni(2+)-EDTA-chitosan and Zn(2+)-EDTA-chitosan had high affinity toward the His-tagged proteins, thus isolating them from protein mixture. The target fluorescent-labeled hexahistidine protein remained its fluorescent characteristic throughout the purification procedure when Zn(2+)-EDTA-chitosan was used as a sorbent, wherein the real-time monitor was performed to examine the immigration of fluorescent-labeled His-tagged protein. Comparatively, Zn(2+)-EDTA-chitosan showed more specific binding ability for the target protein, but with less binding capacity. It was further proved that this purification system could be recovered and reused at least for 5 times and could run on large scales. The presented M(2+)-EDTA-chitosan system, with the capability to specifically bind His-tagged proteins, make the purification of His-tagged proteins easy to handle, leaving out fussy preliminary treatment, and with the possibility of continuous processing and a reduction in operational cost in relation to the costs of conventional processes.

Multi-frequency phase-coded microwave signal generation based on polarization modulation and balanced detection.

Photonic multi-frequency phase-coded microwave signal generation is proposed and demonstrated based on polarization modulation and balanced detection. Consisting of only a polarization modulator (PolM) driven by an electrical coding data, a polarization beam splitter (PBS) and a balanced photodetector (BPD), the proposed microwave phase coder has no requirement on the wavelength, intensity modulation format, or modulation index of the input optical microwave signal, and allows phase coding of arbitrary-format RF signals, which enables multi-frequency phase coding with compact structure, simple operation, and high flexibility. A proof-of-concept experiment is performed, achieving simultaneous phase coding of 15 and 30 GHz, or 10 and 20 GHz RF signals with a coding rate of 5 Gb/s.

An AIL/IL-based liquid/liquid extraction system for the purification of His-tagged proteins.

A sorbent based on affinity ionic liquid (AIL), triazacyclononane-ionic liquid, was synthesized, characterized, and applied to the extraction of histidine (His)-tagged proteins from aqueous buffer to ionic liquid (IL) phase. The adsorbed His-tagged proteins could be back-extracted from the IL phase to the aqueous buffer with an imidazole solution. The specific binding of His-tagged proteins with AIL/IL could be affected by a few factors including the ionic strength and coordinated metal ions. In the case of His-tagged enhanced green fluorescent protein (EGFP), the maximum binding capacity of Cu(2+)-AIL/IL reached 2.58 µg/µmol under the optimized adsorption conditions. The eluted His-tagged EGFP kept fluorescent and remained active through the purification process. Moreover, a tandem extraction process successively using Cu(2+)-AIL/IL and Zn(2+)-AIL/IL systems was developed, which was proven very efficient to obtain the ultimate protein with a purity of about 90 %. An effective reclamation method for the AIL/IL extraction system was further established. The sorbent could be easily regenerated by removing metal ions with EDTA and the followed reimmobilization of metal ions. Easy handling of the presented M(2+)-AIL/IL system and highly specific ability to absorb His-tagged proteins make it attractive and potentially applicable in biomolecular separation.

Sensitization of sodium channels by cystathionine ß-synthetase activation in colon sensory neurons in adult rats with neonatal maternal deprivation.

BACKGROUND: The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood and treatment remains difficult. We have previously reported that TTX-resistant (TTX-R) sodium channels in colon-specific dorsal root ganglion (DRG) neurons were sensitized and the expression of the endogenous hydrogen sulfide producing enzyme cystathionine ß-synthetase (CBS) was upregulated in a rat model of visceral hypersensitivity induced by neonatal maternal deprivation (NMD). However, the detailed molecular mechanism for activation of sodium channels remains unknown. This study was designed to examine roles for CBS-H2S signaling in sensitization of sodium channels in a previously validated rat model of IBS. METHODS: Neonatal male rats (postnatal days 2-15) were exposed to a 3 hour period of daily maternal separation with temperature maintained at ~33 °C. Colon-specific dorsal root ganglion (DRG) neurons were labeled with DiI and acutely dissociated for measuring excitability and sodium channel current under whole-cell patch clamp configurations. The expression of Na(V)1.8 was analyzed by Western blot and Immunofluorescence study. The endogenous H2S producing enzyme CBS antagonist was injected intraperitoneally. RESULTS: We showed that CBS was colocalized with Na(V)1.8 in colon-specific DRG neurons pre-labeled with DiI. Pretreatment of O-(Carboxymethyl) hydroxylamine hemihydrochloride (AOAA), an inhibitor of CBS, significantly reduced expression of Na(V)1.8 in NMD rats. AOAA treatment also inhibited the TTX-R sodium current density, right-shifted the V1/2 of activation curve, and reversed hyperexcitability of colon-specific DRG neurons in NMD rats. Conversely, addition of NaHS, a donor of H2S, greatly enhanced TTX-R sodium current density, left shifted the activation curve and enhanced excitability of colon DRG neurons in age-matched healthy rats. Furthermore, application of H-89, an inhibitor of protein kinase A, markedly attenuated the potentiation of TTX-R sodium current density by NaHS. CONCLUSION: These data suggest that sensitization of sodium channels of colon DRG neurons in NMD rats is most likely mediated by CBS-H2S signaling, thus identifying a potential target for treatment for chronic visceral pain in patients with IBS.

One-step cyclization: synthesis of N-heteroalkyl-N'-tosylpiperazines.

Piperazine derivatives are important intermediates in organic synthesis and useful building blocks in pharmaceutical and fine chemical industries. Currently available synthetic routes for these heterocyclic compounds have limited scope owing to the harsh reaction conditions, low yields, and multistep process. Herein, we reported a practical method for synthesis of alkyl-, alcohol-, amine-, and ester-extended tosylpiperazines under mild conditions with moderate to high yields. This protocol exhibits potential applicability in the synthesis of pharmaceuticals and natural products because of the operational simplicity and the conveniently available reactants. On the basis of the experimental and theoretical results, a plausible mechanism of aliphatic nucleophilic substitution (S(N)) in the cyclization has been postulated and evidence for the formation of a six-membered ring has also been confirmed by means of density functional theory (DFT) calculations.