Improving In Vivo Tumor Accumulation and Efficacy of Platinum Antitumor Agents by Electronic Tuning of the Kinetic Lability.

The impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O ß-diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3 )2 Pt(L1-H)]NO3 and [(DACH)Pt(L1-H)]NO3 (L1=4,4,4-trifluoro-1-ferrocenylbutane-1,3-dione, DACH=1R,2R-cyclohexane-1,2-diamine) containing an electron deficient [L1-H]- O˄O leaving ligand and [(NH3 )2 Pt(L2-H)]NO3 and [(DACH)Pt(L2-H)]NO3 (L2=1-ferrocenylbutane-1,3-dione) containing an electron-rich [L2-H]- O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron-withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.

Photodynamic Therapy with Targeted Release of Boron-Dipyrromethene Dye from Cobalt(III) Prodrugs in Red Light.

Boron-dipyrromethene (BODIPY) dyes are promising photosensitizers for cellular imaging and photodynamic therapy (PDT) owing to their excellent photophysical properties and the synthetically tunable core. Metalation provides a convenient way to overcome the drawbacks arising from their low aqueous solubility. New photo-/redox-responsive Co(III) prodrug chaperones are developed as anticancer PDT agents for efficient cellular delivery of red-light-active BODIPY dyes. The photobiological activity of heteroleptic Co(III) complexes derived from tris(2-pyridylmethyl)amine (TPA) and acetylacetone-conjugated PEGylated distyryl BODIPY (HL1) or its dibromo analogue (HL2), [CoIII(TPA)(L1/L2)](ClO4)2 (1 and 2), are investigated. The Co(III)/Co(II) redox potential is tuned using the Co(III)-TPA scaffold. Complex 1 displays the in vitro release of BODIPY on red light irradiation. Complex 2, having good singlet oxygen quantum yield (ΦΔ âˆ¼ 0.28 in DMSO), demonstrates submicromolar photocytotoxicity to HeLa cancer cells (IC50 ≈ 0.23 µM) while being less toxic to HPL1D normal cells in red light. Cellular imaging using the emissive complex 1 shows mitochondrial localization and significant penetration into the HeLa tumor spheroids. Complex 2 shows supercoiled DNA photocleavage activity and apoptotic cell death through phototriggered generation of reactive oxygen species. The Co(III)-BODIPY prodrug conjugates exemplify new type of phototherapeutic agents with better efficacy than the organic dyes alone in the phototherapeutic window.

Cobalt(III) Complexes for Light-Activated Delivery of Acetylacetonate-BODIPY, Cellular Imaging, and Photodynamic Therapy.

Cobalt(III) complexes [Co(TPA)(L1)](ClO4)2 (1), [Co(4-COOH-TPA)(L1)](ClO4)2 (2), [Co(TPA)(L2)]Cl2 (3), and [Co(4-COOH-TPA)(L2)]Cl2 (4) having acetylacetonate-linked boron-dipyrromethene ligands (L1, acac-BODIPY; L2, acac-diiodo-BODIPY) were prepared and characterized, and their utility as bioimaging and phototherapeutic agents was evaluated (TPA, tris-(2-pyridylmethyl)amine; 4-COOH-TPA, 2-((bis-(2-pyridylmethyl)amino)methyl)isonicotinic acid). HL1, HL2, and complex 1 were structurally characterized by X-ray crystallography. Complexes 1 and 2 on photoactivation or in a reducing environment (excess GSH, ascorbic acid, and 3-mercaptopropionic acid) released the acac-BODIPY ligand. They exhibited strong absorbance near 501 nm (ε ∼ (5.2-5.8) × 104 M-1 cm-1) and emission bands near 513 nm (ΦF ∼ 0.13, λex = 490 nm) in dimethyl sulfoxide (DMSO). Complexes 3 and 4 with absorption maxima at ∼536 and ∼538 nm (ε ∼ (1.2-1.8) × 104 M-1 cm-1), respectively, afforded high singlet oxygen quantum yield (ΦΔ âˆ¼ 0.79) in DMSO. Complexes 1-4 showed Co(III)-Co(II) redox responses near -0.2 V versus saturated calomel electrode (SCE) in dimethylformamide (DMF)-0.1 M tetrabutylammonium perchlorate (TBAP). The photocleavage of pUC19 DNA by complex 4 revealed the formation of both singlet oxygen and superoxide anion radicals as the reactive oxygen species (ROS). Confocal fluorescence microscopy showed the selective accumulation of complex 1 in the endoplasmic reticulum (ER) in A-549 cells. Complex 4 exhibited a high phototherapeutic index value (PI > 7000) in HeLa cancer cells (IC50 ∼ 0.007 µM in visible light of 400-700 nm, total dose ∼5 J cm-2). The ancillary ligands in the complexes demonstrated a structure-activity relationship and modulated the Co(III)-Co(II) redox potential, the complex solubility, acac-BODIPY ligand release kinetics, and phototherapeutic efficacy.

BODIPY-Ruthenium(II) Bis-Terpyridine Complexes for Cellular Imaging and Type-I/-II Photodynamic Therapy.

A series of multichromophoric ruthenium(II) complexes with the formulation [Ru(tpy-BODIPY)(tpy-R)]Cl2 (1-4), having a heteroleptic Ru(II)-bis-tpy (tpy = 4'-phenyl-2,2':6',2″-terpyridine) moiety covalently linked to a boron-dipyrromethene (BODIPY) pendant, have been prepared and characterized and their application as a phototherapeutic and photodetection agent in cancer therapy has been explored. Ligand L1 with a terpyridine-BODIPY moiety and complex 1 as its PF6 salt (1a) have been structurally characterized by a single-crystal X-ray diffraction study. Complex 1a has a distorted-octahedral RuN6 core with a Ru(II)-bis-terpyridine unit that is covalently linked to one photoactive BODIPY unit. The complexes exhibit strong absorbance near 502 nm (ε ≈ (3.7-7.8) × 104 M-1 cm-1) and high singlet oxygen sensitization ability, giving singlet oxygen quantum yield (ΦΔ) values ranging from 0.57 to 0.75 in DMSO. An emission-based study using complex 4 and Singlet Oxygen Sensor Green (SOSG) displays the formation of singlet oxygen inside the cells and also in the buffer medium upon light irradiation. DNA (pUC19) photocleavage experiments using ROS scavengers/stabilizers reveal photoinduced generation of singlet oxygen by a type-II process and of the superoxide anion radical by a type-I process. Complex 4 having a pendant biotin moiety as a cancer cell targeting group shows high photocytotoxicity with a remarkable phototherapeutic index (PI) value of >1400 in HeLa cancer cells with a low light dose activation (400-700 nm, 2.2 J cm-2). The complexes display reduced activity in noncancerous HPL1D cells. The emission property of the complexes is used for cellular imaging, thus making them suitable as next-generation theranostic PDT agents.

Ruthenium(II) Conjugates of Boron-Dipyrromethene and Biotin for Targeted Photodynamic Therapy in Red Light.

The ruthenium(II) complexes [RuCl(L1)(L3)]Cl (1), [RuCl(L1)(L4)]Cl (2), [RuCl(L2)(L4)]Cl (3), [RuCl(L1)(L5)]Cl (4), and [RuCl(L2)(L5)]Cl (5) of NNN-donor dipicolylamine (dpa) bases (L4, L5) having BODIPY (boron-dipyrromethene) moieties, NN-donor phenanthroline derivatives (L1, L2), and benzyldipicolylamine (bzdpa, L3) were prepared and characterized by spectroscopic techniques and their cellular localization/uptake and photocytotoxicity studied. Complex 1, as its PF6 salt (1a), has been structurally characterized with help of a single-crystal X-ray diffraction technique. It has a RuN5Cl core with the Cl bonded trans to the amine nitrogen atom of bzdpa. The complexes showed intense absorption spectral bands near 500 nm (ε ≈ 58000 M-1 cm-1) in 2 and 3 and 654 nm (ε ≈ 80000 M-1 cm-1) in 4 and 5 in 1/1 DMSO/DPBS (v/v). Complex 5 having biotin and PEGylated-disteryl BODIPY gave a singlet oxygen quantum yield (ΦΔ) of ∼0.65 in DMSO. Complex 5 exhibited remarkable PDT (photodynamic therapy) activity (IC50 ≈ 0.02 µM) with a photocytotoxicity index (PI) value of >5000 in red light of 600-720 nm in A549 cancer cells. The biotin-conjugated complexes showed better photocytotoxicity in comparison to nonbiotinylated analogues in A549 cells. The complexes displayed less toxicity in HPL1D normal cells in comparison to A549 cancer cells. The emissive BODIPY complexes 3 and 5 (ΦF ≈ 0.07 in DMSO) showed significant mitochondrial localization.

Bifunctional RuII -Complex-Catalysed Tandem C-C Bond Formation: Efficient and Atom Economical Strategy for the Utilisation of Alcohols as Alkylating Agents.

Catalytic activities of a series of functional bipyridine-based RuII complexes in ß-alkylation of secondary alcohols using primary alcohols were investigated. Bifunctional RuII complex (3 a) bearing 6,6'-dihydroxy-2,2'-bipyridine (6DHBP) ligand exhibited the highest catalytic activity for this reaction. Using significantly lower catalyst loading (0.1 mol %) dehydrogenative carbon-carbon bond formation between numerous aromatic, aliphatic and heteroatom substituted alcohols were achieved with high selectivity. Notably, for the synthesis of ß-alkylated secondary alcohols this protocol is a rare one-pot strategy using a metal-ligand cooperative RuII system. Remarkably, complex 3 a demonstrated the highest reactivity compared to all the reported transition metal complexes in this reaction.

Investigation of the Thermodynamic and Kinetic Behavior of Acid Dyes in Relation to Wool Fiber Morphology.

Wool fibers from several different sheep breeds in the UK have very limited applications. The main aim of this study was to establish an understanding of the dye sorption properties of different wool fibers through thermodynamics and kinetics of dyeing using Acid Red 1 dye. Wool fibers from Leicester, Ryeland, and Dartmoor sheep breeds were pretreated (to remove impurities) and dyed using Acid Red 1. Leicester showed 7% higher dye exhaustion than Dartmoor wool fibers (20% on mass of fiber). Dyeing equilibrium results for both Leicester and Dartmoor wool fibers were fitted to Langmuir and Freundlich isotherms, and the theoretical maximum sorption capacities were 164 and 144 mg g-1, respectively. Leicester, Ryeland, and Dartmoor also followed the pseudo-second-order reaction kinetics. Thermodynamic parameters like Gibb's free energy (ΔG°) and standard affinity (Δµ°) of the fibers were calculated to understand the interaction of the Acid Red 1 with wool fibers. The difference in dye uptake was explained through the possible involvement of the scale opening gap (surface morphology) of the wool fibers.

Environment-specific virocell metabolic reprogramming.

Viruses impact microbial systems through killing hosts, horizontal gene transfer, and altering cellular metabolism, consequently impacting nutrient cycles. A virus-infected cell, a "virocell," is distinct from its uninfected sister cell as the virus commandeers cellular machinery to produce viruses rather than replicate cells. Problematically, virocell responses to the nutrient-limited conditions that abound in nature are poorly understood. Here we used a systems biology approach to investigate virocell metabolic reprogramming under nutrient limitation. Using transcriptomics, proteomics, lipidomics, and endo- and exo-metabolomics, we assessed how low phosphate (low-P) conditions impacted virocells of a marine Pseudoalteromonas host when independently infected by two unrelated phages (HP1 and HS2). With the combined stresses of infection and nutrient limitation, a set of nested responses were observed. First, low-P imposed common cellular responses on all cells (virocells and uninfected cells), including activating the canonical P-stress response, and decreasing transcription, translation, and extracellular organic matter consumption. Second, low-P imposed infection-specific responses (for both virocells), including enhancing nitrogen assimilation and fatty acid degradation, and decreasing extracellular lipid relative abundance. Third, low-P suggested virocell-specific strategies. Specifically, HS2-virocells regulated gene expression by increasing transcription and ribosomal protein production, whereas HP1-virocells accumulated host proteins, decreased extracellular peptide relative abundance, and invested in broader energy and resource acquisition. These results suggest that although environmental conditions shape metabolism in common ways regardless of infection, virocell-specific strategies exist to support viral replication during nutrient limitation, and a framework now exists for identifying metabolic strategies of nutrient-limited virocells in nature.

Joint Latent Space Model for Social Networks with Multivariate Attributes.

In social, behavioral and economic sciences, researchers are interested in modeling a social network among a group of individuals, along with their attributes. The attributes can be responses to survey questionnaires and are often high dimensional. We propose a joint latent space model (JLSM) that summarizes information from the social network and the multivariate attributes in a person-attribute joint latent space. We develop a variational Bayesian expectation-maximization estimation algorithm to estimate the attribute and person locations in the joint latent space. This methodology allows for effective integration, informative visualization and prediction of social networks and attributes. Using JLSM, we explore the French financial elites based on their social networks and their career, political views and social status. We observe a division in the social circles of the French elites in accordance with the differences in their attributes. We analyze user networks and behaviors in multimodal social media systems like YouTube. A R package "jlsm" is developed to fit the models proposed in this paper and is publicly available from the CRAN repository https://cran.r-project.org/web/packages/jlsm/jlsm.pdf .

Development of novel parameters for characterising scale morphology of wool fibre and its correlation with dye diffusion coefficient of acid dye.

This paper reports the development of novel surface parameters which can be used to characterise the scale structure of wool fibres obtained from different breeds. Scanning electron microscopy and subsequent image analysis technique were used to study wool fibres from Leicester, Dartmoor, Ryeland and Herdwick breeds of sheep. Novel scale parameters related to wool fibre's effective chemical diffusion pathway were developed. Namely, the total scale perimeter per 100 µm fibre length and scale perimeter index, which is the total scale perimeter per 100 µm length divided by the fibre diameter. Wool fibres obtained from different breeds showed significant differences in their scale pattern with the change in fibre diameter. The scale perimeter per 100 µm length increased with the fibre diameter and showed a polynomial correlation. It was also demonstrated that an increase in the diameter of the wool fibre resulted in an increase in the apparent dye diffusion coefficient, which contrasts the established theory that finer fibres are associated with a higher dyeing rate. The increase in effective diffusion pathway (total scale perimeter per 100 µm) for the wool fibres (among different breeds) resulted in a higher dye diffusion rate at the initial phase of dyeing (liquor to surface).

Development of a Highly In Vivo Efficacious Dual Antitumor and Antiangiogenic Organoiridium Complex as a Potential Anti-Lung Cancer Agent.

While the phenomenal clinical success of blockbuster platinum (Pt) drugs is highly encouraging, the inherent and acquired resistance and dose-limiting side effects severely limit their clinical application. To find a better alternative with translational potential, we synthesized a library of six organo-IrIII half-sandwich [(η5-CpX)Ir(N∧N)Cl]+-type complexes. In vitro screening identified two lead candidates [(η5-CpXPh)Ir(Ph2Phen)Cl]+ (5, CpXPh = tetramethyl-phenyl-cyclopentadienyl and Ph2Phen = 4,7-diphenyl-1,10-phenanthroline) and [(η5-CpXBiPh)Ir(Ph2Phen)Cl]+ (6, CpXBiPh = tetramethyl-biphenyl-cyclopentadienyl) with nanomolar IC50 values. Both 5 and 6 efficiently overcame Pt resistance and presented excellent cancer cell selectivity in vitro. Potent antiangiogenic properties of 6 were demonstrated in the zebrafish model. Satisfyingly, 6 and its nanoliposome Lipo-6 presented considerably higher in vivo antitumor efficacy as compared to cisplatin, as well as earlier reported IrIII half-sandwich complexes in mice bearing the A549 non-small lung cancer xenograft. In particular, complex 6 is the first example of this class that exerted dual in vivo antiangiogenic and antitumor properties.

Bichromophoric ruthenium(II) bis-terpyridine-BODIPY based photosensitizers for cellular imaging and photodynamic therapy.

Two multichromophoric homoleptic ruthenium(II) complexes [Ru(tpy-BODIPY)2]Cl2 (complexes 1 and 2, tpy = 4-phenyl-2,2:6,2-terpyridine, BODIPY = boron-dipyrromethene) were prepared, characterized and their phototherapeutic activity and bioimaging properties were studied. The complexes having structural similarity differ only by a phenylethynyl linker, and its overall influence on their physicochemical and photobiological behavior was evaluated. The terpyridine-BODIPY ligand L1 was structurally characterized by X-ray crystallography. The complexes showed intense absorption near 500 nm (ε: ∼1.5 × 105 M-1 cm-1 in DMSO), have a high singlet oxygen quantum yield (ΦΔ: ∼0.6 in DMSO), and displayed low photobleaching thus making them suitable for PDT applications. The complexes showed high DNA binding affinity and induced DNA damage on light activation via multiple types of ROS production. Confocal laser scanning microscopy experiments revealed their incorporation in the cancer cells and complex 1 predominantly accumulated in lysosomes. The complexes displayed a significant PDT effect in cancerous cells with visible light activation with a high photocytotoxicity index (PI) value in HeLa cells. Both type-I and type-II photosensitization processes were involved in the PDT effect. The photodynamic action of complex 2 initiated cellular apoptosis. Finally, their diagnostic potential was evaluated against clinically relevant 3D multicellular tumor spheroids (MCTs).

Gut microbiota and age shape susceptibility to clostridial enteritis in lorikeets under human care.

BACKGROUND: Enteritis is a common cause of morbidity and mortality in lorikeets that can be challenging to diagnose and treat. In this study, we examine gut microbiota in two lorikeet flocks with enteritis (Columbus Zoo and Aquarium-CZA; Denver Zoo-DZ). Since 2012, the CZA flock has experienced repeated outbreaks of enteritis despite extensive diet, husbandry, and clinical modifications. In 2018, both CZA and DZ observed a spike in enteritis. Recent research has revealed that the gut microbiota can influence susceptibility to enteropathogens. We hypothesized that a dysbiosis, or alteration in the gut microbial community, was making some lorikeets more susceptible to enteritis, and our goal was to characterize this dysbiosis and determine the features that predicted susceptibility. RESULTS: We employed 16S rRNA sequencing to characterize the cloacal microbiota in lorikeets (CZA n = 67, DZ n = 24) over time. We compared the microbiota of healthy lorikeets, to lorikeets with enteritis, and lorikeets susceptible to enteritis, with "susceptible" being defined as healthy birds that subsequently developed enteritis. Based on sequencing data, culture, and toxin gene detection in intestinal contents, we identified Clostridium perfringens type A (CZA and DZ) and C. colinum (CZA only) at increased relative abundances in birds with enteritis. Histopathology and immunohistochemistry further identified the presence of gram-positive bacilli and C. perfringens, respectively, in the necrotizing intestinal lesions. Finally, using Random Forests and LASSO models, we identified several features (young age and the presence of Rhodococcus fascians and Pseudomonas umsongensis) associated with susceptibility to clostridial enteritis. CONCLUSIONS: We identified C. perfringens type A and C. colinum associated with lorikeet necrohemorrhagic enteritis at CZA and DZ. Susceptibility testing of isolates lead to an updated clinical treatment plan which ultimately resolved the outbreaks at both institutions. This work provides a foundation for understanding gut microbiota features that are permissive to clostridial colonization and host factors (e.g. age, prior infection) that shape responses to infection.

Underutilization of Palliative Care in Metastatic Foregut Cancer Patients Is Associated with Socioeconomic Disparities.

BACKGROUND: Metastatic foregut cancers (MFC) are associated with debilitating symptoms that negatively impact patients' quality of life. Palliative care (PC) is effective in mitigating disease-, psychosocial-, and treatment-related effects and may improve survival in select cases. Our study characterizes PC utilization rates in MFC and identifies factors associated with PC receipt. METHODS: We conducted a retrospective review of 228,027 National Cancer Database patients diagnosed with MFC between 2004 and 2016. Chi-squared tests were used to analyze differences between groups receiving and not receiving PC. Logistic regression was performed to assess the impact of factors on the likelihood of receiving PC. RESULTS: Overall PC utilization was low (17.8%). A greater proportion of patients not receiving PC were in the lowest median income quartile of < $38,000/year versus those receiving PC (18.1% vs 17.8%, p < 0.0001). Higher education was associated with increased likelihood of receiving PC (OR 1.23 for communities with < 6.3% no high school degree vs ≥ 17.6%, p < 0.0001). Hispanics were significantly less likely to receive PC compared to Whites (OR 0.72, 95% CI 0.68-0.76). Patients treated at academic centers were also more likely to receive PC compared to those treated in the community (OR 1.10, 95% CI 1.05-1.14). CONCLUSIONS: PC is a key component in improving quality of life among MFC patients. Despite slight increases in PC rates over time, PC remains drastically underutilized. Significant racial and socioeconomic disparities in patterns of PC delivery exist. Further studies are needed to understand these disparities in order to identify key targets for interventions aimed at improving equity.

Phage-specific metabolic reprogramming of virocells.

Ocean viruses are abundant and infect 20-40% of surface microbes. Infected cells, termed virocells, are thus a predominant microbial state. Yet, virocells and their ecosystem impacts are understudied, thus precluding their incorporation into ecosystem models. Here we investigated how unrelated bacterial viruses (phages) reprogram one host into contrasting virocells with different potential ecosystem footprints. We independently infected the marine Pseudoalteromonas bacterium with siphovirus PSA-HS2 and podovirus PSA-HP1. Time-resolved multi-omics unveiled drastically different metabolic reprogramming and resource requirements by each virocell, which were related to phage-host genomic complementarity and viral fitness. Namely, HS2 was more complementary to the host in nucleotides and amino acids, and fitter during infection than HP1. Functionally, HS2 virocells hardly differed from uninfected cells, with minimal host metabolism impacts. HS2 virocells repressed energy-consuming metabolisms, including motility and translation. Contrastingly, HP1 virocells substantially differed from uninfected cells. They repressed host transcription, responded to infection continuously, and drastically reprogrammed resource acquisition, central carbon and energy metabolisms. Ecologically, this work suggests that one cell, infected versus uninfected, can have immensely different metabolisms that affect the ecosystem differently. Finally, we relate phage-host genome complementarity, virocell metabolic reprogramming, and viral fitness in a conceptual model to guide incorporating viruses into ecosystem models.

Zinc Stannate Nanostructure: Is It a New Class of Material for Multifunctional Cotton Textiles?

This study demonstrates the synthesis of nano-zinc stannate and its application as a novel multifunctional finishing agent on cotton fabric. Nano-zinc stannate has been synthesized by the co-precipitation method, and the nanostructures produced have been characterized to investigate their morphology and microstructure by using scanning electron microscopy, transmission electron microscopy, and X-ray diffraction techniques. The synthesized nano-zinc stannate has been applied on cotton fabric and the multifunctional efficacies of the treated fabric, like UV resistance, antibacterial property, self-cleaning, as well as thermal stability, were analyzed. The as-synthesized zinc stannate-treated cotton fabric showed excellent efficiency in self-cleaning, antibacterial property, and flame-resistant action compared to the annealed nano-zinc stannate-treated cotton fabric. It was observed that the ultraviolet protection factor of the treated (annealed zinc stannate-treated) fabric shoot up more than 45 after treatment, and the same fabric showed more than 90% bacterial resistance against both Gram-positive and Gram-negative bacteria. Concerning thermal kinetics, the as-synthesized zinc stannate-treated fabric registered a 39% reduction in the peak heat release rate compared to the untreated cotton fabric, and it also showed catalyzed pyrolysis action and more amount of char mass (30-40% more compared to the control cotton) formation at higher temperature. The self-cleaning efficacy of the treated fabric has been examined against coffee stain and basic methylene blue dye. The treated fabric exhibited a good efficiency in cleaning of stain due to the free-radical scavenging behavior. Finally, it also has been proved that the integration of these nanostructure did not have any detrimental effect on the important physical properties (tensile strength, flexibility, and crease resistance) of the treated fabric.

Functional Brain Changes During Mindfulness-Based Cognitive Therapy Associated With Tinnitus Severity.

Mindfulness-based therapies have been introduced as a treatment option to reduce the psychological severity of tinnitus, a currently incurable chronic condition. This pilot study of twelve subjects with chronic tinnitus investigates the relationship between measures of both task-based and resting state functional magnetic resonance imaging (fMRI) and measures of tinnitus severity, assessed with the Tinnitus Functional Index (TFI). MRI was measured at three time points: before, after, and at follow-up of an 8-week long mindfulness-based cognitive therapy intervention. During the task-based fMRI with affective sounds, no significant changes were observed between sessions, nor was the activation to emotionally salient compared to neutral stimuli significantly predictive of TFI. Significant results were found using resting state fMRI. There were significant decreases in functional connectivity among the default mode network, cingulo-opercular network, and amygdala across the intervention, but no differences were seen in connectivity with seeds in the dorsal attention network (DAN) or fronto-parietal network and the rest of the brain. Further, only resting state connectivity between the brain and the amygdala, DAN, and fronto-parietal network significantly predicted TFI. These results point to a mostly differentiated landscape of functional brain measures related to tinnitus severity on one hand and mindfulness-based therapy on the other. However, overlapping results of decreased amygdala connectivity with parietal areas and the negative correlation between amygdala-parietal connectivity and TFI is suggestive of a brain imaging marker of successful treatment.

Pravastatin-induced improvement in coronary reactivity and circulating ATP and ADP levels in young adults with type 1 diabetes.

AIMS: Extracellular ATP and ADP regulate diverse inflammatory, prothrombotic and vasoactive responses in the vasculature. Statins have been shown to modulate their signaling pathways in vitro. We hypothesized that altered intravascular nucleotide turnover modulates vasodilation in patients with type 1 diabetes (T1DM), and this can be partly restored with pravastatin therapy. METHODS: In this randomized double blind study, plasma ATP and ADP levels and echocardiography-derived coronary flow velocity response to cold pressor test (CPT) were concurrently assessed in 42 normocholesterolemic patients with T1DM (age 30 ± 6 years, LDL cholesterol 2.5 ± 0.6 mmol/L) before and after four-month treatment with pravastatin 40 mg/day or placebo (n = 22 and n = 20, respectively), and in 41 healthy control subjects. RESULTS: Compared to controls, T1DM patients had significantly higher concentrations of ATP (p < 0.01) and ADP (p < 0.01) and these levels were partly restored after treatment with pravastatin (p = 0.002 and p = 0.007, respectively), but not after placebo (p = 0.06 and p = 0.14, respectively). Coronary flow velocity acceleration was significantly lower in T1DM patients compared to control subjects, and it increased from pre- to post-intervention in the pravastatin (p = 0.02), but not in placebo group (p = 0.15). CONCLUSIONS: Pravastatin treatment significantly reduces circulating ATP and ADP levels of T1DM patients, and concurrently improves coronary flow response to CPT. This study provides a novel insight in purinergic mechanisms involved in pleiotropic effects of pravastatin.