Case Report: Relapsing Leptospirosis in an Immunocompromised Host.

Leptospirosis is typically a self-limited febrile illness; when it occurs, meningitis usually develops early in the course. Here, we describe a patient who had engaged in freshwater activities in Kauai that was immunocompromised due to a history of mantle cell lymphoma, autologous hematopoietic cell transplant, and hypogammaglobulinemia. He developed leptospiral meningoencephalitis 11 weeks after illness onset and persistently detectable Leptospira DNA in blood and cerebrospinal fluid along with ongoing clinical illness, despite appropriate treatment.

A Targeted Computational Screen of the SWEETLEAD Database Reveals FDA-Approved Compounds with Anti-Dengue Viral Activity.

Affordable and effective antiviral therapies are needed worldwide, especially against agents such as dengue virus that are endemic in underserved regions. Many antiviral compounds have been studied in cultured cells but are unsuitable for clinical applications due to pharmacokinetic profiles, side effects, or inconsistent efficacy across dengue serotypes. Such tool compounds can, however, aid in identifying clinically useful treatments. Here, computational screening (Rapid Overlay of Chemical Structures) was used to identify entries in an in silico database of safe-in-human compounds (SWEETLEAD) that display high chemical similarities to known inhibitors of dengue virus. Inhibitors of the dengue proteinase NS2B/3, the dengue capsid, and the host autophagy pathway were used as query compounds. Three FDA-approved compounds that resemble the tool molecules structurally, cause little toxicity, and display strong antiviral activity in cultured cells were selected for further analysis. Pyrimethamine (50% inhibitory concentration [IC50] = 1.2 µM), like the dengue proteinase inhibitor ARDP0006 to which it shows structural similarity, inhibited intramolecular NS2B/3 cleavage. Lack of toxicity early in infection allowed testing in mice, in which pyrimethamine also reduced viral loads. Niclosamide (IC50 = 0.28 µM), like dengue core inhibitor ST-148, affected structural components of the virion and inhibited early processes during infection. Vandetanib (IC50 = 1.6 µM), like cellular autophagy inhibitor spautin-1, blocked viral exit from cells and could be shown to extend survival in vivo Thus, three FDA-approved compounds with promising utility for repurposing to treat dengue virus infections and their potential mechanisms were identified using computational tools and minimal phenotypic screening.IMPORTANCE No antiviral therapeutics are currently available for dengue virus infections. By computationally overlaying the three-dimensional (3D) chemical structures of compounds known to inhibit dengue virus over those of compounds known to be safe in humans, we identified three FDA-approved compounds that are attractive candidates for repurposing as antivirals. We identified targets for two previously identified antiviral compounds and revealed a previously unknown potential anti-dengue compound, vandetanib. This computational approach to analyze a highly curated library of structures has the benefits of speed and cost efficiency. It also leverages mechanistic work with query compounds used in biomedical research to provide strong hypotheses for the antiviral mechanisms of the safer hit compounds. This workflow to identify compounds with known safety profiles can be expanded to any biological activity for which a small-molecule query compound has been identified, potentially expediting the translation of basic research to clinical interventions.

Association of Ankle-Brachial and Toe-Brachial Indexes With Mortality in Patients With CKD.

RATIONALE & OBJECTIVE: A low ankle-brachial index (ABI) is used to diagnose peripheral artery disease (PAD) but may be normal or elevated in patients with medial arterial calcification and stiff vessels, as is common in chronic kidney disease (CKD). The toe-brachial index (TBI) has been recommended because it is not influenced by medial arterial calcification, but alone the TBI does not capture risk associated with medial arterial calcification. We hypothesized that the difference between ABI and TBI (ABI - TBI) would capture both PAD and medial arterial calcification and thus better identify mortality risk from PAD, particularly in those with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 471 patients with clinical suspicion for PAD referred for vascular testing. EXPOSURES: ABI, TBI, and ABI - TBI. OUTCOME: All-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models evaluating the association of ABI - TBI with mortality over 7 years. RESULTS: Mean age was 68 years, 89% were men, 35% had diabetes, 64% had CKD, and mean estimated glomerular filtration rate was 55 mL/min/1.73 m2. Median ABI was 0.96 (interquartile range [IQR], 0.73-1.08), median TBI was 0.62 (IQR, 0.46-0.81), and median ABI - TBI was 0.23 (IQR, 0.14-0.39). Higher ABI - TBI values were associated with increased risk in mortality only among participants with ABI values ≥ 0.9 (P = 0.03). Among participants with CKD and ABI values ≥ 0.9, participants with ABI - TBI values higher than the median had greater (HR, 1.79; 95% CI, 1.18-2.72) risk for mortality (P = 0.005). This was attenuated after age adjustment (HR, 1.41; 95% CI, 0.91-2.20) but did not change after further adjustment for confounders. LIMITATIONS: Mainly male cohort derived from a vascular laboratory; lack of limb outcomes and data for albuminuria. CONCLUSIONS: A high ABI - TBI value may be associated with higher risk for mortality in persons with CKD and a normal ABI. Age affects this association, and further studies evaluating ABI - TBI in larger populations are required.

The association of the ankle-brachial index, the toe-brachial index, and their difference, with mortality and limb outcomes in dialysis patients.

INTRODUCTION: The ankle-brachial index (ABI) is the most common test to diagnose peripheral artery disease (PAD). In dialysis patients, the ABI may under-diagnose PAD, due to a high prevalence of concomitant medial arterial calcification (MAC). The toe-brachial index (TBI) is not as susceptible to misclassification by MAC. Taking the ABI and TBI together in the form of their difference, the ABI-TBI, may provide a single measure for assessing both atherosclerosis and calcification. The relationship of these variables in dialysis patients has not been well studied. METHODS: We identified 37 dialysis patients referred for vascular studies between 2009 and 2017 in the San Diego Veterans Administration Medical Center (SDVAMC). The ABI and TBI were performed systematically for each patient, and TBI was performed regardless of ABI or waveform. We examined associations between ABI, TBI, and the difference between them (ABI-TBI) with all-cause mortality and major adverse limb events (MALE), which includes revascularizations and amputations. FINDINGS: The mean age was 65 years and 30% were African American. All patients were men, reflecting the Veterans Administration population. There were 26 deaths during follow-up and mortality was highest in patients who had low ABI and low TBI and least in those with high ABI and high TBI. Persons with TBI < 0.7 had an increased risk of all-cause mortality. The ABI-TBI, and the ABI itself, were not significantly associated with all-cause mortality although the patterns were similar. DISCUSSION: Although ABI may be an important initial risk stratification tool, the TBI may be a more informative predictor of mortality in dialysis patients. Strengths of this study include a high rate of MALE and deaths. The TBI, and the difference between ABI and TBI, should be studied further in a larger cohort of persons with advanced kidney disease.

Triphenyltin(IV) benzoates with diazenyl/imino scaffold exhibiting remarkable apoptosis mediated by reactive oxygen species.

The cytotoxic potency of a series of triphenyltin(IV) compounds of general composition [Ph3Sn(Ln)] (1-6) has been probed in vitro employing MDA-MB-231 (human breast cancer) and HeLa (human cervical cancer) cell lines, where Ln=L1-3; isomeric 2/3/4-{(E)-2-[4-(dimethylamino)phenyl]diazenyl}benzoates and L4-6 are their corresponding isoelectronic imino analogues 2/3/4-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]benzoates. Compounds 1-6 have been characterized by elemental analysis and their spectroscopic properties were studied using IR and NMR (1H, 13C, 119Sn) techniques. The molecular structures of a pro-ligand 2-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]benzoic acid (HL4) and two representative molecules, Ph3Sn(L2) 2 and Ph3Sn(L5) 5, have been determined by X-ray crystallography. Structural analyses of 2 and 5 revealed distorted tetrahedral geometries within C3O donor sets owing to monodentate modes of coordination of the respective carboxylate ligands, close intramolecular Sn…O(carbonyl) interactions notwithstanding. Cytotoxic studies in vitro in MDA-MB-231 and HeLa cell lines revealed high activity, in sub-micromolar range, for all investigated compounds. Among these, 1 and 3 exhibited potent cytotoxicity most effectively towards MDA-MB-231 cells with a IC50 value of 1.19 and 1.44µM, respectively, whereas 5 showed remarkable activity towards HeLa cells with a IC50 value of 0.88µM, yet the series of compounds had minimal cytotoxic effect on normal HEK 293 (human embryonic kidney) cell line. The underlying investigation suggested that the compounds exert potent antitumor effect by elevating intracellular reactive oxygen species generation and cause delay in cell cycle by inhibiting cells at G2/M phase. The results presented herein suggest further development of this class of triphenyltin(IV) compounds-based drugs as potential anti-cancer therapies should be pursued.

Dendrobium chrysanthum ethanolic extract induces apoptosis via p53 up-regulation in HeLa cells and inhibits tumor progression in mice.

Background Dendrobium is one of the diverse genus of orchid plants. It possesses a number of pharmacological activities and has long been used in traditional system of medicine. The goal of this study was to investigate the apoptosis inducing property of the ethanolic extract from the leaves of Dendrobium chrysanthum, a species of Dendrobium whose anticancer role has not been ascertained yet. Methods To evaluate the anticancer activity of the ethanolic extract of D. chrysanthum in vitro in HeLa (human cervical cancer) cells, cytotoxic activity, generation of reactive oxygen species (ROS), induction of apoptosis and effect on cell cycle were determined. The in vivo study was carried out in Dalton's lymphoma (DL) bearing mice to assess the tumor growth delay. Results Our study demonstrated that the ethanolic extract showed dose-dependent cytotoxicity against HeLa cells. The extract exhibited dose-dependent increase in ROS production as well as apoptotic cell death which was further confirmed through presence of DNA fragmentation. Cell cycle analysis by flow cytometry suggests that the ethanolic extract perturbed cell cycle progression and leads to the delay of the cells in S phase. Further, the real-time PCR studies also showed up-regulation of apoptotic genes p53 and Bax. The in vivo antitumor activity exhibited significant increase in the life span of DL bearing mice as compared to control with significant decrease in abdominal size along with reduced tumor ascites. Conclusions These observations demonstrate the anticancer potential of the D. chrysanthum ethanolic extract mediated through p53-dependent apoptosis.

Enhanced red upconversion emission, magnetoluminescent behavior, and bioimaging application of NaSc0.75Er0.02Yb0.18Gd0.05F4@AuNPs nanoparticles.

The present study reports significant enhancement in the red upconversion emission of Er(3+) in NaSc0.8Er0.02Yb0.18F4 upconversion nanoparticles (UCNPs), via a two step process, (i) codoping of Gd(3+) ion at Sc(3+) site and (ii) attaching gold nanoparticles (AuNPs) at the surface of these codoped nanostructures, and further probes the use of these Gd:UCNPs@AuNPs for bioimaging application. The Gd(3+) codoping tailors the particle size (reduces) of UCNPs and bring out Er(3+)-Yb(3+) ion pair in close proximity, which promotes the cross relaxation mechanism and boosts the population in red emitting level (4)F9/2. Further, attachment of AuNPs on the surface of UCNPs gives 2-fold advantages, that is, reduction in green band (through resonance energy transfer with efficiency 31.54%) and enhancement in red band (through plasmonic effect). It gives red to green (R/G) ratio nearly 20:1 (almost single band red UC), which is quite promising for imaging application. In addition to this, codoping of Gd(3+) enhances the magnetic moment appreciably and the obtained magnetic moment for NaSc0.75Er0.02Yb0.18Gd0.05F4 UCNPs (∼1.7 emu/g) is close to the reported values for bioseparation in case of NPs. This shows the potential of the material for multimodal (optical and magnetic both) imaging application. These magnetoluminescence particles were found safe up to 1 mg/mL dose as assessed by cytotoxicity measurement in human cervical cancer (HeLa) and lung cancer (A549) cells. Ultrafine nanoparticles, transparent, and stable colloidal solution and the unique red UC emission endow these NPs as optical probe for imaging applications.

Antitumor activity of ethanolic extract of Dendrobium formosum in T-cell lymphoma: an in vitro and in vivo study.

Dendrobium, a genus of orchid, was found to possess useful therapeutic activities like anticancer, hypoglycaemic, antimicrobial, immunomodulatory, hepatoprotective, antioxidant, and neuroprotective activities. The study was aimed to evaluate the anticancer property of the ethanolic extract of Dendrobium formosum on Dalton's lymphoma. In vitro cytotoxicity was determined by MTT assay, apoptosis was determined by fluorescence microscopy, and cell cycle progression was analysed using flow cytometry; in vivo antitumor activity was performed in Dalton's lymphoma bearing mice. The IC50 value of ethanolic extract was obtained at 350 µg/mL in Dalton's lymphoma cells. Fluorescence microscopy analysis showed significant increase in apoptotic cell death in dose- and time-dependent manner which was further confirmed through the resulting DNA fragmentation. Further, flow cytometry analysis showed that the ethanolic extract arrests the cells in G2/M phase of the cell cycle. The in vivo anticancer activity study illustrates significant increase in the survival time of Dalton's lymphoma bearing mice on treatment with ethanolic extract when compared to control. These results substantiate the antitumor properties of ethanolic extract of Dendrobium formosum and suggest an alternative in treatment of cancer. Further studies are required regarding the isolation and characterization of bioactive components along with the analysis of molecular mechanism involved.

DNA binding and anti-cancer activity of redox-active heteroleptic piano-stool Ru(II), Rh(III), and Ir(III) complexes containing 4-(2-methoxypyridyl)phenyldipyrromethene.

The synthesis of four novel heteroleptic dipyrrinato complexes [(η(6)-arene)RuCl(2-pcdpm)] (η(6)-arene = C6H6, 1; C10H14, 2) and [(η(5)-C5Me5)MCl(2-pcdpm)] (M = Rh, 3; Ir, 4) containing a new chelating ligand 4-(2-methoxypyridyl)-phenyldipyrromethene (2-pcdpm) have been described. The complexes 1-4 have been fully characterized by various physicochemical techniques, namely, elemental analyses, spectral (ESI-MS, IR, (1)H, (13)C NMR, UV/vis) and electrochemical studies (cyclic voltammetry (CV) and differential pulse voltammetry (DPV)). Structures of 3 and 4 have been determined crystallographically. In vitro antiproliferative and cytotoxic activity of these complexes has been evaluated by trypan blue exclusion assay, cell morphology, apoptosis, acridine orange/ethidium bromide (AO/EtBr) fluorescence staining, and DNA fragmentation assay in Dalton lymphoma (DL) cell lines. Interaction of 1-4 with calf thymus DNA (CT DNA) has also been supported by absorption titration and electrochemical studies. Our results suggest that in vitro antitumor activity of 1-4 lies in the order 2 > 1 > 4 > 3.