Blocking the angiopoietin-2-dependent integrin ß-1 signaling axis abrogates small cell lung cancer invasion and metastasis.

Small cell lung cancer (SCLC) is the most aggressive lung cancer entity with an extremely limited therapeutic outcome. Most patients are diagnosed at an extensive stage. However, the molecular mechanisms driving SCLC invasion and metastasis remain largely elusive. We used an autochthonous SCLC mouse model and matched samples from patients with primary and metastatic SCLC to investigate the molecular characteristics of tumor metastasis. We demonstrate that tumor cell invasion and liver metastasis in SCLC are triggered by an Angiopoietin-2 (ANG-2)/Integrin ß-1-dependent pathway in tumor cells, mediated by focal adhesion kinase/Src kinase signaling. Strikingly, CRISPR-Cas9 KO of Integrin ß-1 or blocking Integrin ß-1 signaling by an anti-ANG-2 treatment abrogates liver metastasis formation in vivo. Interestingly, analysis of a unique collection of matched samples from patients with primary and metastatic SCLC confirmed a strong increase of Integrin ß-1 in liver metastasis in comparison with the primary tumor. We further show that ANG-2 blockade combined with PD-1-targeted by anti-PD-1 treatment displays synergistic treatment effects in SCLC. Together, our data demonstrate a fundamental role of ANG-2/Integrin ß-1 signaling in SCLC cells for tumor cell invasion and liver metastasis and provide a potentially new effective treatment strategy for patients with SCLC.

Effects of Intrathecal Morphine Administration in Patients Undergoing Primary Total Hip Arthroplasty Under Spinal Anesthesia With Quadratus Lumborum Block for Postoperative Analgesia.

Introduction Quadratus lumborum (QL) block has previously been shown to provide improved analgesia in patients undergoing primary total hip arthroplasty (THA) under spinal anesthesia when compared to spinal anesthesia alone. Additionally, recent studies have shown the addition of intrathecal morphine (ITM) to provide superior postoperative analgesia in patients undergoing various surgical interventions including total knee arthroplasty under spinal anesthesia with peripheral nerve blockade. At this time, however, there has not been a study evaluating the effects of intrathecal morphine in patients undergoing THA under spinal anesthesia with QL block. This study aims to assess if the addition of intrathecal morphine can provide adequate or even superior postoperative analgesia in patients undergoing primary THA. Methods This retrospective study included 26 patients in the spinal/QL block/intrathecal morphine (SA+QLB+ITM) group, 31 patients in the spinal/QL block group (SA+QLB), and 28 patients in the spinal only (SA or control) group. Twenty-six patients undergoing primary THA under a combination of spinal anesthesia and peripheral nerve blockade (quadratus lumborum block) were given a dose of 100 mcg of intrathecal morphine. Various parameters were evaluated including Post-Anesthesia Care Unit (PACU) and 24-hour visual analog scale (VAS) scores, time to first opioid use, 24- and 48-hour total opioid use as oral morphine equivalents (OME), 24-hour ambulation distance, and time from block placement to hospital discharge. The results were analyzed and compared to patients undergoing primary THA under spinal anesthesia with QL block (no intrathecal morphine) and compared to a control group of patients undergoing primary THA under spinal anesthesia only. Results The study analysis included 26 patients in the SA+QLB+ITM group, 31 patients in the SA+QLB group, and 28 patients in the SA (control) group. When compared with the control group, the SA+QLB+ITM had lower 24-hour total opioid usage (mean difference 20.80 OME, CI 6.454 to 35.15, p-value 0.0025), longer time to 1st opioid use (mean difference -20.51 hours later, p-value .0052), lower 24-hr VAS (difference 2.421, p-value 0.0012, CI 0.8559 to 3.987), and faster time to discharge (16.00 hr earlier, p-value 0.0459). When compared to the SA+QLB group, the SA+QLB+ITM group only showed a statistically significant difference in faster time to discharge (19.46 hr earlier, p-value 0.0068). However, while there was no statistically significant difference in time to 1st opioid use between the control and SA+QLB group, the difference did become significant when comparing the control to the SA+QLB+ITM group (mean difference -20.51 hours later (p-value .0052). There was no significant difference in either of the three groups in ambulation distance at 24 hours, PACU VAS, or 48-hour total opioid use. Conclusion Our study concludes that the addition of 100 mcg ITM for total hip arthroplasty under spinal anesthesia improved postoperative analgesia compared to the control group. Also, the ITM group did better with respect to delay in first opioid use and decreased hospital stay compared to the control and block-only groups. Our study warrants no more concerns of PONV, pruritus, or respiratory depression with this dose of ITM and requires standard postoperative care.

Complete genome sequence of Brucella abortus isolated from a human blood culture sample in Tanzania.

Brucella abortus causes infections in humans and livestock. Bacterial isolates are challenging to obtain, and very little is known about the genomic epidemiology of this species in Africa. Here, we report the complete genome sequence of a Brucella abortus isolate cultured from a febrile human in northern Tanzania.

Genomic Diversity and Zoonotic Potential of Brucella neotomae.

After reports in 2017 of Brucella neotomae infections among humans in Costa Rica, we sequenced 12 strains isolated from rodents during 1955-1964 from Utah, USA. We observed an exact strain match between the human isolates and 1 Utah isolate. Independent confirmation is required to clarify B. neotomae zoonotic potential.

Intrathecal Morphine Use Improves Postoperative Analgesia and Reduces Opioid Consumption in Patients Undergoing Total Knee Arthroplasty Under Spinal Anesthesia: A Retrospective Study.

Background Intrathecal morphine (ITM) provides effective postoperative analgesia for patients undergoing total knee arthroplasty (TKA) under spinal anesthesia (SA). The management of pain in patients undergoing TKA has remained a challenge for anesthesiologists, as no single regional anesthesia technique is adequate with regard to balancing effective analgesia with minimal side effects. Severe postoperative pain following TKA has been shown to negatively impact patient outcomes and mortality. This study is aimed to describe the effect of intrathecal morphine in patients undergoing total knee arthroplasty. Methods This was a retrospective, descriptive, and single-center study conducted on patients undergoing total knee arthroplasty from June 1, 2022, to June 1, 2023. The sample size consisted of 50 patients who were 18 years and older, American Society of Anesthesiology (ASA) class 1-3, and patients who had received either 150 mcg (experimental) or no ITM dose under spinal anesthesia. Oral morphine requirement (OME) and visual analog pain scale (VAS) were used to assess pain in the first 24 hours after surgery. Results The experimental group had significantly lower OME usage in the post-anesthesia care unit (PACU) (p < 0.001) and at six hours (p = 0.040) postoperatively. At 12 hours and 24 hours postoperatively, the two groups had similar OME use (p > 0.20, for both). The experimental group had significantly less total OME use over the first 24-hour postoperative period. The experimental group had significantly lower pain scores in the PACU (p < 0.001) and at six hours postop (p = 0.002); there were no significant differences between groups at 12- and 24-hours postop. The ambulation distance was clinically significant and better in the ITM group but was not statistically significant (p = 0.080). There was no difference between groups in the incidence of postoperative nausea and vomiting (PONV). Conclusion The careful use of ITM with the optimal dose offers an effective addition to regional anesthesia for improved analgesia with minimal side effects. The 150 mcg ITM dose provided good analgesic effects with longer duration and was not associated with respiratory depression.

Zoonotic tuberculosis in a high bovine tuberculosis burden area of Ethiopia.

Background: Tuberculosis (TB) is a major cause of ill health and one of the leading causes of death worldwide, caused by species of the Mycobacterium tuberculosis complex (MTBC), with Mycobacterium tuberculosis being the dominant pathogen in humans and Mycobacterium bovis in cattle. Zoonotic transmission of TB (zTB) to humans is frequent particularly where TB prevalence is high in cattle. In this study, we explored the prevalence of zTB in central Ethiopia, an area highly affected by bovine TB (bTB) in cattle. Method: A convenient sample of 385 patients with pulmonary tuberculosis (PTB, N = 287) and tuberculous lymphadenitis (TBLN, N = 98) were included in this cross-sectional study in central Ethiopia. Sputum and fine needle aspirate (FNA) samples were obtained from patients with PTB and TBLN, respectively, and cultures were performed using BACTEC™ MGIT™ 960. All culture positive samples were subjected to quantitative PCR (qPCR) assays, targeting IS1081, RD9 and RD4 genomic regions for detection of MTBC, M. tuberculosis and M. bovis, respectively. Results: Two hundred and fifty-five out of 385 sampled patients were culture positive and all were isolates identified as MTBC by being positive for the IS1081 assay. Among them, 249 (97.6%) samples had also a positive RD9 result (intact RD9 locus) and were consequently classified as M. tuberculosis. The remaining six (2.4%) isolates were RD4 deficient and thereby classified as M. bovis. Five out of these six M. bovis strains originated from PTB patients whereas one was isolated from a TBLN patient. Occupational risk and the widespread consumption of raw animal products were identified as potential sources of M. bovis infection in humans, and the isolation of M. bovis from PTB patients suggests the possibility of human-to-human transmission, particularly in patients with no known contact history with animals. Conclusion: The detected proportion of culture positive cases of 2.4% being M. bovis from this region was higher zTB rate than previously reported for the general population of Ethiopia. Patients with M. bovis infection are more likely to get less efficient TB treatment because M. bovis is inherently resistant to pyrazinamide. MTBC species identification should be performed where M. bovis is common in cattle, especially in patients who have a history of recurrence or treatment failure.

Somatic rearrangements causing oncogenic ectodomain deletions of FGFR1 in squamous cell lung cancer.

The discovery of frequent 8p11-p12 amplifications in squamous cell lung cancer (SQLC) has fueled hopes that FGFR1, located inside this amplicon, might be a therapeutic target. In a clinical trial, only 11% of patients with 8p11 amplification (detected by FISH) responded to FGFR kinase inhibitor treatment. To understand the mechanism of FGFR1 dependency, we performed deep genomic characterization of 52 SQLCs with 8p11-p12 amplification, including 10 tumors obtained from patients who had been treated with FGFR inhibitors. We discovered somatically altered variants of FGFR1 with deletion of exons 1-8 that resulted from intragenic tail-to-tail rearrangements. These ectodomain-deficient FGFR1 variants (ΔEC-FGFR1) were expressed in the affected tumors and were tumorigenic in both in vitro and in vivo models of lung cancer. Mechanistically, breakage-fusion-bridges were the source of 8p11-p12 amplification, resulting from frequent head-to-head and tail-to-tail rearrangements. Generally, tail-to-tail rearrangements within or in close proximity upstream of FGFR1 were associated with FGFR1 dependency. Thus, the genomic events shaping the architecture of the 8p11-p12 amplicon provide a mechanistic explanation for the emergence of FGFR1-driven SQLC. Specifically, we believe that FGFR1 ectodomain-deficient and FGFR1-centered amplifications caused by tail-to-tail rearrangements are a novel somatic genomic event that might be predictive of therapeutically relevant FGFR1 dependency.

Sociodemographic Disparities in Postoperative Nausea and Vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) prophylaxis is consistently considered a key indicator of anesthesia care quality. PONV may disproportionately impact disadvantaged patients. The primary objectives of this study were to examine the associations between sociodemographic factors and the incidence of PONV and clinician adherence to a PONV prophylaxis protocol. METHODS: We conducted a retrospective analysis of all patients eligible for an institution-specific PONV prophylaxis protocol (2015-2017). Sociodemographic and PONV risk data were collected. Primary outcomes were PONV incidence and clinician adherence to PONV prophylaxis protocol. We used descriptive statistics to compare sociodemographics, procedural characteristics, and protocol adherence for patients with and without PONV. Multivariable logistic regression analysis followed by Tukey-Kramer correction for multiple comparisons was used to test for associations between patient sociodemographics, procedural characteristics, PONV risk, and (1) PONV incidence and (2) adherence to PONV prophylaxis protocol. RESULTS: Within the 8384 patient sample, Black patients had a 17% lower risk of PONV than White patients (adjusted odds ratio [aOR], 0.83; 95% confidence interval [CI], 0.73-0.95; P = .006). When there was adherence to the PONV prophylaxis protocol, Black patients were less likely to experience PONV compared to White patients (aOR, 0.81; 95% CI, 0.70-0.93; P = .003). When there was adherence to the protocol, patients with Medicaid were less likely to experience PONV compared to privately insured patients (aOR, 0.72; 95% CI, 0.64-1.04; P = .017). When the protocol was followed for high-risk patients, Hispanic patients were more likely to experience PONV than White patients (aOR, 2.96; 95% CI, 1.18-7.42; adjusted P = .022). Compared to White patients, protocol adherence was lower for Black patients with moderate (aOR, 0.76; 95% CI, 0.64-0.91; P = .003) and high risk (aOR, 0.57; 95% CI, 0.42-0.78; P = .0004). CONCLUSIONS: Racial and sociodemographic disparities exist in the incidence of PONV and clinician adherence to a PONV prophylaxis protocol. Awareness of such disparities in PONV prophylaxis could improve the quality of perioperative care.

Whole genome sequencing of Ethiopian Brucella abortus isolates expands the known diversity of an early branching sub-Saharan African lineage.

Brucellosis remains one of the most significant zoonotic diseases globally, responsible for both considerable human morbidity and economic losses due to its impacts on livestock productivity. Despite this, there remain significant evidence gaps in many low- and middle-income countries, including those of sub-Saharan Africa. Here we report the first molecular characterisation of Brucella sp. from Ethiopia. Fifteen Brucella sp. isolates from an outbreak in cattle from a herd in central Ethiopia were identified as Brucella abortus, using bacterial culture and molecular methods. Sequencing of the Ethiopian B. abortus isolates allowed their phylogenetic comparison with 411 B. abortus strains of diverse geographical origins, using whole genome single nucleotide polymorphisms (wgSNP). The Ethiopian isolates belonged to an early-branching lineage (Lineage A) previously only represented by data from two strains, both of sub-Saharan African origin (Kenya and Mozambique). A second B. abortus lineage (Lineage B), also comprised solely of strains originating from sub-Saharan Africa, was identified. The majority of strains belonged to one of two lineages of strains originating from a much broader geographical range. Further analyses based on multi-locus sequence typing (MLST) and multi-locus variable-number tandem repeat analysis (MLVA) expanded the number of B. abortus strains available for comparison with the Ethiopian isolates and were consistent with the findings from wgSNP analysis. MLST profiles of the Ethiopian isolates expanded the sequence type (ST) diversity of the early branching lineage of B. abortus, equivalent to wgSNP Lineage A. A more diverse cluster of STs, equivalent to wgSNP Lineage B, was comprised solely of strains originating from sub-Saharan Africa. Similarly, analysis of B. abortus MLVA profiles (n = 1891) confirmed that the Ethiopian isolates formed a unique cluster, similar to only two existing strains, and distinct from the majority of other strains of sub-Saharan African origin. These findings expand the known diversity of an under-represented lineage of B. abortus and suggest a potential evolutionary origin for the species in East Africa. In addition to providing information concerning Brucella species extant within Ethiopia this work serves as the basis for further studies on the global population structure and evolutionary history of a major zoonotic pathogen.

Mimonoside D: a new triterpenoid saponin from Mimosa diplotricha Sauvalle (Fabaceae).

A new triterpenoid saponin (Mimonoside D: 3-O-α-L-arabinopyranosyl-3ß-hydroxyolean-12-en-28-oic acid 28-O-ß-D-xylopyranosyl-(1→2)-ß-D- glucopyranoside ester (1)) was isolated from the aerial parts of Mimosa diplotricha Sauvalle together with nine known compounds: 7,4'-dihydroxyflavone (2), kaempferol (3), lupeol (4), betulinic acid (5), ß-sitosterol (6), ß-sitosterol-3-O-ß-D-glucopyranoside (7), lutein (8), 5,2'-dihydroxy-7,4',5'-trimethoxyflavone (9) and vitexin (10). Their structures were elucidated on the basis of spectroscopic (1 D and 2 D nuclear magnetic resonance) and high-resolution mass spectrometric data as well as by comparison of their spectral data with those of related compounds. Compounds 2, 7 and 8 had already been isolated from M. diplotricha, while compounds 3, 4, 5 and 6 have been isolated from other Mimosa species. Compound 2 moderately inhibited Proteus mirabilis (MIC = 32 µg/mL), weakly inhibited Pseudomonas aeruginosa (MIC = 64 µg/mL) and very weakly inhibited Staphylococcus aureus (MIC = 128 µg/mL) and Enterococus faecalis (MIC = 128 µg/mL).

Trophoblast Cell Surface Antigen 2 (TROP2) as a Predictive Bio-Marker for the Therapeutic Efficacy of Sacituzumab Govitecan in Adenocarcinoma of the Esophagus.

INTRODUCTION: The Trophoblast cell surface antigen 2 (TROP2) is expressed in many carcinomas and may represent a target for treatment. Sacituzumab govitecan (SG) is a TROP2-directed antibody-drug conjugate (ADC). Nearly nothing is known about the biological effectiveness of SG in esophageal adenocarcinoma (EAC). MATERIAL AND METHODS: We determined the TROP2 expression in nearly 600 human EAC. In addition, we used the EAC cell lines (ESO-26, OACM5.1C, and FLO-1) and a xenograft mouse model to investigate this relationship. RESULTS: Of 598 human EACs analyzed, 88% showed varying degrees of TROP2 positivity. High TROP2 positive ESO-26 and low TROP2 positive OACM5.1C showed high sensitivity to SG in contrast to negative FLO-1. In vivo, the ESO-26 tumor shows a significantly better response to SG than the TROP2-negative FLO-1 tumor. ESO-26 vital tumor cells show similar TROP2 expression on all carcinoma cells as before therapy initiation, FLO-1 is persistently negative. DISCUSSION: Our data suggest that sacituzumab govitecan is a new therapy option in esophageal adenocarcinoma and the TROP2 expression in irinotecan-naïve EAC correlates with the extent of treatment response by sacituzumab govitecan. TROP2 is emerging as a predictive biomarker in completely TROP2-negative tumors. This should be considered in future clinical trials.

Tripartite antigen-agnostic combination immunotherapy cures established poorly immunogenic tumors.

BACKGROUND: Single-agent immunotherapy has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response. Combination immunotherapy approaches that are effective in such poorly immunogenic tumors mostly rely on precise knowledge of antigenic determinants on tumor cells. Creating an antigen-agnostic combination immunotherapy that is effective in poorly immunogenic tumors for which an antigenic determinant is not known is a major challenge. METHODS: We use multiple cell line and poorly immunogenic syngeneic, autochthonous, and autologous mouse models to evaluate the efficacy of a novel combination immunotherapy named tripartite immunotherapy (TRI-IT). To elucidate TRI-ITs mechanism of action we use immune cell depletions and comprehensive tumor and immune infiltrate characterization by flow cytometry, RNA sequencing and diverse functional assays. RESULTS: We show that combined adoptive cellular therapy (ACT) with lymphokine-activated killer cells, cytokine-induced killer cells, Vγ9Vδ2-T-cells (γδ-T-cells) and T-cells enriched for tumor recognition (CTLs) display synergistic antitumor effects, which are further enhanced by cotreatment with anti-PD1 antibodies. Most strikingly, the full TRI-IT protocol, a combination of this ACT with anti-PD1 antibodies, local immunotherapy of agonists against toll-like receptor 3, 7 and 9 and pre-ACT lymphodepletion, eradicates and induces durable anti-tumor immunity in a variety of poorly immunogenic syngeneic, autochthonous, as well as autologous humanized patient-derived models. Mechanistically, we show that TRI-IT coactivates adaptive cellular and humoral, as well as innate antitumor immune responses to mediate its antitumor effect without inducing off-target toxicity. CONCLUSIONS: Overall, TRI-IT is a novel, highly effective, antigen-agnostic, non-toxic combination immunotherapy. In this study, comprehensive insights into its preclinical efficacy, even in poorly immunogenic tumors, and mode of action are given, so that translation into clinical trials is the next step.

EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer.

EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC.

Anticandidal activity of green synthesised silver nanoparticles and extract loaded chitosan nanoparticles of Euphorbia prostata.

This study aimed to synthesize the silver nanoparticles (SNPs) and loaded chitosan nanoparticles (LCNPs) using Euphorbia prostata based on their anticandidal activity. Antioxidant capacity and the total phenolic and total flavonoid content of plant samples and synthesized nanoparticles (NPs) were also evaluated. SNPs and LCNPs were prepared, respectively using chemical reduction of silver salt solution and ionotropic gelation method. The anticandidal activity was assessed by broth micro-dilution method and the antioxidant activity was determined using free-radical scavenging assays. The synthesized NPs after the optimization process were found to be spherical with sizes ranging from 12 to 100 nm. Spectroscopic analysis of NPs showed the appearance of peaks in prescribed wavelength ranging between 402 and 493 nm. The synthesized NPs showed potent anticandidal activity compared to the free extract. The SNPs formulations NpEPM 7.5 and NpEPMR 7.5, showed significantly low MIC values ranging between 2 and 128 µg/mL. In the case of LCNPs, NpEPM (4:1) and NpEPME (4:1) also showed lower MIC values ranging from 32 to 256 µg/mL. The plant samples as well as NPs showed antioxidant potential. In addition, plant extracts and NPs possess the potent biological potential and can be further investigated through in vivo experiments.

Anaplastic Large Cell Lymphoma Presenting as Ulcerative Facial Mass: A Case Report.

Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin lymphoma (NHL) that can be aggressive with rapid speed, thus mandating a timely diagnosis to optimize treatment and deter progression. NHL classically presents with lymphadenopathy and constitutional symptoms. However, ALCL can present with nonspecific cutaneous manifestations with minimal or absent constitutional symptoms. The cutaneous involvement may resemble common dermatologic conditions, delaying diagnosis. We present a case of an aggressive cutaneous ALCL lesion mimicking facial cellulitis that rapidly progressed from a small comedone to a large, exophytic mass over the course of 1 month. Prior to presentation at our institution, the patient was previously diagnosed and treated for suspected bacterial infection with no response to therapy. Core needle biopsy of the forehead lesion confirmed the diagnosis of anaplastic lymphoma kinase-negative ALCL. Chemotherapy with brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone was planned for a total of 6-8 cycles with curative intent. By cycle 5, positron emission tomography and computed tomography demonstrated response to therapy with no enlarged or metabolically active lymph nodes appreciated. Our case report highlights the importance of developing a broad differential diagnosis for ulcerative facial masses, particularly when unresponsive to antimicrobial therapies. Lymphomas should be included in the differential diagnosis of patients with rapidly growing facial lesions.

New antimicrobial cyclolignan and others constituents from the leaves of Scyphocephalium mannii (Benth. & Hook.f.) Warb.

Chemical investigation of the MeOH extract of the leaves of Scyphocephalium mannii (Benth. & Hook.f.) Warb. (Myristicaceae) led to the isolation and characterization of one new metabolite (+)-(7'S, 8S, 8'S)-4,4'-dihydroxy-3,3',5,5'-tetramethoxy-2,7'-cyclolignan (1) along with five known compounds. Their structures were elucidated by spectroscopic means, including 1 D and 2 D NMR, HRESI-MS and by comparison with published data. The absolute configuration of compound 1 was determined by single-crystal X-RAY diffraction. Compound 1 showed moderate antifungal activity against Cryptococcus neoformans with respective MIC and MMC values of 64 and 256 µg/mL.

Molecular characterization of zoonotic Brucella species isolated from animal and human samples in Iran.

Brucellosis is an endemic infection in Iran and represents a serious health problem in humans and livestock causing important economic losses. The objective of this study was to undertake molecular characterization of Brucella spp. isolated from humans and livestock in several provinces of Iran including by multi-locus sequence typing (MLST), in order to understand the genotypes circulating in Iran and their relationship to genotypes globally. A total of 23 Brucella isolates were isolated from eight milk samples (seven cows, and one camel), human blood samples (seven), bovine lymph nodes (two), and samples from aborted fetuses (three sheep, two cows, and one goat). Phenotypic and molecular identification of Brucella isolates was performed on all isolated bacteria and showed that all were either Brucella melitensis or Brucella abortus. B. melitensis was associated with ovine/caprine and camel samples, most human isolates, and a significant minority of cattle isolates. In contrast B. abortus from livestock was associated only with isolations from bovine samples, as well as a single human sample. These results indicate that both B. melitensis and B. abortus contribute to the human brucellosis burden in Iran. B. melitensis isolates comprised three MLST-9 genotypes, the common and globally distributed ST8, a single representative of ST7, and several additional examples of ST102, a genotype previously only reported in a single isolate from a human brucellosis case believed to be acquired through travel to Iran. B. abortus isolates represented two globally common MLST-9 genotypes (ST1 and ST2), with relationships to biotype and other PCR-based typing methods consistent with previous observations. The results provide the basis for further studies examining the molecular epidemiology of Brucella circulating in Iran and the relationships of local isolates to those present globally.

Guanidinium solvents with exceptional hydrogen bond donating abilities.

Guanidinium chloride-based solvents have been prepared using deep eutectic solvent principles. Strong hydrogen-bond (H-bond) donating abilities are established based on a range of measures of solvent polarity, including a novel 31P NMR chemical shift method. The physical properties and origin of the strong H-bonding ability of these solvents have been explored.

Spectral and lifetime resolution of fundus autofluorescence in advanced age-related macular degeneration revealing different signal sources.

PURPOSE: To determine the fundus autofluorescence (FAF) lifetimes and spectral characteristics of individual drusen and hyperpigmentation independent of those with retinal pigment epithelium (RPE) in geographic atrophy (GA) areas in late-stage age-related macular degeneration (AMD). METHODS: Three consecutive patients with complete RPE and outer retinal atrophy (cRORA) exhibiting drusen that were calcified or associated with hyperpigmentation were investigated with multimodal non-invasive ophthalmic imaging including colour fundus photography (CFP), optical coherence tomography (OCT), near-infrared reflectance (NIR), blue FAF and fluorescence lifetime imaging ophthalmoscopy (FLIO). Fluorescence lifetimes were measured in two spectral channels (short-wavelength spectral channel (SSC): 500-560 nm and long-wavelength spectral channel (LSC): 560-720 nm). RESULTS: Drusen lacking RPE coverage, as confirmed by CFP and OCT, had longer FAF lifetimes than surrounding cRORA by 127 ± 66 ps (SSC) and 113 ± 48 ps (LSC, both p = 0.008 in Wilcoxon test, N = 9) and by 209 ± 100 ps (SSC) and 121 ± 56 ps (LSC, p < 0.001, N = 14) in two patients. Hyperpigmentation in CFP in a third patient shows strong FAF with prolonged lifetimes. In the SSC, persistent FAF was found inside cRORA. A crescent-shaped hyperfluorescence in an area of continuous RPE but lacking outer retina was seen in one eye with a history of anti-VEGF treatment. CONCLUSIONS: Short-wavelength fluorescence in cRORA points to fluorophores beyond RPE organelles. Fluorescence properties of drusen within cRORA differ from in vivo drusen covered by RPE. These limited findings from three patients give new insight into the sources of FAF that can be further elucidated in larger cohorts.