Novel South African Rare Actinomycete Kribbella speibonae Strain SK5: A Prolific Producer of Hydroxamate Siderophores Including New Dehydroxylated Congeners.

In this paper, we report on the chemistry of the rare South African Actinomycete Kribbella speibonae strain SK5, a prolific producer of hydroxamate siderophores and their congeners. Two new analogues, dehydroxylated desferrioxamines, speibonoxamine 1 and desoxy-desferrioxamine D1 2, have been isolated, together with four known hydroxamates, desferrioxamine D1 3, desferrioxamine B 4, desoxy-nocardamine 5 and nocardamine 6, and a diketopiperazine (DKP) 7. The structures of 1-7 were characterized by the analysis of HRESIMS and 1D and 2D NMR data, as well as by comparison with the relevant literature. Three new dehydroxy desferrioxamine derivatives 8-10 were tentatively identified in the molecular network of K. speibonae strain SK5 extracts, and structures were proposed based on their MS/MS fragmentation patterns. A plausible spb biosynthetic pathway was proposed. To the best of our knowledge, this is the first report of the isolation of desferrioxamines from the actinobacterial genus Kribbella.

Estimating vocal repertoire size is like collecting coupons: a theoretical framework with heterogeneity in signal abundance.

Vocal repertoire size is an important behavioural measure in songbirds and mammals with complex vocal communication systems, and has traditionally been used as an indicator of individual fitness, cognitive ability, and social structure. Estimates of asymptotic repertoire size have typically been made using curve fitting techniques. However, the exponential model usually applied in these techniques has never been provided with a theoretical justification based on probability theory, and the model has led to inaccurate estimates. We derived the precise expression for the expected number of distinct signal types observed for a fixed sampling effort: a variation of what is known in the statistical literature as the "Coupon Collector׳s problem". We used empirical data from three species (northern mockingbird, Carolina chickadee, and rock hyrax) to assess the performance of the Coupon Collector model compared to commonly used techniques, such as exponential fitting and repertoire enumeration, and also tested the different models against simulated artificial data sets with the statistical properties of the empirical data. We found that when signal probabilities are dissimilar, the Coupon Collector model provides far more accurate estimates of repertoire size than traditional techniques. Enumeration and exponential curve fitting greatly underestimated repertoire size, despite appearing to have reached saturation. Application of the Coupon Collector model can generate more accurate estimates of repertoire size than the commonly used exponential model of repertoire discovery, and could go a long way towards re-establishing repertoire size as a useful indicator in animal communication research.

"All things must pass" - Cutaneous migration of an endobronchial valve.

The Zephyr (PulmonX Inc., Redwood, CA) endobronchial valve (EBV), predominantly designed for lung volume reduction in emphysema, can also be used to close a spontaneous or post-operative prolonged air leak (PAL). We describe a previously unreported complication of cutaneous migration of an EBV, inserted for management of a PAL from a postoperative bronchopleural fistula (BPF), in a 62-year-old male following a right upper lobe posterior-apical (S1,2) segmentectomy. His PAL resulted in a chronic empyema which failed to respond to surgical debridement, anterior cavernostomy and pectoral myoplasty. Bronchoscopic closure of the air leak by EBV insertion resulted in clinical improvement but there was a residual chronic wound sinus through which the patient reported protrusion of a foreign body that was causing irritation. It was the EBV. We hypothesise that the BPF healed beneath the EBV causing it to dislodge but its route to the skin remains a mystery.

Identification of Antimycobacterial Natural Products from a Library of Marine Invertebrate Extracts.

Tuberculosis (TB) remains a public health crisis, requiring the urgent identification of new anti-mycobacterial drugs. We screened several organic and aqueous marine invertebrate extracts for their in vitro inhibitory activity against the causative organism, Mycobacterium tuberculosis. Here, we report the results obtained for 54 marine invertebrate extracts. The chemical components of two of the extracts were dereplicated, using 1H NMR and HR-LCMS with GNPS molecular networking, and these extracts were further subjected to an activity-guided isolation process to purify the bioactive components. Hyrtios reticulatus yielded heteronemin 1 and Jaspis splendens was found to produce the bengamide class of compounds, of which bengamides P 2 and Q 3 were isolated, while a new derivative, bengamide S 5, was putatively identified and its structure predicted, based on the similarity of its MS/MS fragmentation pattern to those of other bengamides. The isolated bioactive metabolites and semi-pure fractions exhibited M. tuberculosis growth inhibitory activity, in the range <0.24 to 62.50 µg/mL. This study establishes the bengamides as potent antitubercular compounds, with the first report of whole-cell antitubercular activity of bengamides P 2 and Q 3.

Mockingbird Morphing Music: Structured Transitions in a Complex Bird Song.

The song of the northern mockingbird, Mimus polyglottos, is notable for its extensive length and inclusion of numerous imitations of several common North American bird species. Because of its complexity, it is not widely studied by birdsong scientists. When they do study it, the specific imitations are often noted, and the total number of varying phrases. What is rarely noted is the systematic way the bird changes from one syllable to the next, often with a subtle transition where one sound is gradually transformed into a related sound, revealing an audible and specific compositional mode. It resembles a common strategy in human composing, which can be described as variation of a theme. In this paper, we present our initial attempts to describe the specific compositional rules behind the mockingbird song, focusing on the way the bird transitions from one syllable type to the next. We find that more often than chance, syllables before and after the transition are spectrally related, i.e., transitions are gradual, which we describe as morphing. In our paper, we categorize four common modes of morphing: timbre change, pitch change, squeeze (shortening in time), and stretch (lengthening in time). This is the first time such transition rules in any complex birdsong have been specifically articulated.

Preoperative Physical Activity Predicts Surgical Outcomes Following Lung Cancer Resection.

OBJECTIVES: To assess whether preoperative levels of physical activity predict the incidence of post-operative complications following anatomical lung resection. METHODS: Levels of physical activity (daily steps) were measured for 15 consecutive days using pedometers in 90 consecutive patients (prior to admission). Outcomes measured were cardiac and respiratory complications, length of stay, and 30-day re-admission rate. RESULTS: A total of 78 patients' datasets were analysed (12 patients were excluded due to non-compliance). Based on steps performed they were divided into quartiles; 1 (low physical activity) to 4 (high physical activity). There were no significant differences in age, smoking history, COPD, BMI, percentage predicted FEV1 and KCO and cardiovascular risk factors between the groups. There were significantly fewer total complications in quartiles 3 and 4 (high physical activity) compared to quartiles 1 and 2 (low physical activity) (8 vs 22; P = .01). There was a trend (P > .05) towards shorter hospital length of stay in quartiles 3 and 4 (median values of 4 and 5 days, respectively) compared to quartiles 1 and 2 (6 days for both groups). CONCLUSIONS: Preoperative physical activity can help to predict postoperative outcome and can be used to stratify risk of postoperative complications and to monitor impact of preoperative interventions, ultimately improving short term outcomes.

Conjugates of plumbagin and phenyl-2-amino-1-thioglucoside inhibit MshB, a deacetylase involved in the biosynthesis of mycothiol.

N-Acetylglucosaminylinositol (GlcNAc-Ins)-deacetylase (MshB) and mycothiol-S-conjugate amidase (Mca), structurally related amidases present in mycobacteria and other Actinomycetes, are involved in the biosynthesis of mycothiol and in the detoxification of xenobiotics as their mycothiol-S-conjugates, respectively. With substrate analogs of GlcNAc-Ins, MshB showed a marked preference for inositol as the aglycon present in GlcNAc-Ins. The inhibition of MshB and Mca by 10 thioglycosides, 7 cyclohexyl-2-deoxy-2-C-alkylglucosides, and 4 redox cyclers was evaluated. The latter contained plumbagin tethered via 2 to 5 methylene carbons and an amide linkage to phenyl-2-deoxy-2-amino-1-thio-alpha-d-glucopyranoside. These proved to be the most potent amongst the 21 compounds tested as inhibitors of MshB. Their inhibitory potency varied with the length of the spacer, with the compound with longest spacer being the most effective.

Note types and coding in Parid vocalizations: the chick-a-dee call of the chestnut-backed chickadee (Poecile rufuscens).

A first step to understanding how a species communicates acoustically is to identify, categorize, and quantify the acoustic parameters of the elements that make up their vocalizations. The "chick-a-dee" call notes of the chestnut-backed chickadee (Poecile rufescens) were sorted into four call note categories, A, C, D, and Dh notes, based on their acoustic structure as observed in sound spectrograms, and evaluated based on the syntactical ordering of the note types within calls. The notes were then analyzed using quantitative measures and it was determined which features have the potential to convey information to discriminate note type, individual, and the geographic origin of the producer. The findings were comparable to previous research of congeners in that chestnut-backed chickadee calls were produced with a relatively fixed syntax and contained similarly structured note types across all geographic regions. Overall this information will form a base for future research on chestnut-backed chickadee vocalizations and will strengthen the foundation for future comparative evolutionary studies.

Mockingbirds imitate frogs and toads across North America.

Vocal mimicry is taxonomically widespread among birds, but little is known about mimicry of non-avian models. Prior studies show preferential imitation of avian models whose sounds are acoustically similar to the non-imitative songs of the vocal mimic. Based on these studies and anecdotes about frog imitations by northern mockingbirds (Mimus polyglottos), we hypothesized which anuran models would be most likely to get imitated by mockingbirds across their geographic range. We tested our hypothesis using >40 h of archived mockingbird recordings. Our results showed that mockingbirds imitated at least 12 anuran species, and calls were disproportionately mimicked when they contained dominant frequencies within the vocal range of the mockingbird (750-7000 Hz). Mockingbirds also frequently modified model anuran sounds by leaving out formants and/or truncating call duration. Our results represent the most comprehensive survey for any mimicking species of the imitation of anurans.

Anti-mycobacterial activity of five plant species used as traditional medicines in the Western Cape Province (South Africa).

ETHNOPHARMACOLOGICAL RELEVANCE: Five plants used in traditional medicine in the Western Cape Province of South Africa, have been investigated for anti-mycobacterial activity: Olea capensis, Tulbaghia alliacea, Dittrichia graveolens, Leysera gnaphalodes and Buddleja saligna. AIM OF THE STUDY: The aim was to assess antimycobacterial activity in plants used in treatment of symptoms of TB, and through activity-guided fractionation of extracts to isolate compounds or mixtures with potential as anti-TB drug leads. MATERIALS AND METHODS: Extracts and derived fractions were assayed against strains of Escherichia coli, Staphylococcus aureus, and Mycobacterium aurum A+. Isolated pure compounds were further tested against Mycobacterium species M. avium ATCC 25291, M. scrofulaceum ATCC 19981, M. microti ATCC 19422 and Mtb H37Rv, and for cytotoxicity against Chinese hamster ovarian cells. RESULTS: Extracts of B. saligna and L. gnaphaloides exhibited significant anti-mycobacterial activity, primarily associated with the presence of non-cytotoxic triterpenoids oleanolic acid in B. saligna and both oleanolic and ursolic acids in L. gnaphaloides. CONCLUSIONS: Anti-mycobacterial activity of extracts of selected plants is consistent with their traditional use. The identification of oleanolic and ursolic acids in these plants, and verification of their activity, underlines the potential for exploring structure-activity relationships of derivatives of these ubiquitous triterpenoids.

Synthesis of fused bicyclic thioglycosides of N-acylated glucosamine as analogues of mycothiol.

The synthesis of a fused bicyclic thioglycoside analogue of mycothiol, (3R)-3-acetylamino-4-one-6,7-dihydro-(1',2'-dideoxy-beta-D-glucopyranoso)[2',1'-f]-1,5-thiazepane (5), is reported. Treatment of phthalimido-protected peracetylated glucosamine with N-acetyl-cysteine and boron trifluoride-etherate gave the beta-linked thioglycoside, which was deprotected and cyclized, using HOBt and EDCl to form the lactam and giving the target structure. This mycothiol mimic and its tri-O-acetate will be investigated as potential inhibitors of enzymes involved in the biosynthesis of mycothiol. The protected derivative also has the potential to be an alpha-selective N-cysteinyl glucosamine donor; however, initial glycosylation attempts failed due to the apparent stability of the fused bicyclic system.

Clinical and quality of life outcomes following anatomical lung resection for lung cancer in high-risk patients.

BACKGROUND: Surgery remains the gold standard for patients with resectable nonsmall cell lung cancer. Current guidance identifies patients with poor pulmonary reserve to fall within a high-risk cohort. The aim of this study was to determine the clinical and quality of life outcomes of anatomical lung resection in patients deemed high risk based on pulmonary function measurements. METHODS: A retrospective review of patients undergoing anatomical lung resection for nonsmall cell lung cancer between January 2013 and January 2015 was performed. All patients with limited pulmonary reserve defined as predicted postoperative forced expiratory volume in 1 s or transfer factor of the lung for carbon monoxide of <40% were included in the study. Postoperative complications, admission to the Intensive Care Unit, length of stay, and 30-day in-hospital mortality were recorded. The European Organization for Research and Treatment of Cancer quality of life questionnaire lung cancer 13 questionnaire was used to assess quality of life outcomes. RESULTS: Fifty-three patients met the inclusion criteria. There was no in-hospital mortality, and 30-day mortality was 1.8%. No complications were seen in 64% (n = 34), minor complications occurred in 26% (n = 14), while 9% had a major complication (n = 5). Quality of life outcomes were above the reference results for patients with early stage lung cancer. CONCLUSION: Anatomical lung resection can be performed safely in selected high-risk patients based on pulmonary function without significant increase in morbidity or mortality and with acceptable quality of life outcomes. Given that complications following lung resection are multifactorial, fitness for surgery should be thoroughly assessed in all patients with resectable disease within a multidisciplinary setting. High operative risk by pulmonary function tests alone should not preclude surgical resection.

Reduced-dose rasburicase in the treatment of adults with hyperuricemia associated with malignancy.

Tumor lysis syndrome is a life-threatening complication of chemotherapy for patients with leukemia and large tumors with a high proliferative index, such as Burkitt's lymphoma. The syndrome is characterized by hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia. The standard of care for hyperuricemia consists of hydration with or without alkalinization and administration of allopurinol. When treated in this manner, patients often experience persistent hyperuricemia that lasts several days after the start of antineoplastic therapy; sometimes they develop uric acid nephropathy as a consequence. Rasburicase, a recombinant urate oxidase enzyme, quickly removes large amounts of uric acid from plasma. The drug is approved by the United States Food and Drug Administration for management of elevated plasma uric acid levels in pediatric patients with leukemia, lymphoma, or solid tumor malignancies who are receiving chemotherapy. We undertook a retrospective review of adult patients treated with a single dose of rasburicase 6 mg for hyperuricemia associated with malignancy. Ten patients received one 6-mg dose of rasburicase, and one patient received two 6-mg doses as an adjuvant therapy to normalize uric acid levels. In most of the patients, a single 6-mg dose of rasburicase was effective in correcting uric acid levels in the typical time between diagnosis and start of antineoplastic therapy.

Intrathecal topotecan in adult patients with neoplastic meningitis.

PURPOSE: The efficacy and safety of intrathecal topotecan were assessed in patients with neoplastic meningitis (NM) by retrospective chart review. SUMMARY: Fourteen patients (median age, 57 years) with NM were treated with the standard of care (i.e., regional or systemic chemotherapy or irradiation or both) plus intrathecal topotecan between January 2004 and September 2005. Three patients developed NM in the setting of systemic cancer; 11 patients had primary central nervous system (CNS) malignancies. All patients received 0.4 mg of topotecan intrathecally two times per week. The efficacy of intrathecal topotecan was assessed on the basis of the number of doses to cerebrospinal fluid (CSF) cytologic clearing--defined as the disappearance of malignant cells from a previously positive CSF cytology. Safety was evaluated by chart documentation of adverse events that might have been associated with topotecan given intrathecally. Of the 11 patients with primary CNS tumors, 6 patients achieved CSF clearing after the first dose of intrathecal topotecan, 2 patients after the second dose, and 1 patient after the fifth dose. For the 3 patients with secondary CSF tumors, 1 patient achieved CSF clearing after the third dose and 2 patients did not reach the primary endpoint. Overall, 6 of the 14 patients achieved CSF clearing after the first dose of intrathecal topotecan; in 10 of the 14 patients, CSF clearing of malignant cells was observed at some point during treatment. Toxicity was modest. The most common adverse effect reported was fatigue. CONCLUSION: Intrathecal topotecan appeared to be effective and safe in adult patients with NM.

Safety and cost-effectiveness of paclitaxel administered as a 1-hour infusion versus a 3-hour infusion for various malignancies.

This study challenges the current practice of administering paclitaxel for a variety of malignancies over 3 hours and documents the safety and cost-effectiveness of 1-hour administration in the outpatient setting. The authors investigated opportunities to save nursing time and costs in a cancer clinic without compromising patient safety. These savings are referred to as "opportunity-cost savings" that enable the clinic to schedule more patients during the time normally required to administer a 3-hour paclitaxel dose. Over a 2-year period, the authors were able to document significant time savings with no increase in adverse drug reactions.

Preparation and antimalarial activity of a novel class of carbohydrate-derived, fused thiochromans.

A novel class of fused thiochroman derivatives has been prepared by an efficient and versatile synthetic procedure involving nucleophilic displacement of the side-chain iodo substituent in 2-deoxy-2-C-iodomethyl glucosides by thiophenolate ions, and subsequent intramolecular C-glycoside formation. A range of aromatic substituents is tolerated, and the subsequent facile selective oxidation of the sulfur to the sulfoxide or sulfone level expands the range and molecular diversity of the series of compounds. A selection of the sulfoxide and sulfone derivatives bearing lipophilic substituents on the aromatic portion were found to have antimalarial activities in the low micromolar range.

Conformational preferences of plumbagin with phenyl-1-thioglucoside conjugates in solution and bound to MshB determined by aromatic association.

Here we show that a series of inhibitors, constructed from plumbagin conjugated to a phenyl thioglucoside via an alkyl chain of variable length, are bound in solution-favoured ligand conformations to a mycothiol biosynthetic enzyme MshB, a GlcNAc-Ins deacetylase. The kinetic studies of this ligand series show that MshB is more strongly inhibited as a function of increasing alkyl chain length. While docking studies yielded highest ranked conformations in which the ligands extended along the catalytic site, these conformations produced free energy values prone to large errors and which were inconsistent with experimental kinetic measurements. Solution-favoured conformations of the inhibitors feature a preference for intramolecular aromatic association that results in curled conformations. Free energy perturbation calculations of MshB bound to the inhibitors in the preconfigured solution-favoured curled conformations gave the same binding pattern observed in the kinetic experiments. On investigation of these conformations lodged in the catalytic domain, we found that the selective feature determining their relative binding strength was the result of an optimisation of the dispersion interactions between the ligand aromatic groups phenyl and plumbagin, and the enzyme aromatic groups His144 and Tyr142 respectively. These results show that rather than deform the preferred folded ligand solution conformation, such that the hydrophobic C-2 acyl chain is linearly projected into a buried hydrophobic rich binding cavity adjacent to the active site, MshB binds preconfigured solution inhibitor curled conformations with a preference for aromatic association.

Extending the scope of the Ferrier reaction: fragmentation-rearrangement reactions of selectively substituted 1,2-cyclopropanated glucose derivatives.

Two further variations of the Ferrier-type allylic rearrangements of 1,2-cyclopropanated glucose derivatives bearing an acetoxylated carbon at the 1'-position are described. In the first, treatment of the cyclopropanated sugar with a nucleophile (ROH, PhSH, azide) and Lewis acid (BF(3)·Et(2)O or Al(OTf)(3)), gives 2-C-vinyl glucosides in good yields and α-selectivities. Alternatively, treatment with a combination of Lewis acid and acetic acid leads to a novel fragmentation-rearrangement to form a 2,3-dehydro-2-formyl-C-glycoside.

Armed-disarmed effect on the stability of cysteine thioglucosides.

Thioglucosides of cysteine show variable stability depending on the nature of the protecting groups on the glycosyl donor. Armed protecting groups (benzyl) lead to products that decompose readily while disarmed protecting groups (acetyl) lead to more stable products. Since this armed/disarmed effect of the protecting group on the stability of the thioglucosides is more pronounced for cysteine with an unprotected carboxylic group, the proposed mechanism is that decomposition is initiated by an intramolecular protonation of glycosyl sulfide and subsequent displacement of the sulfide by adventitious nucleophiles.

Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy in the treatment of peritoneal carcinomatosis.

PURPOSE: Cytoreductive surgery (CS) and intraperitoneal hyperthermic chemotherapy (IPHC) in the treatment of peritoneal carcinomatosis (PC) in 15 patients are described. SUMMARY: Fifteen patients with PC who were treated with CS and IPHC were retrospectively identified between January 2002 and December 2006. All patients underwent cytoreduction immediately followed by IPHC with mitomycin or cisplatin. The time between undergoing CS and IPHC and the date of the last follow-up appointment or the date of death was used to calculate survival data for each patient. Nine patients had complete cytoreduction, and all but one patient had evidence of invasive disease at the time of surgery. Eleven patients required concomitant bowel resection at the time of debulking. Thirteen patients required blood transfusions during the perioperative period. Nine patients were discharged home, and four were discharged to a rehabilitation facility. Two patients died during the perioperative hospital admission, both of whom had a preoperative Eastern Cooperative Oncology Group (ECOG) performance status score of 2. The median survival time was 8.4 months, similar to the findings of previously published studies. Further studies are needed to see if tumor type, ECOG performance status score, degree of cytoreduction, and the chemotherapy agent used in IPHC can be correlated to quality of life and survival in patients with heterogeneous primary sources of intraabdominal malignancies. CONCLUSION: Combination treatment with CS followed by IPHC in 15 patients with heterogeneous primary sources of intraabdominal malignancies resulted in a median survival time of 8.4 months.