A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition

Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin–trypanothione reductase–NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis

Variability of indication criteria in knee and hip replacement: an observational study

<p>Abstract</p> <p>Background</p> <p>Total knee (TKR) and hip (THR) replacement (arthroplasty) are effective surgical procedures that relieve pain, improve patients' quality of life and increase functional capacity. Studies on variations in medical practice usually place the indications for performing these procedures to be highly variable, because surgeons appear to follow different criteria when recommending surgery in patients with different severity levels. We therefore proposed a study to evaluate inter-hospital variability in arthroplasty indication.</p> <p>Methods</p> <p>The pre-surgical condition of 1603 patients included was compared by their personal characteristics, clinical situation and self-perceived health status. Patients were asked to complete two health-related quality of life questionnaires: the generic SF-12 (Short Form) and the specific WOMAC (Western Ontario and Mcmaster Universities) scale. The type of patient undergoing primary arthroplasty was similar in the 15 different hospitals evaluated.</p> <p>The variability in baseline WOMAC score between hospitals in THR and TKR indication was described by range, mean and standard deviation (SD), mean and standard deviation weighted by the number of procedures at each hospital, high/low ratio or extremal quotient (EQ_5-95), variation coefficient (CV_5-95) and weighted variation coefficient (WCV_5-95) for 5-95 percentile range. The variability in subjective and objective signs was evaluated using median, range and WCV_5-95. The appropriateness of the procedures performed was calculated using a specific threshold proposed by Quintana et al for assessing pain and functional capacity.</p> <p>Results</p> <p>The variability expressed as WCV_5-95was very low, between 0.05 and 0.11 for all three dimensions on WOMAC scale for both types of procedure in all participating hospitals. The variability in the physical and mental SF-12 components was very low for both types of procedure (0.08 and 0.07 for hip and 0.03 and 0.07 for knee surgery patients). However, a moderate-high variability was detected in subjective-objective signs. Among all the surgeries performed, approximately a quarter of them could be considered to be inappropriate.</p> <p>Conclusions</p> <p>A greater inter-hospital variability was observed for objective than for subjective signs for both procedures, suggesting that the differences in clinical criteria followed by surgeons when indicating arthroplasty are the main responsible factors for the variation in surgery rates.</p

Homochirality in biomineral suprastructures induced by assembly of single-enantiomer amino acids from a nonracemic mixture

© 2019, The Author(s). Since Pasteur first successfully separated right-handed and left-handed tartrate crystals in 1848, the understanding of how homochirality is achieved from enantiomeric mixtures has long been incomplete. Here, we report on a chirality dominance effect where organized, three-dimensional homochiral suprastructures of the biomineral calcium carbonate (vaterite) can be induced from a mixed nonracemic amino acid system. Right-handed (counterclockwise) homochiral vaterite helicoids are induced when the amino acid l-Asp is in the majority, whereas left-handed (clockwise) homochiral morphology is induced when d-Asp is in the majority. Unexpectedly, the Asp that incorporates into the homochiral vaterite helicoids maintains the same enantiomer ratio as that of the initial growth solution, thus showing chirality transfer without chirality amplification. Changes in the degree of chirality of the vaterite helicoids are postulated to result from the extent of majority enantiomer assembly on the mineral surface. These mechanistic insights potentially have major implications for high-level advanced materials synthesis

Intestinal infection with Mycobacterium avium in acquired immune deficiency syndrome (AIDS)

At endoscopy, a 30-year-old man with acquired immune deficiency syndrome (AIDS), Kaposi's sarcoma, diarrhea, and unexplained malabsorption showed erythematous macular duodenal lesions consistent with Whipple's disease by histology and electron microscopy. Symptoms did not respond to tetracycline. Subsequent cultures revealed systemic Mycobacterium avium (M. avium) infection. Tissue from this patient, from patients with Whipple's disease and from a macaque with M. avium were compared. All contained PAS-positive macrophages but M. avium could be distinguished by positive acid-fast stains and a difference in pattern of indirect immunofluorescence staining with bacterial typing antisera. PAS-positive macrophages in the intestinal lamina propria are no longer pathognomonic of Whipple's disease. Ultrastructural and histological similarities between Whipple's disease and M. avium infection suggest that both are manifestations of immune deficits limiting macrophage destruction of particular bacteria after phagocytosis. M. avium must be considered in the differential diagnosis of diarrhea in patients with AIDS and other immunosuppressed conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44396/1/10620_2005_Article_BF01318186.pd

Magnetism of the Keweenawan age Chengwatana lava flows, northwest Wisconsin

The Chengwatana Volcanics are subaerial plateau basalts which appear to be stratigraphically above the North Shore Volcanic Group of the Lake Superior Region. Sixty five oriented cores were collected at six sites near St. Croix Falls, Wisconsin. Magnetic cleaning of the samples was primarily step-wise alternating field (A.F.) demagnetization to 100 mT. Thermal demagnetization and hysteresis property measurements indicate the dominant magnetic mineralogy is multidomain magnetite. However, a stable remanence is present which we attribute to grains with single domain behavior. The mean remanent direction is D= 287.5°, 1= 45.8°, α-95 = 8.0°, with a mean pole at 186.1°E., 30.9°N. This result is consistent with the 1.1 Ga. apparent pole for the North American craton. Two sites mapped as stratigraphically equivalent show distinct reversed directions. Both A.F. and thermal demagnetization isolate the same reversed direction which is interpreted as being primary. These particular flows record a short reversal in an otherwise normal sequence. This strengthens the evidence for more than one reversal in the Middle Keweenawan, and may be the same short reversal noted at Mamainse Point. Copyright 1997 by the American Geophysical Union.link_to_subscribed_fulltex

The musculoskeletal abnormalities of the Similaun Iceman (“ÖTZI”): clues to chronic pain and possible treatments

BACKGROUND AND INTRODUCTION: In 1991, a deceased human male was found frozen in a glacier pool in the Italian Alps in north west Italy, and is now carefully preserved in the South Tyrol Museum of Archaeology, in Bolzano, Italy. The bodily tissues of the 5,300 year old male (colloquially referred to as the Iceman or Ötzi) were well preserved despite damage related to freezing, and glacial movement. Associated articles of well-preserved clothing, tools, weapons and other devices were also present and have been studied in detail. Clinical examination and imaging investigations have also shown that the Icemen had experienced possible illnesses in his lifetime and had identifiable areas of arthritis and musculoskeletal injury. This report includes some key observations on the musculoskeletal state of Ötzi and reference to the involvement of tattoo markings. Some aspects about the aetiology of his abnormalities and inflammatory arthritis are considered along with possible treatments that he might have employed. METHODS AND RESULTS: We (WFK and MK) undertook a clinical musculoskeletal examination of the Iceman, details of which with available photographs and radiographic imaging pertaining to the musculoskeletal findings of the Iceman are reported here. The skin of the Iceman has numerous linear carbon tattoos, which are not of a decorative type. These have been presumed to possibly be "medicinal" tattoos administered for therapeutic reasons and may have been used in acupuncture-like treatment of pain. Spinal imaging identified areas of spinal damage and our observations have provided clues as to possible sites of spinal initiated pain and hence sites for administration of the "medicinal" tattoos. We observed body areas of the Iceman, in which imaging demonstrated arthritis and other forms of long-term musculoskeletal damage, but which do not have adjacent or corresponding "medicinal" tattoos. We contend that the back and leg "medicinal" tattoos correspond directly to sites of chronic right knee and right ankle pain, and left thoracolumbar pain. They also correspond to lower lumbar and sciatic referred radicular pain which may have a contributory cause related to the presence of a transitional lumbar 5 vertebra. Using recent published data (Keller et al. in Nature Commun 3:698, 2012. doi: 10.1038/ncomms1701 ) of the genome structure of the Iceman, we suggest some potential causes of the osteoarthritis or inflammatory joint injury may relate to presence of coronary heart disease (CHD) and Lyme disease (Borrelia burgdorferi) infection. We speculate on possible medical applications of natural products for self-medication. CONCLUSIONS: These observations highlight several diagnostic features of musculoskeletal conditions in the Iceman with the possibility that tattoos may have been used for diagnosis or location of his painful states. The origins of his musculoskeletal conditions are unclear but there are indications that Lyme disease and CHD may have been factors. The associations or use of natural products may give insights into their applications at the time of the life of the Iceman.</p