This interesting case report from South Africa focuses on a difficult diagnostic challenge: apparent Cushing syndrome with inconsistent laboratory findings.

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Purpose:

We hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas. Virally encoded IL15Rα-IL15 as the T-cell activating stimulus and a prostaglandin synthesis inhibitor as the anti-immunosuppressant were combined with adoptive transfer of tumor-specific T cells.

Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome bc₁ complex, a target critical to the survival of both liver- and blood-stage parasites, making these drugs useful as both prophylaxis and treatment. Recently, several derivatives of endochin have been optimized to produce novel quinolones that are active in vitro and in animal models. While these quinolones exhibit potent ex vivo activity against Plasmodium falciparum and Plasmodium vivax, their activity against the zoonotic agent Plasmodium knowlesi is unknown. We screened several of these novel endochin-like quinolones (ELQs) for their activity against P. knowlesi in vitro and compared this with their activity against P. falciparum tested under identical conditions. We demonstrated that ELQs are potent against P. knowlesi (50% effective concentration, <117 nM) and equally effective against P. falciparum. We then screened selected quinolones and partner drugs using a longer exposure (2.5 life cycles) and found that proguanil is 10-fold less potent against P. knowlesi than P. falciparum, while the quinolones demonstrate similar potency. Finally, we used isobologram analysis to compare combinations of the ELQs with either proguanil or atovaquone. We show that all quinolone combinations with proguanil are synergistic against P. falciparum. However, against P. knowlesi, no evidence of synergy between proguanil and the quinolones was found. Importantly, the combination of the novel quinolone ELQ-300 with atovaquone was synergistic against both species. Our data identify potentially important species differences in proguanil susceptibility and in the interaction of proguanil with quinolones and support the ongoing development of novel quinolones as potent antimalarials that target multiple species.

New drugs or therapeutic combinations are urgently needed against Mycobacterium abscessus. Previously, we demonstrated the potent activity of indole-2-carboxamides 6 and 12 against M. abscessus. We show here that these compounds act synergistically with imipenem and cefoxitin in vitro and increase the bactericidal activity of the β-lactams against M. abscessus. In addition, compound 12 also displays synergism with imipenem and cefoxitin within infected macrophages. The clinical potential of these new drug combinations requires further evaluation.

Infections with nontuberculous mycobacteria (NTM) have a poor prognosis in patients with underlying respiratory diseases. Clofazimine (CFZ) showed both experimental and clinical promising results against clinically relevant NTM. However, there are no data on CFZ in combination with the current recommended treatment; therefore, we aimed to study its in vivo activity in an aerosol mouse model of Mycobacterium avium. In an aerosol infection BALB/c mouse model using M. avium strain Chester, we treated 58 mice with four combinations of rifampin (RIF) at 10 mg/kg, CFZ at 25 mg/kg, and clarithromycin (CLR) and ethambutol (EMB) at 100 mg/kg. Treatment efficacy was assessed on the basis of lung CFU counts after 2 (M2) and 4 (M4) months of treatment. At M2, CLR-RIF-EMB was slightly but significantly more efficient than CFZ-RIF-EMB (3.02 ± 0.12 versus 3.55 ± 0.28, respectively, P < 0.01), whereas CLR-CFZ-EMB and CLR-CFZ-RIF-EMB dramatically decreased lung CFU counts by 4.32 and 4.47 log₁₀, respectively, compared to untreated group. At M4, CLR-RIF-EMB was significantly more efficient than CFZ-RIF-EMB (2 ± 0.53 versus 2.66 ± 0.22, respectively, P = 0.01). The addition of CLZ to CLR dramatically decreased the lung CFU count, with CFU counts 5.41 and 5.79 log₁₀ lower in the CLR-CFZ-EMB and CLR-CFZ-RIF-EMB groups, respectively, than in the untreated group. The addition of CFZ to CLR seems to improve the efficacy of CLR as early as M2 and was confirmed at M4. CFZ, in addition to RIF and EMB, on the other hand, is less effective than CLR-RIF-EMB. These results need to be confirmed by similar studies along with CFZ potential for shortening treatment.

Lactoferrin (LF) is a multifunctional milk protein with antimicrobial activity against a range of pathogens. While numerous studies report that LF is active against fungi, there are considerable differences in the level of antifungal activity and the capacity of LF to interact with other drugs. Here we undertook a comprehensive evaluation of the antifungal spectrum of activity of three defined sources of LF across 22 yeast and 24 mold species and assessed its interactions with six widely used antifungal drugs. LF was broadly and consistently active against all yeast species tested (MICs, 8 to 64 μg/ml), with the extent of activity being strongly affected by iron saturation. LF was synergistic with amphotericin B (AMB) against 19 out of 22 yeast species tested, and synergy was unaffected by iron saturation but was affected by the extent of LF digestion. LF-AMB combination therapy significantly prolonged the survival of Galleria mellonella wax moth larvae infected with Candida albicans or Cryptococcus neoformans and decreased the fungal burden 12- to 25-fold. Evidence that LF directly interacts with the fungal cell surface was seen via scanning electron microscopy, which showed pore formation, hyphal thinning, and major cell collapse in response to LF-AMB synergy. Important virulence mechanisms were disrupted by LF-AMB treatment, which significantly prevented biofilms in C. albicans and C. glabrata, inhibited hyphal development in C. albicans, and reduced cell and capsule size and phenotypic diversity in Cryptococcus. Our results demonstrate the potential of LF-AMB as an antifungal treatment that is broadly synergistic against important yeast pathogens, with the synergy being attributed to the presence of one or more LF peptides.

Advances in synthetic biology have enabled the production of a variety of compounds using bacteria as a vehicle for complex compound biosynthesis. Violacein, a naturally occurring indole pigment with antibiotic properties, can be biosynthetically engineered in Escherichia coli expressing its nonnative synthesis pathway. To explore whether this synthetic biosynthesis platform could be used for drug discovery, here we have screened bacterially derived violacein against the main causative agent of human malaria, Plasmodium falciparum. We show the antiparasitic activity of bacterially derived violacein against the P. falciparum 3D7 laboratory reference strain as well as drug-sensitive and -resistant patient isolates, confirming the potential utility of this drug as an antimalarial agent. We then screen a biosynthetic series of violacein derivatives against P. falciparum growth. The varied activity of each derivative against asexual parasite growth points to the need to further develop violacein as an antimalarial. Towards defining its mode of action, we show that biosynthetic violacein affects the parasite actin cytoskeleton, resulting in an accumulation of actin signal that is independent of actin polymerization. This activity points to a target that modulates actin behavior in the cell either in terms of its regulation or its folding. More broadly, our data show that bacterial synthetic biosynthesis could become a suitable platform for antimalarial drug discovery, with potential applications in future high-throughput drug screening with otherwise chemically intractable natural products.

The new complexes Zn(ITZ)₂Cl₂ (1) and Zn(ITZ)₂(OH)₂ (2) were synthetized by a reaction of itraconazole with their respective zinc salts under reflux. These Zn-ITZ complexes were characterized by elemental analyses, molar conductivity, mass spectrometry, ¹H and ¹³C{¹H} nuclear magnetic resonance, and UV-vis and infrared spectroscopies. The antiparasitic and antifungal activity of Zn-ITZ complexes was evaluated against three protozoans of medical importance, namely, Leishmania amazonensis, Trypanosoma cruzi, and Toxoplasma gondii, and two fungi, namely, Sporothrix brasiliensis and Sporothrix schenckii. The Zn-ITZ complexes exhibited a broad spectrum of action, with antiparasitic and antifungal activity in low concentrations. The strategy of combining zinc with ITZ was efficient to enhance ITZ activity since Zn-ITZ-complexes were more active than the azole alone. This study opens perspectives for future applications of these Zn-ITZ complexes in the treatment of parasitic diseases and sporotrichosis.

Originally published by The Vinyl Factory. “It is a living instrument producing a living sound.” Soulwax, aka David & Stephen Dewaele, explore their love of the EMS Synthi 100 in a new album and book that pay tribute to the bulky hybrid synth. Both will be released via The Vinyl Factory and DEEWEE this May, and […]

The post Soulwax celebrate the EMS Synthi 100 in new trailer appeared first on FACT Magazine.

The majority of these children have tested positive for the virus or seem to carry antibodies from an earlier infection.

A 7-year-old boy from Westchester County is the second child in New York state to die from pediatric multi-symptom inflammatory syndrome tied to COVID-19 since the pandemic began. A 5-year-old boy died earlier in the week from the same syndrome at Mount Sinai Kravis Children’s Hospital in New York City.

The childhood ailment has affected at least 73 children in New York state and authorities are now looking for other potential cases across the country. Cases have also been reported in Washington, D.C., California, Delaware, Louisiana, Massachusetts, Pennsylvania, Washington state and New Jersey, where a 4-year-old died with symptoms last month.

It has been previously thought that children are less likely to suffer any serious complications from the coronavirus.

Read more at The Daily Beast.

Conditions like chronic fatigue syndrome have been linked to viral infections, so it’s possible that the covid-19 virus may go on to trigger similar conditions

As Quebec prepares to reopen schools, doctors are poring over 15-20 cases of children with what seems to be the same illnesses reported in U.S. and Europe

Singer Lance Bass turned 41 on 4 May.

Doctors have been sent an alert by the NHS warning of a coronavirus-related syndrome that could be emerging in children in the UK.

Some children have died of a new illness that could be linked to coronavirus, the Health Secretary has said.

A solar-driven hydrogen-producing machine that makes more copies of itself.

Prof. ZHONG Zhicheng's team at the Ningbo Institute of Materials Technology and Engineering has investigated the electronic structure of the recently discovered nickelate superconductors NdNiO₂. They successfully explained the experimental difficulties in synthesizing superconducting nickelates, in cooperation with Prof. Karsten Held at Vienna University of Technology.

A report published in The Lancet appeared to show there was a link between Covid-19 and a deadly syndrome that affects some children.

With children presenting at intensive care units across France with a Kawasaki-like syndrome following COVID-19 infection, Medscape's France Edition talks to an expert about this rare complication.
Medscape Medical News

Although rare, health authorities advise any children presenting with Kawasaki-like symptoms be taken immediately to a specialist in pediatric infectious disease, rheumatology, or critical care.
Medscape Medical News

The experimental 5-HT1A receptor agonist and D2 receptor antagonist was not effective on primary or secondary endpoints

Germany’s science and technology company Merck KGaA today announced its investment in SynSense (formerly…

The Department announced the filing of a lawsuit in U.S. District Court in Salt Lake City on behalf of Jose A. Ortega, a Utah National Guard member, against Synapse Data and Telecom Inc., and Matthew Mossbarger, Synapse’s owner and operator, alleging violations of the Uniformed Services Employment and Reemployment Rights Act of 1994 (USERRA).

Christian Rodney Ice, of Mobile, Ala., pleaded guilty today in federal court in Mobile to one count of violating the Church Arson Act by placing threatening graffitti and neo-Nazi markings on a synagogue in Mobile.

The Department has entered into a consent decree with Synapse Data and Telecom Inc., and Matthew Mossbarger, the owner of Synapse, to resolve the Department’s complaint filed on behalf of Utah National Guard member Jose A. Ortega, alleging violations of the Uniformed Services Employment and Reemployment Rights Act of 1994 (USERRA).

A federal grand jury in Mobile, Ala., has returned a three-count indictment charging Thomas Hayward Lewis, 24, of Mobile, with violating and conspiring to violate the civil rights of congregants of the Congregation Tree of Life Messianic Synagogue in Mobile, as well as possession of an unregistered firearm.

Brian Lewis of Modesto, Calif., and Abel Mark Gonzalez of Morgan Hill, Calif., pleaded guilty today before U.S. District Judge Lawrence J. O’Neill to conspiring to violate the civil rights of congregants of Congregation Beth Shalom, a synagogue in Modesto, Calif.

A judge sentenced Thomas Hayward Lewis to 12 months and one day in prison, followed by three years of supervised release, for violating the civil rights of congregants of the Congregation Tree of Life Messianic Synagogue, as well as possession of an unregistered firearm.

Andrew Kerber, 22, of Chico, Calif., pleaded guilty today before U.S. District Judge Lawrence J. O’Neill in Fresno, Calif., to violating the civil rights of congregants of Congregation Beth Shalom, a synagogue in Modesto, Calif.

The Justice Department announced today that Brian Lewis, Abel Mark Gonzalez and Andrew Kerber were sentenced for their roles in violating the civil rights of congregants of several houses of worship in Modesto, Calif.

A federal complaint has been unsealed charging Dante Phearse, 32, of Houston, with calling in bomb threats to two synagogues located in Houston.

Acting Assistant Attorney General for the Civil Rights Division Jocelyn Samuels and U.S. Attorney for the District of North Dakota Timothy Q. Purdon announced that Dominique Jason Flanigan was arraigned today on civil rights and threats charges.

The Department of Justice announced today that a federal grand jury sitting in Salt Lake City returned a superseding indictment charging Macon Openshaw, 21, of Salt Lake City, on gun possession charges and a federal hate crime charge relating to a bias-motivated attack at a local synagogue.

The Department of Justice’s Civil Rights Division and the U.S. Attorney’s Office for the Southern District of Texas announced today that a federal grand jury in Houston returned a six count indictment charging Dante Phearse, 33, with calling in bomb threats to two Houston synagogues, a municipal courthouse and a private business.

Macon Openshaw, 21, pleaded guilty in the U.S. District Court for the District of Utah today to a federal civil rights crime relating to a bias-motivated weapons discharge aimed at a local synagogue and to two unlawful gun possession charges.

Dante Phearse, 33, has entered a plea of guilty to calling in a bomb threat to Congregation Beth Israel, a synagogue in Houston.

Dante Phearse, 33, was sentenced today by U.S. District Judge Kenneth M. Hoyt to serve 33 months in prison for calling in a bomb threat to Congregation Beth Israel, a synagogue in Houston

Macon Openshaw, 22, was sentenced today by U.S. District Court Judge Tena Campbell for the District of Utah to serve 60 months in prison for a bias-motivated attack at a local synagogue and for two unlawful gun possession charges

Valensa International announced today a joint venture agreement between Valensa’s parent company EID Parry and Synthite Industries Ltd., expanding plans to lead development and distribution of value-added microalgae extracts.

Doctors have recently identified a condition called pediatric inflammatory multi-system syndrome among children who have tested positive for antibodies against COVID-19.