Unnecessary Deaths nad Unnecessary Costs: Getting Patented Drugs to Patients Most in Need

Medical epidemics that are constrained in the developed world are wrecking havoc on developing countries, which are bearing the brunt of HIV/AIDS, malaria, tuberculosis, and other infectious diseases. Because medicines used to treat these conditions are patented, they are expensive and inaccessible to poor countries. In 1994, the United Nations established a system of international patent protection through the World Trade Organization’s Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), and simultaneously tried to accommodate its commitment to making life-saving pharmaceuticals available to developing countries. When TRIPS failed to accomplish this goal, Article 31bis, an amendment to TRIPS, was introduced in 2003, seeking to make it easier for developing countries to acquire low-cost drugs. However, the amendment has been criticized and has largely gone unused. This Note addresses ways in which Article 31bis can be employed to deliver treatment to the neediest. In particular, this Note advocates that, whether or not the amendment is used, life-saving drugs must be provided at low-cost to developing countries

An Early Abdominal Wall Ectopic Pregnancy Successfully Treated with Ultrasound Guided Intralesional Methotrexate: A Case Report

Background. The upper anterior abdominal wall is a very unusual location for an ectopic pregnancy making optimal management uncertain. Case. We report the case of a 26-year-old gravida 4, para 1, aborta 2 with a rising quantitative human chorionic gonadotropin level following a negative diagnostic laparoscopic examination. She was subsequently diagnosed with an abdominal wall ectopic pregnancy 2 cm inferior to the liver. A single percutaneous intralesional injection of methotrexate was successful after initial failure with systemic methotrexate. Conclusion. Systemic methotrexate is a logical first choice for management of a stable early abdominal wall pregnancy. Direct intralesional injection of methotrexate as the next treatment choice may avoid the morbidity linked with operative management

Natural and Induced Mitochondrial Phosphate Carrier Loss: DIFFERENTIAL DEPENDENCE OF MITOCHONDRIAL METABOLISM AND DYNAMICS AND CELL SURVIVAL ON THE EXTENT OF DEPLETION.

The relevance of mitochondrial phosphate carrier (PiC), encoded by SLC25A3, in bioenergetics is well accepted. However, little is known about the mechanisms mediating the cellular impairments induced by pathological SLC25A3 variants. To this end, we investigated the pathogenicity of a novel compound heterozygous mutation in SLC25A3 First, each variant was modeled in yeast, revealing that substituting GSSAS for QIP within the fifth matrix loop is incompatible with survival on non-fermentable substrate, whereas the L200W variant is functionally neutral. Next, using skin fibroblasts from an individual expressing these variants and HeLa cells with varying degrees of PiC depletion, PiC loss of ∼60% was still compatible with uncompromised maximal oxidative phosphorylation (oxphos), whereas lower maximal oxphos was evident at ∼85% PiC depletion. Furthermore, intact mutant fibroblasts displayed suppressed mitochondrial bioenergetics consistent with a lower substrate availability rather than phosphate limitation. This was accompanied by slowed proliferation in glucose-replete medium; however, proliferation ceased when only mitochondrial substrate was provided. Both mutant fibroblasts and HeLa cells with 60% PiC loss showed a less interconnected mitochondrial network and a mitochondrial fusion defect that is not explained by altered abundance of OPA1 or MFN1/2 or relative amount of different OPA1 forms. Altogether these results indicate that PiC depletion may need to be profound (\u3e85%) to substantially affect maximal oxphos and that pathogenesis associated with PiC depletion or loss of function may be independent of phosphate limitation when ATP requirements are not high

Plasma Carotenoid Concentrations of Incubating American Kestrels (\u3cem\u3eFalco sparverius\u3c/em\u3e) Show Annual, Seasonal, and Individual Variation and Explain Reproductive Outcome

In wild birds, the proximate and ultimate factors that affect circulating carotenoid concentrations remain poorly understood. We studied variation in plasma carotenoid concentrations across several scales: annual, seasonal, pair, territory and individual, and evaluated whether plasma carotenoid concentrations explained reproductive outcome of wild American kestrels (Falco sparverius). We sampled plasma carotenoid concentrations of 99 female and 80 male incubating kestrels from April to June in 2008 to 2012. Plasma carotenoid concentrations were explained by an interaction between year and sex, date, and random effects for pair and individual identity. In general, plasma carotenoid concentrations of males were significantly higher than females, but this depended on year. Within a breeding season, earlier nesting kestrels had higher carotenoid concentrations than later nesting kestrels, a pattern that is coincident with seasonal trends in local fitness. Pair and individual identity explained variation in carotenoid concentrations suggesting that carotenoid concentrations of mated birds were correlated, and some individuals consistently maintained higher carotenoid levels than others. Male carotenoid concentrations were positively associated with number of young fledged per pair. These results are consistent with the hypothesis that higher quality individuals have higher carotenoid levels compared to lower quality individuals, despite annual variations in carotenoid availability

Differences in beliefs about COVID-19 by gun ownership: a cross-sectional survey of Texas adults

OBJECTIVES: We investigated the association between gun ownership and perceptions about COVID-19 among Texas adults as the pandemic emerged. We considered perceived likelihood that the pandemic would lead to civil unrest, perceived importance of taking precautions to prevent transmission and perceptions that the threat of COVID-19 has been exaggerated. METHODS: Data were collected from 5 to 12 April 2020, shortly after Texas’ stay-at-home declaration. We generated a sample using random digit dial methods for a telephone survey (n=77, response rate=8%) and by randomly selecting adults from an ongoing panel to complete the survey online (n=1120, non-probability sample). We conducted a logistic regression to estimate differences in perceptions by gun ownership. To account for bias associated with use of a non-probability sample, we used Bayesian data integration and ran linear regression models to produce more accurate measures of association. RESULTS: Among the 60% of Texas adults who reported gun ownership, estimates of past 7-day gun purchases, ammunition purchases and gun carrying were 15% (n=78), 20% (n=100) and 24% (n=130), respectively. We found no evidence of an association between gun ownership with perceived importance of taking precautions to prevent transmission or with perceived likelihood of civil unrest. Results from the logistic regression (OR 1.27, 95% CI 0.99 to 1.63) and the linear regression (β=0.18, 95% CI 0.07 to 0.29) suggest that gun owners may be more likely to believe the threat of COVID-19 was exaggerated. CONCLUSIONS: Compared with those without guns, gun owners may have been inclined to downplay the threat of COVID-19 early in the pandemic

Amphotericin forms an extramembranous and fungicidal sterol sponge.

For over 50 years, amphotericin has remained the powerful but highly toxic last line of defense in treating life-threatening fungal infections in humans with minimal development of microbial resistance. Understanding how this small molecule kills yeast is thus critical for guiding development of derivatives with an improved therapeutic index and other resistance-refractory antimicrobial agents. In the widely accepted ion channel model for its mechanism of cytocidal action, amphotericin forms aggregates inside lipid bilayers that permeabilize and kill cells. In contrast, we report that amphotericin exists primarily in the form of large, extramembranous aggregates that kill yeast by extracting ergosterol from lipid bilayers. These findings reveal that extraction of a polyfunctional lipid underlies the resistance-refractory antimicrobial action of amphotericin and suggests a roadmap for separating its cytocidal and membrane-permeabilizing activities. This new mechanistic understanding is also guiding development of what are to our knowledge the first derivatives of amphotericin that kill yeast but not human cells

Evaluation of the ability of C. albicans to form biofilm in the presence of phage-resistant phenotypes of P. aeruginosa

Pseudomonas aeruginosa and Candida albicans are disparate microbial species, but both are known to be opportunistic pathogens frequently associated with nosocomial infections. The aim of this study was to provide a better understanding of the interactions between these microorganisms in dual-species biofilms. Several bacteriophage-resistant P. aeruginosa phenotypes have been isolated and were used in dual-species mixed-biofilm studies. Twenty-four and 48 h mixed-biofilms were formed using the isolated phenotypes of phage-resistant P. aeruginosa and these were compared with similar experiments using other P. aeruginosa strains with a defined lipopolysaccharide (LPS) deficiency based on chromosomal knockout of specific LPS biosynthetic genes. Overall, the results showed that the variants of phage-resistant P. aeruginosa and LPS mutants were both less effective in inhibiting the growth of C. albicans in mixed-biofilms compared to the wild-type strains of P. aeruginosa. Conversely, the proliferation of P. aeruginosa was not influenced by the presence of C. albicans. In conclusion, the ability of strains of P. aeruginosa to inhibit the formation of a biofilm of C. albicans appears to be correlated with the LPS chain lengths of phenotypes of P. aeruginosa, suggesting that LPS has a suppressive effect on the growth of C. albicans.D. P. P. acknowledges the grant from the project [PTDC/EBB-BIO/114760/2009] from the Portuguese Foundation for Science and Technology (FCT). J.S.L. holds a Canada Research Chair in Cystic Fibrosis and Microbial Glycobiology and research in his laboratory is supported by operating grants from Cystic Fibrosis Canada and the Canadian Institutes of Health Research (CIHR) [Grant MOP-14687]