Type II topoisomerase mutations in Bacillus anthracis associated with high-level fluoroquinolone resistance

OBJECTIVES: To identify and characterize the mechanisms of high-level fluoroquinolone resistance in two strains of Bacillus anthracis following serial passage in increasing concentrations of fluoroquinolones. METHODS: Fluoroquinolone-resistant isolates of the Sterne and Russian Anthrax Vaccine STi strains were obtained following serial passage in the presence of increasing concentrations of four different fluoroquinolones. The quinolone-resistance-determining regions of the type II topoisomerase genes from the resistant strains were amplified by PCR and characterized by DNA sequence analysis. The MICs in the presence and absence of reserpine were determined using broth microdilution as a means of detecting active efflux. RESULTS: Single and double amino acid substitutions in the GyrA (Ser-85-Leu; Glu-89-Arg/Gly/Lys) and GrlA (Ser-81-Tyr; Val-96-Ala; Asn-70-Lys) were most common. A single amino acid substitution in GyrB (Asp-430-Asn) was also identified. Efflux only applied to isolates selected for by either levofloxacin or ofloxacin. CONCLUSIONS: Specific amino acid substitutions in the type II topoisomerase enzymes significantly contributed to the development of high-level fluoroquinolone resistance in B. anthracis. However, notable differences between the strains and the drugs tested were identified including the role of efflux and the numbers and types of mutations identified.     

Convection-enhanced drug delivery: increased efficacy and magnetic resonance image monitoring

Convection-enhanced drug delivery (CED) is a novel approach to directly deliver drugs into brain tissue and brain tumors. It is based on delivering a continuous infusion of drugs via intracranial catheters, enabling convective distribution of high drug concentrations over large volumes of the target tissue while avoiding systemic toxicity. Efficient formation of convection depends on various physical and physiologic variables. Previous convection-based clinical trials showed significant diversity in the extent of convection among patients and drugs. Monitoring convection has proven to be an essential, yet difficult task. The current study describes the application of magnetic resonance imaging for immediate assessment of convection efficiency and early assessment of cytotoxic tissue response in a rat brain model. Immediate assessment of infusate distribution was obtained by mixing Gd-diethylenetriaminepentaacetic acid in the infusate prior to infusion. Early assessment of cytotoxic tissue response was obtained by subsequent diffusion-weighted magnetic resonance imaging. In addition, the latter imaging methodologies were used to establish the correlation between CED extent and infusate's viscosity. It was found that low-viscosity infusates tend to backflow along the catheter track, whereas high-viscosity infusates tend to form efficient convection. These results suggest that CED formation and extent may be significantly improved by increasing the infusate's viscosities, thus increasing treatment effects.     

Randomised trial of outpatient induction of labor with vaginal PGE2 at 40–41 weeks of gestation versus expectant management

Two hundred consecutive women with uncomplicated pregnancies, at or within 4 days of their expected date of confinement, were prospectively randomized into 2 groups. One group had expectant management, with twice weekly surveillance tests, while the other group had 3 mg of vaginal prostaglandin E₂ as outpatient treatment. There were 104 women in the expectant group and 70 in the induction group (26 women allocated to induction preferred no treatment). The average number of days to delivery was 1.6 in the induction group and 5.2 in the expectant group (p < 0.001). While meconium was much less frequent in the induction group (p < 0.002), all other outcome measures, including cesarean section rates, incidence of macrosomia, and Apgar scores, were similar in the two groups. Received: 26 June 1995 / Accepted: 1 December 1995     

Personality core dynamics and drug preference

The aim of this study is to investigate the possible link between Shoham's personality-core theory [1] and addiction to hard drugs. Basing ourselves on Kleinean premises, that the oral stage is critical in the formation of behavioural patterns, which are influential throughout life, we hypothesize that in the oral stage two opposing vectors, ‘separation’ and ‘participation’ are initiated. By ‘participation’ we refer to the identification of ego with an external object or symbol, and continuous tendency to lose the personal identity by fusion with this object or symbol. ‘Separation’ is the opposite vector and expresses ego's tendency to incorporate the external object or symbol. These vectors form two multidimensional personality axes, on which the different personality types and behavioral patterns can be anchored.This study aims at investigating the connection between these two vectors and drug addiction. We view drug addiction as a functional behaviour pattern, which brings the individual to a state of internal balance.Shoham's personality theory hypothesizes the derivation of behavioural patterns of different personality ‘types’, according to the strength of the two vector — the ‘separant’ and ‘participant’ types.It is hypothesized that the drug use and the experience gained by using the specific drug by different personality types will vary according to the prominence of the core personality vector. The potency of these vectors is related to an early oral (participant) or a later oral (separant) fixation. The main hypotheses of the study are: (a) There are two polar types of addicts, which may be placed at the extremes of the ‘separant-participant’ personality continuum. (b) The drug preference varies according to the strength of the ‘separant’ and ‘participant’ vectors. The ‘participant’ addicts will prefer depressant drugs, whereas ‘separant’ addicts will prefer stimulants. The results of the present study support these hypotheses.     

Cellular and humoral response to the fourth BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL

We assessed the humoral and cellular response to the fourth BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL. A total of 67 patients with CLL and 85 age matched controls tested for serologic response and pseudo-neutralization assay. We also tested the functional T-cell response by interferon gamma (IFNγ) to spike protein in 26 patients. Two weeks after the fourth vaccine antibody serologic response was evident in 37 (55.2%) patients with CLL, 20 /22 (91%) of treatment naïve, and 9/32 (28%) patients with ongoing therapy, compared with 100% serologic response in age matched controls. The antibody titer increased by 10-fold in patients with CLL, however, still 88-folds lower than age matched controls. Predictors of better chances of post fourth vaccination serologic response were previous positive serologies after second, third, and pre-fourth vaccination, neutralizing assay, and treatment naïve patients. T-cell response improved from 42.3% before the fourth vaccine to 84.6% 2 weeks afterwards. During the time period of 3 months after the fourth vaccination, 14 patients (21%) developed COVID-19 infection, all recovered uneventfully. Our data demonstrate that fourth SARS-CoV-2 vaccination improves serologic response in patients with CLL to a lesser extent than healthy controls and induces functional T-cell response.