The perspective of antibiotic therapeutic challenges of brucellosis in the Middle East and North African countries: Current situation and therapeutic management.

Brucellosis is among the most prevalent zoonotic infections in Middle Eastern and North African (MENA) countries, critically impacting human and animal health. A comprehensive review of studies on antibiotic susceptibility and therapeutic regimes for brucellosis in ruminants and humans in the MENA region was conducted to evaluate the current therapeutic management in this region. Different scientific databases were searched for peer-reviewed original English articles published from January 1989 to February 2021. Reports from research organizations and health authorities have been taken into consideration. Brucella melitensis and Brucella abortus have been reported from the majority of MENA countries, suggesting a massive prevalence particularly of B. melitensis across these countries. Several sporadic cases of brucellosis relapse, therapeutic failure, and antibiotic resistance of animal and human isolates have been reported from the MENA region. However, several studies proved that brucellae are still in-vitro susceptible to the majority of antibiotic compounds and combinations in current recommended World Health Organization (WHO) treatment regimens, for example, levofloxacin, tetracyclines, doxycycline, streptomycin, ciprofloxacin, chloramphenicol, gentamicin, tigecycline, and trimethoprim/sulfamethoxazole. The current review presents an overview on resistance development of brucellae and highlights the current knowledge on effective antibiotics regimens for treating human brucellosis.

A probabilistic Poisson-based model accounts for an extensive set of absolute auditory threshold measurements.

Thresholds for detecting sounds in quiet decrease with increasing sound duration in every species studied. The neural mechanisms underlying this trade-off, often referred to as temporal integration, are not fully understood. Here, we probe the human auditory system with a large set of tone stimuli differing in duration, shape of the temporal amplitude envelope, duration of silent gaps between bursts, and frequency. Duration was varied by varying the plateau duration of plateau-burst (PB) stimuli, the duration of the onsets and offsets of onset-offset (OO) stimuli, and the number of identical bursts of multiple-burst (MB) stimuli. Absolute thresholds for a large number of ears (>230) were measured using a 3-interval-3-alternative forced choice (3I-3AFC) procedure. Thresholds decreased with increasing sound duration in a manner that depended on the temporal envelope. Most commonly, thresholds for MB stimuli were highest followed by thresholds for OO and PB stimuli of corresponding durations. Differences in the thresholds for MB and OO stimuli and in the thresholds for MB and PB stimuli, however, varied widely across ears, were negative in some ears, and were tightly correlated. We show that the variation and correlation of MB-OO and MB-PB threshold differences are linked to threshold microstructure, which affects the relative detectability of the sidebands of the MB stimuli and affects estimates of the bandwidth of auditory filters. We also found that thresholds for MB stimuli increased with increasing duration of the silent gaps between bursts. We propose a new model and show that it accurately accounts for our results and does so considerably better than a leaky-integrator-of-intensity model and a probabilistic model proposed by others. Our model is based on the assumption that sensory events are generated by a Poisson point process with a low rate in the absence of stimulation and higher, time-varying rates in the presence of stimulation. A subject in a 3I-3AFC task is assumed to choose the interval in which the greatest number of events occurred or randomly chooses among intervals which are tied for the greatest number of events. The subject is further assumed to count events over the duration of an evaluation interval that has the same timing and duration as the expected stimulus. The increase in the rate of the events caused by stimulation is proportional to the time-varying amplitude envelope of the bandpass-filtered signal raised to an exponent. We find the exponent to be about 3, consistent with our previous studies. This challenges models that are based on the assumption of the integration of a neural response that is directly proportional to the stimulus amplitude or proportional to its square (i.e., proportional to the stimulus intensity or power).

Why longer song elements are easier to detect: threshold level-duration functions in the Great Tit and comparison with human data.

Our study estimates detection thresholds for tones of different durations and frequencies in Great Tits (Parus major) with operant procedures. We employ signals covering the duration and frequency range of communication signals of this species (40-1,010 ms; 2, 4, 6.3 kHz), and we measure threshold level-duration (TLD) function (relating threshold level to signal duration) in silence as well as under behaviorally relevant environmental noise conditions (urban noise, woodland noise). Detection thresholds decreased with increasing signal duration. Thresholds at any given duration were a function of signal frequency and were elevated in background noise, but the shape of Great Tit TLD functions was independent of signal frequency and background condition. To enable comparisons of our Great Tit data to those from other species, TLD functions were first fitted with a traditional leaky-integrator model. We then applied a probabilistic model to interpret the trade-off between signal amplitude and duration at threshold. Great Tit TLD functions exhibit features that are similar across species. The current results, however, cannot explain why Great Tits in noisy urban environments produce shorter song elements or faster songs than those in quieter woodland environments, as detection thresholds are lower for longer elements also under noisy conditions.

Effectiveness of an antimicrobial treatment scheme in a confined glanders outbreak.

BACKGROUND: Glanders is a contagious and fatal zoonotic disease of solipeds caused by the Gram-negative bacterium Burkholderia (B.) mallei. Although regulations call for culling of diseased animals, certain situations e.g. wild life conservation, highly valuable breeding stock, could benefit from effective treatment schemes and post-exposure prophylaxis. RESULTS: Twenty three culture positive glanderous horses were successfully treated during a confined outbreak by applying a treatment protocol of 12 weeks duration based on the parenteral administration of enrofloxacin and trimethoprim plus sulfadiazine, followed by the oral administration of doxycycline. Induction of immunosupression in six randomly chosen horses after completion of treatment did not lead to recrudescence of disease. CONCLUSION: This study demonstrates that long term treatment of glanderous horses with a combination of various antibiotics seems to eliminate the agent from the organism. However, more studies are needed to test the effectiveness of this treatment regime on B. mallei strains from different endemic regions. Due to its cost and duration, this treatment can only be an option in certain situations and should not replace the current "testing and culling" policy, in conjunction with adequate compensation to prevent spreading of disease.

An improved model for the rate-level functions of auditory-nerve fibers.

Acoustic information is conveyed to the brain by the spike patterns in auditory-nerve fibers (ANFs). In mammals, each ANF is excited via a single ribbon synapse in a single inner hair cell (IHC), and the spike patterns therefore also provide valuable information about those intriguing synapses. Here we reexamine and model a key property of ANFs, the dependence of their spike rates on the sound pressure level of acoustic stimuli (rate-level functions). We build upon the seminal model of Sachs and Abbas (1974), which provides good fits to experimental data but has limited utility for defining physiological mechanisms. We present an improved, physiologically plausible model according to which the spike rate follows a Hill equation and spontaneous activity and its experimentally observed tight correlation with ANF sensitivity are emergent properties. We apply it to 156 cat ANF rate-level functions using frequencies where the mechanics are linear and find that a single Hill coefficient of 3 can account for the population of functions. We also demonstrate a tight correspondence between ANF rate-level functions and the Ca(2+) dependence of exocytosis from IHCs, and derive estimates of the effective intracellular Ca(2+) concentrations at the individual active zones of IHCs. We argue that the Hill coefficient might reflect the intrinsic, biochemical Ca(2+) cooperativity of the Ca(2+) sensor involved in exocytosis from the IHC. The model also links ANF properties with properties of psychophysical absolute thresholds.

Spontaneous activity of auditory-nerve fibers: insights into stochastic processes at ribbon synapses.

In several sensory systems, the conversion of the representation of stimuli from graded membrane potentials into stochastic spike trains is performed by ribbon synapses. In the mammalian auditory system, the spiking characteristics of the vast majority of primary afferent auditory-nerve (AN) fibers are determined primarily by a single ribbon synapse in a single inner hair cell (IHC), and thus provide a unique window into the operation of the synapse. Here, we examine the distributions of interspike intervals (ISIs) of cat AN fibers under conditions when the IHC membrane potential can be considered constant and the processes generating AN fiber activity can be considered stationary, namely in the absence of auditory stimulation. Such spontaneous activity is commonly thought to result from an excitatory Poisson point process modified by the refractory properties of the fiber, but here we show that this cannot be the case. Rather, the ISI distributions are one to two orders of magnitude better and very accurately described as a result of a homogeneous stochastic process of excitation (transmitter release events) in which the distribution of interevent times is a mixture of an exponential and a gamma distribution with shape factor 2, both with the same scale parameter. Whereas the scale parameter varies across fibers, the proportions of exponentially and gamma distributed intervals in the mixture, and the refractory properties, can be considered constant. This suggests that all of the ribbon synapses operate in a similar manner, possibly just at different rates. Our findings also constitute an essential step toward a better understanding of the spike-train representation of time-varying stimuli initiated at this synapse, and thus of the fundamentals of temporal coding in the auditory pathway.

Spatial organization of EEG coherence during listening to consonant and dissonant chords.

Theories of harmony state that the contribution of both sensory and cognitive components is important for musical consonance perception. The aims of the present study were to analyze (a) functional intra- and inter-hemispheric connectivity associated with listening to consonant and dissonant chords using EEG coherence method; (b) relationships between affective responsiveness, sensory aspects of perceived consonance and associated brain connectivity. We identified two lines of inter-hemispheric connectivity in the theta band; one localized anterior being sensitive to consonance and one localized posterior sensitive to dissonance. Stronger right intra-hemispheric connectivity for consonance than dissonance in the theta band was associated with higher pleasantness ratings. The relationship between sensory aspects of perceived consonance and left intra-hemispheric connectivity found in theta-2 was interpreted as processing of vertical harmony without emotional involvement. The stronger connectivity along the axis "left anterior-right posterior" for dissonance than consonance in the alpha-1 band is discussed as a correlate of novelty processing. By introducing a "auditory object dissociation" hypothesis we suggest to extend the present concept of harmony perception. We believe that "auditory object dissociation" is a component of "sensory dissonance."

Failure of a short-term antibiotic therapy for human brucellosis using ciprofloxacin. A study on in vitro susceptibility of Brucella strains.

BACKGROUND: Human brucellosis is characterized byfocal complications, chronic courses, and therapeutic failures. METHODS: In a relapsed case of brucellosis after short-term antibiotic therapy using doxycycline and ciprofloxacin two Brucella strains were isolated, before and after treatment. In vitro susceptibilities of both isolates were determined by E tests including a great variety of antibiotics. In a killing rate experiment the bactericidal activities of doxycycline, streptomycin, rifampin and ciprofloxacin as single agents and in combinations were determined. RESULTS: Lowest MIC values were measured for doxycycline and ciprofloxacin. MICs did not change under therapy. Streptomycin alone exhibited the most effective killing within 6 h, whereas the other single agents did not show bactericidal activity. Doxycycline plus ciprofloxacin was the most active combination in vitro. CONCLUSION: Routine susceptibility testing of Brucellae is not obligatory as most of the 'traditional' anti-Brucella antibiotics are active in vitro and bactericidal efficacy may differ in vivo.