Metal-based antimicrobial protease inhibitors.

Limitations associated with the production cost, metabolic instability, side-effects, resistance and poor pharmacokinetics of organic protease inhibitors (PIs), which form an essential component of the front line HAART treatment for HIV, have fuelled efforts into finding novel, transition metal-based alternatives. Some of the attractive features of metalbased therapeutics include synthetic simplicity, solubility control, redox capability, expansion of coordination number and topography matching of the complex to the protein's active site. Building asymmetry into the complex, which may offer better discrimination between host and rogue cell, can readily be achieved through coordination of chiral ligands to the metal centre. Although the scope of this review has been limited to metal-based agents that have been reported to bind/inhibit HIV-1 and parasitic proteases, some desirables, such as high activity, low dosage, minimal toxicity, crossinhibition, unique binding modes and selectivity, have already been delivered. The variability of the d-block metals, coupled with the availability of designer organic ligands, augers well for the future development of clinical metallo-drugs for deployment against protease-associated, fatal diseases.

Deciphering the antimicrobial activity of phenanthroline chelators.

The opportunistic fungal pathogen, Candida albicans, causes a range of diseases in susceptible individuals. The adverse side effects of many of the current anti-fungal prescription drugs and the emergence of C. albicans isolates and other Candida species which are resistant to these compounds have accelerated the search for new drug candidates which have different modes of action. A family of metal chelators, which are based on the 1,10-phenanthroline core, exhibit excellent growth inhibitory effects in vitro against a number of Candida species, including clinical isolates. The compounds sequester transition metal ions, damage mitochondrial function and uncouple cell respiration. Additionally, fungal cell morphology undergoes dramatic changes and there is evidence of apoptotic cell death. Importantly, in vivo studies have confirmed that the compounds have an acceptably low toxicity profile.

Antimicrobial action of chelating agents: repercussions on the microorganism development, virulence and pathogenesis.

Infections caused by resistant microorganisms often fail to respond to conventional therapy, resulting in prolonged illness, increased treatment costs and greater risk of death. Consequently, the development of novel antimicrobial drugs is becoming more demanding every day since the existing drugs either have too many side-effects or they tend to lose effectiveness due to the selection of resistant strains. In view of these facts, a number of new strategies to obstruct vital biological processes of a microbial cell have emerged; one of these is focused on the use of metal-chelating agents, which are able to selectively disturb the essential metal metabolism of the microorganism by interfering with metal acquisition and bioavailability for crucial reactions. The chelation activity is able to inhibit the biological role of metal-dependent proteins (e.g., metalloproteases and transcription factors), disturbing the microbial cell homeostasis and culminating in the blockage of microbial nutrition, growth and development, cellular differentiation, adhesion to biotic (e.g., extracellular matrix components, cell and/or tissue) and abiotic (e.g., plastic, silicone and acrylic) structures as well as controlling the in vivo infection progression. Interestingly, chelating agents also potentiate the activity of classical antimicrobial compounds. The differences between the microorganism and host in terms of the behavior displayed in the presence of chelating agents could provide exploitable targets for the development of an effective chemotherapy for these diseases. Consequently, metal chelators represent a novel group of antimicrobial agents with potential therapeutic applications. This review will focus on the anti-fungal and anti-protozoan action of the most common chelating agents, deciphering and discussing their mode of action.

Otoacoustic emissions recorded at rapid stimulus rates.

Otoacoustic emissions were evoked by clicks presented according to maximum length sequences. The analysis disentangled the overlapping responses that occur when stimuli are presented at intervals shorter than the duration of the response. Two types of sequence were used: a "monopolar" sequence in which clicks were present or absent, and a "bipolar" sequence in which both condensation and rarefaction clicks occurred. Emissions can be recorded at stimulus rates of up to 1000/sec although the amplitude of the response decreases at these rapid rates. This decrease in amplitude requires a compensatory increase in the number of stimuli to maintain the same signal-to-noise ratio. Optimal efficiency can be attained at rates between 200 and 500/sec. At these rates the emissions can be recorded in about one half the time required for conventional averaging at regular rates of 50/sec.

Human auditory evoked potentials recorded using maximum length sequences.

A maximum length sequence (MLS) is a specially constructed pseudorandom binary sequence that can be used to control the presentation of sensory stimuli. The evoked potentials to such a sequence of stimuli can be analyzed to give the response to one stimulus in the sequence. This procedure allows auditory evoked potentials to be recorded at stimulus rates that would cause a confusing overlap of responses with regular averaging. The MLS technique can be used with auditory evoked potentials at all latencies although it is most effective for the brain-stem and middle-latency responses. By demonstrating different refractory periods for different parts of the response, the technique may help delineate the component structure of the evoked potential. As well, an MLS analysis can disentangle the auditory brain-stem response from overlapping middle-latency responses during evoked potential audiometry.

Terconazole for the treatment of vulvovaginal candidiasis.

A double-blind, randomized trial was conducted to evaluate the efficacy and safety of terconazole for vulvovaginal candidiasis. Treatment consisted of daily intravaginal application of one of the following regimens: 80-mg terconazole suppositories for 3 days, miconazole nitrate suppositories for 7 days or placebo suppositories for 7 days. The terconazole and miconazole nitrate groups had significantly higher therapeutic cure rates than did the placebo group. Evaluation of vaginal secretions with microscopic examination showed no evidence of leukocyte proliferation. Proline aminopeptidase activity, present in patients who have bacterial vaginosis, could not be detected in the vaginal secretions from patients with yeast vulvovaginitis.

Growth of Trichomonas vaginalis in commercial culture media.

There are only two commercially available, ready-to-use culture media which are approved by the Food and Drug Administration for clinical diagnosis of vaginal trichomoniasis: Kupferberg's STS and Diamond's medium (modified). Diamond's medium (Klaas modification), recommended by the Centers for Disease Control for the isolation of Trichomonas vaginalis, was compared in vitro to Kupferberg's (STS) medium. Growth studies using six fresh clinical isolates, all from different patients, showed that while generation time was about 6 h in both STS and Diamond's, the period of exponential growth was longer in Diamond's. More important, in STS there was a 4-h lag period during which the population significantly decreased prior to exponential growth. This did not occur in Diamond's medium. Three hundred organisms inoculated into Diamond's reached a population of over 10(5) organisms in 72 h. In STS, the same inoculum could multiply to only 6 x 10(3) organisms. The fact that there is a lag phase in STS which is not seen in Diamond's could explain why low numbers of T. vaginalis do not multiply in STS but do multiply and can be detected in Diamond's. We conclude that because Diamond's medium (modified) allows more prolific growth over a shorter period of time, it is more suitable than Kupferberg's (STS) for detecting T. vaginalis in patients with vaginitis.

Human evoked potentials to shifts in the lateralization of a noise.

A continuous noise was generated by running a sequence of random numbers through a digital-analog converter and connecting the output through an amplifier and filter to an earphone. Two channels were programmed to generate identical noise stimuli with one channel delayed relative to the other. When these stimuli were presented through earphones, the subject lateralized the noise to the side receiving the leading stimulus. Changes in the relative timing of the two stimuli caused the noise to shift its lateralization. Since these shifts occurred without any detectable change in the ongoing monaural noise, any potentials they evoked were specifically related to binaural interaction. The response recorded from the vertex contained a positive-negative-positive complex with peak latencies of 75, 136 and 220 ms. This response was similar to that evoked by the onset of a monaural stimulus although it was slightly smaller and significantly later. Despite several attempts, we were unable to record any definite earlier evoked potentials.

Interweaving and overlapping of evoked potentials.

The refractory effect of one stimulus upon the response to a closely following stimulus in a different modality is much less than upon the response to a stimulus in the same modality. It is therefore far more efficient to record responses to stimuli in different modalities concurrently than to record each one separately. We evaluated 2 techniques for concurrent recording. Interweaving involves recording the response to one stimulus in the intervals between recording responses to other stimuli. Overlapping occurs when two or more responses are at times being simultaneously recorded. Interweaving and overlapping reduced the time required to record auditory brain-stem responses, short-latency somatosensory evoked potentials and pattern-reversal visual evoked potentials by a factor of 3 over the time required to record each response separately. Overlapping caused no significant change in the evoked potentials. Depending upon the actual timing schedule, interweaving may distort the evoked potentials if later parts of the response to one stimulus override the evoked potential to a following stimulus. Filtering and randomization of stimulus timing may attenuate the effects of these overriding potentials.

Potentials evoked by the sinusoidal modulation of the amplitude or frequency of a tone.

Steady state responses to the sinusoidal modulation of the amplitude or frequency of a tone were recorded from the human scalp. For both amplitude modulation (AM) and frequency modulation (FM), the responses were most consistent at modulation frequencies between 30 and 50 Hz. However, reliable responses could also be recorded at lower frequencies, particularly at 2-5 Hz for AM and at 3-7 Hz for FM. With increasing modulation depth at 40 Hz, both the AM and FM response increased in amplitude, but the AM response tended to saturate at large modulation depths. Neither response showed any significant change in phase with changes in modulation depth. Both responses increased in amplitude and decreased in phase delay with increasing intensity of the carrier tone, the FM response showing some saturation of amplitude at high intensities. Both responses could be recorded at modulation depths close to the subjective threshold for detecting the modulation and at intensities close to the subjective threshold for hearing the stimulus. The responses were variable but did not consistently adapt over periods of 10 min. The 40-Hz AM and FM responses appear to originate in the same generator, this generator being activated by separate auditory systems that detect changes in either amplitude or frequency.

On trial: nursing.

PIP: 2 nurses in Missouri who provide family planning service to 3000-5000 patients annually were accused by state authorities in 1980 of practicing medicine and the physicians with whom they work were charged with aiding this practice. The services provided by these nurses include pregnancy testing, counseling, IUD insertion, provision of oral contraceptives, and treatment of vaginitis, for which physician backup and standard protocols were available. The nursing profession's right to practice autonomously and serve as an entry point for consumers into the health care system was questioned in this trial. Physicians and nurses debated whether nurses can practice without the supervision of a physician and the issue of reimbursement to the physicians for services provided by the nurse was brought up as well. If nurses are not allowed to make independent diagnoses, the health care system will be severely disabled. A decision will be made in this case in 5-6 months.^ieng