Susceptibility of cat fleas (Siphonaptera: Pulicidae) to fipronil and imidacloprid using adult and larval bioassays.

The monitoring of the susceptibility offleas to insecticides has typically been conducted by exposing adults on treated surfaces. Other methods such as topical applications of insecticides to adults and larval bioassays on treated rearing media have been developed. Unfortunately, baseline responses of susceptible strains of cat flea, Ctenocephalides felis (Bouchè), except for imidacloprid, have not been determined for all on-animal therapies and new classes of chemistry now being used. However, the relationship between adult and larval bioassays of fleas has not been previously investigated. The adult and larval bioassays of fipronil and imidacloprid were compared for both field-collected isolates and laboratory strains. Adult topical bioassays of fipronil and imidacloprid to laboratory strains and field-collected isolates demonstrated that LD50s of fipronil and imidacloprid ranged from 0.11 to 0.40 nanograms per flea and 0.02 to 0.18 nanograms per flea, respectively. Resistance ratios for fipronil and imidacloprid ranged from 0.11 to 2.21. Based on the larval bioassay published for imidacloprid, a larval bioassay was established for fipronil and reported in this article. The ranges of the LC50s of fipronil and imidacloprid in the larval rearing media were 0.07-0.16 and 0.11-0.21 ppm, respectively. Resistance ratios for adult and larval bioassays ranged from 0.11 to 2.2 and 0.58 to 1.75, respectively. Both adult and larval bioassays provided similar patterns for fipronil and imidacloprid. Although the adult bioassays permitted a more precise dosage applied, the larval bioassays allowed for testing isolates without the need to maintain on synthetic or natural hosts.

Genome sequences of Mycoplasma alligatoris A21JP2T and Mycoplasma crocodyli MP145T.

Mycoplasma alligatoris and Mycoplasma crocodyli are closely related siblings, one being highly virulent and the other relatively attenuated. We compared their genomes to better understand the mechanisms and origins of M. alligatoris' remarkable virulence amid a clade of harmless or much less virulent species. Although its chromosome was refractory to closure, M. alligatoris differed most notably by its complement of sialidases and other genes of the N-acetylneuraminate scavenging and catabolism pathway.

Evaluation of an imidacloprid (8.8% w/w)--permethrin (44.0% w/w) topical spot-on and a fipronil (9.8% w/w)--(S)-methoprene (8.8% w/w) topical spot-on to repel, prevent attachment, and kill adult Ixodes scapularis and Amblyomma americanum ticks on dogs.

This study evaluated the effectiveness of two topical spot-on formulations -- imidacloprid(8.8% w/w)-permethrin (44.0% w/w) and fipronil (9.8% w/w)-(S)-methoprene (8.8% w/w)--to repel, prevent the attachment of, and kill adult Ixodes scapularis and Amblyomma americanum on dogs. Twelve purpose-bred beagles were distributed into three groups of four dogs each; one group served as untreated controls, and each of the other two groups received one of the test products. Dogs were exposed to 25 adult ticks of each species for 10 minutes on posttreatment days 3, 7, 14, 21, and 28. Unattached or repelled ticks were collected and evaluated for viability, and on-dog tick counts were conducted at 3, 24, and 48 hours after tick exposure. The imidacloprid-permethrin formulation provided significant repellency against I. scapularis for up to 3 weeks after treatment, and both formulations provided good overall control of I. scapularis and A. americanum during the study period.

Evaluation of an imidacloprid (8.8% w/w)--permethrin (44.0% w/w) topical spot-on and a fipronil (9.8% w/w)--(S)-methoprene (8.8% w/w) topical spot-on to repel, prevent attachment, and kill adult Rhipicephalus sanguineus and Dermacentor variabilis ticks on dogs.

This study evaluated the effectiveness of two topical spot-on formulations, imidacloprid (8.8% w/w)--permethrin (44.0% w/w) and fipronil (9.8% w/w)--(S)-methoprene (8.8% w/w), to repel, prevent the attachment of, and kill adult Rhipicephalus sanguineus and Dermacentor variabilis on dogs. Twelve purpose-bred beagles were distributed into three groups of four dogs each; one group served as untreated controls and each of the other two groups received one of the test products. Dogs were exposed to 25 adult ticks of each species for 10 minutes on posttreatment days 3, 7, 14, 21, and 28. Nonattached or repelled ticks were collected and evaluated for viability, and on-dog tick counts were conducted at 3, 24, and 48 hours after tick exposure. The imidacloprid-permethrin formulation provided significant repellency of R. sanguineus and D. variabilis for up to 3 and 4 weeks after treatment, respectively; and provided good overall control for R. sanguineus and D. variabilis during the study period. The fipronil--(S)-methoprene formulation provided good overall tick control during the study period.

Efficacy of imidacloprid (8.8% w/w) plus permethrin (44% w/w) spot-on topical solution against Amblyomma americanum infesting dogs using a natural tick exposure model.

This study evaluated the efficacy of an imidacloprid 8.8% w/w + permethrin 44% w/w spot-on topical solution (K9 Advantix, Bayer Animal Health) against Amblyomma americanum using a natural field exposure model. Sixteen beagles were divided into two groups of eight dogs each. One group of dogs was treated with K9 Advantix and the other group served as untreated controls. On day -1 and at 3, 7, 14, 21 and 28 days after treatment, the dogs were walked for 80 minutes in an A. americanum-infested habitat at the Konza Prairie Biological Station in Northeastern Kansas. Postexposure tick counts (efficacy evaluations) were conducted on each dog at 3 and 48 hours after exposure. At 3 days after treatment, the efficacy of K9 Advantix within 3 hours of natural tick exposure was 88.0% and declined slowly during the study. The 48-hour postexposure efficacy remained above 93.5% throughout the study.

Measurement of the electron-phonon coupling factor dependence on film thickness and grain size in Au, Cr, and Al.

Femtosecond thermoreflectance data for thin films and bulk quantities of Au, Cr, and Al are compared with the parabolic two-step thermal diffusion model for the purpose of determining the electron-phonon coupling factor. The thin films were evaporated and sputtered onto different substrates to produce films that vary structurally. The measurement of the electron-phonon coupling factor is shown to be sensitive to grain size and film thickness. The thin-film thermoreflectance data are compared with that of the corresponding bulk material and to a theoretical model relating the coupling rate to the grain-boundary scattering and size effects on the mean free path of the relevant energy carrier.

NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

Indefinite survival of human skin allografts in patients with long-term immunosuppression.

The transplantation of a sufficient quantity of good quality skin is of great clinical importance. Severe burn patients lack adequate skin donor sites to cover their wounds with autografts. Patients with severe injuries and burns of areas such as the entire face are presently reconstructed with multiple full- or split-thickness skin grafts. The final result is a patchwork appearance of skin with inferior qualities to normal full-thickness facial skin. Before structures such as hands should be transplanted, each individual tissue component should be evaluated to determine whether the tissue will survive and function with immunosuppression. Skin is obviously an important part of the hand. One hypothesis tested is the ability of transplanted human skin to survive indefinitely with long-term immunosuppression. The early detection of rejection of transplanted organs is paramount in reversing the rejection phenomena and hence saving the transplanted organ. Another hypothesis tested is the ability of a synchronously placed, same-donor, same-recipient skin graft to be used to detect rejection of a transplanted organ. As the skin and kidney from the same donor have similar antigens and the transplantation of both these tissues is to the same recipient and immunological system, it is hypothesized that there will be a correlation of rejection between the transplanted skin and the transplanted organ. To test the above hypotheses a small skin graft was placed on renal transplant patients synchronously with renal transplantation. The skin allografts were followed by direct observation and biopsy at regular intervals and at the time of suspected rejection. The patients were treated with the usual renal transplant immunosuppressant drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of coccidioidomycosis with SCH 39304.

A new oral triazole antifungal, SCH 39304, was administered to 54 patients with progressive infections due to Coccidioides immitis from six collaborating centers. Patients were grouped according to site of infection including chronic pulmonary (25), bone/joint (17) and skin/soft tissue (12). The median age was 40 years; 83% were male, 52% white, 13% HIV-infected and 35% had failed previous therapy. The majority of patients were treated with either 100 mg or 200 mg day-1. One patient on renal dialysis received 300 mg day-1. Baseline abnormalities were reassessed for evidence of efficacy every 4 months and expressed in a standardized scoring system. Cumulative overall response rates at 4, 8 and 12 months were 7%, 36% and 66% respectively. Twelve month response rates by disease were 77% (pulmonary), 62% (skin/soft tissue) and 31% (bone/joint). Fifteen patients failed therapy although seven of these were still on treatment when the study was discontinued. Two failed due to toxicity. Possible symptoms or signs of toxicity occurred in 24 (44%) patients and were generally mild. SCH 39304 is an effective and well tolerated therapy for progressive forms of coccidioidomycosis.

Preventing substance abuse. An interview paradigm.

In summary, substance use and abuse is a major health problem in the United States affecting adolescents of both sexes and of every socioeconomic level. Family physicians have numerous opportunities to improve the health of future generations by using specific skills and expertise to prevent, identify, and intervene with adolescents' abuse of alcohol and other chemical substances. The first step is taking an effective alcohol and drug-use history.

Effect of anti-IL-4, interferon-gamma and an antifungal triazole (SCH 42427) in paracoccidioidomycosis: correlation of IgE levels with outcome.

Paracoccidioidomycosis is characterized by depressed cellular but enhanced humoral immune responses, which suggests a Th2 type of response to infection. We investigated possible therapeutic roles for anti-IL-4, interferon-gamma (IFN-gamma) and/or SCH 42427 (SCH), a new triazole antifungal agent, and their effect on serum IgE levels in a murine model of chronic Paracoccidioides brasiliensis infection. BALB/c mice infected by the pulmonary route were studied with three programmes. The subacute model and one acute model experiment investigated cytokine secretion by lymph node cells (LNC), and in a second acute experiment mice were given anti-IL-4, IFN-gamma or nothing 24 h post infection, then killed at 4 weeks. In the chronic model, mice began treatment at 4 weeks post infection, receiving either SCH, IFN-gamma alone, SCH+IFN-gamma, or no treatment for 8 weeks. At 2-week intervals lung and spleen burdens of infection and serum polyclonal IgE levels were determined. In the subacute model (non-progressive infection), initially there was dual production of IL-4 and IFN-gamma by antigen-stimulated LNC. In the acute progressive infection model IL-4, but not IFN-gamma, was secreted. Anti-IL-4 treatment of the acute phase resulted in enhanced host resistance to infection, which correlated with decreased serum IgE. The chronic model, in which the in vivo efficacy of SCH against P. brasiliensis was shown, suggests possible synergy between immunomodulation and antimicrobial chemotherapy (IFN-gamma and SCH). Decreased organ burdens of infection in the chronic model after treatment with SCH, SCH plus IFN-gamma, or anti-IL-4 correlated with decreased serum IgE. These promising novel approaches to treatment of systemic fungal infections suggest a Th2 type of response to P. brasiliensis infection, which can be reversed with successful therapy.

Discrepancies in bioassay and chromatography determinations explained by metabolism of itraconazole to hydroxyitraconazole: studies of interpatient variations in concentrations.

Pharmacologic studies of itraconazole (IZ), a triazole antifungal, indicated unexplained differences between bioassay and chromatographic determinations and large variations in steady-state blood concentrations. We show that concentrations of a hydroxylated metabolite, hydroxyitraconazole (HIZ), are approximately twofold higher than IZ over a range of concentrations. Though HIZ and IZ appear equipotent against selected pathogens, HIZ is two to three times more active against a commonly used bioassay fungus but minimally affects IZ activity. Hence, HIZ probably contributes importantly to the therapeutic activity attributed to IZ and contributes approximately four to six times the activity of IZ in bioassays, explaining discrepancies observed between assay methods.

Ulcerative and plaque-like tracheobronchitis due to infection with Aspergillus in patients with AIDS.

Tracheobronchitis is an uncommon manifestation of infection due to Aspergillus species, occurring in < 7% of cases of pulmonary aspergillosis. At least 58 cases of invasive aspergillus tracheobronchitis have been described since 1962. We describe four patients with AIDS, all of whom were severely immunocompromised, who had ulcerative tracheobronchitis due to Aspergillus species demonstrated histologically. Three patients had received corticosteroids or were neutropenic at presentation. At bronchoscopy, three patients had some degree of diffuse tracheobronchitis, multiple ulcerative or "plaque-like" inflammatory lesions, and occasionally nodules involving the mainstem and segmental bronchi. The remaining patient had a single deep ulceration of the proximal trachea. Aspergillus was isolated from biopsy specimens from all four patients. There were varied degrees of invasion of the mucosa, submucosa, and cartilage on histological examination in three patients, one of whom had evidence of disseminated aspergillosis. Two patients subsequently developed pulmonary parenchymal disease due to Aspergillus. A review of aspergillus tracheobronchitis, including a discussion of airway disease in patients infected with human immunodeficiency virus, is presented.

Treatment of sporotrichosis with itraconazole. NIAID Mycoses Study Group.

PURPOSE: To describe the clinical presentation and outcomes of treatment with itraconazole in patients with sporotrichosis. METHODS: A culture for Sporothrix schenckii or compatible histopathology was required for inclusion in the study. Patients with both cutaneous and systemic sporotrichosis were treated. Patients received from 100 to 600 mg of itraconazole daily for 3 to 18 months. Patients were classified as responders or nonresponders. Responders were further classified as remaining on treatment, relapsed, or free of disease. Nonresponders included patients who failed to respond or progressed during treatment with itraconazole. RESULTS: Twenty-seven patients (mean age: 53 years) were treated with 30 courses of itraconazole. Diabetes mellitus and alcoholism were present in eight and seven patients, respectively. Sites of involvement included lymphocutaneous alone in 9 patients, articular/osseous in 15 (multifocal in 3), and lung in 3. Prior therapy was unsuccessful in 11 patients. Among the 30 courses, there were 25 responders and 5 nonresponders. All 5 nonresponders received at least 200 mg daily of itraconazole for durations that ranged from 6 to 18 months. Of the 25 responders, 7 relapsed 1 to 7 months after treatment durations of 6 to 18 months. Of the 7 who relapsed, 2 are responding to a second course. One responder was lost to follow-up after 10 months of treatment with itraconazole. Of the remaining 17 responders, 3 remain on treatment, and 14 are free of disease over follow-up durations of 6 to 42 months (mean: 17.6 months). Itraconazole was well tolerated with few side effects noted. CONCLUSIONS: These results document the efficacy of itraconazole in the treatment of cutaneous and systemic sporotrichosis.

Effect of hydroxypropyl-beta-cyclodextrin on efficacy of oral itraconazole in disseminated murine cryptococcosis.

The therapeutic efficacy of itraconazole solubilized in either the commonly used vehicle, polyethylene-glycol-200 (PEG) or hydroxypropyl beta-cyclodextrin was compared in a murine model of disseminated cryptococcosis. Itraconazole at doses of up to 120 mg/kg/day solubilized in PEG were found not to be effective. However, itraconazole at doses > or = 30 mg/kg/day solubilized in hydroxypropyl-beta-cyclodextrin markedly prolonged survival and a relationship between dose and survival was seen.

Efficacy and safety of amphotericin B colloidal dispersion compared with those of amphotericin B deoxycholate suspension for treatment of disseminated murine cryptococcosis.

The efficacy and safety of amphotericin B colloidal dispersion (ABCD) were compared with those of amphotericin B deoxycholate suspension (ABDS) (Fungizone) in a murine model of disseminated cryptococcosis. Mice were treated intravenously with either ABDS at 0.2, 0.8, or 3.2 mg/kg of body weight per dose or ABCD at 0.8, 3.2, 6.4, 12.8, or 19.2 mg/kg dose three times per week for 2 weeks. Excluding mice treated with ABDS at 3.2 mg/kg, which was acutely lethal in 100% of mice, and ABCD at 19.2 mg/kg, which also resulted in two early deaths, the survival of ABCD- and ABDS-treated groups was prolonged over survival of controls (P < or = 0.05). Survival of ABCD (3.2 mg/kg)-treated mice was improved over that of ABDS (0.2 mg/kg)-treated mice (P < 0.05); however, comparisons of mice given all other dosages of ABCD with mice given sublethal dosages of ABDS did not demonstrate differences in survival. Comparative fungal burdens in organs showed a decrease in liver (P < 0.05) and spleen (P < 0.05) burdens for ABCD with the 19.2-mg/kg therapy versus those with ABDS with the 0.8-mg/kg therapy and liver burdens for ABCD with the 12.8-mg/kg therapy versus ABDS with the 0.8-mg/kg therapy (P < 0.05). There was no difference in organ burdens between therapy with ABCD at 0.8 mg/kg and ABDS at 0.8 mg/kg. These data show that the efficacy of ABCD is equal to that of ABDS on a milligram-per-kilogram basis for murine disseminated cryptococcosis. Because of its decreased toxicity, greater efficacy with ABCD could be achieved through doses fourfold higher than the 100% lethal dose for ABDS. Thus, ABCD shows promise as an effective but less toxic alternative to ABDS for the treatment of disseminated cryptococcosis.

Cortisol regulates secretion and pituitary content of the two gonadotropins differentially in female rats: effects of gonadotropin-releasing hormone antagonist.

To determine if LH and FSH respond to cortisol exposure the same way in females as they do in males, metestrous females were implanted with cholesterol or cortisol (F) subcutaneously, and either ovariectomized or left intact 4 days later. Tail vein injections of 1000 ng of GnRH in saline, or saline alone, were given 4.5, 23.5, or 47.5 h after the time of ovariectomy. Animals were killed 30 min after the injections at 5, 24, and 48 h after surgery. F attenuated the postovariectomy increase in serum LH at 48 h. F also suppressed GnRH-stimulated LH release 24 and 48 h after surgery in ovariectomized animals and in intact animals at 48 h. Pituitary content of LH was increased moderately by F at 5 h. These effects of F are similar to those seen in males. In contrast to LH, F increased serum FSH in intact females and suppressed levels in ovariectomized animals at 24 and 48 h, while inducing a remarkable increase in pituitary FSH content at all three times. These divergent effects of F on serum FSH (suppression in gonadectomized and stimulation in intact groups) were not seen in males, and the increase in pituitary FSH as a result of exposure to F was much more profound and reliable in females than in males. To determine if the F-induced increase in pituitary FSH was dependent on endogenous secretion of GnRH, intact metestrous females were implanted with either cholesterol or F pellets. Each implant group received sc injections of 100 micrograms GnRH antagonist or control injections every 48 h beginning at the time of steroid implantation. Animals were killed 5 days after implantation. The antagonist suppressed both serum and pituitary LH. F also suppressed serum LH levels, but had no effect on pituitary content of LH. Neither the antagonist nor F affected serum FSH. F greatly increased pituitary content of FSH in the presence or absence of GnRH antagonist. These data suggest that 1) LH responds to F treatment in a similar way in females and males; 2) pituitary FSH content is more sensitive to the enhancing effect of F in females than in males; 3) the ability of F to increase pituitary FSH in females is not dependent on GnRH.

Effect of cyclodextrin on the pharmacology of antifungal oral azoles.

Concentrations of oral azoles in serum were compared in a single-dose pharmacologic study in mice. When hydroxypropyl-beta-cyclodextrin was used as a carrier and compared with a standard carrier, polyethylene glycol, drug concentrations determined by bioassay showed that the peak concentration and area under the concentration-time curve were greatly enhanced for itraconazole and saperconazole; moderately enhanced for ketoconazole; but negligibly affected for fluconazole, miconazole, and SCH 42427.