Fungal peritonitis in continuous ambulatory peritoneal dialysis--the Auckland experience.

Fungal infection is an uncommon cause of peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD). We report our center's experience with 38 episodes of fungal peritonitis occurring in 33 patients, out of a total of 503 patients managed on CAPD over 11 1/2 years, and review the relevant literature. Our usual management philosophy has been one of early peritoneal catheter removal without antifungal therapy. In those with worsening clinical features, and in those with persistence of signs and symptoms beyond 48 hours after catheter removal, antifungal drugs were administered. Only five patients received antifungal therapy initially, followed by later catheter removal. Seventy-six percent of patients treated by catheter removal alone (N = 21) and 64% of patients treated by catheter removal followed by antifungal therapy (N = 11) were successfully reestablished on CAPD. A policy of early catheter removal, usually alone, but followed by antifungal therapy in select cases, can be associated with a mortality rate of less than 15% and a high rate of return to effective peritoneal dialysis.     

Bilateral emphysematous pyelonephritis resolving to medical therapy.

We describe a case of bilateral emphysematous pyelonephritis, in a diabetic female, that responded to medical therapy alone. Her complete improvement is documented radiologically. Emphysematous pyelonephritis, as a cause of serious infection in diabetic patients, is briefly reviewed.     

Eosinophilic granuloma of mandible in an adult (a case report)

A case of mono-ostotic eosinophilic granuloma localised to the mandible of an adult patient is described. The role of low dose radiation therapy as a curative modality is discussed.     

Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications

Although brain-derived neurotrophic factor (BDNF) has emerged as a key regulator of activity-dependent synaptic plasticity, a conceptually challenging question is how this diffusible molecule achieves local and synapse-specific modulation. One hypothesis is that neuronal activity enhances BDNF signaling by selectively modulating TrkB receptors at active neurons or synapses without affecting receptors on neighboring, less-active ones. Growing evidence suggests that neuronal activity facilitates cell-surface expression of TrkB. BDNF secreted from active synapses and neurons recruits TrkB from extrasynaptic sites into lipid rafts, microdomains of membrane that are enriched at synapses. Postsynaptic rises in cAMP concentrations facilitate translocation of TrkB into the postsynaptic density. Finally, neuronal activity promotes BDNF-induced TrkB endocytosis, a signaling event important for many long-term BDNF functions. These mechanisms could collectively underlie synapse-specific regulation by BDNF.     

Probiotic Escherichia coli Ameliorates Antibiotic-Associated Anxiety Responses in Mice

Despite the beneficial actions of antibiotics against bacterial infections, the use of antibiotics is a crucial etiological factor influencing microbial dysbiosis-associated adverse outcomes in human health. Based on the assumption that gut microbial dysbiosis can provoke behavioral or psychological disorders, the present study evaluated anxiety-linked behavioral changes in a mouse model of streptomycin-induced dysbiosis. Measuring anxiety-like behavior using the light–dark box and elevated plus maze tests indicated that streptomycin treatment caused acute anxiety in mice. As an intervention for dysbiosis-associated distress, the probiotic strain Escherichia coli Nissle 1917 (EcN) was evaluated for its effects on streptomycin-induced behavioral changes in mice. EcN supplementation persistently ameliorated anxiety responses in mice with streptomycin-induced dysbiosis. As an outcome of anxiety, body weight changes were marginally affected by antibiotic treatment. However, mice supplemented with EcN displayed acute retardation of body weight gain, since EcN is known to reduce food intake and increase energy expenditure. Taken together, EcN treatment prominently counteracted streptomycin-induced anxiety in mice, with the metabolically beneficial retardation of body weight gain. The present model simulates psychological disorders in antibiotic users. As a promising intervention, EcN treatment can facilitate psychological relief under conditions of dysbiotic stress by blocking the pathologic gut–brain circuit.     

Assessment of the In Vitro Kinetic Activity of Caspofungin against Candida glabrata

Echinocandins have become the drug of choice in infections caused by Candida glabrata. The objective of this study was to evaluate the in vitro activity of caspofungin alone and in combination against C. glabrata. In vitro assays demonstrated that caspofungin alone showed excellent fungicidal activity against C. glabrata, including fluconazole-resistant strains. The combination of caspofungin and azole antifungals showed potential synergy against C. glabrata. Overall, caspofungin demonstrated excellent in vitro activity, alone and in combination, against strains of C. glabrata.Over the last two decades, Candida albicans has been replaced by the non-albicans Candida species, especially C. glabrata, as the cause of candidemia and invasive candidiasis (36). Fluconazole resistance and reduced susceptibility to azole antifungals, especially fluconazole, may explain the increasing prevalence of infections due to C. glabrata. The increasing prevalence of fungal infections due to C. glabrata has created the need for more-effective antifungals (12). For the past few decades, fluconazole and amphotericin B have been the drugs of choice in the management of candidiasis (23, 31). However, amphotericin B has well-known side effects, such as nephrotoxicity, and the azoles, especially fluconazole, are fungistatic, and there is documented primary and secondary resistance to them (23). Additionally, recent epidemiologic studies have shown that up to 25% of C. glabrata isolates have been found to be intrinsically resistant to fluconazole (27).Caspofungin belongs to the echinocandin class of antifungals (10, 18, 22). Several in vitro studies have demonstrated the excellent in vitro activity of caspofungin against many non-albicans Candida species, especially C. glabrata, including those that are fluconazole resistant (6, 25-28). Several clinical trials have also demonstrated excellent response rates to caspofungin in cases of C. glabrata infection (2, 19, 35).Despite the numerous in vitro and in vivo studies evaluating the antifungal activity of caspofungin against C. glabrata, there is a lack of data evaluating the fungicidal activity of caspofungin (1, 4-6, 11). It would be beneficial to evaluate and compare the fungicidal activity of caspofungin and that of conventional antifungal agents against C. glabrata.Recently, combination antifungal therapy has received increased attention. Most of the literature has evaluated combination therapy in cases of invasive aspergillosis. Due to the different mechanisms of action of caspofungin and other antifungals, combination antifungal therapy has excellent potential and may play a key role in the treatment of fungal infections. Several studies have demonstrated synergy, whereas others have reported indifference and occasionally antagonism (20, 33). Few studies have evaluated the effect of caspofungin in combination with other antifungals against Candida species (13, 14). Most in vitro combination studies evaluating caspofungin have used C. albicans or Aspergillus spp. as the prototype (7, 8, 32).The goal of this study was to evaluate the in vitro activity of caspofungin against clinical isolates of C. glabrata and compare the results with those for standard antifungal agents. Kinetic in vitro studies using time-kill assays (TKA) were used to evaluate both strains of C. glabrata. In addition, we also evaluated the antifungal activity of caspofungin with either fluconazole, voriconazole, or amphotericin B.Fifty isolates of C. glabrata were obtained from clinical samples from patients seen in a chronic vaginitis clinic. Quality control isolates were used in each testing batch and were obtained from American Type Culture Collection (ATCC; Rockville, MD). Quality control isolates included ATCC 90028 (C. albicans) and 6258 (C. krusei). All in vitro assays were performed in duplicate.Caspofungin was obtained as powder from Merck Research Laboratories, Rahway, NJ, and amphotericin B (AmB), fluconazole (Flz), and voriconazole (Vcz) were obtained from their respective manufacturers.In vitro susceptibility testing was done using broth microdilution assays in RPMI 1640 medium using CLSI M27-A2 guidelines (21). The minimal fungicidal concentration (MFC) was defined as the lowest concentration of an antifungal needed to produce a 99.9% kill.TKA were performed as previously described (11, 15). Two different C. glabrata isolates were evaluated, one fluconazole-susceptible strain (MIC, 1 μg/ml) and one fluconazole-resistant strain (MIC, >64 μg/ml). The MIC of caspofungin for these two isolates was 1 μg/ml. Time-kill curves for caspofungin and fluconazole using two different concentrations were compared. The concentrations of caspofungin tested were 1 and 4 μg/ml, while the concentrations of fluconazole were 8 and 128 μg/ml. The lowest limit of accurate and reproducible detectable colony counts was 100.Synergy studies were done using the checkerboard broth microdilution method. Drug interactions were assessed with a checkerboard titration, based on CLSI recommendations (21). The fractional inhibitory concentration index (FICI) was calculated for each combination. The FICI was calculated as FICI = MIC A combination/MIC A alone + MIC B combination/MIC B. A FICI of <0.5 indicates a synergistic effect, >0.5 to <1 indicates an additive effect, 1 to 2 indicates indifference, and >2 indicates an antagonistic effect. Synergy allows a >4-fold reduction in the MICs of individual drugs, compared to the MIC of the combination (20).The MIC of caspofungin against C. glabrata ranged from 0.125 to 1 μg/ml, whereas the MIC of fluconazole against C. glabrata ranged from 2 to 64 μg/ml; the MIC of voriconazole ranged from 0.03 to 16 μg/ml, and the MIC for amphotericin B ranged from 0.5 to 1 μg/ml. The MIC₉₀ of caspofungin, amphotericin B, and voriconazole was 1 μg/ml, whereas the MIC₉₀ of fluconazole was 32 μg/ml (Table ​(Table11).

TABLE 1.

MIC range, MIC₅₀, MIC₉₀, and MFC of caspofungin, amphotericin B, fluconazole, and voriconazole against 50 C. glabrata isolates

Synthesis of size-controlled and highly monodispersed silica nanoparticles using a short alkyl-chain fluorinated surfactant

Highly monodispersed silica nanoparticles (SiNPs) were synthesised using a fluorinated surfactant, HOCH₂CH(CF₃)CO₂H, and its efficiency was compared with efficiencies of five other surfactants. The size of the SiNPs (∼50–200 nm) was controlled by controlling the surfactant amount. The short alkyl-chain fluoro surfactant was found to be more efficient at producing monodispersed SiNPs than its long alkyl-chain fluoro or non-fluorinated surfactant counterparts.

Shape, size, and morphology controlled synthesis of monodispersed silica nanoparticles using 3-hydroxy-2-(trifluoromethyl)-propanoic acid (MAF-OH) surfactant.     

Development and validation of a sensitive LC-MS/MS method for pioglitazone: application towards pharmacokinetic and tissue distribution study in rats

In the present study, a sensitive LC-MS/MS method was developed and validated to measure pioglitazone (PGZ) concentrations in rat plasma and tissues. The chromatographic separation was achieved by using a YMC Pro C₁₈ column (100 mm × 4.6 mm, 3μ) with a mobile phase consisting of formic acid (0.1% v/v) and acetonitrile (5 : 95) at a flow rate of 0.7 mL min⁻¹ and injection volume of 10 μL (IS: rosiglitazone). Mass spectrometric detection was done using triple quadrupole mass spectrometry using the ESI interface operating in a positive ionization mode. The developed method was validated over a linearity range of 1–500 ng mL⁻¹ with detection and a lower quantification limit of 0.5 ng mL⁻¹ and 1 ng mL⁻¹. The method accuracy ranged from 95.89–98.78% (inter-day) & 93.39–97.68% (intra-day) with a precision range of 6.09–8.12% for inter-day & 7.55–9.87% for intra-day, respectively. The PGZ shows the highest C_max of 495.03 ng mL⁻¹ in plasma and the lowest C_max, 24.50 ± 2.71 ng mL⁻¹ in bone. The maximum T_max of 5.00 ± 0.49 h was observed in bone and a minimum of 1.01 ± 0.05 h in plasma. The AUC_{(0–24 h and 0–∞)} values are highest in plasma (1056.58 ± 65.78 & 1069.38 ± 77.50 ng h⁻¹ mL⁻¹) and lowest in brain (166.93 ± 15.70 &167.12 ± 16.77 ng h⁻¹ mL⁻¹), and the T_1/2 was highest in plasma (5.62 ± 0.74 h) and lowest in kidney (2.78 ± 0.19). The developed method was successfully used to measure the PGZ pharmacokinetic and tissue distribution. Further, the developed method could be utilized for validating target organ (adipose tissue) specific delivery of PGZ (nano-formulations) in addition to conventional dosage forms.

The developed method was investigated for target and off-target distribution of pioglitazone and could be applied to validate the site-specific delivery systems.