Alveolar macrophages from susceptible mice are more competent than those of resistant mice to control initial Paracoccidioides brasiliensis infection

Alveolar macrophages ( AM) are the first host cells to interact with Paracoccidioides brasiliensis (Pb), a primary human pathogen that causes severe pulmonary infections in Latin America. To better understand innate immunity in pulmonary paracoccidioidomycosis, we decided to study the fungicidal and secretory abilities of AM from resistant (A/J) and susceptible (B10.A) mice to infection. Untreated, IFN-gamma and IL-12 primed AM from B10. A and A/J mice were challenged with P. brasiliensis yeasts and cocultured for 72 h. B10. A macrophages presented an efficient fungicidal ability, were easily activated by both cytokines, produced high levels of nitric oxide ( NO), IL-12, and MCP-1 associated with low amounts of IL-10 and GM-CSF. In contrast, A/J AM showed impaired cytokine activation and fungal killing, secreted high levels of IL- 10 and GM-CSF but low concentrations of NO, IL- 12, and MCP-1. The fungicidal ability of B10. A but not of A/J macrophages was diminished by aminoguanidine treatment, although only the neutralization of TGF-beta restored the fungicidal activity of A/J cells. This pattern of macrophage activation resulted in high expression of MHC class II antigens by A/J cells, while B10. A macrophages expressed elevated levels of CD40. Unexpectedly, our results demonstrated that susceptibility to a fungal pathogen can be associated with an efficient innate immunity, while a deficient innate response can ultimately favor the development of a resistant pattern to infection. Moreover, our data suggest that different pathogen recognition receptors are used by resistant and susceptible hosts to interact with P. brasiliensis yeasts, resulting in divergent antigen presentation, acquired immunity, and disease outcomes.

Resistant starch in the Australian diet

We set out to estimate resistant starch (RS) intakes using the 24-hour food intake data from the 1995 National Nutrition Survey (NNS) database of 13 858 Australians. As there are often significant differences in the RS content of foods reported by various authors. we calculated intakes based on both published maximum and minimum value, for individual food,. RS intakes (mean and SEM) for all persons were in the range 3.4 ± 0.03 g/d (minimum estimate) to 9.4 ± 0.07 g/d (maximum estimate). Adult males (19+ years) consumed more RS (10.7 ± 0.11 g/day maximum estimale) than adult females (19+ years) (8.2 g ± 0.08 g/day maximum estimate). RS comprised a greater proportion of the total starch intake in the very young and in the older age groups. Across the population. foods contributing most to RS intake were potatoes, bananas and white bread.

An individualized psychosocial approach for "treatment resistant" behavioral symptoms of dementia among aged care residents

Background: Behavioral symptoms of dementia are common among residents in mainstream aged care settings, and have a substantial impact on residents and professional caregivers. This study evaluated the impact of individualized psychosocial interventions for behavioral symptoms through a small preliminary study.
Method: Interventions were delivered to a patient group of 31 psychogeriatric aged care residents who presented with behavioral symptoms of dementia that had failed to respond to pharmacological treatment approaches. Outcome data on severity of behaviors, health service utilization and staff burden of care were collected.
Results: A modest but significant reduction in staff ratings of the severity of aggressive and verbally agitated behavioral symptoms was found, with an associated reduction in their perceptions of the burden of caring for these patients. Reduced behavioral disturbance was associated with a reduction in the requirement for primary care consultations, and all participants were able to continue to reside in mainstream aged care facilities, despite an increase in the severity of dementia.
Conclusions: This study supported the use of individualized psychological strategies for behavioral symptoms at all stages of dementia. Methodological limitations of this preliminary study are discussed.

The Isolation and Characterization of Multiply Antibiotic Resistant Strains of Fish Pathogenic Flavobacterium Species

Since the development of the first antibiotics in the 1940’s, there has been widespread overuse in both clinical and agricultural applications. Antibiotic resistance has become a significant problem as a result of subsequent dissemination of antibiotics into the environment, and multiply-resistant strains of bacteria are now a major pathogenic threat. In this study eight separate strains of Flavobacterium responsible for recent disease outbreaks in fish hatcheries throughout Maine were collected and analyzed. All eight strains were found to be resistant to high levels of a number of different antibiotics, including those used for aquaculture as well as human chemotherapeutic applications. Flavobacterium isolates were also shown phenotypically to transfer antibiotic resistance determinants using a conjugation mating system in which Flavobacterium was the donor and Escherichia coli DH5- alpha was the recipient. This experiment suggests that it may be possible for Flavobacterium strains to transfer their multiple antibiotic resistance determinants to human pathogenic bacterial strains. Importantly, none of the hatcheries from which the Flavobacterium isolates were obtained had ever used antibiotics to treat their fish stock. It is possible that there is another selective agent responsible for the development of antibiotic resistance in the absence of antibiotic pressure. Mercury is one possible candidate, as all of the strains tested were resistant to mercuric chloride and it is known that genes encoding antibiotic resistance can be carried on the same mobile genetic elements that encode for mercury resistance. Preliminary data also suggest that the majority of the Flavobacterium isolates contain genes for mercuric ion reduction, which would confirm the mercury resistance genotype.

Fowl play and the price of petrel: long-living Procellariiformes have peroxidation-resistant membrane composition compared with short-living Galliformes

The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species. We tested this hypothesis by comparing the fatty acid composition of heart phospholipids from long-living Procellariiformes (petrels and albatrosses) to those of shorter living Galliformes (fowl). The seabirds were obtained from by-catch of commercial fishing operations and the fowl values from published data. The 3.8-fold greater predicted longevity of the seabirds was associated with elevated content of peroxidation-resistant monounsaturates and reduced content of peroxidation-prone polyunsaturates and, consequently, a significantly reduced peroxidation index in heart membrane lipids, compared with fowl. Peroxidation-resistant membrane composition may be an important physiological trait for longevous species.

Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer

Background: Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC.

Patients and methods: We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m2 dose every three weeks

Results: Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6–99 weeks) and 1-year survival was 71%.

Conclusions: The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

Community-onset Escherichia coli infection resistant to expanded- spectrum cephalosporins in low-prevalence countries

Background
By global standards the prevalence of community onset expanded-spectrum cephalosporin resistant Escherichia coli (ESC-R-EC) remains low in Australia and New Zealand. Of concern, our countries are in a unique position with high extramural resistance pressure from close population and trade links to Asia-Pacific neighbours with high ESC-R-EC rates. We aim to characterize the risks and dynamics of community onset ESC-R-EC in our low-prevalence region.

Methods
A case-control methodology was used. Patients with ESC-R-EC or susceptible E. coli isolated from blood or urine were recruited at six geographically dispersed tertiary hospitals in Australia and New Zealand. Epidemiological data was prospectively collected and bacteria were retained for analysis.

Results
In total, 182 patients (91 cases and 91 controls) were recruited. Multivariate logistic regression identified risk factors for ESC-R amongst E. coli including birth on the Indian subcontinent (OR=11.13, 2.17-56.98, p=0.003), urinary tract infection in the past year (per infection OR=1.430, 1.13-1.82, p=0.003), travel to South East Asia, China, Indian subcontinent, Africa and the Middle East (OR=3.089, 1.29-7.38, p=0.011), prior exposure to trimethoprim+/-sulfamethoxazole &/or an expanded-spectrum cephalosporin (OR=3.665, 1.30-10.35, p=0.014) and healthcare exposure in the previous six months (OR=3.16, 1.54-6.46, p=0.02).

Amongst our ESC-R-EC the blaCTX-M ESBLs was dominant (83% of ESC-R-EC), and the worldwide pandemic clone ST-131 was frequent (45% of ESC-R-EC).

Conclusion
In our low prevalence setting, ESC-R amongst community onset E. coli may be associated with both ‘export’ from healthcare facilities into the community and direct ‘import’ into the community from high-prevalence regions.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean=35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 μg than 100 μg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 μg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.Molecular Psychiatry advance online publication, 15 April 2014; doi:10.1038/mp.2014.33.

N-acetylcysteine for therapy-resistant tobacco use disorder: a pilot study

Introduction N-Acetylcysteine (NAC) may have efficacy in treating tobacco use disorder (TUD) by reducing craving and smoking reward. This study examines whether treatment with NAC may have a clinical efficacy in the treatment of TUD. Methods A 12-week double blind randomized controlled trial was conducted to compare the clinical efficacy of NAC 3 g/day versus placebo. We recruited 34 outpatients with therapy resistant TUD concurrently treated with smoking-focused group behavioral therapy. Participants had assessments of daily cigarette use (primary outcome), exhaled carbon monoxide (COEXH) (secondary outcome), and quit rates as defined by COEXH<6 ppm. Depression was measured with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using conventional and modified intention-to-treat endpoint analyses. Results NAC treatment significantly reduced the daily number of cigarettes used (Δ mean±SD = -10.9 ± 7.9 in the NAC-treated versus -3.2 ± 6.1 in the placebo group) and COEXH (Δ mean± SD = -10.4 ± 8.6 ppm in the NAC-treated versus -1.5 ± 4.5 ppm in the placebo group); 47.1% of those treated with NAC versus 21.4% of placebo-treated patients were able to quit smoking as defined by COEXH<6 ppm. NAC treatment significantly reduced the HDRS score in patients with tobacco use disorder. Conclusions These data show that treatment with NAC may have a clinical efficacy in TUD. NAC combined with appropriate psychotherapy appears to be an efficient treatment option for TUD.

Activity of cabazitaxel in castration-resistant prostate cancer progressing after docetaxel and next-generation endocrine agents

Background Cabazitaxel, abiraterone, and enzalutamide are survival-prolonging treatments in men with castration-resistant prostate cancer (CRPC) progressing following docetaxel chemotherapy. The sequential activity of these agents has not been studied and treatment sequencing remains a key dilemma for clinicians. Objective To describe the antitumour activity of cabazitaxel after docetaxel and next-generation endocrine agents. Design, setting, and participants We report on a cohort of 59 men with progressing CRPC treated with cabazitaxel, 37 of whom had received prior abiraterone and 9 of whom had received prior enzalutamide. Outcome measurements and statistical analysis Changes in prostate-specific antigen (PSA) level were used to determine activity on abiraterone, enzalutamide, and cabazitaxel treatment. Radiologic tumour regressions according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel therapy. Results and limitations The post-endocrine-therapy patients received abiraterone (n = 32), sequential abiraterone and enzalutamide (n = 5) or enzalutamide (n = 4). These patients received a median of 7 mo of abiraterone and 11 mo of enzalutamide. A median of six cabazitaxel cycles (range: 1-10 cycles) were delivered, with ≥50% PSA declines in 16 of 41 (39%) patients, soft tissue radiologic responses in 3 of 22 (14%) evaluable patients, and symptomatic benefit in 9 of 37 evaluable patients (24%). Median overall survival and progression-free survival were 15.8 and 4.6 mo, respectively. Antitumor activity on cabazitaxel was less favourable in the abiraterone- and enzalutamide-naïve cohort (n = 18), likely reflecting biologic differences in this cohort. These data were obtained from a retrospective analysis. Conclusions This is the first report of cabazitaxel activity in CRPC progressing after treatment with docetaxel and abiraterone or enzalutamide. We demonstrate significant cabazitaxel activity in this setting. Patient summary We looked at the antitumour activity of the chemotherapy drug cabazitaxel in men previously treated with docetaxel chemotherapy and the hormonal drugs abiraterone and enzalutamide. Cabazitaxel appeared active when given after abiraterone and enzalutamide. We can reassure men that cabazitaxel can be used after these novel endocrine treatments. © 2013 European Association of Urology.

Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age

Many women with schizophrenia remain symptomatic despite optimal use of current therapies. While previous studies suggest that adjunctive oestrogen therapy might be effective, large-scale clinical trials are required before clinical applications are possible. This study is the first large-scale randomized-controlled trial in women with treatment-resistant schizophrenia. This Definitive Oestrogen Patch Trial was an 8-week, three-arm, double-blind, randomized-controlled trial conducted between 2006 and 2011. The 183 female participants were aged between 18 and 45 (mean=35 years), with schizophrenia or schizoaffective disorder and ongoing symptoms of psychosis (Positive and Negative Syndrome Scale, PANSS score>60) despite a stable dose of antipsychotic medication for at least 4 weeks. Mean duration of illness was more than 10 years. Participants received transdermal estradiol 200 μg, transdermal estradiol 100 μg or an identical placebo patch. For the 180 women who completed the study, the a priori outcome measure was the change in PANSS score measured at baseline and days 7, 14, 28 and 56. Cognition was assessed at baseline and day 56 using the Repeatable Battery of Neuropsychological Status. Data were analysed using latent growth curve modelling. Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 μg than 100 μg estradiol. The largest effect size was for the positive subscale of PANSS in the estradiol 200 μg treatment group (effect size 0.44, P<0.01). This study shows estradiol is an effective and clinically significant adjunctive therapy for women with treatment-resistant schizophrenia, particularly for positive symptoms.

Future directions for pharmacotherapies for treatment-resistant bipolar disorder

Current pharmacological treatments for bipolar disorder (BD) are limited and efficacy has historically been discovered through serendipity. There is now scope for new drug development, focused on the underlying biology of BD that is not targeted by current therapies. The need for novel treatments is urgent when considering treatment resistant BD, where current therapies have failed. While established drugs targeting the monoamine systems continue to be worthwhile, new biological targets including inflammatory and oxidative an nitrosative pathways, apoptotic and neurotrophic pathways, mitochondrial pathways, the N-methyl-Daspartate (NMDA)-receptor complex, the purinergic system, neuropeptide system, cholinergic system and melatonin pathways are all being identified as potential anchors for the discovery of new agents. Many agents are experimental and efficacy data is limited, however further investigation may provide a new line for drug discovery, previously stalled by lack of corporate interest.

Antimicrobial use and incidence of multidrug-resistant Pseudomonas aeruginosa in a teaching hospital: an ecological approach

Introduction: Multidrug-resistant Pseudomonas aeruginosa is a major threat in healthcare settings. The use of antimicrobials can influence the incidence of resistant strains by direct and indirect mechanisms. The latter can be addressed by ecological studies. Methods: Our group attempted to analyze the relation between the use of antipseudomonal drugs and the incidence of MDR-PA among 18 units from a 400-bed teaching hospital. The study had a retrospective, ecological design, comprising data from 2004 and 2005. Data on the use of four antimicrobials (amikacin, ciprofloxacin, ceftazidime and imipenem) were tested for correlation with the incidence of MDR-PA (defined as isolates resistant to the four antimicrobials of interest) in clinical cultures. Univariate and multivariate linear regression analyses were performed. Results: Significant correlations were determined between use and resistance for all antimicrobials in the univariate analysis: amikacin (standardized correlation coefficient = 0.73, p = 0.001); ciprofloxacin (0.71, p = 0.001); ceftazidime (0.61, p = 0.007) and imipenem (0.87, p < 0.001). In multivariate analysis, only imipenem (0.67, p = 0.01) was independently related to the incidence of multidrug-resistant strains. Conclusions: These findings share similarities with those reported in individual-based observational studies, with possible implications for infection control.

A morphometric study of the midgut in resistant and non-resistant Anticarsia gemmatalis (Hubner) (Lepidoptera: Noctuidae) larvae to its nucleopolyhedrovirus (AgMNPV)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)