Influence of Serum and Albumin on Echinocandin In Vitro Potency and Pharmacodynamics

The echinocandins target fungi by inhibiting the production of (1,3)-β-d-glucan, an essential component of the fungal cell wall. These agents have less toxicity to mammalian cells, as compared to other antifungals; however, they maintain potent activity against many pathogenic fungi, including polyene- and azole-resistant isolates. Members of this class are highly protein-bound, and the addition of serum or albumin to the growth medium has profound effects on their in vitro potency and pharmacodynamics. In addition, studies have demonstrated an association between in vitro activity, in the presence of serum, and outcomes in animal models of invasive fungal infections. Serum and albumin may also be useful to help detect echinocandin-resistant Candida isolates with point mutations in the gene that encodes for glucan synthase. Thus, in vitro studies evaluating echinocandins in the presence of protein can provide valuable insight regarding their potency and pharmacodynamics.     

Spectrum of Ocular Manifestations in?CLN2-Associated Batten (Jansky-Bielschowsky)?Disease Correlate with Advancing Age and Deteriorating Neurological Function

Background

Late infantile neuronal ceroid lipofuscinosis (LINCL), one form of Batten’s disease is a progressive neurodegenerative disorder resulting from a CLN2 gene mutation. The spectrum of ophthalmic manifestations of LINCL and the relationship with neurological function has not been previously described.

Methods

Patients underwent ophthalmic evaluations, including anterior segment and dilated exams, optical coherence tomography, fluorescein and indocyanine green angiography. Patients were also assessed with the LINCL Neurological Severity Scale. Ophthalmic findings were categorized into one of five severity scores, and the association of the extent of ocular disease with neurological function was assessed.

Results

Fifty eyes of 25 patients were included. The mean age at the time of exam was 4.9 years (range 2.5 to 8.1). The mean ophthalmic severity score was 2.6 (range 1 to 5). The mean neurological severity score was 6.1 (range 2 to 11). Significantly more severe ophthalmic manifestations were observed among older patients (p<0.005) and patients with more severe neurological findings (p<0.03). A direct correlation was found between the Ophthalmic Severity Scale and the Weill Cornell Neurological Scale (p<0.002). A direct association was also found between age and the ophthalmic manifestations (p<0.0002), with older children having more severe ophthalmic manifestations.

Conclusions

Ophthalmic manifestations of LINCL correlate closely with the degree of neurological function and the age of the patient. The newly established LINCL Ophthalmic Scale may serve as an objective marker of LINCL severity and disease progression, and may be valuable in the evaluation of novel therapeutic strategies for LINCL, including gene therapy.     

The Long-Term Effects of Stress on Partner Weight Characteristics

Background

Recent experimental evidence suggests that stressed males find heavier women more attractive than non-stressed males. The aim of this study is to examine whether these results also appear in actual mating patterns of adults from a national sample.

Methods

Regression analysis linking partner weight measures to own measures of childhood stress, as measured by mistreatment. Cross-sectional data from the National Longitudinal Study of Adolescent Health, Romantic Partners Sample is used to measure partner weight, childhood stressful events, and socio-demographic characteristics. Childhood experiences of adult mistreatment are retrospectively collected.

Results

Men who experienced childhood mistreatment are more likely to have obese female partners during young adulthood. The results are strongest for interactions with social services, adult neglect and physical abuse. We also present novel evidence of the opposite association in similarly stressed women whose male partners are more likely to be thin.

Conclusions

These results suggest that preferences for partner characteristics are sensitive to histories of stress and that previously hypothesized patterns occur outside the experimental setting.     

Multivoxel Patterns in Fusiform Face Area Differentiate Faces by Sex and Race

Although prior research suggests that fusiform gyrus represents the sex and race of faces, it remains unclear whether fusiform face area (FFA)–the portion of fusiform gyrus that is functionally-defined by its preferential response to faces–contains such representations. Here, we used functional magnetic resonance imaging to evaluate whether FFA represents faces by sex and race. Participants were scanned while they categorized the sex and race of unfamiliar Black men, Black women, White men, and White women. Multivariate pattern analysis revealed that multivoxel patterns in FFA–but not other face-selective brain regions, other category-selective brain regions, or early visual cortex–differentiated faces by sex and race. Specifically, patterns of voxel-based responses were more similar between individuals of the same sex than between men and women, and between individuals of the same race than between Black and White individuals. By showing that FFA represents the sex and race of faces, this research contributes to our emerging understanding of how the human brain perceives individuals from two fundamental social categories.     

Peronosporomycetes (Oomycota) from a Middle Permian Permineralised Peat within the Bainmedart Coal Measures,Prince Charles Mountains,Antarctica

The fossil record of Peronosporomycetes (water moulds) is rather sparse, though their distinctive ornamentation means they are probably better reported than some true fungal groups. Here we describe a rare Palaeozoic occurrence of this group from a Guadalupian (Middle Permian) silicified peat deposit in the Bainmedart Coal Measures, Prince Charles Mountains, Antarctica. Specimens are numerous and comprise two morphologically distinct kinds of ornamented oogonia, of which some are attached to hyphae by a septum. Combresomyces caespitosus sp. nov. consists of spherical oogonia bearing densely spaced, long, hollow, slender, conical papillae with multiple sharply pointed, strongly divergent, apical branches that commonly form a pseudoreticulate pattern under optical microscopy. The oogonia are attached to a parental hypha by a short truncated stalk with a single septum. Combresomyces rarus sp. nov. consists of spherical oogonia bearing widely spaced, hollow, broad, conical papillae that terminate in a single bifurcation producing a pair of acutely divergent sharply pointed branches. The oogonium bears a short truncate extension where it attaches to the parental hypha. We propose that similarities in oogonium shape, size, spine morphology and hyphal attachment between the Permian forms from the Prince Charles Mountains and other reported Peronosporomycetes from Devonian to Triassic strata at widely separated localities elsewhere in the world delimit an extinct but once cosmopolitan Palaeozoic to early Mesozoic branch of the peronosporomycete clade. We name this order Combresomycetales and note that it played an important role in late Palaeozoic and early Mesozoic peatland ecosystems worldwide.     

Toward Patient-Specific,Biologically Optimized Radiation Therapy Plans for the Treatment of Glioblastoma

Purpose

To demonstrate a method of generating patient-specific, biologically-guided radiotherapy dose plans and compare them to the standard-of-care protocol.

Methods and Materials

We integrated a patient-specific biomathematical model of glioma proliferation, invasion and radiotherapy with a multiobjective evolutionary algorithm for intensity-modulated radiation therapy optimization to construct individualized, biologically-guided plans for 11 glioblastoma patients. Patient-individualized, spherically-symmetric simulations of the standard-of-care and optimized plans were compared in terms of several biological metrics.

Results

The integrated model generated spatially non-uniform doses that, when compared to the standard-of-care protocol, resulted in a 67% to 93% decrease in equivalent uniform dose to normal tissue, while the therapeutic ratio, the ratio of tumor equivalent uniform dose to that of normal tissue, increased between 50% to 265%. Applying a novel metric of treatment response (Days Gained) to the patient-individualized simulation results predicted that the optimized plans would have a significant impact on delaying tumor progression, with increases from 21% to 105% for 9 of 11 patients.

Conclusions

Patient-individualized simulations using the combination of a biomathematical model with an optimization algorithm for radiation therapy generated biologically-guided doses that decreased normal tissue EUD and increased therapeutic ratio with the potential to improve survival outcomes for treatment of glioblastoma.     

The Incubation Period of Buruli Ulcer (Mycobacterium ulcerans Infection)

Introduction

Buruli Ulcer (BU) is caused by the environmental microbe Mycobacterium ulcerans. Despite unclear transmission, contact with a BU endemic region is the key known risk factor. In Victoria, Australia, where endemic areas have been carefully mapped, we aimed to estimate the Incubation Period (IP) of BU by interviewing patients who reported defined periods of contact with an endemic area prior to BU diagnosis.

Method

A retrospective review was undertaken of 408 notifications of BU in Victoria from 2002 to 2012. Telephone interviews using a structured questionnaire and review of notification records were performed. Patients with a single visit exposure to a defined endemic area were included and the period from exposure to disease onset determined (IP).

Results

We identified 111 of 408 notified patients (27%) who had a residential address outside a known endemic area, of whom 23 (6%) reported a single visit exposure within the previous 24 months. The median age of included patients was 30 years (range: 6 to 73) and 65% were male. 61% had visited the Bellarine Peninsula, currently the most active endemic area. The median time from symptom onset to diagnosis was 71 days (range: 34–204 days). The midpoint of the reported IP range was utilized to calculate a point estimate of the IP for each case. Subsequently, the mean IP for the cohort was calculated at 135 days (IQR: 109–160; CI 95%: 113.9–156), corresponding to 4.5 months or 19.2 weeks. The shortest IP recorded was 32 days and longest 264 days (Figure 1 & 2). IP did not vary for variables investigated.Open in a separate windowFigure 1Geographic representation of Bellarine Peninsula, considered endemic for BU as of 2012.Bellarine Peninsula – east of line from Geelong to Torquay. Mornington and Westernport – southwest of line from Hampton to Tooradin (including Phillip Island).Open in a separate windowFigure 2Geographic representation of East Gippsland, considered endemic for BU as of 2012.East Gippsland: East of Sale and south of the great divide.

Conclusions

The estimated mean IP of BU in Victoria is 135 days (IQR: 109–160 days), 4.5 months. The shortest recorded was IP 34 days and longest 264 days. A greater understanding of BU IP will aid clinical risk assessment and future research.     

Developability studies before initiation of process development

Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other therapeutic proteins, examples of projects that are suspended due to the instability of the molecule are not uncommon. Developability assessment studies have therefore been devised to identify early during process development problems associated with stability, solubility that is insufficient to meet expected dosing or sensitivity to stress. This set of experiments includes short-term stability studies at 2−8 þC, 25 þC and 40 þC, freeze-thaw studies, limited forced degradation studies and determination of the viscosity of high concentration samples. We present here three case studies reflecting three typical outcomes: (1) no major or unexpected degradation is found and the study results are used to inform early identification of degradation pathways and potential critical quality attributes within the Quality by Design framework defined by US Food and Drug Administration guidance documents; (2) identification of specific degradation pathway(s) that do not affect potency of the molecule, with subsequent definition of proper process control and formulation strategies; and (3) identification of degradation that affects potency, resulting in program termination and reallocation of resources.     

Genome sequence of the clover-nodulating Rhizobium leguminosarum bv. trifolii strain TA1

Rhizobium leguminosarum bv. trifolii strain TA1 is an aerobic, motile, Gram-negative, non-spore-forming rod that is an effective nitrogen fixing microsymbiont on the perennial clovers originating from Europe and the Mediterranean basin. TA1 however is ineffective with many annual and perennial clovers originating from Africa and America. Here we describe the features of R. leguminosarum bv. trifolii strain TA1, together with genome sequence information and annotation. The 8,618,824 bp high-quality-draft genome is arranged in a 6 scaffold of 32 contigs, contains 8,493 protein-coding genes and 83 RNA-only encoding genes, and is one of 20 rhizobial genomes sequenced as part of the DOE Joint Genome Institute 2010 Community Sequencing Program.