Acquisition of the Sda1-encoding bacteriophage does not enhance virulence of the serotype M1 Streptococcus pyogenes strain SF370

The resurgence of invasive disease caused by Streptococcus pyogenes (group A Streptococcus [GAS]) in the past 30 years has paralleled the emergence and global dissemination of the highly virulent M1T1 clone. The GAS M1T1 clone has diverged from the ancestral M1 serotype by horizontal acquisition of two unique bacteriophages, encoding the potent DNase Sda1/SdaD2 and the superantigen SpeA, respectively. The phage-encoded DNase promotes escape from neutrophil extracellular traps and is linked to enhanced virulence of the M1T1 clone. In this study, we successfully used in vitro lysogenic conversion to transfer the Sda1-encoding phage from the M1T1 clonal strain 5448 to the nonclonal M1 isolate SF370 and determined the impact of this horizontal gene transfer event on virulence. Although Sda1 was expressed in SF370 lysogens, no capacity of the phage-converted strain to survive human neutrophil killing, switch to a hyperinvasive covRS mutant form, or cause invasive lethal infection in a humanized plasminogen mouse model was observed. This work suggests that the hypervirulence of the M1T1 clone is due to the unique synergic effect of the M1T1 clone bacteriophage-specific virulence factor Sda1 acting in concert with the M1T1 clone-specific genetic scaffold

Hybrid off-river augmentation system as an alternative raw water resource: the hydrogeochemistry of abandoned mining ponds

The use of water from abandoned mining ponds under a hybrid off-river augmentation system (HORAS) has been initiated as an alternative water resource for raw water. However, it raises the questions over the safety of the use of such waters. In this study, the hydrogeochemical analysis of the waters is presented to assess the degree to which the water has been contaminated. Comparisons were made between sampling sites, i.e. abandoned mining ponds, active sand mining ponds and the receiving streams within Bestari Jaya, Selangor River basin. The aqueous geochemistry analysis showed different hydrochemical signatures of major elements between sites, indicating different sources of minerals in the water. Discharges from the sand mining ponds were found to contain elevated availability of dissolved concentrations of iron, manganese, lead, copper and zinc, among others. However, the quality of the water (from the main river) that is supplied for potable water consumption is at a satisfactory level despite being partly sourced from the abandoned mining ponds. In fact, all the metal concentrations detected were well below the Malaysia Ministry of Health guideline limits for untreated raw water. In addition, the results of the geochemical index analysis (i.e. geoaccumulation index, enrichment factor and modified contamination factor) showed that the rivers and abandoned mining ponds were generally unpolluted with respect to the metals found in sediments

Quantum Gravity in 2+1 Dimensions: The Case of a Closed Universe

In three spacetime dimensions, general relativity drastically simplifies, becoming a ``topological'' theory with no propagating local degrees of freedom. Nevertheless, many of the difficult conceptual problems of quantizing gravity are still present. In this review, I summarize the rather large body of work that has gone towards quantizing (2+1)-dimensional vacuum gravity in the setting of a spatially closed universe.Comment: 61 pages, draft of review for Living Reviews; comments, criticisms, additions, missing references welcome; v2: minor changes, added reference

In Vivo Methods to Study Uptake of Nanoparticles into the Brain

Several in vivo techniques have been developed to study and measure the uptake of CNS compounds into the brain. With these techniques, various parameters can be determined after drug administration, including the blood-to-brain influx constant (Kin), the permeability-surface area (PS) product, and the brain uptake index (BUI). These techniques have been mostly used for drugs that are expected to enter the brain via transmembrane diffusion or by carrier-mediated transcytosis. Drugs that have limitations in entering the brain via such pathways have been encapsulated in nanoparticles (based on lipids or synthetic polymers) to enhance brain uptake. Nanoparticles are different from CNS compounds in size, composition and uptake mechanisms. This has led to different methods and approaches to study brain uptake in vivo. Here we discuss the techniques generally used to measure nanoparticle uptake in addition to the techniques used for CNS compounds. Techniques include visualization methods, behavioral tests, and quantitative methods

Blood group terminology 2004: from the International Society of Blood Transfusion committee on terminology for red cell surface antigens

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73460/1/j.1423-0410.2004.00564.x.pd

Absorption of silicon from artesian aquifer water and its impact on bone health in postmenopausal women: a 12 week pilot study

<p>Abstract</p> <p>Background</p> <p>Decreased bone mineral density and osteoporosis in postmenopausal women represents a growing source of physical limitations and financial concerns in our aging population. While appropriate medical treatments such as bisphosphonate drugs and hormone replacement therapy exist, they are associated with serious side effects such as osteonecrosis of the jaw or increased cardiovascular risk. In addition to calcium and vitamin D supplementation, previous studies have demonstrated a beneficial effect of dietary silicon on bone health. This study evaluated the absorption of silicon from bottled artesian aquifer water and its effect on markers of bone metabolism.</p> <p>Methods</p> <p>Seventeen postmenopausal women with low bone mass, but without osteopenia or osteoporosis as determined by dual x-ray absorptiometry (DEXA) were randomized to drink one liter daily of either purified water of low-silicon content (PW) or silicon-rich artesian aquifer water (SW) (86 mg/L silica) for 12 weeks. Urinary silicon and serum markers of bone metabolism were measured at baseline and after 12 weeks and analyzed with two-sided t-tests with p < 0.05 defined as significant.</p> <p>Results</p> <p>The urinary silicon level increased significantly from 0.016 ± 0.010 mg/mg creatinine at baseline to 0.037 ± 0.014 mg/mg creatinine at week 12 in the SW group (p = 0.003), but there was no change for the PW group (0.010 ± 0.004 mg/mg creatinine at baseline vs. 0.009 ± 0.006 mg/mg creatinine at week 12, p = 0.679). The urinary silicon for the SW group was significantly higher in the silicon-rich water group compared to the purified water group (p < 0.01). NTx, a urinary marker of bone resorption did not change during the study and was not affected by the silicon water supplementation. No significant change was observed in the serum markers of bone formation compared to baseline measurements for either group.</p> <p>Conclusions</p> <p>These findings indicate that bottled water from artesian aquifers is a safe and effective way of providing easily absorbed dietary silicon to the body. Although the silicon did not affect bone turnover markers in the short-term, the mineral's potential as an alternative prevention or treatment to drug therapy for osteoporosis warrants further longer-term investigation in the future.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier: NCT01067508</p

A Unique Carrier for Delivery of Therapeutic Compounds beyond the Blood-Brain Barrier

BACKGROUND: Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB) that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a "holy grail" in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin), across the BBB. Here, we explored the hypothesis that therapeutic drugs "piggybacked" as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors. APPROACH: Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX) or adriamycin (ADR) and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially. PRINCIPAL FINDINGS: Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1-2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR. SIGNIFICANCE: This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders, including classes of resident and metastatic brain tumors. It may be prudent, therefore, to consider implementation of this novel delivery platform in various clinical settings for therapeutic intervention in acute and chronic neurological diseases

Quality of Life and Affective Well-Being in Middle-Aged and Older People with Chronic Medical Illnesses: A Cross-Sectional Population Based Study

Background: There has been considerable research into the impact of chronic illness on health-related quality of life. However, few studies have assessed the impact of different chronic conditions on general quality of life (QOL). The objective of this paper was to compare general (rather than health-related) QOL and affective well-being in middle aged and older people across eight chronic illnesses.Methods and Findings: This population-based, cross-sectional study involved 11,523 individuals aged 50 years and older, taking part in wave 1 of the English Longitudinal Study of Ageing. General QOL was assessed using the CASP-19, happiness was evaluated using two items drawn from the GHQ-12, and depression was measured with the CES-D. Analysis of covariance and logistic regression, adjusting for age, gender and wealth, were performed. General QOL was most impaired in people with stroke (mean 37.56, CI 36.73-38.39), and least in those reporting cancer (mean 41.78, CI 41.12-42.44, respectively), compared with no illness (mean 44.15, CI 43.92-44.39). Stroke (mean 3.65, CI 3.58-3.73) was also associated with the greatest reduction in positive well-being whereas diabetes (mean 3.81, CI 3.76-3.86) and cancer were least affected (3.85, CI 3.79-3.91), compared with no illness (mean 3.97, CI 3.95-4.00). Depression was significantly elevated in all conditions, but was most common in chronic lung disease (OR 3.04, CI 2.56-3.61), with more modest elevations in those with osteoarthritis (OR 2.08, CI 1.84-2.34) or cancer (OR 2.07, CI 1.69-2.54). Multiple co-morbidities were associated with greater decrements in QOL and affective well-being.Conclusion: The presence of chronic illness is associated with impairments in broader aspects of QOL and affective wellbeing, but different conditions vary in their impact. Further longitudinal work is needed to establish the temporal links between chronic illness and impairments in QOL and affective well-being