Modernizing Surveillance of Antituberculosis Drug Resistance: From Special Surveys to Routine Testing

Availability of new diagnostic tools and global commitment towards universal access to tuberculosis care will accelerate capacity of resource-limited countries to monitor anti-tuberculosis drug resistance. Special surveys will be replaced by routine surveillance of drug resistance linked to patient care

Dislocation-Mediated Melting: The One-Component Plasma Limit

The melting parameter $\Gamma_m$ of a classical one-component plasma is estimated using a relation between melting temperature, density, shear modulus, and crystal coordination number that follows from our model of dislocation-mediated melting. We obtain $\Gamma_m=172\pm 35,$ in good agreement with the results of numerous Monte-Carlo calculations.Comment: 8 pages, LaTe

HIV prevention programmes for female sex workers in Andhra Pradesh, India: outputs, cost and efficiency

BACKGROUND: Female sex workers and their clients play a prominent role in the HIV epidemic in India. Systematic data on the outputs, cost and efficiency for HIV prevention programmes for female sex workers in India are not readily available to understand programme functioning and guide efficient use of resources. METHODS: Detailed output and cost data for the 2002–2003 fiscal year were obtained using standardised methods at 15 HIV prevention programmes for female sex worker in the state of Andhra Pradesh in southern India. The services provided and their relation to the total and unit economic costs were analysed using regression techniques. The trends for the number of sex workers provided services by the programmes since inception up to fiscal year 2004–2005 were examined. RESULTS: The 15 programmes provided services to 33941 sex workers in fiscal year 2002–2003 (range 803–6379, median 1970). Of the total number of contacts with sex workers, 41.6% were by peer educators and 58.4% by other programme staff. The number of sex worker contacts in a year by peer educators varied 74-fold across programmes as compared with a 2.7-fold variation in sex worker contacts by other programme staff. The annual economic cost of providing services to a sex worker varied 6-fold between programmes from Indian Rupees (INR) 221.8 (US$4.58) to INR 1369 (US$ 28.29) with a median of INR 660.9 (US$13.66) and mean of INR 517.8 (US$ 10.70). Personnel salaries made up 34.7% of the total cost, and recurrent goods made up 38.4% of which 82.1% was for condoms. The cost per sex worker provided services had a significant inverse relation with the number of sex workers provided services by a programme (p < 0.001, R(2 )= 0.75; power function). There was no correlation between the full time equivalents of programme staff and the number of sex workers provided services by the programmes, but there was a modest inverse correlation between the number of sex workers served and the average time spent with each sex worker in the year adjusted for the full-time equivalents of programme staff (p = 0.011, R(2 )= 0.40; exponential function). The average number of sex workers provided services annually by the first batch of 7 programmes started in early 1999 plateaued after the fourth fiscal year to 3500, whereas the 8 second-batch programmes started in late 2000 reached an average of 2000 sex workers in 2004–2005 with an increasing trend up to this fourth fiscal year. CONCLUSION: The HIV prevention efforts in this Indian state would benefit from standardisation of the highly variable services provided by peer educators, who form an important part of the sex worker programmes. The cost per sex worker served decreases with increasing number of sex workers served annually, but this has to be weighed against an associated modest trend of decrease in time spent with each sex worker in some programmes

Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease

Severe amyloidosis and plaque-localized neuro-inflammation are key pathological features of Alzheimer’s disease (AD). In addition to astrocyte and microglial reactivity, emerging evidence suggests a role of gut microbiota in regulating innate immunity and influencing brain function. Here, we examine the role of the host microbiome in regulating amyloidosis in the APP(SWE)/PS1(ΔE9) mouse model of AD. We show that prolonged shifts in gut microbial composition and diversity induced by long-term broad-spectrum combinatorial antibiotic treatment regime decreases Aβ plaque deposition. We also show that levels of soluble Aβ are elevated and that levels of circulating cytokine and chemokine signatures are altered in this setting. Finally, we observe attenuated plaque-localised glial reactivity in these mice and significantly altered microglial morphology. These findings suggest the gut microbiota community diversity can regulate host innate immunity mechanisms that impact Aβ amyloidosis

Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

SummaryAlzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Aβ42 levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Aβ40 levels while concomitantly elevating levels of Aβ38 and Aβ37. Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Aβ42; chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs)

Effects of Heparin and Enoxaparin on APP Processing and Aβ Production in Primary Cortical Neurons from Tg2576 Mice

Alzheimer's disease (AD) is caused by accumulation of Aβ, which is produced through sequential cleavage of β-amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE1) and γ-secretase. Enoxaparin, a low molecular weight form of the glycosaminoglycan (GAG) heparin, has been reported to lower Aβ plaque deposition and improve cognitive function in AD transgenic mice

Amyloid Precursor Protein Is Trafficked and Secreted via Synaptic Vesicles

A large body of evidence has implicated amyloid precursor protein (APP) and its proteolytic derivatives as key players in the physiological context of neuronal synaptogenesis and synapse maintenance, as well as in the pathology of Alzheimer's Disease (AD). Although APP processing and release are known to occur in response to neuronal stimulation, the exact mechanism by which APP reaches the neuronal surface is unclear. We now demonstrate that a small but relevant number of synaptic vesicles contain APP, which can be released during neuronal activity, and most likely represent the major exocytic pathway of APP. This novel finding leads us to propose a revised model of presynaptic APP trafficking that reconciles existing knowledge on APP with our present understanding of vesicular release and recycling

The Intracellular Threonine of Amyloid Precursor Protein That Is Essential for Docking of Pin1 Is Dispensable for Developmental Function

Background: Processing of Ab-precursor protein (APP) plays an important role in Alzheimer’s Disease (AD) pathogenesis. Thr residue at amino acid 668 of the APP intracellular domain (AID) is highly conserved. When phosphorylated, this residue generates a binding site for Pin1. The interaction of APP with Pin1 has been involved in AD pathogenesis. Methodology/Principal Findings: To dissect the functions of this sequence in vivo, we created an APP knock-in allele, in which Thr 668 is replaced by an Ala (T 668 A). Doubly deficient APP/APP-like protein 2 (APLP2) mice present postnatal lethality and neuromuscular synapse defects. Previous work has shown that the APP intracellular domain is necessary for preventing early lethality and neuromuscular junctions (NMJ) defects. Crossing the T 668 A allele into the APLP2 knockout background showed that mutation of Thr 668 does not cause a defective phenotype. Notably, the T 668 A mutant APP is able to bind Mint1. Conclusions/Significance: Our results argue against an important role of the Thr 668 residue in the essential function of APP in developmental regulation. Furthermore, they indicate that phosphorylation at this residue is not functionally involved i

An Integrated Framework for Intersectorality: Nonprofitness and Its Influence on Society and Public Administration Programs

Cross-sector interactions have long occurred in the public delivery of goods, services, and interests. While scholars have often addressed cross-sector interactions using the dimensions of publicness (state) and privateness (market), an intersectoral framework necessitates the understanding and incorporation of nonprofitness to account for the dimensions of nonprofits along the public-private continuum. This article proposes a framework for identifying the dimensions of nonprofits in an intersectoral world and draws on relevant examples to illustrate the presence and influence of nonprofitness. The article then focuses on the future of education in the field of public administration and, in light of the proposed framework, makes and considers recommendations to help educational programs better equip students to appreciate work across sectors