Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis, achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with persistent mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC), a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC.
The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed.
Macrophages infected with persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in promoting clearance of mycobacteria from infected host cells.
These findings provide a novel mechanistic explanation for mycobacterial intracellular persistence, and suggest that targeting interactions between the mycobacteria and host cell pathways may provide a novel avenue for development of anti-TB therapies.
Tuberculosis; Niemann-Pick Disease Type C; Lysosomal Storage Diseases; Lysosomal Calcium
medication reconciliation; medication review; pharmacist
The reported prevalence of cognitive impairment (CI) varies widely in cohorts of people living with HIV (PLWH); this may partly be due to the use of different diagnostic criteria. Agreement between diagnostic criteria of CI, the optimal definition to use, and associations with patient-reported cognitive symptoms have not been fully investigated.
Two hundred ninety PLWH aged >50 years and 97 matched negative controls completed a detailed assessment of cognitive function and three questions regarding cognitive symptoms. Age- and education-adjusted test scores (T-scores) determined if subjects met the following definitions of CI: Frascati, global deficit score (GDS) and the multivariate normative comparison (MNC) method.
PLWH were more likely than controls to meet each definition of CI (ORs were 2.17, 3.12 and 3.64 for Frascati, GDS and MNC, respectively). Agreement of MNC with Frascati and GDS was moderate (Cohen’s k = 0.42 and 0.48, respectively), whereas that between Frascati and GDS was good (k = 0.74). A significant association was found between all the three criteria and reporting of memory loss but not with attention and reasoning problems. The 41 (14 %) PLWH meeting all the three criteria had the lowest median global T-score (36.9) and highest rate of symptom reporting (42 %).
Different CI criteria show fair diagnostic agreement, likely reflecting their ability to exclude CI in the same group of individuals. Given the lower overall cognitive performance and higher rates of symptom reporting in those meeting all three criteria of CI, further work assessing this as a definition of CI in PLWH is justified.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-016-1970-8) contains supplementary material, which is available to authorized users.
HIV; Cognitive impairment; Patient-reported cognitive symptoms; Neurology; HIV-associated neurocognitive disorder
Smith-Lemli-Opitz syndrome (SLOS) is a malformation disorder caused by mutations in DHCR7, impairing the reduction of 7-dehydrocholesterol to cholesterol. SLOS results in cognitive impairment, behavioral abnormalities, and nervous system defects, though neither cellular targets nor affected signaling pathways are defined. Whether 7-dehydrocholesterol accumulation or cholesterol loss is primarily responsible for disease pathogenesis is also unclear. Using induced pluripotent stem cells (iPSCs) from SLOS subjects, we identified cellular defects leading to precocious neuronal specification within SLOS derived neural progenitors. We also demonstrated that 7-dehydrocholesterol accumulation, not cholesterol deficiency, is critical for SLOS-associated defects. We further identified downregulation of Wnt/β-catenin signaling as a key initiator of aberrant SLOS iPSCs differentiation through the direct inhibitory effects of 7-dehydrocholesterol on the formation of an active Wnt receptor complex. Activation of canonical Wnt signaling prevented the neural phenotypes observed in SLOS iPSCs, suggesting that Wnt signaling may be a promising therapeutic target for SLOS.
This large outbreak of foodborne salmonellosis demonstrated the complexity of investigating outbreaks linked to poultry products. The outbreak also highlighted the importance of efforts to strengthen food safety policies related to Salmonella in chicken parts and has implications for future changes within the poultry industry.
To investigate a large multistate outbreak of multidrug resistant Salmonella Heidelberg infections.
Epidemiologic and laboratory investigations of patients infected with the outbreak strains of Salmonella Heidelberg and traceback of possible food exposures.
United States. Outbreak period was March 1, 2013 through July 11, 2014
A case was defined as illness in a person infected with a laboratory-confirmed Salmonella Heidelberg with 1 of 7 outbreak pulsed-field gel electrophoresis (PFGE) XbaI patterns with illness onset from March 1, 2013 through July 11, 2014. A total of 634 case-patients were identified through passive surveillance; 200/528 (38%) were hospitalized, none died.
Interviews were conducted with 435 case-patients: 371 (85%) reported eating any chicken in the 7 days before becoming ill. Of 273 case-patients interviewed with a focused questionnaire, 201 (74%) reported eating chicken prepared at home. Among case-patients with available brand information, 152 (87%) of 175 patients reported consuming Company A brand chicken. Antimicrobial susceptibility testing was completed on 69 clinical isolates collected from case-patients; 67% were drug resistant, including 24 isolates (35%) that were multidrug resistant. The source of Company A brand chicken consumed by case-patients was traced back to 3 California production establishments from which 6 of 7 outbreak strains were isolated.
Epidemiologic, laboratory, traceback, and environmental investigations conducted by local, state, and federal public health and regulatory officials indicated that consumption of Company A chicken was the cause of this outbreak. The outbreak involved multiple PFGE patterns, a variety of chicken products, and 3 production establishments, suggesting a reservoir for contamination upstream from the production establishments. Sources of bacteria and genes responsible for resistance, such as farms providing birds for slaughter or environmental reservoir on farms that raise chickens, might explain how multiple PFGE patterns were linked to chicken from 3 separate production establishments and many different poultry products.
Protein hyperacetylation is associated with glucose intolerance and insulin resistance, suggesting that the enzymes regulating the acetylome play a role in this pathological process. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it is hypothesized that the dysregulation of the mitochondrial acetylation state, via genetic deletion of SIRT3, will amplify the deleterious effects of a high-fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, for the first time, that mice lacking SIRT3 exhibit increased insulin resistance due to defects in skeletal muscle glucose uptake. Permeabilized muscle fibers from HFD-fed SIRT3 knockout (KO) mice showed that tricarboxylic acid cycle substrate–based respiration is decreased while fatty acid–based respiration is increased, reflecting a fuel switch from glucose to fatty acids. Consistent with reduced muscle glucose uptake, hexokinase II (HKII) binding to the mitochondria is decreased in muscle from HFD-fed SIRT3 KO mice, suggesting decreased HKII activity. These results show that the absence of SIRT3 in HFD-fed mice causes profound impairments in insulin-stimulated muscle glucose uptake, creating an increased reliance on fatty acids. Insulin action was not impaired in the lean SIRT3 KO mice. This suggests that SIRT3 protects against dietary insulin resistance by facilitating glucose disposal and mitochondrial function.
Lysosomal storage diseases are inherited monogenic disorders in which lysosome function is compromised. Although individually very rare, they occur at a collective frequency of approximately one in five thousand live births and usually have catastrophic consequences for health. The lysosomal storage diseases Niemann‐Pick disease type C (NPC) is caused by mutations predominantly in the lysosomal integral membrane protein NPC1 and clinically presents as a progressive neurodegenerative disorder. In this article we review data that demonstrate significant dysregulation of innate immunity in NPC, which occurs both in peripheral organs and the CNS. In particular pro‐inflammatory responses promote disease progression and anti‐inflammatory drugs provide benefit in animal models of the disease and are an attractive target for clinical intervention in this disorder.
Niemann‐Pick disease type C is a rare, devastating, inherited lysosomal storage disease with a unique cellular phenotype characterized by lysosomal accumulation of sphingosine, various glycosphingolipids and cholesterol and a reduction in lysosomal calcium. In this review we highlight the impact of the disease on innate immune activities in both the central nervous system (CNS) and peripheral tissues and discuss their contributions to pathology and the underlying mechanisms.
cytokine; inflammation; lysosomal storage disease; lysosome; microglia; neurodegeneration; Niemann Pick type C
With HIV treatment prolonging survival and HIV managed as a chronic illness, quality of life (QOL) is important to evaluate in persons living with HIV (PLWH). We assessed QOL at study entry in the Strategic Timing of AntiRetroviral Treatment clinical trial of antiretroviral-naive PLWH with >500 CD4 cells/μL.
QOL was assessed with: 1) visual analogue scale (VAS) for self-assessment of overall current health; 2) SF-12V2 Health Survey®, summarised into eight individual QOL domains plus component summary scores for physical health (PCS) and mental health (MCS). The VAS and eight domain scores were scaled 0–100. Mean QOL measures were calculated overall and by demographic, clinical and behavioural factors.
4631 participants completed the VAS and 4119 the SF-12. Mean VAS score was 80.9 ±15.7. Mean SF-12 domain scores were lowest for vitality (66.3 ±26.4) and mental health (68.6 ±21.4), and highest for physical functioning (89.3 ±23.0) and bodily pain (88.0 ±21.4). Using multiple linear regression, PCS scores were lower (p<0.001) for Asians, North Americans, females, older age, less education, longer duration of known HIV, alcoholism/substance dependence, and body mass index ≥30 kg/m2. MCS scores were highest (p<0.001) for Africans, South Americans, and older age and lowest for females, current smokers, and alcoholism/ substance dependence.
In this primarily healthy population, QOL was mostly favorable, emphasising importance that HIV treatments do not negatively impact QOL. Self-assessed physical health was higher than mental health. Factors such as older age and geographic region have different influences on perceived physical and mental health.
Quality of life; HIV; antiretroviral therapy
DFT calculations for methyl cation complexed within a constrained cage of water molecules permit the controlled manipulation of the “axial” donor/acceptor distance and the “equatorial” distance to hydrogen‐bond acceptors. The kinetic isotope effect k(CH3)/k(CT3) for methyl transfer within a cage with a short axial distance becomes less inverse for shorter equatorial C⋅⋅⋅O distances: a decrease of 0.5 Å results in a 3 % increase at 298 K. Kinetic isotope effects in AdoMet‐dependent methyltransferases may be m∧odulated by CH⋅⋅⋅O hydrogen bonding, and factors other than axial compression may contribute, at least partially, to recently reported isotope‐effect variations for catechol‐O‐methyltransferase and its mutant structures.
computational chemistry; enzyme catalysis; hydrogen bonds; isotope effects; methyl transfer
Meat tenderness and texture can be influenced by the connective tissue content. Dietary lecithin offers a means of improving fat digestibility of pigs and reducing the connective tissue of pork. This feeding study confirmed that dietary lecithin decreased the chewiness and improved the fatty acid composition of pork without impacting on growth performance of pigs. Therefore, dietary lecithin supplementation has the potential to improve the quality attributes of pork.
Forty crossbred (Large White × Landrace × Duroc) female pigs (16.4 kg ± 0.94 kg) were used to investigate the effect of dietary lecithin supplementation on growth performance and pork quality. Pigs were randomly allocated to a commercial diet containing either 0, 3, 15 or 75 g lecithin/kg of feed during the grower and finisher growth phase. Pork from pigs consuming the diets containing 15 g and 75 g lecithin/kg had lower hardness (P < 0.001) and chewiness (P < 0.01) values compared to the controls. Dietary lecithin supplementation at 75 g/kg significantly increased (P < 0.05) the linoleic acid and reduced (P < 0.05) the myristic acid levels of pork compared to the control and the 3 g/kg and 15 g/kg lecithin supplemented treatments. Pigs fed the 75 g/kg lecithin supplemented diet had lower plasma cholesterol (P < 0.05) at slaughter compared to pigs fed the control diet and the 3 g/kg and 15 g/kg lecithin supplemented treatments. These data indicate that dietary lecithin supplementation has the potential to improve the quality attributes of pork from female pigs.
lecithin; pork quality; texture; compression
In the solid-state photodimerization of cinnamic acid polymorphs, can mechanical properties tell us whether Schmidt ‘minimal molecular movement’ or Kaupp ‘molecular migration’ is more important?
photomechanical properties; solid-state reactions; crystal engineering; cinnamic acid; nanoindentation
Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options.
In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.
Between Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (−0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI −1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events.
Protease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection.
National Institute for Health Research.
On 7 and 11 July 2007, health officials in Texas and Indiana, respectively, reported 4 possible cases of type A foodborne botulism to the US Centers for Disease Control and Prevention. Foodborne botulism is a rare and sometimes fatal illness caused by consuming foods containing botulinum neurotoxin.
Investigators reviewed patients’ medical charts and food histories. Clinical specimens and food samples were tested for botulinum toxin and neurotoxin-producing Clostridium species. Investigators conducted inspections of the cannery that produced the implicated product.
Eight confirmed outbreak associated cases were identified from Indiana (n = 2), Texas (n = 3), and Ohio (n = 3). Botulinum toxin type A was identified in leftover chili sauce consumed by the Indiana patients and 1 of the Ohio patients. Cannery inspectors found violations of federal canned-food regulations that could have led to survival of Clostridium botulinum spores during sterilization. The company recalled 39 million cans of chili. Following the outbreak, the US Food and Drug Administration inspected other canneries with similar canning systems and issued warnings to the industry about the danger of C. botulinum and the importance of compliance with canned food manufacturing regulations.
Commercially produced hot dog chili sauce caused these cases of type A botulism. This is the first US foodborne botulism outbreak involving a commercial cannery in >30 years. Sharing of epidemiologic and laboratory findings allowed for the rapid identification of implicated food items and swift removal of potentially deadly products from the market by US food regulatory authorities.
botulism; commercial canning; outbreak; foodborne botulism
To examine the relationship between inflammatory and coagulation biomarkers and cardiac autonomic function (CAF) as measured by heart rate variability in persons with HIV.
Materials & methods
This analysis included 4073 HIV-infected persons from the Strategies for Management of Antiretroviral Therapy study. We examined the association between IL-6, high-sensitivity C-reactive protein (hsCRP) and d-dimer with heart rate variability measures (SDNN and rMSSD), both cross-sectionally and longitudinally.
Cross-sectional analysis revealed significant inverse associations between IL-6, hsCRP and d-dimer with SDNN and rMSSD (p < 0.01 for all comparisons). However, longitudinal analysis failed to show a significant association between baseline IL-6, hsCRP and d-dimer with change in CAF over time.
Cross-sectionally, higher levels of inflammatory and coagulation biomarkers were associated with lower levels of CAF in the Strategies for Management of Antiretroviral Therapy trial. Although deterioration in CAF was observed during followup, baseline levels of inflammatory and coagulation markers were not predictive of the decline in CAF over time.
biomarkers; cardiac autonomic function; coagulation; d-dimer; heart rate variability; high-sensitivity C-reactive protein; HIV; inflammation; IL-6
HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts. The contribution of this hybrid spreading mechanism, which is also a characteristic of some important computer worm outbreaks, to HIV-1 progression in vivo remains unknown. Here we present a new mathematical model that explicitly incorporates the ability of HIV-1 to use hybrid spreading mechanisms and evaluate the consequences for HIV-1 pathogenenesis. The model captures the major phases of the HIV-1 infection course of a cohort of treatment naive patients and also accurately predicts the results of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trial. Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression. Notably, the model predicts that cell-to-cell spread becomes increasingly effective as infection progresses and thus may present a considerable treatment barrier. Deriving predictions of various treatments’ influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS. This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.
The ability to spread using more than once mechanism, named hybrid spreading, is a ubiquitous feature of many real world epidemics including HIV and Hepatitis C virus infection in vivo, and computer worms spreading on the Internet. Hybrid spreading of HIV is well documented experimentally but its importance to HIV progression has been unclear. In this paper, we introduce a mathematical model of HIV dynamics that explicitly incorporates hybrid spreading. The model output shows excellent agreement to two sets of clinical data from a treatment naive cohort and from the Short Pulse Anti-Retroviral Therapy at Seroconversion trial. The model demonstrates that hybrid spreading is an essential feature of HIV progression, a result which has significant implications for future therapeutic strategies against HIV.
Higher plasma D-dimer levels are strong predictors of mortality in HIV+ individuals. The factors associated with D-dimer levels during HIV infection, however, remain poorly understood.
In this cross-sectional study, participants in three randomized controlled trials with measured D-dimer levels were included (N = 9,848). Factors associated with D-dimer were identified by linear regression. Covariates investigated were: age, gender, race, body mass index, nadir and baseline CD4+ count, plasma HIV RNA levels, markers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6]), antiretroviral therapy (ART) use, ART regimens, co-morbidities (hepatitis B/C, diabetes mellitus, prior cardiovascular disease), smoking, renal function (estimated glomerular filtration rate [eGFR] and cystatin C) and cholesterol.
Women from all age groups had higher D-dimer levels than men, though a steeper increase of D-dimer with age occurred in men. Hepatitis B/C co-infection was the only co-morbidity associated with higher D-dimer levels. In this subgroup, the degree of hepatic fibrosis, as demonstrated by higher hyaluronic acid levels, but not viral load of hepatitis viruses, was positively correlated with D-dimer. Other factors independently associated with higher D-dimer levels were black race, higher plasma HIV RNA levels, being off ART at baseline, and increased levels of CRP, IL-6 and cystatin C. In contrast, higher baseline CD4+ counts and higher high-density lipoprotein cholesterol were negatively correlated with D-dimer levels.
D-dimer levels increase with age in HIV+ men, but are already elevated in women at an early age due to reasons other than a higher burden of concomitant diseases. In hepatitis B/C co-infected individuals, hepatic fibrosis, but not hepatitis viral load, was associated with higher D-dimer levels.
The interaction of positive and negative relationships (i.e. I like you, but you dislike me – referred to as relational dissonance) is an underexplored phenomenon. Further, it is often only poor (or negative) mental health that is examined in relation to social networks, with little regard for positive psychological wellbeing. Finally, these issues are compounded by methodological constraints. This study explores a new concept of relational dissonance alongside mutual antipathies and friendships and their association with mental health using multivariate exponential random graph models with an Australian sample of secondary school students. Results show male students with relationally dissonant ties have lower positive mental health measures. Girls with relationally dissonant ties have lower depressed mood, but those girls being targeted by negative ties are more likely to have depressed mood. These findings have implications for the development of interventions focused on promoting adolescent wellbeing and consideration of the appropriate measurement of wellbeing and mental illness.
Introduction: Abnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-Schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia. Methods: We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis. Results: Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies. Discussion: The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.
psychosis; schizophrenia; bipolar disorder; EEG; ERP; P300; DISC1; endophenotype; neurophysiology; family study; haplotype analysis; biomarker
Accurate models of proprioceptive neural patterns could 1 day play an important role in the creation of an intuitive proprioceptive neural prosthesis for amputees. This paper looks at combining efficient implementations of biomechanical and proprioceptor models in order to generate signals that mimic human muscular proprioceptive patterns for future experimental work in prosthesis feedback. A neuro-musculoskeletal model of the upper limb with 7 degrees of freedom and 17 muscles is presented and generates real time estimates of muscle spindle and Golgi Tendon Organ neural firing patterns. Unlike previous neuro-musculoskeletal models, muscle activation and excitation levels are unknowns in this application and an inverse dynamics tool (static optimization) is integrated to estimate these variables. A proprioceptive prosthesis will need to be portable and this is incompatible with the computationally demanding nature of standard biomechanical and proprioceptor modeling. This paper uses and proposes a number of approximations and optimizations to make real time operation on portable hardware feasible. Finally technical obstacles to mimicking natural feedback for an intuitive proprioceptive prosthesis, as well as issues and limitations with existing models, are identified and discussed.
proprioceptive feedback; neuroprosthesis; neuromusculoskeletal model; upper limb; biomechanics; muscle spindles; golgi tendon organ; static optimization
Neuromodulation has wide ranging potential applications in replacing impaired neural function (prosthetics), as a novel form of medical treatment (therapy), and as a tool for investigating neurons and neural function (research). Voltage and current controlled electrical neural stimulation (ENS) are methods that have already been widely applied in both neuroscience and clinical practice for neuroprosthetics. However, there are numerous alternative methods of stimulating or inhibiting neurons. This paper reviews the state-of-the-art in ENS as well as alternative neuromodulation techniques—presenting the operational concepts, technical implementation and limitations—in order to inform system design choices.
neuromodulation; neural modulation; neurostimulation; neural stimulation; neuroprosthetics; neural prosthesis
Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed.
The replication of plasma virus isolates generated from subjects acutely infected with HIV-1 and molecularly cloned founder HIV-1 strains could be reduced but not fully suppressed by type 1 IFNs in vitro. The mean IC50 value for IFNα2 (22 U/ml) was lower than that for IFNβ (346 U/ml), although at maximally-inhibitory concentrations both IFN subtypes inhibited virus replication to similar extents. Individual virus isolates exhibited differential susceptibility to inhibition by IFNα2 and IFNβ, likely reflecting variation in resistance to differentially up-regulated IFN-stimulated genes. Virus isolates from subjects acutely infected with HIV-1 were significantly more resistant to in vitro control by IFNα than virus isolates generated from the same individuals during chronic, asymptomatic infection. Viral IFN resistance declined rapidly after the acute phase of infection: in five subjects, viruses derived from six-month consensus molecular clones were significantly more sensitive to the antiviral effects of IFNs than the corresponding founder viruses.
The establishment of systemic HIV-1 infection by relatively IFNα-resistant founder viruses lends strong support to the hypothesis that IFNα plays an important role in the control of HIV-1 replication during the earliest stages of infection, prior to systemic viral spread. These findings suggest that it may be possible to harness the antiviral activity of type 1 IFNs in prophylactic and potentially also therapeutic strategies to combat HIV-1 infection.
Human immunodeficiency virus type 1; Type 1 interferon; Viral inhibition; Founder virus; Acute infection
Therapies to decrease immune activation might be of benefit in slowing HIV disease progression.
To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline.
Design, Setting, and Patients
Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL.
Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks.
Main Outcome Measures
The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models.
There was no significant difference in CD8 cell activation between the 2 groups (−4.8% and −4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, −0.6%; 95% CI, −4.8% to 3.6%; P=.80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (−85 cells/μL vs −23 cells/μL at week 48; difference, −62 cells/μL; 95% CI, −115 to −8; P=.03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P=.003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P=.03).
Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication.
isrctn.org Identifier: ISRCTN30019040
There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.
persistence; transmitted; HIV-1; resistance; mutations
To determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.
Resistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.
Four hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84–3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.
Viral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.
HIV; drug resistance mutations; naive patients; protease inhibitors; virological failure