Do genetic variations in proximal tubule transporters influence tenofovir-induced renal dysfunction? An exploratory study in a Ghanaian population.

OBJECTIVES: To assess associations between polymorphisms within genes encoding proximal tubule transporters implicated in tenofovir renal clearance and kidney tubular dysfunction (KTD), chronic kidney disease (CKD) and individual biochemical parameters. PATIENTS AND METHODS: The study included a cohort of HIV-positive Ghanaians receiving regimens containing tenofovir disoproxil fumarate (n = 66) for at least 6 months prior to study enrolment. SNPs in ABCC10, ABCC2 and ABCC4 were selected for analysis based on previous published associations. All SNPs were genotyped by real-time PCR allelic discrimination. Creatinine clearance (CLCR), serum and urine creatinine concentrations and biochemical measures of KTD were assessed. Statistical significance was determined through univariate linear or binary logistical regression (P ≤ 0.05). RESULTS: None of the SNPs evaluated was associated with CKD or KTD. A trend between body weight and higher incidence of CKD (P = 0.012, OR = 0.9) was observed. ABCC10 2843T>C (rs2125739) was significantly associated with lower log10 baseline creatinine (P = 0.001, ß= -0.4), higher baseline CLCR (P = 0.008, ß = 65.2) and lower CLCR after 1 year (P = 0.024, ß= -26.6). CONCLUSIONS: This study demonstrates an association of ABCC10 rs2125739 with indicators of declining renal function and builds on current knowledge of this interaction within a Ghanaian cohort.

Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study.

SETTING: Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues. OBJECTIVE: niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI). DESIGN: PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval. RESULTS: The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing. CONCLUSION: We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed.

White matter predicts functional connectivity in premanifest Huntington's disease.

OBJECTIVES: The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. METHODS: Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. RESULTS: We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. INTERPRETATION: Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero-posterior dissociation that is in keeping with the caudo-rostral gradient of striatal pathology in HD.

Mid-infrared nonlinear optical response of Si-Ge waveguides with ultra-short optical pulses.

We characterize the nonlinear optical response of low loss Si(0.6)Ge(0.4) / Si waveguides in the mid-infrared between 3.3 µm and 4 µm using femtosecond optical pulses. We estimate the three and four-photon absorption coefficients as well as the Kerr nonlinear refractive index from the experimental measurements. The effect of multiphoton absorption on the optical nonlinear Kerr response is evaluated and the nonlinear figure of merit estimated providing some guidelines for designing nonlinear optical devices in the mid-IR. Finally, we compare the impact of free-carrier absorption at mid-infrared wavelengths versus near-infrared wavelengths for these ultra-short pulses.

EBV-Specific Immune Response: Early Research and Personal Reminiscences.

Early research on Epstein-Barr virus (EBV) developed from serological observations that were made soon after the discovery of the virus. Indeed, the definition of the humoral response to a variety of EBV proteins dominated the early literature and was instrumental in providing the key evidence for the association of the virus with infectious mononucleosis (IM), Burkitt's lymphoma (BL), and nasopharyngeal carcinoma (NPC). Each of these disease associations involved a distinct pattern of serological reactivity to the EBV membrane antigens (MA), early antigens (EA), and the EBV nuclear antigen (EBNA). When it became generally accepted that the marked lymphocytosis , which is a hallmark of acute IM, was dominated by T cells, considerable effort was directed toward untangling the specificities that might be associated with restricting the proliferation of newly infected B cells. Early evidence was divided between support for both EBV non-specific and/or HLA non-restricted components. However, all results needed to be reassessed in light of the observation that T cells died by apoptosis within hours of separation from fresh blood from acute IM patients. The observation that EBV-infected cultures from immune (but not non-immune) individuals began to die (termed regression) about 10 days post-seeding, provided the first evidence of a specific memory response which was apparently capable of controlling the small pool of latently infected B cells which all immune individuals possess. In this early era, CD8(+) T cells were thought to be the effector population responsible for this phenomenon, but later studies suggested a role for CD4(+) cells. This historical review includes reference to key early observations in regard to both the specific humoral and cellular responses to EBV infection from the time of the discovery of the virus until 1990. As well, we have included personal recollections in regard to the events surrounding the discovery of the memory T cell response since we believe they add a human dimension to a chapter focussed on early history.

Nonlinear optical response of low loss silicon germanium waveguides in the mid-infrared.

We have investigated the nonlinear optical response of low loss Si(0.6)Ge(0.4) / Si waveguides in the mid-infrared wavelength range from 3.25- 4.75µm using picosecond optical pulses. We observed and measured the three and four-photon absorption coefficients as well as the Kerr nonlinear refractive index. The dynamics of the spectral broadening suggests that, in addition to multiphoton absorption, the corresponding higher order nonlinear refractive phenomena also needs to be included when high optical pulse intensities are used at mid-infrared wavelengths in this material.

Cellular memory of hypoxia elicits neuroblastoma metastasis and enables invasion by non-aggressive neighbouring cells.

Therapies targeting cancer metastasis are challenging owing to the complexity of the metastatic process and the high number of effectors involved. Although tumour hypoxia has previously been associated with increased aggressiveness as well as resistance to radio- and chemotherapy, the understanding of a direct link between the level and duration of hypoxia and the individual steps involved in metastasis is still missing. Using live imaging in a chick embryo model, we have demonstrated that the exposure of neuroblastoma cells to 1% oxygen for 3 days was capable of (1) enabling cell migration towards blood vessels, (2) slowing down their velocity within blood vessels to facilitate extravasation and (3) promoting cell proliferation in primary and secondary sites. We have shown that cells do not have to be hypoxic anymore to exhibit these acquired capabilities as a long-term memory of prior hypoxic exposure is kept. Furthermore, non-hypoxic cells can be influenced by neighbouring hypoxic preconditioned cells and be entrained in the metastatic progression. The acquired aggressive phenotype relies on hypoxia-inducible factor (HIF)-dependent transcription of a number of genes involved in metastasis and can be impaired by HIF inhibition. Altogether, our results demonstrate the need to consider both temporal and spatial tumour heterogeneity because cells can 'remember' an earlier environment and share their acquired phenotype with their close neighbours. As a consequence, it is necessary to monitor the correct hypoxic markers to be able to predict the consequences of the cells' history on their behaviour and their potential response to therapies.

Seroepidemiology of Toxoplasma in a coastal region of Haiti: multiplex bead assay detection of immunoglobulin G antibodies that recognize the SAG2A antigen.

Toxoplasma gondii is a globally distributed parasitic protozoan that infects most warm-blooded animals. We incorporated a bead coupled with recombinant SAG2A protein into our Neglected Tropical Disease (NTD) multiplex bead assay (MBA) panel and used it to determine Toxoplasma infection rates in two studies in Haiti. In a longitudinal cohort study of children aged 0-11 years, the infection rate varied with age reaching a maximum of 0·131 infections/year in children aged 3 years [95% confidence interval (CI) 0·065-0·204]. The median time to seroconversion was estimated to be 9·7 years (95% CI 7·6-∞). In a cross-sectional, community-wide survey of residents of all ages, we determined an overall seroprevalence of 28·2%. The seroprevalence age curve from the cross-sectional study also suggested that the force of infection varied with age and peaked at 0·057 infections/year (95% CI 0·033-0·080) at age 2·6 years. Integration of the Toxoplasma MBA into NTD surveys may allow for better estimates of the potential burden of congenital toxoplasmosis in underserved regions.

A meta-analysis of the prevalence of attention deficit hyperactivity disorder in incarcerated populations.

BACKGROUND: Studies report the variable prevalence of attention deficit hyperactivity disorder (ADHD) in incarcerated populations. The aim of this meta-analysis was to determine the prevalence of ADHD in these populations. METHOD: Primary research studies reporting the prevalence (lifetime/current) of ADHD in incarcerated populations were identified. The meta-analysis used a mixed log-binomial model, including fixed effects for each covariate and a random study effect, to estimate the significance of various risk factors. RESULTS: Forty-two studies were included in the analysis. ADHD prevalence was higher with screening diagnoses versus diagnostic interview (and with retrospective youth diagnoses versus current diagnoses). Using diagnostic interview data, the estimated prevalence was 25.5% and there were no significant differences for gender and age. Significant country differences were noted. CONCLUSIONS: Compared with published general population prevalence, there is a fivefold increase in prevalence of ADHD in youth prison populations (30.1%) and a 10-fold increase in adult prison populations (26.2%).

Blackbody emission from light interacting with an effective moving dispersive medium.

Intense laser pulses excite a nonlinear polarization response that may create an effective flowing medium and, under appropriate conditions, a blocking horizon for light. Here, we analyze in detail the interaction of light with such laser-induced flowing media, fully accounting for the medium dispersion properties. An analytical model based on a first Born approximation is found to be in excellent agreement with numerical simulations based on Maxwell's equations and shows that when a blocking horizon is formed, the stimulated medium scatters light with a blackbody emission spectrum. Based on these results, diamond is proposed as a promising candidate medium for future studies of Hawking emission from artificial, dispersive horizons.

Interactions between tenofovir and nevirapine in CD4+ T cells and monocyte-derived macrophages restrict their intracellular accumulation.

OBJECTIVES: There is no pharmacokinetic interaction between tenofovir and nevirapine, but a higher emergence rate of resistance mutations has been reported when these drugs are coadministered. We sought to examine if there is a potential intracellular interaction that may account for the emergence of resistant virus. METHODS: Primary CD4+ and CD14+ cells were isolated from healthy volunteer blood. Monocyte-derived macrophages were differentiated from CD14+ cells. Accumulation of radiolabelled tenofovir and nevirapine was then assessed in these cells. RESULTS: We show here that tenofovir and nevirapine immune cell intracellular concentrations are lower when coincubated in CD4+ cells and monocyte-derived macrophages, but not in CD14+ cells. CONCLUSIONS: These data indicate a potential intracellular drug-drug interaction between these drugs that warrants further investigation.

Amorphous silicon nanowires combining high nonlinearity, FOM and optical stability.

We demonstrate optically stable amorphous silicon nanowires with both high nonlinear figure of merit (FOM) of ~5 and high nonlinearity Re(γ) = 1200W(-1)m(-1). We observe no degradation in these parameters over the entire course of our experiments including systematic study under operation at 2 W coupled peak power (i.e. ~2GW/cm(2)) over timescales of at least an hour.

Demonstration of a stable ultrafast laser based on a nonlinear microcavity.

Ultrashort pulsed lasers, operating through the phenomenon of mode-locking, have had a significant role in many facets of our society for 50 years, for example, in the way we exchange information, measure and diagnose diseases, process materials, and in many other applications. Recently, high-quality resonators have been exploited to demonstrate optical combs. The ability to phase-lock their modes would allow mode-locked lasers to benefit from their high optical spectral quality, helping to realize novel sources such as precision optical clocks for applications in metrology, telecommunication, microchip-computing, and many other areas. Here we demonstrate the first mode-locked laser based on a microcavity resonator. It operates via a new mode-locking method, which we term filter-driven four-wave mixing, and is based on a CMOS-compatible high quality factor microring resonator. It achieves stable self-starting oscillation with negligible amplitude noise at ultrahigh repetition rates, and spectral linewidths well below 130 kHz.

Risk of bleeding after thyroid surgery: matched pairs analysis.

OBJECTIVE: To identify those patients most at risk of developing a compressive post-operative haematoma following thyroid surgery. METHOD: Retrospective analysis of patients undergoing thyroid surgery. Factors associated with the group of patients who developed a post-operative haematoma were examined using a matched pairs, case-control design. RESULTS: Following 355 thyroid operations, seven patients developed a post-operative haematoma requiring return to the operating theatre for bleeding control. A post-operative systolic blood pressure of greater than 150 mmHg, in the post-anaesthetic care unit, was the major significant factor identified by regression analysis (p = 0.002). Current smoking status was also a significant factor (p = 0.04). CONCLUSION: In our facility, a post-anaesthetic systolic blood pressure in excess of 150 mmHg was associated with an increased risk of haemorrhage following thyroid surgery.

Exploitation of chick embryo environments to reprogram MYCN-amplified neuroblastoma cells to a benign phenotype, lacking detectable MYCN expression.

Neuroblastoma is a paediatric cancer that arises from the sympathetic ganglia (SG) or adrenal gland. Tumours that occur in patients under 18 months of age have a particularly good prognosis and frequently undergo spontaneous regression. This led to the hypothesis that developmental cues in the youngest patients may prompt belated differentiation and/or apoptosis of the tumour cells. To test our hypothesis, we have injected MYCN-amplified neuroblastoma cells into the extra embryonic veins of chick embryos at embryonic day 3 (E3) and E6 and analysed the response of these Kelly cells at E10 and E14. Amplification of the MYCN gene occurs in up to 30% of tumours and is normally associated with a very poor prognosis. Kelly cells injected at E3 follow neural crest pathways and integrate into neural locations such as SG and the enteric nervous system although never into the adrenal gland. Additionally they migrate to non-neural locations such as the heart, meninges, jaw regions and tail. The cells respond to their respective microenvironments and in SG, some cells differentiate, they show reduced cell division and crucially all cells have undetectable MYCN expression by E10. In non-neural locations, cells form more rapidly dividing clumps and continue to express MYCN. The downregulation of MYCN is dependent on continuous and direct interaction with the sympathetic ganglion environment. We propose that the MYCN-amplicon in the Kelly cells retains the ability to correctly interpret the environmental cues leading to downregulation of MYCN.

All-optical wavelength conversion for 10 Gb/s DPSK signals in a silicon ring resonator.

We demonstrate all-optical wavelength conversion at 10 Gb/s for differential phase-shift keyed (DPSK) data signals in the C-band, based on four-wave mixing (FWM) in a silicon ring resonator. Error-free operation with a system penalty of ~4.1 dB at 10⁻9 BER is achieved.

All-optical XOR logic gate for 40Gb/s DPSK signals via FWM in a silicon nanowire.

We demonstrate an all-optical XOR logic function for 40Gb/s differential phase-shift keyed (DPSK) data signals in the C-band, based on four-wave mixing (FWM) in a silicon nanowire. Error-free operation with a system penalty of ~3.0dB and ~4.3dB at 10⁻9 BER is achieved.

Ultrafast strain-induced current in a GaAs Schottky diode.

Picosecond acoustic pulses generated by femtosecond laser excitation of a metal film induce a transient current with subnanosecond rise time in a GaAs/Au Schottky diode. The signal consists of components due to the strain pulse crossing the edge of the depletion layer in the GaAs and also the GaAs/Au interface. A theoretical model is presented for the former and is shown to be in very good agreement with the experiment.

On-chip CMOS-compatible all-optical integrator.

All-optical circuits for computing and information processing could overcome the speed limitations intrinsic to electronics. However, in photonics, very few fundamental 'building blocks' equivalent to those used in multi-functional electronic circuits exist. In this study, we report the first all-optical temporal integrator in a monolithic, integrated platform. Our device--a lightwave 'capacitor-like' element based on a passive micro-ring resonator--performs the time integral of the complex field of an arbitrary optical waveform with a time resolution of a few picoseconds, corresponding to a processing speed of ∼200 GHz, and a 'hold' time approaching a nanosecond. This device, compatible with electronic technology (complementary metal-oxide semiconductor), will be one of the building blocks of next-generation ultrafast data-processing technology, enabling optical memories and real-time differential equation computing units.