ING116070: a study of the pharmacokinetics and antiviral activity of dolutegravir in cerebrospinal fluid in HIV-1-infected, antiretroviral therapy-naive subjects.

BackgroundDolutegravir (DTG), a once-daily, human immunodeficiency virus type 1 (HIV-1) integrase inhibitor, was evaluated for distribution and antiviral activity in cerebrospinal fluid (CSF).MethodsING116070 is an ongoing, single-arm, open-label, multicenter study in antiretroviral therapy-naive, HIV-1-infected adults. Subjects received DTG (50 mg) plus abacavir/lamivudine (600/300 mg) once daily. The CSF and plasma (total and unbound) DTG concentrations were measured at weeks 2 and 16. The HIV-1 RNA levels were measured in CSF at baseline and weeks 2 and 16 and in plasma at baseline and weeks 2, 4, 8, 12, and 16.ResultsThirteen white men enrolled in the study; 2 withdrew prematurely, 1 because of a non-drug-related serious adverse event (pharyngitis) and 1 because of lack of treatment efficacy. The median DTG concentrations in CSF were 18 ng/mL (range, 4-23 ng/mL) at week 2 and 13 ng/mL (4-18 ng/mL) at week 16. Ratios of DTG CSF to total plasma concentration were similar to the unbound fraction of DTG in plasma. Median changes from baseline in CSF (n = 11) and plasma (n = 12) HIV-1 RNA were -3.42 and -3.04 log10 copies/mL, respectively. Nine of 11 subjects (82%) had plasma and CSF HIV-1 RNA levels <50 copies/mL and 10 of 11 (91%) had CSF HIV-1 RNA levels <2 copies/mL at week 16.ConclusionsThe DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/mL), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma. Clinical Trials Registration. NCT01499199

Temporal Stability of the Ford Insomnia Response to Stress Test (FIRST)

Study objectives: The Ford Insomnia Response to Stress Test (FIRST) is a self-report tool that measures sleep reactivity (i.e., vulnerability to experience situational insomnia under stressful conditions). Sleep reactivity has been termed a "trait-like" vulnerability; however, evidence of its long-term stability is lacking. The main objective of the current psychometric study was to investigate the temporal stability of the FIRST over two 6-mo intervals in a population-based sample of adults with and without insomnia. The temporal stability of the FIRST was also compared with the temporal stability of other scales associated with insomnia (trait-anxiety, arousability). Methods: Participants included 1,122 adults (mean age = 49.9 y, standard deviation = 14.8; 38.8% male) presenting with an insomnia syndrome (n = 159), insomnia symptoms (n = 152), or good sleep (n = 811). Participants completed the FIRST, the State-Trait Anxiety Inventory (trait-anxiety), and the Arousal Predisposition Scale (arousability) on three different occasions: baseline and at 6- and 12-mo follow-up. Intraclass correlation coefficients (ICCs) were computed for all scales (baseline to 6 mo and 6 to 12 mo). Results: The FIRST yielded strong temporal stability from baseline to 6 mo among those with insomnia syndrome (ICC = 0.81), symptoms (ICC = 0.78), and good sleep (ICC = 0.81). Similar results were observed for 6 to 12 mo among those with insomnia syndrome (ICC = 0.74), insomnia symptoms (ICC = 0.82), and good sleep (ICC = 0.84). The stability of the FIRST was not comparable with the stability of trait-anxiety, but was somewhat comparable with the stability of arousability. Conclusions: Overall, the FIRST is a temporally reliable stable scale over 6-mo intervals. Future research is needed to corroborate the stability and trait-like measures of sleep reactivity with physiological, behavioural and personality measures

Tbx20 Is Required in Mid-Gestation Cardiomyocytes and Plays a Central Role in Atrial Development.

RationaleMutations in the transcription factor TBX20 (T-box 20) are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by embryonic day 9.5. Because Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endoderm, cardiogenic mesoderm, endocardium, and myocardium, the cell type-specific requirement for TBX20 in early myocardial development remains to be explored.ObjectiveHere, we investigated roles of TBX20 in midgestation cardiomyocytes for heart development.Methods and resultsAblation of Tbx20 from developing cardiomyocytes using a doxycycline inducible cTnTCre transgene led to embryonic lethality. The circumference of developing ventricular and atrial chambers, and in particular that of prospective left atrium, was significantly reduced in Tbx20 conditional knockout mutants. Cell cycle analysis demonstrated reduced proliferation of Tbx20 mutant cardiomyocytes and their arrest at the G1-S phase transition. Genome-wide transcriptome analysis of mutant cardiomyocytes revealed differential expression of multiple genes critical for cell cycle regulation. Moreover, atrial and ventricular gene programs seemed to be aberrantly regulated. Putative direct TBX20 targets were identified using TBX20 ChIP-Seq (chromatin immunoprecipitation with high throughput sequencing) from embryonic heart and included key cell cycle genes and atrial and ventricular specific genes. Notably, TBX20 bound a conserved enhancer for a gene key to atrial development and identity, COUP-TFII/Nr2f2 (chicken ovalbumin upstream promoter transcription factor 2/nuclear receptor subfamily 2, group F, member 2). This enhancer interacted with the NR2F2 promoter in human cardiomyocytes and conferred atrial specific gene expression in a transgenic mouse in a TBX20-dependent manner.ConclusionsMyocardial TBX20 directly regulates a subset of genes required for fetal cardiomyocyte proliferation, including those required for the G1-S transition. TBX20 also directly downregulates progenitor-specific genes and, in addition to regulating genes that specify chamber versus nonchamber myocardium, directly activates genes required for establishment or maintenance of atrial and ventricular identity. TBX20 plays a previously unappreciated key role in atrial development through direct regulation of an evolutionarily conserved COUPT-FII enhancer

Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response

Cell based immunotherapy is rapidly emerging as a promising cancer treatment. A modest increase in salt (sodium chloride) concentration in immune cell cultures is known to induce inflammatory phenotypic differentiation. In our current study, we analyzed the ability of salt treatment to induce ex vivo expansion of tumor-primed CD4 (cluster of differentiation 4)+T cells to an effector phenotype. CD4+T cells were isolated using immunomagnetic beads from draining lymph nodes and spleens from tumor bearing C57Bl/6 mice, 28 days post-injection of Py230 syngeneic breast cancer cells. CD4+T cells from non-tumor bearing mice were isolated from splenocytes of 12-week-old C57Bl/6 mice. These CD4+T cells were expanded ex vivo with five stimulation cycles, and each cycle comprised of treatment with high salt (Δ0.035 M NaCl) or equimolar mannitol controls along with anti-CD3/CD28 monoclonal antibodies for the first 3 days, followed by the addition of interleukin (IL)-2/IL-7 cytokines and heat killed Py230 for 4 days. Ex vivo high salt treatment induced a two-fold higher Th1 (T helper type 1) expansion and four-fold higher Th17 expansion compared to equimolar mannitol treatment. Importantly, the high salt expanded CD4+T cells retained tumor-specificity, as demonstrated by higher in vitro cytotoxicity against Py230 breast cancer cells and reduced in vivo syngeneic tumor growth. Metabolic studies revealed that high salt treatment enhanced the glycolytic reserve and basal mitochondrial oxidation of CD4+T cells, suggesting a role of high salt in enhanced pro-growth anabolic metabolism needed for inflammatory differentiation. Mechanistic studies demonstrated that the high salt induced switch to the effector phenotype was mediated by tonicity-dependent transcription factor, TonEBP/NFAT5. Using a transgenic murine model, we demonstrated that CD4 specific TonEBP/NFAT5 knock out (CD4cre/creNFAT5flox/flox) abrogated the induction of the effector phenotype and anti-tumor efficiency of CD4+T cells following high salt treatment. Taken together, our data suggest that high salt-mediated ex vivo expansion of tumor-primed CD4+T cells could induce effective tumor specific anti-cancer responses, which may have a novel cell-based cancer immunotherapeutic application

Relation of Parkinson\u27s Disease Subtypes to Visual Activities of Daily Living

Visual perceptual problems are common in Parkinson\u27s disease (PD) and often affect activities of daily living (ADLs). PD patients with non-tremor symptoms at disease onset (i.e., rigidity, bradykinesia, gait disturbance or postural instability) have more diffuse neurobiological abnormalities and report worse non-motor symptoms and functional changes than patients whose initial symptom is tremor, but the relation of motor symptom subtype to perceptual deficits remains unstudied. We assessed visual ADLs with the Visual Activities Questionnaire in 25 non-demented patients with PD, 13 with tremor as the initial symptom and 12 with an initial symptom other than tremor, as well as in 23 healthy control participants (NC). As expected, the non-tremor patients, but not the tremor patients, reported more impairment in visual ADLs than the NC group, including in light/dark adaptation, acuity/spatial vision, depth perception, peripheral vision and visual processing speed. Non-tremor patients were significantly worse than tremor patients overall and on light/dark adaptation and depth perception. Environmental enhancements especially targeted to patients with the non-tremor PD subtype may help to ameliorate their functional disability

Recent and future trends in synthetic greenhouse gas radiative forcing

Atmospheric measurements show that emissions of hydrofluorocarbons (HFCs) and hydrochlorofluorocarbons are now the primary drivers of the positive growth in synthetic greenhouse gas (SGHG) radiative forcing. We infer recent SGHG emissions and examine the impact of future emissions scenarios, with a particular focus on proposals to reduce HFC use under the Montreal Protocol. If these proposals are implemented, overall SGHG radiative forcing could peak at around 355 mW m[superscript −2] in 2020, before declining by approximately 26% by 2050, despite continued growth of fully fluorinated greenhouse gas emissions. Compared to “no HFC policy” projections, this amounts to a reduction in radiative forcing of between 50 and 240 mW m[superscript −2] by 2050 or a cumulative emissions saving equivalent to 0.5 to 2.8 years of CO2 emissions at current levels. However, more complete reporting of global HFC emissions is required, as less than half of global emissions are currently accounted for.Natural Environment Research Council (Great Britain) (Advanced Research Fellowship NE/I021365/1)United States. National Aeronautics and Space Administration (Upper Atmospheric Research Program Grant NNX11AF17G)United States. National Oceanic and Atmospheric Administratio