Dose escalation of a curcuminoid formulation

BACKGROUND: Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. METHODS: A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C(3 )Complex™, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg. RESULTS: Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. CONCLUSION: The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent

The Repertoire and Dynamics of Evolutionary Adaptations to Controlled Nutrient-Limited Environments in Yeast

The experimental evolution of laboratory populations of microbes provides an opportunity to observe the evolutionary dynamics of adaptation in real time. Until very recently, however, such studies have been limited by our inability to systematically find mutations in evolved organisms. We overcome this limitation by using a variety of DNA microarray-based techniques to characterize genetic changes—including point mutations, structural changes, and insertion variation—that resulted from the experimental adaptation of 24 haploid and diploid cultures of Saccharomyces cerevisiae to growth in either glucose, sulfate, or phosphate-limited chemostats for ∼200 generations. We identified frequent genomic amplifications and rearrangements as well as novel retrotransposition events associated with adaptation. Global nucleotide variation detection in ten clonal isolates identified 32 point mutations. On the basis of mutation frequencies, we infer that these mutations and the subsequent dynamics of adaptation are determined by the batch phase of growth prior to initiation of the continuous phase in the chemostat. We relate these genotypic changes to phenotypic outcomes, namely global patterns of gene expression, and to increases in fitness by 5–50%. We found that the spectrum of available mutations in glucose- or phosphate-limited environments combined with the batch phase population dynamics early in our experiments allowed several distinct genotypic and phenotypic evolutionary pathways in response to these nutrient limitations. By contrast, sulfate-limited populations were much more constrained in both genotypic and phenotypic outcomes. Thus, the reproducibility of evolution varies with specific selective pressures, reflecting the constraints inherent in the system-level organization of metabolic processes in the cell. We were able to relate some of the observed adaptive mutations (e.g., transporter gene amplifications) to known features of the relevant metabolic pathways, but many of the mutations pointed to genes not previously associated with the relevant physiology. Thus, in addition to answering basic mechanistic questions about evolutionary mechanisms, our work suggests that experimental evolution can also shed light on the function and regulation of individual metabolic pathways

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Engagement in Care and Housing Instability Influence HIV Screening Among Transgender Individuals in South Florida

Purpose: HIV screening is a critical step in the HIV care continuum to lowering incidence and achieving viral load suppression among at-risk populations. Few studies assess factors associated with HIV screening among transgender individuals living in the southeast region of the United States. This study was conducted to determine factors that influence HIV screening among transgender individuals in South Florida.Methods: During Fall 2016, 68 participants were recruited to complete a questionnaire as part of a pilot pre-exposure prophylaxis study. Correlations were examined between sociodemographic factors, HIV risk, and access to and engagement in care. Significant correlations were entered into one logistic regression model to estimate predictors of HIV screening and knowledge of HIV status.Results: Almost half (48.5%) of the respondents were Latinx, 38.2% Black, 10.3% non-Latinx White, and 3% other. Seventy-eight percent reported access and routine engagement in care within the past year, 25% had not screened for HIV in the past year, and of those who knew their status, 16.7% reported living with HIV. Regression analysis revealed that participants with routine engagement in care were twice as likely to screen for HIV (p=0.02). Unstable housing was associated with no HIV screening in the past year (p=0.05).Conclusion: Stable housing is linked to engagement in routine care that can increase the likelihood of an at-risk transgender individual screening for HIV. Further research is needed to develop interventions to improve engagement in care among transgender individuals who do not have adequate housing or access to care

Quantification of recA gene expression as an indicator of repair potential in marine bacterioplankton communities of Antarctica

Marine bacteria in surface waters must cope daily with the damaging effects of exposure to solar radiation (containing both UV-A and UV-B wavelengths), which produces lesions in their DNA. As the stratospheric ozone layer is depleted, these coping mechanisms are likely to play an even more important role in the viability of marine bacterial communities. The recA gene is ubiquitous among eubacteria and is highly conserved both in nucleotide and amino acid sequence. Besides its role in generalized recombination, the gene's translational product, RecA, is the regulator of 'dark repair' activity (DNA-repair mechanisms that do not require visible light as a cofactor). We have taken advantage of this function and used recA gene expression as a barometer of the DNAdamage repair capacity of bacterial assemblages in the Southern Ocean. Studies were conducted in the Gerlache Strait, Antarctica, in the austral springs of 1995 and 1996. Analysis of both recA mRNA and RecA protein extracted from natural communities indicated that the level of expression of this gene varied in a diel fashion, suggesting an increased repair capacity in these organisms. These included an early morning rise in RecA levels followed by a plateau or even a reduction in RecA concentration during the remainder of the day. A much greater increase in RecA was consistently observed after sunset, followed by a constant decrease during the night. Microcosm experiments with a RecA+ Gerlache Strait g-proteobacteria isolate, RM11001, demonstrated a similar diel pattern of expression. These studies demonstrate the usefulness of RecA as a biological indicator of DNA repair capacity in natural bacterial assemblages. They indicate that 'dark repair' of DNA damage is an important coping mechanism for bacteria in the marine environment of Antarctica.Peer reviewedMicrobiology and Molecular Genetic

A System for Resilience Learning: Developing a Community-Driven, Multi-Sector Research Approach for Greater Preparedness and Resilience to Long-Term Climate Stressors and Extreme Events in the Miami Metropolitan Region

There is a growing need for integrated approaches that align community priorities with strategies that build resilience to climate hazards, societal shocks, and economic crises to ensure more equitable and sustainable outcomes. We anticipate that adaptive management and resilience learning are central elements for these approaches. In this paper, we describe an approach to build and test a Resilience Learning System to support research and implementation of a resilience strategy developed for the Greater Miami and the Beaches or the Resilient305 Strategy. Elements foundational to the design of this integrated research strategy and replicable Resilience Learning System are: (1) strong partnerships among community members, government and non-government organization leaders, and researchers from multiple academic institutions; (2) contributions of subject matter expertise and local knowledge to identify information and translational gaps, formulate metrics and evaluate outcomes of Resilient305 Strategy actions from the community perspective; and (3) a comprehensive understanding of civic engagement activities, technological tools, and resilience-building capacities, including policy and financial innovations, from which to advance socio-technological, smart and connected regional-to-hyperlocal community translation through co-design/co-production. Initial results on co-produced metrics are provided. This work produces a new, replicable framework for resilience research that includes a comprehensive set of metrics, translation to communities through structured dialogues, a collaborative process involving all stakeholders and researchers, and evaluation of resilience actions to inform new investments and improve understanding and effectiveness over time

A System for Resilience Learning: Developing a Community-Driven, Multi-Sector Research Approach for Greater Preparedness and Resilience to Long-Term Climate Stressors and Extreme Events in the Miami Metropolitan Region

There is a growing need for integrated approaches that align community priorities with strategies that build resilience to climate hazards, societal shocks, and economic crises to ensure more equitable and sustainable outcomes. We anticipate that adaptive management and resilience learning are central elements for these approaches. In this paper, we describe an approach to build and test a Resilience Learning System to support research and implementation of a resilience strategy developed for the Greater Miami and the Beaches or the Resilient305 Strategy. Elements foundational to the design of this integrated research strategy and replicable Resilience Learning System are: (1) strong partnerships among community members, government and non-government organization leaders, and researchers from multiple academic institutions; (2) contributions of subject matter expertise and local knowledge to identify information and translational gaps, formulate metrics and evaluate outcomes of Resilient305 Strategy actions from the community perspective; and (3) a comprehensive understanding of civic engagement activities, technological tools, and resilience-building capacities, including policy and financial innovations, from which to advance socio-technological, smart and connected regional-to-hyperlocal community translation through co-design/co-production. Initial results on co-produced metrics are provided. This work produces a new, replicable framework for resilience research that includes a comprehensive set of metrics, translation to communities through structured dialogues, a collaborative process involving all stakeholders and researchers, and evaluation of resilience actions to inform new investments and improve understanding and effectiveness over time