A clinical laboratory's experience using GeneMatcher-Building stronger gene-disease relationships.

The use of whole-genome sequencing (WGS) has accelerated the pace of gene discovery and highlighted the need for open and collaborative data sharing in the search for novel disease genes and variants. GeneMatcher (GM) is designed to facilitate connections between researchers, clinicians, health-care providers, and others to help in the identification of additional patients with variants in the same candidate disease genes. The Illumina Clinical Services Laboratory offers a WGS test for patients with suspected rare and undiagnosed genetic disease  and regularly submits potential candidate genes to GM to strengthen gene-disease relationships. We describe our experience with GM, including criteria for evaluation of candidate genes, and our workflow for the submission and review process. We have made 69 submissions, 36 of which are currently active. Ten percent of submissions have resulted in publications, with an additional 14 submissions part of ongoing collaborations and expected to result in a publication.

MicroRNAs as the Sentinels of Redox and Hypertrophic Signalling.

Oxidative stress and inflammation are associated with skeletal muscle function decline with ageing or disease or inadequate exercise and/or poor diet. Paradoxically, reactive oxygen species and inflammatory cytokines are key for mounting the muscular and systemic adaptive responses to endurance and resistance exercise. Both ageing and lifestyle-related metabolic dysfunction are strongly linked to exercise redox and hypertrophic insensitivity. The adaptive inability and consequent exercise intolerance may discourage people from physical training resulting in a vicious cycle of under-exercising, energy surplus, chronic mitochondrial stress, accelerated functional decline and increased susceptibility to serious diseases. Skeletal muscles are malleable and dynamic organs, rewiring their metabolism depending on the metabolic or mechanical stress resulting in a specific phenotype. Endogenous RNA silencing molecules, microRNAs, are regulators of these metabolic/phenotypic shifts in skeletal muscles. Skeletal muscle microRNA profiles at baseline and in response to exercise have been observed to differ between adult and older people, as well as trained vs. sedentary individuals. Likewise, the circulating microRNA blueprint varies based on age and training status. Therefore, microRNAs emerge as key regulators of metabolic health/capacity and hormetic adaptability. In this narrative review, we summarise the literature exploring the links between microRNAs and skeletal muscle, as well as systemic adaptation to exercise. We expand a mathematical model of microRNA burst during adaptation to exercise through supporting data from the literature. We describe a potential link between the microRNA-dependent regulation of redox-signalling sensitivity and the ability to mount a hypertrophic response to exercise or nutritional cues. We propose a hypothetical model of endurance exercise-induced microRNA "memory cloud" responsible for establishing a landscape conducive to aerobic as well as anabolic adaptation. We suggest that regular aerobic exercise, complimented by a healthy diet, in addition to promoting mitochondrial health and hypertrophic/insulin sensitivity, may also suppress the glycolytic phenotype and mTOR signalling through miRNAs which in turn promote systemic metabolic health.

Understanding the Development, Standardization, and Validation Process of Alternative In Vitro Test Methods for Regulatory Approval from a Researcher Perspective.

Due to economic, practical, ethical, and scientific reasons, researchers, among others, are pushing for alternative in vitro test methods to replace or reduce existing animal experiments. In order for these tests to be more broadly used by the industrial sector and regulatory bodies, orchestrated efforts are required to show the robustness and reliability of in vitro methods, which can accelerate the use for early screening testing. Another way of increasing the use of alternatives is to coordinate validation studies, that is, multi-laboratory trials, and to gain regulatory approval and instatement as test guidelines or standard method. However, awareness of the exact standardization, validation, and approval process has been a major obstacle for many researchers. Herein, the process has been broken down into three main phases: i) test method development; ii) intra- and inter-laboratory validation; and iii) regulatory acceptance. This general process applies to all alternative methods seeking validation and approval, although the intricacies of different toxicological endpoints and/or chemical sectors may lead to additional work, particularly in the validation stage. The authors' aim is to provide insight in the development process of alternative methods with a focus on in vitro cell culture methods over validation to regulatory acceptance.

Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease.

PURPOSE: Current diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, genome sequencing (GS) can detect all genomic pathogenic variant types on a single platform. Here we evaluate copy-number variant (CNV) calling as part of a clinically accredited GS test. METHODS: We performed analytical validation of CNV calling on 17 reference samples, compared the sensitivity of GS-based variants with those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis of GS-based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases. RESULTS: We found that CNV calls from GS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed, all of which were confirmed by an orthogonal approach. The pipeline also enabled discovery of a uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of select CNVs enabled breakpoint level resolution of genomic rearrangements and phasing of de novo CNVs. CONCLUSION: Robust identification of CNVs by GS is possible within a clinical testing environment.

Cerebral ß-Amyloid Angiopathy Is Associated with Earlier Dementia Onset in Alzheimer's Disease.

BACKGROUND: Cerebral ß-amyloid angiopathy (CAA) occurs when ß-amyloid (Aß) is deposited in the vascular media and adventitia. It is a common pathology in the brains of older individuals and has been linked to cognitive decline, but relatively little is known about the influence that CAA has on the clinical manifestation of Alzheimer's disease (AD). The aim of this retrospective analysis was to quantify the effect that CAA had on the manifestation of initial AD-related cognitive change and subsequent progression of dementia. METHODS: We analyzed neuropathological data from the National Alzheimer's Coordinating Center's data set, performing parametric analyses to assess differences in age of progression to moderate-stage dementia. RESULTS: We found that individuals with both CAA burden and Aß neuritic plaque burden at death had the greatest risk of earlier conversion to very mild and moderate-stage dementia, but not necessarily faster progression. CONCLUSIONS: Our results suggest that CAA contributes to changes in early AD pathogenesis. This supports the idea that vascular change and neuritic plaque deposition are not just parallel processes but reflect additive pathological cascades that influence the course of clinical AD manifestation. Further inquiry into the role of CAA and its contribution to early cognitive change in AD is suggested.

Exposure to the aryl hydrocarbon receptor agonist dioxin disrupts formation of the muscle, nerves, and vasculature in the developing jaw.

Human exposure to environmental pollutants can disrupt embryonic development and impact juvenile and adult health outcomes by adversely affecting cell and organ function. Notwithstanding, environmental contamination continues to increase due to industrial development, insufficient regulations, and the mobilization of pollutants as a result of extreme weather events. Dioxins are a class of structurally related persistent organic pollutants that are highly toxic, carcinogenic, and teratogenic. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the most potent dioxin compound and has been shown to induce toxic effects in developing organisms by activating the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor targeted by multiple persistent organic pollutants. Contaminant-induced AHR activation results in malformations of the craniofacial cartilages and neurocranium; however, the mechanisms mediating these phenotypes are not well understood. In this study, we utilized the optically transparent zebrafish model to elucidate novel cellular targets and potential transcriptional targets underlying TCDD-induced craniofacial malformations. To this end, we exposed zebrafish embryos at 4 h post fertilization to TCDD and employed a mixed-methods approach utilizing immunohistochemistry staining, transgenic reporter lines, fixed and in vivo confocal imaging, and timelapse microscopy to determine the targets mediating TCDD-induced craniofacial phenotypes. Our data indicate that embryonic TCDD exposure reduced jaw and pharyngeal arch Sox10+ chondrocytes and Tcf21+ pharyngeal mesoderm progenitors. Exposure to TCDD correspondingly led to a reduction in collagen type II deposition in Sox10+ domains. Embryonic TCDD exposure impaired development of tissues derived from or guided by Tcf21+ progenitors, namely: nerves, muscle, and vasculature. Specifically, TCDD exposure disrupted development of the hyoid and mandibular arch muscles, decreased neural innervation of the jaw, resulted in compression of cranial nerves V and VII, and led to jaw vasculature malformations. Collectively, these findings reveal novel structural targets and potential transcriptional targets of TCDD-induced toxicity, showcasing how contaminant exposures lead to congenital craniofacial malformations.

Supporting pregnant and parenting women who use alcohol during pregnancy: A scoping review of trauma-informed approaches.

Alcohol is legalized and used for a variety of reasons, including socially or as self-medication for trauma in the absence of accessible and safe supports. Trauma-informed approaches can help address the root causes of alcohol use, as well as the stigma around women's alcohol use during pregnancy. However, it is unclear how these approaches are used in contexts where pregnant and/or parenting women access care. Our objective was to synthesize existing literature and identify promising trauma-informed approaches to working with pregnant and/or parenting women who use alcohol. A multidisciplinary team of scholars with complementary expertise worked collaboratively to conduct a rigorous scoping review. All screening, extraction, and analysis was independently conducted by at least two authors before any differences were discussed and resolved through team consensus. The Joanna Briggs Institute method was used to map existing evidence from peer-reviewed articles found in PubMed, CINAHL, PsycINFO, Social Work Abstracts, and Web of Science. Data were extracted to describe study demographics, articulate trauma-informed principles in practice, and gather practice recommendations. Thirty-six studies, mostly from the United States and Canada, were included for analysis. Studies reported on findings of trauma-informed practice in different models of care, including live-in treatment centers, case coordination/management, integrated and wraparound supports, and outreach-for pregnant women, mothers, or both. We report on how the following four principles of trauma-informed practices were applied and articulated in the included studies: (1) trauma awareness; (2) safety and trustworthiness; (3) choice, collaboration, and connection; and (4) strengths-based approach and skill building. This review advances and highlights the importance of understanding trauma and applying trauma-informed practice and principles to better support women who use alcohol to reduce the risk of alcohol-exposed pregnancies. Relationships and trust are central to trauma-informed care. Moreover, when applying trauma-informed practices with pregnant and parenting women who use alcohol, we must consider the unique stigma attached to alcohol use.

Exposure to the persistent organic pollutant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) disrupts development of the zebrafish inner ear.

Dioxins are a class of highly toxic and persistent environmental pollutants that have been shown through epidemiological and laboratory-based studies to act as developmental teratogens. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent dioxin congener, has a high affinity for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. TCDD-induced AHR activation during development impairs nervous system, cardiac, and craniofacial development. Despite the robust phenotypes previously reported, the characterization of developmental malformations and our understanding of the molecular targets mediating TCDD-induced developmental toxicity remains limited. In zebrafish, TCDD-induced craniofacial malformations are produced, in part, by the downregulation of SRY-box transcription factor 9b ( sox9b ), a member of the SoxE gene family. sox9b , along with fellow SoxE gene family members sox9a and sox10 , have important functions in the development of the otic placode, the otic vesicle, and, ultimately, the inner ear. Given that sox9b in a known target of TCDD and that transcriptional interactions exist among SoxE genes, we asked whether TCDD exposure impaired the development of the zebrafish auditory system, specifically the otic vesicle, which gives rise to the sensory components of the inner ear. Using immunohistochemistry, in vivo confocal imaging, and time-lapse microscopy, we assessed the impact of TCDD exposure on zebrafish otic vesicle development. We found exposure resulted in structural deficits, including incomplete pillar fusion and altered pillar topography, leading to defective semicircular canal development. The observed structural deficits were accompanied by reduced collagen type II expression in the ear. Together, our findings reveal the otic vesicle as a novel target of TCDD-induced toxicity, suggest that the function of multiple SoxE genes may be affected by TCDD exposure, and provide insight into how environmental contaminants contribute to congenital malformations. Highlights: The zebrafish ear is necessary to detect changes in motion, sound, and gravity.Embryos exposed to TCDD lack structural components of the developing ear.TCDD exposure impairs formation of the fusion plate and alters pillar topography.The semicircular canals of the ear are required to detect changes in movement.Following TCDD exposure embryos fail to establish semicircular canals.

Exposure to the persistent organic pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) disrupts development of the zebrafish inner ear.

Dioxins are a class of highly toxic and persistent environmental pollutants that have been shown through epidemiological and laboratory-based studies to act as developmental teratogens. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent dioxin congener, has a high affinity for the aryl hydrocarbon receptor (AHR), a ligand activated transcription factor. TCDD-induced AHR activation during development impairs nervous system, cardiac, and craniofacial development. Despite the robust phenotypes previously reported, the characterization of developmental malformations and our understanding of the molecular targets mediating TCDD-induced developmental toxicity remains limited. In zebrafish, TCDD-induced craniofacial malformations are produced, in part, by the downregulation of SRY-box transcription factor 9b (sox9b), a member of the SoxE gene family. sox9b, along with fellow SoxE gene family members sox9a and sox10, have important functions in the development of the otic placode, the otic vesicle, and, ultimately, the inner ear. Given that sox9b is a known target of TCDD and that transcriptional interactions exist among SoxE genes, we asked whether TCDD exposure impaired the development of the zebrafish auditory system, specifically the otic vesicle, which gives rise to the sensory components of the inner ear. Using immunohistochemistry, in vivo confocal imaging, and time-lapse microscopy, we assessed the impact of TCDD exposure on zebrafish otic vesicle development. We found exposure resulted in structural deficits, including incomplete pillar fusion and altered pillar topography, leading to defective semicircular canal development. The observed structural deficits were accompanied by reduced collagen type II expression in the ear. Together, our findings reveal the otic vesicle as a novel target of TCDD-induced toxicity, suggest that the function of multiple SoxE genes may be affected by TCDD exposure, and provide insight into how environmental contaminants contribute to congenital malformations.

Indigenous communities and the mental health impacts of land dispossession related to industrial resource development: a systematic review.

Globally, many resource extraction projects such as mines and hydroelectric dams are developed on the territories of Indigenous Peoples. Recognising land as a determinant of Indigenous Peoples' health, our objective is to synthesise evidence about the mental health impacts on Indigenous communities who experience land dispossession due to industrial resource development (mining, hydroelectric, petroleum, and agricultural). We systematically reviewed studies that focused on Indigenous land dispossession in Australia, Aotearoa (New Zealand), North and South America, and the Circumpolar North. We searched Scopus, Medline, Embase, PsycINFO, and Global Health on OVID for peer-reviewed articles published in English from database inception to Dec 31, 2020. We also searched for books, research reports, and scholarly journals specialising in Indigenous health or Indigenous research. We included documents that reported on primary research, focused on Indigenous Peoples in settler colonial states, and reported on mental health and industrial resource development. Of the 29 included studies, 13 were related to hydroelectric dams, 11 to petroleum developments, nine to mining, and two to agriculture. Land dispossession due to industrial resource development had predominantly negative mental health impacts on Indigenous communities. The impacts were consequences of colonial relations that threatened Indigenous identities, resources, languages, traditions, spirituality, and ways of life. Health impact assessment processes in industrial resource development must expressly consider risks and potential impacts on mental health and respect Indigenous rights by making knowledge about mental health risks a central component to decisions about free, prior, and informed consent.

Impact on mental health and wellbeing in Indigenous communities due to land loss resulting from industrial resource development: protocol for a systematic review.

BACKGROUND: Indigenous Peoples are impacted by industrial resource development that takes place on, or near, their communities. Existing literature on impacts of industrial resource development on Indigenous Peoples primarily focus on physical health outcomes and rarely focus on the mental health impacts. To understand the full range of long-term and anticipated health impacts of industrial resource development on Indigenous communities, mental health impacts must be examined. It is well-established that there is a connection between the environment and Indigenous wellbeing, across interrelated dimensions of mental, physical, emotional, and spiritual health. METHODS: This paper identifies how the Community Advisory Team and a team of Indigenous and settler scholars will conduct the review. The literature search will use the OVID interface to search Medline, Embase, PsycINFO, and Global Health databases. Non-indexed peer-reviewed journals related to Indigenous health or research will be scanned. Books and book chapters will be identified in the Scopus and PsycINFO databases. The grey literature search will also include Google and be limited to reports published by government, academic, and non-profit organizations. Reference lists of key publications will be checked for additional relevant publications, including theses, dissertations, reports, and other articles not retrieved in the online searches. Additional sources may be recommended by team members. Included documents will focus on Indigenous Peoples in North America, South America, Australia, Aotearoa New Zealand, and Circumpolar regions, research that reports on mental health, and research that is based on land loss connected to dams, mines, agriculture, or petroleum development. Literature that meets the inclusion criteria will be screened at the title/abstract and full-text stages by two team members in Covidence. The included literature will be rated with a quality appraisal tool and information will be extracted by two team members; a consensus of information will be reached and be submitted for analysis. DISCUSSION: The synthesized evidence from this review is relevant for land use policy, health impact assessments, economic development, mental health service planning, and communities engaging in development projects. SYSTEMATIC REVIEW REGISTRATION: Registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration number CRD42021253720 ).

A case of traumatic penile fracture with simultaneous rupture of both corpora cavernosa and complete urethral transection.

Penile fracture is a rare injury to the penis caused by blunt trauma. The presence of urethral injuries sustained during fracture is less than 10%, but very few cases involve complete circumferential urethral transection. We present a case of a patient who presented with traumatic penile fracture involving bilateral corporal cavernosa injury and complete urethral transection.

Emergency Absentee Voting for Hospitalized Patients and Voting During COVID-19: A 50-State Study.

INTRODUCTION: Voters facing illness or disability are disproportionately under-represented in terms of voter turnout. Earlier research has indicated that enfranchisement of these populations may reinforce the implementation of policies improving health outcomes and equity. Due to the confluence of the coronavirus 2019 (COVID-19) pandemic and the 2020 election, we aimed to assess emergency absentee voting processes, which allow voters hospitalized after regular absentee deadlines to still obtain an absentee ballot, and election changes due to COVID-19 in all 50 states. METHODS: We performed a cross-sectional study collecting 34 variables pertaining to emergency voting processes and COVID-19-related election changes, including deadlines, methods of submission for applications and ballots, and specialized services for patients. Data were obtained from, in order of priority, state boards of elections websites, poll worker manuals, application forms, and state legislation. We verified all data through direct correspondence with state boards of elections. RESULTS: Emergency absentee voting processes are in place in 39 states, with the remaining states having universal vote-by-mail (n = 5) or extended regular absentee voting deadlines (n = 6). The emergency absentee period most commonly began within 24 hours following the normal absentee application deadline, which was often seven days before an election (n = 11). Unique aspects of emergency voting processes included patients designating an "authorized agent" to deliver their applications and ballots (n = 38), electronic ballot delivery (n = 5), and in-person teams that deliver ballots directly to patients (n = 18). Documented barriers in these processes nationwide include unavailable online information (n = 11), restrictions mandating agents to be family members (n = 7), physician affidavits or signatures (n = 9), and notary or witness signature requirements (n = 15). For the November 2020 presidential election, 12 states expanded absentee eligibility to allow COVID-19 as a reason to request an absentee ballot, and 18 states mailed absentee ballot applications or absentee ballots to all registered voters. CONCLUSION: While 39 states operate emergency absentee voting processes for hospitalized voters, there are considerable areas for improvement and heterogeneity in guidelines for these protocols. For future election cycles, information on emergency voting and broader election reforms due to COVID-19 may be useful for emergency providers and patients alike to improve the democratic participation of voters experiencing illness.

Emergency Mail-in Voting in Rhode Island: Protecting Civic Participation During COVID-19 and Beyond.

The COVID-19 pandemic challenges safe and equitable voting in the United States' 2020 elections, and in response, several states including Rhode Island (RI) have made significant changes to election policy. In addition to increasing accessibility of mail-in voting by mailing applications to all registered voters, RI has suspended their notary/witness requirement for both the primary and general election. However, RI's "emergency" voting process still plays a crucial role in allowing voters who missed the mail-in ballot application deadline, such as those unexpectedly hospitalized in the days leading up to the election, to still cast their ballot. COVID-19 has also forced RI to modify its emergency voting procedures, most notably allowing healthcare workers to serve on bipartisan ballot delivery teams. This commentary highlights these salient updates to voting procedures and serves as a primer as to how interested health care workers may navigate this process alongside patients and lead in the arena of patient voting rights.

The Impact of Creative Arts in Alzheimer's Disease and Dementia Public Health Education.

Previous research involving dramatic performances about Alzheimer's disease and dementia perception have targeted health care workers or caretakers. We examined the influence of a theater performance on the emotional affect of a general audience to determine the utility of this type of theater in large-scale public health education efforts. Our study included 147 participants that attended a self-revelatory theater performance based on the social/relationship experiences of those with dementia and those who care for them. This type of theater engages the audience and actors in a dual transformative process, supporting the emotional growth of all involved. Participants completed pre- and post-performance questionnaires regarding their beliefs and feelings surrounding the topic of dementia and the importance of the Arts for educating on issues surrounding dementia care. We tested for change in emotional affect pre- and post-performance using sensitivity and center of gravity statistical analyses. We found a significant change in emotional affect from an initial strong negative affect to slightly more positive/relaxed view after viewing the performance. Findings support self-revelatory theater as a resource to destigmatize preconceived notions of dementia. Large-scale community health education efforts could benefit from using this style of theater to elicit a change in audience perception of disease realities.

Tracing nonlegume orthologs of legume genes required for nodulation and arbuscular mycorrhizal symbioses.

Most land plants can form a root symbiosis with arbuscular mycorrhizal (AM) fungi for assimilation of inorganic phosphate from the soil. In contrast, the nitrogen-fixing root nodule symbiosis is almost completely restricted to the legumes. The finding that the two symbioses share common signaling components in legumes suggests that the evolutionarily younger nitrogen-fixing symbiosis has recruited functions from the more ancient AM symbiosis. The recent advances in cloning of the genes required for nodulation and AM symbioses from the two model legumes, Medicago truncatula and Lotus japonicus, provide a unique opportunity to address biological questions pertaining to the evolution of root symbioses in plants. Here, we report that nearly all cloned legume genes required for nodulation and AM symbioses have their putative orthologs in nonlegumes. The orthologous relationship can be clearly defined on the basis of both sequence similarity and microsyntenic relationship. The results presented here serve as a prelude to the comparative analysis of orthologous gene function between legumes and nonlegumes and facilitate our understanding of how gene functions and signaling pathways have evolved to generate species- or family-specific phenotypes.

The effect of 3-methyladenine DNA glycosylase-mediated DNA repair on the induction of toxicity and diabetes by the beta-cell toxicant streptozotocin.

Type 1 diabetes in humans arises from the autoimmune destruction of pancreatic beta-cells and typically presents in childhood. Genetic susceptibility is an underlying cause, but environmental agents, that is, toxins and viruses, are postulated to be initiating factors. The underlying role of beta-cell death in response to environmental or physiologic events has been investigated as a critical event in diabetes onset. A well-studied rodent model for type 1 diabetes utilizes streptozotocin (STZ) to induce beta-cell death. STZ is a selective beta-cell genotoxicant, and when administered in a single high dose it induces rapid onset of diabetes by generating DNA adducts, including N3-methyladenine and O(6)-methylguanine adducts, and subsequently beta-cell death by necrosis. In the present work, we have extended previous studies in which mice deficient in the repair of N3-methyladenine adducts, 3-methyladenine DNA glycosylase (alkyladenine DNA glycosylase [Aag]) null mice, were reported to be resistant to the direct cytotoxic effect of STZ, but later developed autoimmune diabetes (J. W. Cardinal et al., 2001, Mol. Cell. Biol. 231, 5605-5613). We found that Aag(-/-) mice treated with a single high dose of STZ were protected from widespread beta-cell necrosis and diabetes. However, moderate levels of beta-cell apoptosis were observed in the Aag(-/-) STZ-treated mice. While mice became glucose impaired for the duration of study (14 months after STZ injection), overt diabetes did not develop. We conclude that an autoimmune response is not initiated in Aag(-/-) mice in response to beta-cell apoptosis. Furthermore, tumor development is not observed in Aag(-/-) treated mice, suggesting that N3-methyladenine adducts that accumulate in the genome may not be promutagenic in beta-cells.

Vascular inflammatory markers in early-onset obese and type 2 diabetes subjects before and after three months' aerobic exercise training.

Early-onset type 2 diabetes (T2DM) may lead to very early vascular complications. Cardiovascular mortality is two to five times higher in adults with diabetes than in people without diabetes. The cardiovascular risk of young people with T2DM is unknown. T2DM in young people is associated with marked visceral obesity, insulin resistance and microalbuminuria. We recently showed that these subjects did not improve in either fitness (maximum volume of oxygen consumption, VO2max) or glucose disposal after exercise training. Seven subjects with early-onset T2DM (aged 26.1+/-0.9 years, body mass index [BMI] 35.6+/-1.2 kg/m2) and 14 age-matched obese subjects with normal glucose tolerance (aged 25.6+/-0.9 years, BMI 34.3+/-1.4 kg/m2) underwent aerobic training for 12 weeks. Serum vascular inflammatory markers (high-sensitivity C-reactive protein [hsCRP], soluble intercellular adhesion molecule [sICAM-1], soluble vascular cell adhesion molecule [sVCAM-1], E-Selectin and P-Selectin) were measured before and after the training programme. At baseline, plasma concentrations of vascular inflammatory markers were significantly elevated in both groups. They did not improve after exercise.

Flt3 ligand delivered in a pluronic formulation prolongs the survival of mice with orthotopic pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is a devastating disease, characterized by asymptomatic development and extremely poor prognosis. Given the resistance of pancreatic cancer to standard chemo- and radiotherapy, we have focused on the development of immunotherapies for this disease. The number of dendritic cells (DCs), natural killer (NK) cells, and T-cells in the blood and secondary lymphoid organs is regulated by a group of hematopoietic growth factors, which includes fms-like tyrosine kinase-3 ligand (Flt3L). We have demonstrated previously that the bioavailability and in vivo half-life of Flt3L are increased by Flt3L formulation in the pluronic ProGelzx. In this study, we first examined the effectiveness of Flt3L delivered in ProGelz against subcutaneous (s.c.) pancreatic adenocarcinomas in mice. We found that an intramuscular (i.m.) injection of Flt3L in ProGelz significantly increased the survival of mice bearing s.c. pancreatic tumors, compared to the administration of phosphate-buffered saline (PBS) in ProGelz. We then tested Flt3L in ProGelz in an orthotopic pancreatic tumor model, and demonstrated that it significantly enhanced the survival of tumor-bearing mice, compared to PBS in ProGelz. Overall, these observations suggest that Flt3L formulated in ProGelz may have potential clinical utility as a treatment for pancreatic cancer.

Impaired fasting glucose is associated with increased regional cerebral amyloid.

The Alzheimer's disease risk gene apolipoprotein E epsilon 4 (APOE ε4) is associated with increased cerebral amyloid. Although impaired glucose metabolism is linked to Alzheimer's disease risk, the relationship between impaired glycemia and cerebral amyloid is unclear. To investigate the independent effects of APOE ε4 and impaired glycemia on cerebral amyloid, we stratified nondemented subjects (n = 73) into 4 groups: normal glucose, APOE ε4 noncarrier (control [CNT]; n = 31), normal glucose, APOE ε4 carrier (E4 only; n = 14) impaired glycemia, APOE ε4 noncarrier (IG only; n = 18), and impaired glycemia, APOE ε4 carrier (IG+E4; n = 10). Cerebral amyloid differed both globally (p = 0.023) and regionally; precuneus (p = 0.007), posterior cingulate (PCC; p = 0.020), superior parietal cortex (SPC; p = 0.029), anterior cingulate (p = 0.027), and frontal cortex (p = 0.018). Post hoc analyses revealed that E4 only subjects had increased cerebral amyloid versus CNT globally and regionally in the precuneus, PCC, SPC, anterior cingulate, and frontal cortex. In IG only subjects, increased cerebral amyloid compared with CNT was restricted to precuneus, PCC, and SPC. IG+E4 subjects exhibited higher cerebral amyloid only in the precuneus relative to CNT. These results indicate that impaired glycemia and APOE ε4 genotype are independent risk factors for regional cerebral amyloid deposition. However, APOE ε4 and impaired glycemia did not have an additive effect on cerebral amyloid.