The emergence of HIV as a chronic condition means that people living with HIV are required to take more responsibility for the self-management of their condition, including making physical, emotional and social adjustments. This paper describes the design and evaluation of Positive Outlook, an online program aiming to enhance the self-management skills of gay men living with HIV.
This study is designed as a randomised controlled trial in which men living with HIV in Australia will be assigned to either an intervention group or usual care control group. The intervention group will participate in the online group program ‘Positive Outlook’. The program is based on self-efficacy theory and uses a self-management approach to enhance skills, confidence and abilities to manage the psychosocial issues associated with HIV in daily life. Participants will access the program for a minimum of 90 minutes per week over seven weeks. Primary outcomes are domain specific self-efficacy, HIV related quality of life, and outcomes of health education. Secondary outcomes include: depression, anxiety and stress; general health and quality of life; adjustment to HIV; and social support. Data collection will take place at baseline, completion of the intervention (or eight weeks post randomisation) and at 12 week follow-up.
Results of the Positive Outlook study will provide information regarding the effectiveness of online group programs improving health related outcomes for men living with HIV.
HIV; Self-Management; Online Intervention; Quality of Life
To develop a comprehensive set of patient reported items to assess multiple aspects of physical functioning relevant to the lives of people with spinal cord injury (SCI) and to evaluate the underlying structure of physical functioning.
Inpatient and community
Item pools of physical functioning were developed, refined and field tested in a large sample of 855 individuals with traumatic spinal cord injury stratified by diagnosis, severity, and time since injury
Main Outcome Measure
SCI-FI measurement system
Confirmatory factor analysis (CFA) indicated that a 5-factor model, including basic mobility, ambulation, wheelchair mobility, self care, and fine motor, had the best model fit and was most closely aligned conceptually with feedback received from individuals with SCI and SCI clinicians. When just the items making up basic mobility were tested in CFA, the fit statistics indicate strong support for a unidimensional model. Similar results were demonstrated for each of the other four factors indicating unidimensional models.
Though unidimensional or 2-factor (mobility and upper extremity) models of physical functioning make up outcomes measures in the general population, the underlying structure of physical function in SCI is more complex. A 5-factor solution allows for comprehensive assessment of key domain areas of physical functioning. These results informed the structure and development of the SCI-FI measurement system of physical functioning.
Spinal Cord Injuries; Mobility Limitations; Outcome Assessment (Health Care); Activities of Daily Living; Psychometrics; Walking; Self Care; Quality of Life
For auto-oscillators of different nature (e.g. active cells in a human heart under the action of a pacemaker, neurons in brain, spin-torque nano-oscillators, micro and nano-mechanical oscillators, or generating Josephson junctions) a critically important property is their ability to synchronize with each other. The synchronization properties of an auto oscillator are directly related to its sensitivity to external signals. Here we demonstrate that a non-isochronous (having generation frequency dependent on the amplitude) auto-oscillator with delayed feedback can have an extremely high sensitivity to external signals and unusually large width of the phase-locking band near the boundary of the stable auto-oscillation regime. This property could be used for the development of synchronized arrays of non-isochronous auto-oscillators in physics and engineering, and, for instance, might bring a better fundamental understanding of ways to control a heart arrythmia in medicine.
We analyzed the outcomes of 248 (61% male) adult recipients of HLA-matched unrelated and HLA-mismatched related donor hematopoietic cell transplantation (HCT) for non-Hodgkin lymphoma (NHL) after reduced or lower intensity conditioning (RIC), reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1997 to 2004. Median age was 52 (range, 18–72 yrs); 31% had a Karnofsky performance score <90. Follicular NHL (43%) was the major histology. Incidence of grades II–IV acute graft-versus-host disease (GVHD) was 43% at 100 days; and chronic GVHD was 44% at three years. Treatment-related mortality (TRM) at 100 days was 24%. Three-year overall survival (OS) and progression-free survival (PFS) were 41% and 32%, respectively. In multivariate analysis, use of anti-thymocyte globulin (ATG) and HLA mismatch were associated with increased TRM. High-grade histology, ATG use and chemotherapy resistance were associated with lower progression-free survival (PFS). Older age, shorter interval from diagnosis to HCT, non-TBI conditioning regimens, ex vivo T-cell depletion and HLA-mismatched unrelated donors were associated with mortality. GVHD did not influence relapse or PFS. Older age, aggressive histology and chemotherapy resistance correlated with poorer survival. For selected patients with NHL, lack of an available sibling donor should not be a barrier to allogeneic HCT.
Recent studies have shown that mental script-based rehearsal and simulation-based training improves the transfer of surgical skills in various medical disciplines. Despite significant advances in technology and intraoperative techniques over the last several decades, surgical skills training on neurosurgical operations still carries significant risk of serious morbidity or mortality. Potentially avoidable technical errors are well recognized as contributing to poor surgical outcome. Surgical education is undergoing overwhelming change, with reduction of working hours and current trends to focus on patient’s safety and linking reimbursement with clinical outcomes, and there is a need for adjunctive means for neurosurgical training;this has been recent advancement in simulation technology. ImmersiveTouch (IT) is an augmented reality (AR) system that integrates a haptic device and a high-resolution stereoscopic display. This simulation platform utilizes multiple sensory modalities, recreating many of the environmental cues experienced during an actual procedure. Modules available include ventriculostomy, bone drilling, percutaneous trigeminal rhizotomy, in addition to simulated spinal modules such as pedicle screw placement, vertebroplasty, and lumbar puncture. We present our experience with development of such AR neurosurgical modules and the feedback from neurosurgical residents.
Virtual reality; Surgical Simulation; Neurosurgical training; Ventriculostomy; spinal instrumentation
Language has been extensively investigated by functional neuroimaging studies. However, only a limited number of structural neuroimaging studies have examined the relationship between language performance and brain structure in healthy adults, and the number is even less in older adults. The present study sought to investigate correlations between grey matter volumes and three standardized language tests in late life. The participants were 344 non-demented, community-dwelling adults aged 70-90 years, who were drawn from the population-based Sydney Memory and Ageing Study. The three language tests included the Controlled Oral Word Association Task (COWAT), Category Fluency (CF), and Boston Naming Test (BNT). Correlation analyses between voxel-wise GM volumes and language tests showed distinctive GM correlation patterns for each language test. The GM correlates were located in the right frontal and left temporal lobes for COWAT, in the left frontal and temporal lobes for CF, and in bilateral temporal lobes for BNT. Our findings largely corresponded to the neural substrates of language tasks revealed in fMRI studies, and we also observed a less hemispheric asymmetry in the GM correlates of the language tests. Furthermore, we divided the participants into two age groups (70-79 and 80-90 years old), and then examined the correlations between structural laterality indices and language performance for each group. A trend toward significant difference in the correlations was found between the two age groups, with stronger correlations in the group of 70-79 years old than those in the group of 80-90 years old. This difference might suggest a further decline of language lateralization in different stages of late life.
Purpose The L216R mutation, seen in individuals of Polynesian descent, is considered one of the most severe mutations associated with holocarboxylase synthetase (HLCS) deficiency and is regarded as being unresponsive to biotin. This report describes the presentation and outcome in two surviving siblings, homozygous for this highly lethal mutation.
Methods and results Both cases had perinatal head imaging findings of brain hemorrhage and subependymal cysts. Both had metabolic decompensation within 24 h after birth consisting of metabolic acidosis, lactic acidosis, and thrombocytopenia. Biochemical profiles were consistent with HLCS deficiency, and genetic analysis confirmed homozygosity for the L216R mutation. After resolution of neonatal metabolic crisis, dosing of biotin was titrated on an outpatient basis to primarily control dermatitis. The eldest is currently on 1.2 g of oral biotin daily, well above any dose previously reported to treat HLCS deficiency. To date, neither patient has required hospital readmission for acute metabolic decompensation. At the age of 7, the eldest child is, to our knowledge, the oldest patient ever described in the literature who is homozygous for the L216R mutation. She has mild intellectual disability.
Conclusion This report contrasts previous reports of poor outcomes and neonatal deaths in homozygous L216R patients. We also provide data on the potential upper tolerable limit of biotin. These cases suggest that the outcome of HCLS deficiency due to a homozygous L216R mutation, when diagnosed and treated early with high-level neonatal care and biotin, may not be as severe as previously reported.
To investigate the prognostic value of the neurocognitive status measured by screening instruments, the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE), individually and in combination with the stroke severity scale, the National Institute of Health Stroke Scale (NIHSS), obtained at the subacute stroke phase or the baseline (≤2 weeks), for functional outcome 3–6 months later.
Prospective observational study.
Tertiary stroke neurology service.
400 patients with a recent ischaemic stroke or transient ischaemic attack (TIA) received NIHSS, MoCA and MMSE at baseline and were followed up 3–6 months later.
Primary outcome measures
At 3–6 months following the index event, functional outcome was measured by the modified Rankin Scale (mRS) scores.
Most patients (79.8%) had a mild ischaemic stroke and less disability (median NIHSS=2, median mRS=2 and median premorbid mRS=0), while a minority of patients had TIA (20.3%). Baseline NIHSS, MMSE and MoCA scores individually predicted mRS scores at 3–6 months, with NIHSS being the strongest predictor (NIHSS: R2 change=0.043, p<0.001). Moreover, baseline MMSE scores had a small but statistically significant incremental predictive value to the baseline NIHSS for mRS scores at 3–6 months, while baseline MoCA scores did not (MMSE: R2 changes=0.006, p=0.03; MoCA: R2 changes=0.004, p=0.083). However, in patients with more severe stroke at baseline (defined as NIHSS>2), baseline MoCA and MMSE had a significant and moderately large incremental predictive value to the baseline NIHSS for mRS scores at 3–6 months (MMSE: R2 changes=0.021, p=0.010; MoCA: R2 changes=0.017, p=0.021).
Cognitive screening at the subacute stroke phase can predict functional outcome independently and improve the predictive value of stroke severity scores for functional outcome 3–6 months later, particularly in patients with more severe stroke.
GERIATRIC MEDICINE; REHABILITATION MEDICINE
We studied the outcome of allogeneic transplantation after lower-intensity conditioning regimens (reduced-intensity [RIC] and non-myeloablative [NST]) in non-Hodgkin lymphoma (NHL) relapsing after autologous transplantation. Non-relapse mortality (NRM), lymphoma progression/relapse, progression-free survival (PFS) and overall survival (OS) were analyzed in 263 NHL patients. All had relapsed after a prior autologous transplant and then received allogeneic transplantation from related (n = 26) or unrelated donors (n= 237) after RIC (n = 128) or NST (n = 135), and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1996 and 2006. Median follow-up of survivors was 68 months (range, 3–111). Three-year NRM was 44% (95% CI, 37%–50%). Lymphoma progression/relapse at three years was 35% (95% CI, 29%–41%). Three-year probabilities of PFS and OS were 21% (95% CI, 16%–27%) and 32% (95% CI, 27%–38%) respectively. Superior performance score, longer interval between transplants, total-body irradiation-based conditioning regimen and lymphoma remission at transplantation correlated with improved PFS. Allogeneic transplantation after lower-intensity conditioning is associated with significant NRM, but can result in long-term PFS. We describe a quantitative risk model based on pretransplant risk factors in order to identify those likely to benefit from this approach.
Non-Hodgkin Lymphoma; Allogeneic; Relapse
Introduction and hypothesis
The objective of this study was to compare complementary and alternative medicine (CAM) use in women with and without pelvic floor disorders (PFD).
We conducted a survey of women presenting to a specialty urogynecology (Urogyn) and gynecology (Gyn) clinic that examined demographic data, CAM use, and the presence of PFD (validated questionnaires). T tests, Fisher’s exact tests, and logistic regression were used for analysis. To detect a 20% difference between groups, 234 Urogyn and 103 Gyn patients were needed.
Participants included 234 Urogyn and 103 Gyn patients. Urogyn patients reported more CAM use than Gyn patients, even when controlled for differences between groups (51% vs. 32%, adjusted p=0.006). Previous treatment (61% vs. 39%, adjusted p<0.001) and increased number of PFD was associated with increased CAM use (adjusted p=0.02).
Women with PFD use CAM more frequently than women without PFD.
Complementary alternative medicine; Fecal incontinence; Pelvic floor disorders; Pelvic organ prolapse; Urinary incontinence
The clinical characteristics and financial charges associated with treating adult cancer patients receiving chemotherapy as day oncology patients who present to the emergency department with neutropenia are examined.
After completing this course, the reader will be able to:
Identify fever and neutropenia in a cancer patient as a medical emergency requiring prompt assessment and antibiotic therapy.Explain the use of risk assessment scores to determine the risk of complications of fever and neutropenia at presentation.
This article is available for continuing medical education credit at CME.TheOncologist.com
To examine the clinical characteristics and financial charges associated with treating adult cancer patients receiving chemotherapy in outpatient clinics who presented to the emergency department (ED) with neutropenia.
Design and Setting.
A retrospective audit was conducted across two health services involving ED episodes and subsequent hospital admissions of patients who received chemotherapy through day oncology from January 1 to December 31, 2007 and presented to the ED with neutropenia. ED data were collected from the Victorian Emergency Minimum Dataset and charges were collected from Health Information Services. Descriptive and bivariate statistics were used to describe the patient and clinical characteristics and financial outcomes, and to explore associations between these factors.
In total, 200 neutropenic episodes in 159 outpatients were seen in the ED over the survey period. The mean patient age was 56.6 years (standard deviation, 13.2 years) and 47.2% were male. Overall, 70.0% of ED episodes were triaged as Australasian Triage Scale 2 (emergency). The median ED wait time was 10 minutes and the median ED length of stay was 6.8 hours. The median charge for each ED episode was $764.08 Australian dollars. The total combined ED and inpatient charge per episode was in the range of $144.27–$174,732.68, with a median charge of $5,640.87.
This study provides important insights into the clinical and economic burden of neutropenia from both the ED and inpatient perspectives. Alternative treatment models, such as outpatient treatment, early discharge programs or prophylactic interventions to reduce the clinical and economic burden of neutropenia on our health system, must be explored.
Emergency department; Cancer; Oncology; Neutropenia; Financial charges; Clinical burden; Economics
Fruits and vegetables are universally promoted as healthy. The Dietary Guidelines for Americans 2010 recommend you make one-half of your plate fruits and vegetables. Myplate.gov also supports that one-half the plate should be fruits and vegetables. Fruits and vegetables include a diverse group of plant foods that vary greatly in content of energy and nutrients. Additionally, fruits and vegetables supply dietary fiber, and fiber intake is linked to lower incidence of cardiovascular disease and obesity. Fruits and vegetables also supply vitamins and minerals to the diet and are sources of phytochemicals that function as antioxidants, phytoestrogens, and antiinflammatory agents and through other protective mechanisms. In this review, we describe the existing dietary guidance on intake of fruits and vegetables. We also review attempts to characterize fruits and vegetables into groups based on similar chemical structures and functions. Differences among fruits and vegetables in nutrient composition are detailed. We summarize the epidemiological and clinical studies on the health benefits of fruits and vegetables. Finally, we discuss the role of fiber in fruits and vegetables in disease prevention.
We describe an 8-year-old boy with developmental delay, clinical bilateral radial ulnar synostosis, Klippel-Feil anomaly, and other vertebral deformities who was found to have a de novo deletion of 114.5kb at 16p13.3. The deletion contains five genes and three miRNAs. The genes are E4F1, DNASE1L2, ECI1, RNPS1, and ABCA3; miRNAs are MIR3677, MIR940, and MIR4717. The specific deletion has never been previously reported. We describe the phenotype of the boy and review the genes in the deleted region. None of the regulatory elements have any known linkage to skeletal formation and/or maintenance. We believe this deletion is causative given that it was de novo and that this patient cannot be easily explained as having any other specific recognizable pattern of human malformation.
The proximal q arm of chromosome 15 contains breakpoint regions BP1–BP5 with the classic deletion of BP1–BP3 best known to be associated with Prader-Willi and Angelman syndromes. The region is approximately 500 kb and microdeletions within the BP1-BP2 region have been reported in patients with developmental delay, behavioral abnormalities, and motor apraxia as well as dysmorphic features including hypertelorism, cleft or narrow palate, ear abnormalities, and recurrent upper airway infections. We report two patients with unique, never-before-reported 15q11.2 BP1-2 microdeletion syndrome findings, one with proximal esophageal atresia and distal tracheoesophageal fistula (type C) and one with congenital cataracts. Cataracts have been described in Prader-Willi syndrome but we could not find any description of cataracts in Angelman syndrome. Esophageal atresia and tracheoesophageal fistula have not been reported to our knowledge in either syndrome. A chance exists that both cases are sporadic birth defects; however, the findings of the concomitant microdeletion cannot be overlooked as a possible cause. Based on our review of the literature and the presentation of our patients, we recommend that esophageal atresia and distal tracheoesophageal fistula as well as congenital cataracts be included in the phenotypic spectrum of 15q11.2 BP1-2 microdeletion syndrome.
An aging population brings increasing burdens and costs to individuals and society arising from late-life cognitive decline, the causes of which are unclear. We aimed to identify factors predicting late-life cognitive decline.
Participants were 889 community-dwelling 70–90-year-olds from the Sydney Memory and Ageing Study with comprehensive neuropsychological assessments at baseline and a 2-year follow-up and initially without dementia. Cognitive decline was considered as incident mild cognitive impairment (MCI) or dementia, as well as decreases in attention/processing speed, executive function, memory, and global cognition. Associations with baseline demographic, lifestyle, health and medical factors were determined.
All cognitive measures showed decline and 14% of participants developed incident MCI or dementia. Across all participants, risk factors for decline included older age and poorer smelling ability most prominently, but also more education, history of depression, being male, higher homocysteine, coronary artery disease, arthritis, low health status, and stroke. Protective factors included marriage, kidney disease, and antidepressant use. For some of these factors the association varied with age or differed between men and women. Additional risk and protective factors that were strictly age- and/or sex-dependent were also identified. We found salient population attributable risks (8.7–49.5%) for older age, being male or unmarried, poor smelling ability, coronary artery disease, arthritis, stroke, and high homocysteine.
Preventing or treating conditions typically associated with aging might reduce population-wide late-life cognitive decline. Interventions tailored to particular age and sex groups may offer further benefits.
Nail-Patella syndrome (NPS) is an autosomal dominant disorder that is the result of heterozygous loss-of-function mutations in LMX1B, coding for a LIM homeobox (LIM-HD) transcription factor. Analyses of lmx1b mutant mice have revealed the role of Lmx1b in the development of mesencephalic dopaminergic neurons and the serotonergic system; these areas have been linked with symptoms of attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). Fifty adults (38 females, 12 males) with NPS completed the Conners’ Adult ADHD Rating Scales—Self-report: Long Version (CAARS) and Beck Depression Inventory-II (BDI-II). The objective was to describe the neurobehavioral phenotype of these subjects and examine possible relationships between neurobehavioral symptoms and NPS. Elevated levels of DSM-IV-TR ADHD Inattentive symptoms were reported on the CAARS by 22% of the NPS sample. The BDI-II Total score was elevated for 40% of the NPS sample. There was a significant increase in the odds of an elevated BDI-II Total score when any of the three CAARS scales were elevated (odds ratios ranging from 11.455 to 15.615). The CAARS and BDI-II did not significantly differ with gender, age, or education level. There was no significant association between genetic mutation-predicted protein status and elevations on CAARS or BDI-II. Individuals with NPS reported co-occurring symptoms of ADHD and MDD, with higher levels of co-occurrence than reported in the literature for the general population. The co-occurrence of these symptoms may be related to mesencephalic dopaminergic neurologic pathway abnormalities that are a consequence of LMX1B loss of function.
ADHD; MDD; behavior phenotype; neurobehavior
Cornelia de Lange syndrome (CdLS) is a genetic disorder associated with delayed growth, intellectual disability, limb reduction defects and characteristic facial features. Germline mosaicism has been a described mechanism for CdLS when there are several affected offspring of apparently unaffected parents. Presently, the recurrence risk for CdLS has been estimated to be as high as 1.5%; however, this figure may be an underrepresentation. We report on the molecularly defined germline mosaicism cases from a large CdLS database, representing the first large case series on germline mosaicism in CdLS. Of the 12 families, eight have been previously described; however, four have not. No one specific gene mutation, either in the NIPBL or the SMC1A gene, was associated with an increased risk for germline mosaicism. Suspected or confirmed cases of germline mosaicism in our database range from a conservative 3.4% up to 5.4% of our total cohort. In conclusion, the potential reproductive recurrence risk due to germline mosiacism should be addressed in prenatal counseling for all families who have had a previously affected pregnancy or child with CdLS.
Cornelia de Lange syndrome; Germline Mosaicism; Germ Cell; Mosaicism; Genetic Counseling
An increase in Rab1b levels induces changes in Golgi size and in gene expression. These Rab1b-dependent changes require the activity of p38 mitogen-activated protein kinase and the cAMP-responsive element binding protein consensus binding. The results show a Rab1b increase in secretory cells after stimulation and suggest that this increase is required to elicit a secretory response.
Rab1b belongs to the Rab-GTPase family that regulates membrane trafficking and signal transduction systems able to control diverse cellular activities, including gene expression. Rab1b is essential for endoplasmic reticulum–Golgi transport. Although it is ubiquitously expressed, its mRNA levels vary among different tissues. This work aims to characterize the role of the high Rab1b levels detected in some secretory tissues. We report that, in HeLa cells, an increase in Rab1b levels induces changes in Golgi size and gene expression. Significantly, analyses applied to selected genes, KDELR3, GM130 (involved in membrane transport), and the proto-oncogene JUN, indicate that the Rab1b increase acts as a molecular switch to control the expression of these genes at the transcriptional level, resulting in changes at the protein level. These Rab1b-dependent changes require the activity of p38 mitogen-activated protein kinase and the cAMP-responsive element-binding protein consensus binding site in those target promoter regions. Moreover, our results reveal that, in a secretory thyroid cell line (FRTL5), Rab1b expression increases in response to thyroid-stimulating hormone (TSH). Additionally, changes in Rab1b expression in FRTL5 cells modify the specific TSH response. Our results show, for the first time, that changes in Rab1b levels modulate gene transcription and strongly suggest that a Rab1b increase is required to elicit a secretory response.
Human pluripotent stem cells (hPSCs) are potential sources of cells for modeling disease and development, drug discovery, and regenerative medicine. However, it is important to identify factors that may impact the utility of hPSCs for these applications. In an unbiased analysis of 205 hPSC and 130 somatic samples, we identified hPSC-specific epigenetic and transcriptional aberrations in genes subject to X chromosome inactivation (XCI) and genomic imprinting, which were not corrected during directed differentiation. We also found that specific tissue types were distinguished by unique patterns of DNA hypomethylation, which were recapitulated by DNA demethylation during in vitro directed differentiation. Our results suggest that verification of baseline epigenetic status is critical for hPSC-based disease models in which the observed phenotype depends on proper XCI or imprinting, and that tissue-specific DNA methylation patterns can be accurately modeled during directed differentiation of hPSCs, even in the presence of variations in XCI or imprinting.
This study investigated the fermentation and microbiota profiles of three fibers, wheat dextrin (WD), partially hydrolyzed guar gum (PHGG), and inulin, since little is known about the effects of WD and PHGG on gut microbiota. A treatment of salivary amylase, pepsin, and pancreatin was used to better physiologic digestion. Fibers (0.5 g) were fermented in triplicate including a control group without fiber for 0, 4, 8, 12, and 24 h. Analysis of pH, gas volume, hydrogen and methane gases, and short chain fatty acid (SCFA) concentrations were completed at each time point. Quantitative polymerase chain reaction (qPCR) was used to measure Bifidobacteria and Lactobacillus CFUs at 24 h. WD produced the least gas during fermentation at 8, 12, and 24 h (P < 0.0001), while inulin produced the most by 8 h (P < 0.0001). Each fiber reached its lowest pH value at different time points with inulin at 8 h (mean ± SE) (5.94 ± 0.03), PHGG at 12 h (5.98 ± 0.01), and WD at 24 h (6.17 ± 0.03). All fibers had higher total SCFA concentrations compared to the negative control (P < 0.05) at 24 h. At 24 h, inulin produced significantly (P = 0.0016) more butyrate than WD with PHGG being similar to both. An exploratory microbial analysis (log10 CFU/µL) showed WD had CFU for Bifidobacteria (6.12) and Lactobacillus (7.15) compared with the control (4.92 and 6.35, respectively). Rate of gas production is influenced by fiber source and may affect tolerance in vivo. Exploratory microbiota data hint at high levels of Bifidobacteria for WD, but require more robust investigation to corroborate these findings.
short-chain fatty acids; in vitro fermentation; tolerance; prebiotic; microbiota
Glioblastomas (GBM), the most common and aggressive malignant astrocytic tumors, contain a small subpopulation of cancer stem cells (GSCs) that are implicated in therapeutic resistance and tumor recurrence. Here, we study the expression and function of miR-137, a putative suppressor miRNA, in GBM and GSCs. We found that the expression of miR-137 was significantly lower in GBM and GSCs compared to normal brains and neural stem cells (NSCs) and that the miR-137 promoter was hypermethylated in the GBM specimens. The expression of miR-137 was increased in differentiated NSCs and GSCs and overexpression of miR-137 promoted the neural differentiation of both cell types. Moreover, pre-miR-137 significantly decreased the self-renewal of GSCs and the stem cell markers Oct4, Nanog, Sox2 and Shh. We identified RTVP-1 as a novel target of miR-137 in GSCs; transfection of the cells with miR-137 decreased the expression of RTVP-1 and the luciferase activity of RTVP-1 3'-UTR reporter plasmid. Furthermore, overexpression of RTVP-1 plasmid lacking its 3'-UTR abrogated the inhibitory effect of miR-137 on the self-renewal of GSCs. Silencing of RTVP-1 decreased the self-renewal of GSCs and the expression of CXCR4 and overexpression of CXCR4 abrogated the inhibitory effect of RTVP-1 silencing on GSC self-renewal. These results demonstrate that miR-137 is downregulated in GBM probably due to promoter hypermethylation. miR-137 inhibits GSC self-renewal and promotes their differentiation by targeting RTVP-1 which downregulates CXCR4. Thus, miR-137 and RTVP-1 are attractive therapeutic targets for the eradication of GSCs and for the treatment of GBM.
Glioma stem cells; self renewal; miR-137; RTVP-1; CXCR4
Miniature optical sensors that can detect blood vessels in front of advancing instruments will significantly benefit many interventional procedures. Towards this end, we developed a thin and flexible coherence-gated Doppler (CGD) fiber probe (O.D. = 0.125 mm) that can be integrated with minimally-invasive tools to provide real-time audio feedback of blood flow at precise locations in front of the probe. Coherence-gated Doppler (CGD) is a hybrid technology with features of laser Doppler flowmetry (LDF) and Doppler optical coherence tomography (DOCT). Because of its confocal optical design and coherence-gating capabilities, CGD provides higher spatial resolution than LDF. And compared to DOCT imaging systems, CGD is simpler and less costly to produce. In vivo studies of rat femoral vessels using CGD demonstrate its ability to distinguish between artery, vein and bulk movement of the surrounding soft tissue. Finally, by placing the CGD probe inside a 30-gauge needle and advancing it into the brain of an anesthetized sheep, we demonstrate that it is capable of detecting vessels in front of advancing probes during simulated stereotactic neurosurgical procedures. Using simultaneous ultrasound (US) monitoring from the surface of the brain we show that CGD can detect at-risk blood vessels up to 3 mm in front of the advancing probe. The improved spatial resolution afforded by coherence gating combined with the simplicity, minute size and robustness of the CGD probe suggest it may benefit many minimally invasive procedures and enable it to be embedded into a variety of surgical instruments.
(170.4500) Optical coherence tomography; (170.3340) Laser Doppler velocimetry; (280.1415) Biological sensing and sensors