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1.  MHC class II–dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies 
The Journal of Experimental Medicine  2013;210(13):2921-2937.
Antigen presentation, but not antibody secretion, by B cells drives CNS autoimmunity induced by immunization with human MOG.
Whether B cells serve as antigen-presenting cells (APCs) for activation of pathogenic T cells in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) is unclear. To evaluate their role as APCs, we engineered mice selectively deficient in MHC II on B cells (B–MHC II−/−), and to distinguish this function from antibody production, we created transgenic (Tg) mice that express the myelin oligodendrocyte glycoprotein (MOG)–specific B cell receptor (BCR; IgHMOG-mem) but cannot secrete antibodies. B–MHC II−/− mice were resistant to EAE induced by recombinant human MOG (rhMOG), a T cell– and B cell–dependent autoantigen, and exhibited diminished Th1 and Th17 responses, suggesting a role for B cell APC function. In comparison, selective B cell IL-6 deficiency reduced EAE susceptibility and Th17 responses alone. Administration of MOG-specific antibodies only partially restored EAE susceptibility in B–MHC II−/− mice. In the absence of antibodies, IgHMOG-mem mice, but not mice expressing a BCR of irrelevant specificity, were fully susceptible to acute rhMOG-induced EAE, also demonstrating the importance of BCR specificity. Spontaneous opticospinal EAE and meningeal follicle–like structures were observed in IgHMOG-mem mice crossed with MOG-specific TCR Tg mice. Thus, B cells provide a critical cellular function in pathogenesis of central nervous system autoimmunity independent of their humoral involvement, findings which may be relevant to B cell–targeted therapies.
PMCID: PMC3865476  PMID: 24323356
2.  Elevated blood pressure: Our family’s fault? The genetics of essential hypertension 
World Journal of Cardiology  2014;6(5):327-337.
AIM: To provide an updated review on current genetic aspects possibly affecting essential hypertension (EH), and to further elucidate their role in EH.
METHODS: We searched for genetic and epigenetic factors in major studies associated with EH between Jan 2008-Oct 2013 using PubMed. We limited our search to reviews that discussed mostly human studies, and were accessible through the university online resource. We found 11 genome wide association studies (GWAS), as well as five methylation and three miRNA studies that fit our search criteria. A distinction was not made between genes with protective effects or negative effects, as this article is only meant to be a summary of genes associated with any aspect of EH.
RESULTS: We found 130 genes from the studies that met our inclusion/exclusion criteria. Of note, genes with multiple study references include: STK39, CYP17A1, MTHFR-NPPA, MTHFR-NPPB, ATP2B1, CSK, ZNF652, UMOD, CACNB2, PLEKHA7, SH2B3, TBX3-TBX5, ULK4, CSK-ULK3, CYP1A2, NT5C2, CYP171A, PLCD3, SH2B3, ATXN2, CACNB2, PLEKHA7, SH2B3, TBX3-TBX5, ULK4, and HFE. The following genes overlapped between the genetic studies and epigenetic studies: WNK4 and BDKRB2. Several of the identified genes were found to have functions associated with EH. Many epigenetic factors were also correlated with EH. Of the epigenetic factors, there were no articles discussing siRNA and its effects on EH that met the search criteria, thus the topic was not included in this review. Among the miRNA targets found to be associated with EH, many of the genes involved were also identified in the GWAS studies.
CONCLUSION: Genetic hypertension risk algorithms could be developed in the future but may be of limited benefit due to the multi-factorial nature of EH. With emerging technologies, like next-generation sequencing, more direct causal relationships between genetic and epigenetic factors affecting EH will likely be discovered creating a tremendous potential for personalized medicine using pharmacogenomics.
PMCID: PMC4062117  PMID: 24944762
Essential hypertension; Epigenomics; Genome-wide association study; Genes; MicroRNAs
3.  Allogeneic Hematopoietic Cell Transplantation for Fanconi Anemia in Patients With Pretransplantation Cytogenetic Abnormalities, Myelodysplastic Syndrome, or Acute Leukemia 
Journal of Clinical Oncology  2013;31(13):1669-1676.
Allogeneic hematopoietic cell transplantation (HCT) can cure bone marrow failure in patients with Fanconi anemia (FA). Data on outcomes in patients with pretransplantation cytogenetic abnormalities, myelodysplastic syndrome (MDS), or acute leukemia have not been separately analyzed.
Patients and Methods
We analyzed data on 113 patients with FA with cytogenetic abnormalities (n = 54), MDS (n = 45), or acute leukemia (n = 14) who were reported to the Center for International Blood and Marrow Transplant Research from 1985 to 2007.
Neutrophil recovery occurred in 78% and 85% of patients at days 28 and 100, respectively. Day 100 cumulative incidences of acute graft-versus-host disease grades B to D and C to D were 26% (95% CI, 19% to 35%) and 12% (95% CI, 7% to 19%), respectively. Survival probabilities at 1, 3, and 5 years were 64% (95% CI, 55% to 73%), 58% (95% CI, 48% to 67%), and 55% (95% CI, 45% to 64%), respectively. In univariate analysis, younger age was associated with superior 5-year survival (≤ v > 14 years: 69% [95% CI, 57% to 80%] v 39% [95% CI, 26% to 53%], respectively; P = .001). In transplantations from HLA-matched related donors (n = 82), younger patients (≤ v > 14 years: 78% [95% CI, 64% to 90%] v 34% [95% CI, 20% to 50%], respectively; P < .001) and patients with cytogenetic abnormalities only versus MDS/acute leukemia (67% [95% CI, 52% to 81%] v 43% [95% CI, 27% to 59%], respectively; P = .03) had superior 5-year survival.
Our analysis indicates that long-term survival for patients with FA with cytogenetic abnormalities, MDS, or acute leukemia is achievable. Younger patients and recipients of HLA-matched related donor transplantations who have cytogenetic abnormalities only have the best survival.
PMCID: PMC3635221  PMID: 23547077
4.  Carbohydrates, Dietary Fiber, and Resistant Starch in White Vegetables: Links to Health Outcomes12 
Advances in Nutrition  2013;4(3):351S-355S.
Vegetables are universally promoted as healthy. Dietary Guidelines for Americans 2010 recommend that you make half of your plate fruits and vegetables. Vegetables are diverse plants that vary greatly in energy content and nutrients. Vegetables supply carbohydrates, dietary fiber, and resistant starch in the diet, all of which have been linked to positive health outcomes. Fiber lowers the incidence of cardiovascular disease and obesity. In this paper, the important role of white vegetables in the human diet is described, with a focus on the dietary fiber and resistant starch content of white vegetables. Misguided efforts to reduce consumption of white vegetables will lower intakes of dietary fiber and resistant starch, nutrients already in short supply in our diets.
PMCID: PMC3650507  PMID: 23674804
5.  White Potatoes, Human Health, and Dietary Guidance12 
Advances in Nutrition  2013;4(3):393S-401S.
The white potato is a concentrated source of carbohydrate, dietary fiber, and resistant starch and continues to be the staple food of choice for many cultures. The white potato is also a concentrated source of vitamin C and potassium. Two of the nutrients in white potatoes, dietary fiber and potassium, have been designated as nutrients of concern in the 2010 Dietary Guidelines for Americans. Potatoes are often maligned in nutrition circles because of their suspected link to obesity, and popular potato foods often contain more fat calories than carbohydrate calories. Some food guides do not include potatoes in the vegetable group because of their association with high-fat diets. However, potatoes should be included in the vegetable group because they contribute critical nutrients. All white vegetables, including white potatoes, provide nutrients needed in the diet and deserve a prominent position in food guides.
PMCID: PMC3650512  PMID: 23674809
6.  Clinical Outcomes of Patients with Desmoplastic Small Round Cell Tumor of the Peritoneum Undergoing Autologous HCT: a CIBMTR Retrospective Analysis 
Bone marrow transplantation  2012;47(11):1455-1458.
Desmoplastic small round cell tumor of the peritoneum (DSRCTP) is a rare, frequently fatal tumor. This retrospective study, based on CIBMTR registry data, describes the largest reported cohort of DSRCTP patients who have undergone autologous stem cell transplant (ASCT). The probabilities of disease-free survival (DFS) at one year for patients in complete remission (CR) and not in CR were 75% (95% confidence interval: 48–94%) and 35% (15–59%), respectively. The probability of overall survival (OS) at three years was 57% (29–83%) and 28% (9–51%) for patients in CR and not in CR respectively. Median survival for the entire cohort was 31 months (36 months and 21 months for those in CR and not in CR respectively). Engraftment at 42 days was 97% (88–100%). Treatment-related mortality was low, with only one death in the first 100 days. ASCT is a tolerable approach in patients with DSRCTP, with the greatest benefit seen in those patients who obtain CR. For those not in CR, the median OS in this series is greater than previously reported (21 months versus 17 months), suggesting ASCT is useful in prolonging DFS and OS, even in patients with residual or persistent disease pre transplant.
PMCID: PMC3951901  PMID: 22465977
Autologous; Transplant; Outcomes; Desmoplastic; Tumor
7.  Relationship between Trough Plasma and Epithelial Lining Fluid Concentrations of Voriconazole in Lung Transplant Recipients 
Trough (predose) voriconazole concentrations in plasma and pulmonary epithelial lining fluid (ELF) of lung transplant recipients receiving oral voriconazole preemptive treatment were determined. The mean (± standard deviation [SD]) ELF/plasma ratio was 12.5 ± 6.3. A strong positive linear relationship was noted between trough plasma and ELF voriconazole concentrations (r2 = 0.87), suggesting the feasibility of using trough plasma voriconazole concentration as a surrogate to estimate the corresponding concentration in ELF of lung transplant recipients.
PMCID: PMC3754345  PMID: 23817382
8.  The positive outlook study- a randomised controlled trial evaluating the effectiveness of an online self-management program targeting psychosocial issues for men living with HIV: a study protocol 
BMC Public Health  2014;14:106.
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.
Trial registration
PMCID: PMC3915621  PMID: 24491034
HIV; Self-Management; Online Intervention; Quality of Life
9.  The Spinal Cord Injury- Functional Index: Item Banks to Measure Physical Functioning of Individuals with Spinal Cord Injury 
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.
PMCID: PMC3910090  PMID: 22609299
Spinal Cord Injuries; Mobility Limitations; Outcome Assessment (Health Care); Activities of Daily Living; Psychometrics; Walking; Self Care; Quality of Life
11.  Sensitivity to external signals and synchronization properties of a non-isochronous auto-oscillator with delayed feedback 
Scientific Reports  2014;4:3873.
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.
PMCID: PMC3902486  PMID: 24464086
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.
PMCID: PMC3894923  PMID: 22155506
13.  Correction: Grey Matter Correlates of Three Language Tests in Non-demented Older Adults 
PLoS ONE  2014;9(1):10.1371/annotation/2e4d150f-c396-4867-b170-e43ccff9fcd7.
PMCID: PMC3897312
19.  Role of Cranial and Spinal Virtual and Augmented Reality Simulation Using Immersive Touch Modules in Neurosurgical Training 
Neurosurgery  2013;72(0 1):115-123.
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.
PMCID: PMC3676942  PMID: 23254799
Virtual reality; Surgical Simulation; Neurosurgical training; Ventriculostomy; spinal instrumentation
20.  Grey Matter Correlates of Three Language Tests in Non-demented Older Adults 
PLoS ONE  2013;8(11):e80215.
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.
PMCID: PMC3818244  PMID: 24224044
21.  Clinical Presentation and Positive Outcome of Two Siblings with Holocarboxylase Synthetase Deficiency Caused by a Homozygous L216R Mutation 
JIMD Reports  2013;12:109-114.
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.
PMCID: PMC3897791  PMID: 24085707
22.  Cognitive screening improves the predictive value of stroke severity scores for functional outcome 3–6 months after mild stroke and transient ischaemic attack: an observational study 
BMJ Open  2013;3(9):e003105.
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.
PMCID: PMC3773644  PMID: 24002980
24.  Outcome of Lower-Intensity Allogeneic Transplantation in non-Hodgkin Lymphoma After Autologous Transplant Failure 
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.
PMCID: PMC3376237  PMID: 22198543
Non-Hodgkin Lymphoma; Allogeneic; Relapse
25.  Complementary and alternative medicine (CAM) use in women with pelvic floor disorders: a cohort study 
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.
PMCID: PMC3729340  PMID: 19967336
Complementary alternative medicine; Fecal incontinence; Pelvic floor disorders; Pelvic organ prolapse; Urinary incontinence

Results 1-25 (275)