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3.  Galactorrhea associated with juvenile systemic lupus erythematosus: a review of the role of prolactin 
This case report is based on the clinical observation of a patient with juvenile systemic lupus erythematosus (SLE) who developed transient galactorrhea. The subsequent literature review documented an interesting association between prolactin and rheumatic diseases and in particular, hyperprolactinemia and SLE. The discussion that follows the case report explores this relationship and proposes a hypothesis regarding why this patient with juvenile SLE developed galactorrhea.
doi:10.1186/1546-0096-7-17
PMCID: PMC2770548  PMID: 19852783
4.  Inflammatory arthritis in children with osteochondrodysplasias 
Annals of the Rheumatic Diseases  2000;59(11):864-869.
Osteochondrodysplasias are a heterogeneous group of genetic skeletal dysplasias. Patients with these diseases commonly develop an early degenerative arthritis or osteoarthritis. Occasional observations of inflammatory arthritis have been made in this population but such observations are based on clinical grounds alone without confirmatory imaging studies. Four patients followed up in a paediatric rheumatology clinic with three different skeletal dysplasias, who had both clinical and radiological evidence of an inflammatory arthritis and coexistent degenerative arthritis, are described.


doi:10.1136/ard.59.11.864
PMCID: PMC1753032  PMID: 11053062
7.  The neuroanatomy of pure apraxia of speech in stroke 
Brain and language  2014;129:43-46.
The left insula or Broca’s area have been proposed as the neuroanatomical correlate for apraxia of speech (AOS) based on studies of patients with both AOS and aphasia due to stroke. Studies of neurodegenerative AOS suggest the premotor area and the supplementary motor areas as the anatomical correlates. The study objective was to determine the common infarction area in patients with pure AOS due to stroke. Patients with AOS and no or equivocal aphasia due to ischemic stroke were identified through a pre-existing database. Seven subjects were identified. Five had pure AOS, and two had equivocal aphasia. MRI lesion analysis revealed maximal overlap spanning the left premotor and motor cortices. While both neurodegenerative AOS and stroke induced pure AOS involve the premotor cortex, further studies are needed to establish whether stroke-induced AOS and neurodegenerative AOS share a common anatomic substrate.
doi:10.1016/j.bandl.2014.01.004
PMCID: PMC4004427  PMID: 24556336
Apraxia of speech; stroke; aphemia; premotor cortex
8.  The effects of the Omagh bomb on adolescent mental health: a school-based study 
BMC Psychiatry  2015;15:18.
Background
The main objective of this study was to assess psychiatric morbidity among adolescents following the Omagh car bombing in Northern Ireland in 1998.
Methods
Data was collected within schools from adolescents aged between 14 and 18 years via a self-completion booklet comprised of established predictors of PTSD; type of exposure, initial emotional response, long-term adverse physical problems, predictors derived from Ehlers and Clark’s (2000) cognitive model, a PTSD symptoms measure (PDS) and the General Health Questionnaire (GHQ).
Results
Those with more direct physical exposure were significantly more likely to meet caseness on the GHQ and the PDS. The combined pre and peri trauma risk factors highlighted in previous meta-analyses accounted for 20% of the variance in PDS scores but the amount of variance accounted for increased to 56% when the variables highlighted in Ehlers and Clark’s cognitive model for PTSD were added.
Conclusions
High rates of chronic PTSD were observed in adolescents exposed to the bombing. Whilst increased exposure was associated with increased psychiatric morbidity, the best predictors of PTSD were specific aspects of the trauma (‘seeing someone you think is dying’), what you are thinking during the event (‘think you are going to die’) and the cognitive mechanisms employed after the trauma. As these variables are in principle amenable to treatment the results have implications for teams planning treatment interventions after future traumas.
doi:10.1186/s12888-015-0398-9
PMCID: PMC4329658
PTSD; Bombing; Cognitive models; Adolescents; School survey
9.  Evaluation and costs of volunteer telephone cessation follow-up counseling for Veteran smokers discharged from inpatient units: a quasi-experimental, mixed methods study 
Tobacco Induced Diseases  2015;13(1):4.
Background
The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to evaluate the volunteer telephone smoking cessation counseling follow-up program implemented as part of the inpatient Tobacco Tactics intervention in a Veterans Affairs (VA) hospital.
Methods
This was a quasi-experimental, mixed methods design that collected data through electronic medical records (EMR), observations of telephone smoking cessation counseling calls, interviews with staff and Veterans involved in the program, and intervention costs.
Results
Reach: Of the 131 Veterans referred to the smoking cessation telephone follow-up program, 19% were reached 0–1 times, while 81% were reached 2–4 times. Effectiveness: Seven-day point-prevalence 60-day quit rates (abstracted from the EMR) for those who were reached 2–4 times were 26%, compared to 8% among those who were reached 0–1 times (p = 0.06). Sixty-day 24-hour point-prevalence quit rates were 33% for those reached 2–4 times, compared to 4% of those reached 0–1 times (p < 0.01). Adoption and Implementation: The volunteers correctly followed protocol and were enthusiastic about performing the calls. Veterans who were interviewed reported positive comments about the calls. The cost to the hospital was $21 per participating Veteran, and the cost per quit was $92. Maintenance: There was short-term maintenance (about 1 year), but the program was not sustainable long term.
Conclusions
Quit rates were higher among those Veterans that had greater participation in the calls. Joint Commission standards for inpatient smoking with follow-up calls are voluntary, but should these standards become mandatory, there may be more motivation for VA administration to institute a hospital-based, volunteer telephone smoking cessation follow-up program.
Trial registration
ClinicalTrials.Gov NCT01359371.
doi:10.1186/s12971-015-0028-9
PMCID: PMC4324430
Tobacco cessation; Smoking cessation; Peer support; Telephone calls; Veterans
10.  The CLRX.1/NOD24 (NLRP2P) Pseudogene Codes a Functional Negative Regulator of NF-κB, Pyrin-only Protein 4 (POP4) 
Genes and immunity  2014;15(6):392-403.
Pseudogenes are duplicated yet defunct copies of functional parent genes. However, some pseudogenes have gained or retained function. In this study we consider a functional role for the NLRP2-related, higher primate specific, processed pseudogene NLRP2P, which is closely related to Pyrin-only protein 2 (POP2/PYDC2), a regulator of NF-κB and the inflammasome. The NLRP2P open reading frame on chromosome X has features consistent with a processed pseudogene (retrotransposon), yet encodes a 45 amino acid, Pyrin-domain related protein. The open reading frame of NLRP2P shares 80% identity with POP2 and is under purifying selection across Old World primates. Although widely expressed, NLRP2P mRNA is upregulated by LPS in human monocytic cells. Functionally, NLRP2P impairs NF-κB p65 transactivation by reducing activating phosphorylation of RelA/p65. Reminiscent of POP2, NLRP2P reduces production of the NF-κB-dependent cytokines TNFα and IL-6 following TLR stimulation. In contrast to POP2, NLRP2P fails to inhibit the ASC-dependent NLRP3 inflammasome. In addition, beyond regulating cytokine production, NLRP2P has a potential role in cell cycle regulation and cell death. Collectively, our findings suggest that NLRP2P is a resurrected processed pseudogene that regulates NF-κB RelA/p65 activity and thus represents the newest member of the POP family, POP4.
doi:10.1038/gene.2014.30
PMCID: PMC4311403  PMID: 24871464
Pyrin domain; pseudogene; NF-κB; NLR; inflammasome; inflammation
11.  Risk factors for behavioral abnormalities in mild cognitive impairment and mild Alzheimer's disease 
Background
Behavioral symptoms are common in both MCI and AD.
Methods
We analyzed the Neuropsychiatric Inventory Questionnaire data of 3456 MCI and 2641 mild AD NACC participants. Using factor analysis and logistic regression we estimated the effects of age, sex, race, education, MMSE, functional impairment, marital status and family history on presence of behavioral symptoms. We also compared the observed prevalence of behavioral symptoms between amnestic and nonamnestic MCI.
Results
Four factors were identified: affective behaviors (depression, apathy and anxiety); distress/tension behaviors (irritability and agitation); impulse control behaviors (disinhibition, elation and aberrant motor behavior), and psychotic behaviors (delusions and hallucinations). Male gender was significantly associated with all factors. Younger age was associated with higher prevalence of distress/tension, impulse control and psychotic behaviors. Being married was protective against psychotic behaviors. Lower education was associated with the presence of distress/tension behaviors. Caucasians showed higher prevalence of affective behaviors. Functional impairment was strongly associated with all behavioral abnormalities. Amnestic MCI had more elation and agitation relative to nonamnestic MCI.
Conclusions
Younger age, male gender and greater functional impairment were associated with higher overall presence of behavioral abnormalities in MCI and mild AD. Marital status, lower education and race had effect on selected behaviors.
doi:10.1159/000351009
PMCID: PMC4057985  PMID: 24481207
neuropsychiatric symptoms; behavior; MCI; mild cognitive impairment; Alzheimer's disease; AD
12.  A pilot phase II Study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA 
Background
Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression.
Methods
An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3–24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 – 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT ≥ 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.
Results
Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT ≥ 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients.
Conclusions
Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer.
PMCID: PMC4287984  PMID: 25580468
digoxin; prostate cancer; prostate specific antigen; PSA doubling time; HIF-1; VEGF
13.  Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease 
Neurology  2014;83(2):142-150.
Objective:
To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS.
Methods:
Multicenter retrospective study.
Results:
A total of 144 children and adolescents (median age 8 years, range 0.7–17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05–9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1–8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0–2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0–2 was greater in patients given rituximab early in their disease course compared to those treated later.
Conclusion:
While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality.
Classification of evidence:
This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.
doi:10.1212/WNL.0000000000000570
PMCID: PMC4117174  PMID: 24920861
14.  The influence of gender on functional outcomes of lower extremity bypass 
Journal of vascular surgery  2014;60(5):1282-1290.e1.
Objective
Our aim was to evaluate the effect of gender on early and late procedural and functional outcomes of lower extremity bypass (LEB).
Methods
We reviewed the records of 2576 patients (828 women; 32%) who underwent LEB for claudication or critical limb ischemia (CLI) in the Vascular Study Group of New England from 2003 to 2010. Logistic regression and proportional hazards models were used to adjust for potential confounding differences between genders. Morbidity, mortality, graft patency, freedom from major amputation, ambulation, and living status were analyzed postoperatively and over 1 year.
Results
Women were older (70 vs 68 years; P < .001), had more hypertension (89% vs 85%; P = .006), less coronary artery disease (35% vs 39%; P = .03), smoking (73% vs 88%; P < .001), and preoperative statin use (60% vs 64%; P = .04). Women were more likely to have CLI (76% vs 71%; P = .003), and ambulate with assistance at presentation (19% vs 16%; P = .02). Morbidity was similar except women had higher rates of reoperation for thrombosis (4% vs 2%; P < .001) without differences in major amputation (2% vs 1%; P = .13) or in-hospital mortality (1.7% vs 1.7%; P = .96). Women and men with claudication had similar 1-year graft patency rates. Women with CLI had lower rates of primary (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03–1.48; P = .02), assisted primary (HR, 1.42; 95% CI, 1.15–1.76; P = .001) and secondary patency (HR, 1.40; 95% CI, 1.10–1.77; P = .006) during the first year compared with men. Freedom from amputation was similar for men and women with CLI (HR, 1.17; 95% CI, 0.84–1.63; P = .36). There were no differences in late survival between women and men with claudication (HR, 0.89; 95% CI, 0.60–1.31; P = .36) or CLI (HR, 0.94; 95% CI, 0.81–1.09; P = .39). More female claudicants were not independently ambulatory at discharge (30% vs 19%; P = .002) and were discharged to a nursing home (15% vs 5%; P < .001) but these differences did not persist at 1 year. Women with CLI were more likely to be nonambulatory at discharge (13% vs 9%; P = .006) and at 1 year (13% vs 8%; P < .001). More women with CLI were discharged to a nursing home (44% vs 35%; P = .01) and resided there at 1 year (11% vs 7%; P = .02).
Conclusions
Women have complication rates similar to men with inferior early and late functional outcomes after LEB. The reduced patency rates in women with CLI did not translate into differences in limb salvage. These findings might help define physician and patient expectations for women before revascularization.
doi:10.1016/j.jvs.2014.05.008
PMCID: PMC4283108  PMID: 25242270
16.  The association between occupational exposures and cigarette smoking among operating engineers 
Archives of environmental & occupational health  2014;69(3):10.1080/19338244.2013.763760.
The purpose of this study was to determine the relationship between occupational exposures and cigarette smoking among operating engineers. A cross-sectional survey was conducted with operating engineers (N=412) from a mid-western state in the United States. The survey included validated questions on cigarette smoking, occupational exposures, demographics, comorbidities, and health behaviors.
About 35% were current smokers. Those exposed to asphalt fumes, heat stress, concrete dust, and welding fumes were less likely to smoke (OR=.79; 95CI: .64–.98). Other factors associated with smoking included younger age (OR=.97; 95CI:.94–.99), problem drinking (OR=1.07; 95CI:1.03–1.12), lower Body Mass Index (OR=.95; 95CI:.90–.99), and being separated/ widowed/ divorced (OR=2.24; 95CI:1.19–4.20). Further investigation is needed for better understanding about job specific exposure patterns and their impact on cigarette smoking among operating engineers.
doi:10.1080/19338244.2013.763760
PMCID: PMC3863785  PMID: 24325748
Smoking; Occupational exposure; Blue-collar workers; Operating engineers
17.  Lysine Acetylation in Sexual Stage Malaria Parasites Is a Target for Antimalarial Small Molecules 
Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.
doi:10.1128/AAC.02721-13
PMCID: PMC4068603  PMID: 24733477
18.  Microbleeds in the logopenic variant of primary progressive aphasia 
Background
Microbleeds have been associated with Alzheimer’s disease (AD), although it is unclear whether they occur in atypical presentations of AD, such as the logopenic variant of primary progressive aphasia (lvPPA). We aimed to assess the presence and clinical correlates of microbleeds in lvPPA.
Methods
Thirteen lvPPA subjects underwent 3T T2*-weighted and fluid-attenuated inversion recovery MRI and Pittsburgh Compound B (PiB) PET imaging. Microbleeds were identified on manual review and assigned a regional location. Total and regional white matter hyperintensity (WMH) burden was measured.
Results
Microbleeds were observed in four lvPPA subjects (31%); most common in frontal lobe. Subjects with microbleeds were older, more likely female, and had a greater burden of WMH than those without microbleeds. The regional distribution of microbleeds did not match the regional distribution of WMH. All cases were PiB-positive.
Conclusions
Microbleeds occur in approximately 1/3 subjects with lvPPA, with older women at the highest risk.
doi:10.1016/j.jalz.2013.01.006
PMCID: PMC3706560  PMID: 23562427
Logopenic variant of primary progressive aphasia; Alzheimer’s disease; microbleeds; white matter hyperintensities
19.  Immunological off-target effects of standard treatments in gastrointestinal cancers 
Annals of Oncology  2013;25(1):24-32.
The effects on immune cells of standard cancer treatments (chemotherapeutic or biologic agents, interventional radiologic procedures) have become better appreciated. Likewise the contribution of the immune system towards the effectiveness of these treatments. This knowledge can potentially lead to novel applications of existing standard of care therapies in addition to potentiating their effect.
The effects on immune cells and the inflammatory microenvironment of commonly applied cancer treatments (chemotherapeutic or biologic agents, interventional radiologic procedures) have become better appreciated. Likewise, the contribution of the immune system toward the effectiveness of these treatments is clearer. The relevance of immune evasion by developing tumors is endorsed by its inclusion as one of the (updated) hallmarks of cancer. A greater understanding of this dimension can potentially lead to novel applications of existing standard of care therapies, in addition to potentiating their effect. This review summarizes the immune aspects of currently employed therapies—cytotoxic chemotherapeutics, biologic agents and interventional radiologic procedures—in solid tumor malignancies with a particular focus on those agents used in gastrointestinal cancers.
doi:10.1093/annonc/mdt349
PMCID: PMC3868318  PMID: 24201974
pancreatic; immune; myeloid-derived suppressor cells; colorectal; CTLA4
20.  Voxel Based Dipole Orientation Constraints for Distributed Current Estimation 
Distributed electroencephalography (EEG) source localization is a highly ill-posed problem. With measurements on the order of 102, and unknowns in the range of 104 – 105, the range of feasible solutions is quite large. One approach to reducing ill-posedness is to intelligently reduce the number of unknowns. Restricting solutions to grey matter is one approach. A further step is to use the anatomy of each patient to identify and constrain the orientation of the dipole within each voxel.
While dipole orientation constraints for cortical patch based approaches have been proposed, to our knowledge no solutions for full volumetric localizations have been presented. Patch techniques account for patch surface area, but place dipoles only on the surface, rather than throughout the cortex. Variability in human cortical thickness means that thicker regions of cortex will potentially contribute more to the EEG signal, and should be accounted for in modeling. Additionally, patch models require cortical surface identification techniques, which can separate them from the extensive literature on voxel based MR image processing, and require additional adaptation to incorporate more complex information.
We present a volumetric approach for computing voxel based distributed estimates of cortical activity with constrained dipole orientations. Using a tissue thickness estimation approach, we obtain estimates of the cortical surface normal at each voxel. These let us constrain the inverse problem, and yield localizations with reduced spatial blurring and better identification of signal magnitude within the cortex. This is demonstrated for a series of simulated and experimental data using patient-specific bioelectric models.
doi:10.1109/TBME.2014.2312713
PMCID: PMC4203378  PMID: 24951674
21.  Factors Associated with Smokeless Tobacco Use and Dual Use Among Blue Collar Workers 
Objectives
To examine demographic and substance use factors associated with exclusive smokeless tobacco use (SLT) and dual use of both cigarettes and SLT among blue-collar workers.
Design, Sample and Measurements
This cross-sectional study used data from the U.S. 2009 National Survey on Drug Use and Health. The sample (n=5,392) was restricted to respondents who were classified as blue collar workers by self-report primary job title.
Results
Respondents in this blue collar sample were 87% male and 64% Non-Hispanic White. An estimated 9.5% (SE=0.6) of respondents were current SLT users; 5.3% (SE=0.4) were current exclusive SLT users, and 4.2% (SE=0.4) were current dual users of both SLT and cigarettes. Factors related to exclusive SLT use were gender, marital status, age, race/ethnicity, type of blue-collar occupation, current binge drinking, and current marijuana use. Significant factors related to dual use were gender, marital status, age, race/ethnicity, type of blue-collar occupation, current cigar smoking, current binge drinking, and current illicit drug use.
Conclusions
Rates of SLT use and dual use are high among U.S. blue-collar workers, indicating a need for targeted, workplace cessation interventions. These interventions may also serve as a gateway for addressing other substance use behaviors in this population.
doi:10.1111/phn.12095
PMCID: PMC4221847  PMID: 24266896
smokeless; tobacco; smoking; blue collar workers; substance use
22.  Neither the HIV Protease Inhibitor Lopinavir-Ritonavir nor the Antimicrobial Trimethoprim-Sulfamethoxazole Prevent Malaria Relapse in Plasmodium cynomolgi-Infected Non-Human Primates 
PLoS ONE  2014;9(12):e115506.
Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.
doi:10.1371/journal.pone.0115506
PMCID: PMC4277318  PMID: 25541998
23.  Hepatocellular carcinoma from an immunological perspective 
Hepatocellular carcinoma is the 3rd most common cancer worldwide. It is an inflammation-associated cancer. Multiple investigators have demonstrated that analysis of the tumor microenvironment may be used to predict patient outcome indicating the importance of local immune responses in this disease. In contrast to other types of cancer, in which surgery, radiation and systemic cytotoxic chemotherapies dominate the treatment options, in HCC loco-regional treatments are widely applied. Such treatments induce rapid tumor cell death and anti-tumor immune responses, which may favor or impair patients’ outcome. Recent immunotherapy studies demonstrating promising results include trials evaluating intra-tumoral injection of an oncolytic virus expressing GM-CSF, glypican-3 targeting treatments and anti-CTLA4 treatment. While some of these novel approaches may provide benefit as single agents, there is a clear opportunity in HCC to evaluate these in combination with the standard modalities to more effectively harness the immune response.
doi:10.1158/1078-0432.CCR-13-1721
PMCID: PMC3867536  PMID: 24030702
Cancer vaccines; glypican 3; antibody treatment; vaccinia; oncolytic virus
24.  Centromedian-Parafascicular Deep Brain Stimulation Induces Differential Functional Inhibition of the Motor, Associative, and Limbic Circuits in Large Animals 
Biological psychiatry  2013;74(12):917-926.
Background
Deep brain stimulation (DBS) of the centromedian-parafascicular (CM-Pf) thalamic nuclei has been considered an option for treating Tourette syndrome (TS). Using a large animal DBS model, this study was designed to explore the network effects of CM-Pf DBS.
Methods
The combination of DBS and functional MRI (fMRI) is a powerful means of tracing brain circuitry and testing the modulatory effects of electrical stimulation on a neuronal network in vivo. Using a with-in subjects design, we tested the proportional effects of CM and Pf DBS by manipulating current spread and varying stimulation contacts in healthy pigs (n=5).
Results
Our results suggests that CM-Pf DBS has an inhibitory modulating effect in areas that have been suggested as contributing to impaired sensory-motor and emotional processing. The results also help to define the differential neural circuitry effects of the CM and Pf with evidence of prominent sensorimotor/associative effects for CM DBS and prominent limbic/associative effects for Pf DBS.
Conclusions
Our results support the notion that stimulation of deep brain structures, such as the CM-Pf, modulates multiple networks with cortical effects. The networks affected by CM-Pf stimulation in this study reinforce the conceptualization of TS as a condition with psychiatric and motor symptoms and of CM-Pf DBS as a potentially effective tool for treating both types of symptoms.
doi:10.1016/j.biopsych.2013.06.024
PMCID: PMC3910443  PMID: 23993641
Deep brain stimulation (DBS); Tourette syndrome; centromedian; parafascicular; functional magnetic resonance imaging (fMRI); swine model; neural circuitry
25.  An ongoing case–control study to evaluate the NHS Bowel Cancer Screening Programme 
BMC Cancer  2014;14:945.
Background
Colorectal cancer is the third most common cause of cancer death in both males and females in England. A national bowel cancer screening programme was rolled out in England between 2006 and 2010. In the post-randomised controlled trials epoch, assessment of the impact of the programme using observational studies is needed.
This study protocol was set up at the request of the UK Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis to evaluate the effect of the current bowel cancer screening programme on incidence of advanced primary colorectal cancer.
Methods/Design
All incident cases of primary colorectal cancer in England will be included. Cases will be matched to controls with respect to sex, age, area of registration and year of first invitation to screening. Each evaluation round will cover a 2-year period, starting from January 2012, and ongoing thereafter. In the first instance, a pilot will be carried out in a single region. Variables related to colorectal tumour pathology will be obtained to enable selection and matching of cases and controls, and to allow analyses stratification by anatomical subsite within the bowel. Cases at Duke’s stage B or worse will be considered as "advanced stage". The influence of sex will also be investigated. The incidence ratio observed in randomised controlled trials between controls (not invited) and non-attender invitees will be used to correct for self-selection bias overall. Screening participation at other national screening programmes (cervical, breast) will also be collected to derive a more contemporaneous adjustment factor for self-selection bias and assess consistency in self-selection correction in female patients.
Full ethical approval was obtained from the Health Research Authority.
Discussion
The case–control design is potentially prone to a number of biases. The size of the planned study, the design specifications and the development of analytical strategies to cope with bias should enable us to obtain accurate estimates of reduction in incidence of advanced stage disease. The results of analyses by sex and anatomical subsite may highlight the potential need for sex-specific recommendations in the programme.
doi:10.1186/1471-2407-14-945
PMCID: PMC4320602  PMID: 25495609
Bowel cancer; Screening; Case–control; Incidence; Advanced stage

Results 1-25 (1046)