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author:("kohlman, A")
1.  Nocturnal blood pressure fall as predictor of diabetic nephropathy in hypertensive patients with type 2 diabetes 
Hypertensive patients with reduced blood pressure fall (BPF) at night are at higher risk of cardiovascular events (CVE).
We evaluated in hypertensive diabetic patients, if a reduced nocturnal BPF can precedes the development of diabetic nephropathy (DN). We followed 70 patients with normal urinary albumin excretion (UAE) for two years. We performed 24-hours ambulatory BP monitoring in baseline and at the end of the study.
Fourteen (20%) patients (GI) developed DN (N = 11) and/or CVE (n = 4). Compared to the remaining 56 patients (GII) in baseline, GI had similar diurnal systolic (SBP) and diastolic BP (DBP), but higher nocturnal SBP (138 ± 15 vs 129 ± 16 mmHg; p < 0.05) and DBP (83 ± 12 vs 75 ± 11 mmHg; p < 0,05). Basal nocturnal SBP correlated with occurrence of DN and CVE (R = 0.26; P < 0.05) and with UAE at the end of the study (r = 0.3; p < 0.05). Basal BPF (%) correlated with final UAE (r = -0.31; p < 0.05). In patients who developed DN, reductions occurred in nocturnal systolic BPF (12 ± 5 vs 3 ± 6%, p < 0,01) and diastolic BPF (15 ± 8 vs 4 ± 10%, p < 0,01) while no changes were observed in diurnal SBP (153 ± 17 vs 156 ± 16 mmHg, NS) and DBP (91 ± 9 vs 90 ± 7 mmHg, NS). Patients with final UAE < 20 μg/min, had no changes in nocturnal and diurnal BP.
Our results suggests that elevations in nocturnal BP precedes DN and increases the risk to develop CVE in hypertensive patients with T2DM.
PMCID: PMC2928765  PMID: 20704750
2.  Small Macrocycles As Highly Active Integrin α2β1 Antagonists 
ACS Medicinal Chemistry Letters  2014;5(2):193-198.
Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14–18-membered macrocycles turned out to be highly active toward integrin α2β1 with IC50s in the low nanomolar range. The conformation of the macrocycles was found to be highly important for the activity, and an X-ray crystal structure was obtained to clarify this. Subsequent docking into the metal-ion-dependent adhesion site (MIDAS) of a β1 unit revealed a binding model indicating key binding features. Macrocycle 38 was selected for further in vitro and in vivo profiling.
PMCID: PMC4027761  PMID: 24900800
Integrin; macrocycle; platelet collagen receptor; metathesis; restricted conformation
3.  End-organ protection in hypertension by the novel and selective Rho-kinase inhibitor, SAR407899 
World Journal of Cardiology  2015;7(1):31-42.
AIM: To compare the therapeutic efficacy of SAR407899 with the current standard treatment for hypertension [an angiotensin converting enzyme (ACE)-inhibitor and a calcium channel blocker] and compare the frequency and severity of the hypertension-related end-organ damage.
METHODS: Long-term pharmacological characte-rization of SAR407899 has been performed in two animal models of hypertension, of which one is sensitive to ACE-inhibition (LNAME) and the other is insensitive [deoxycorticosterone acetate (DOCA)]. SAR407899 efficiently lowered high blood pressure and significantly reduced late-stage end organ damage as indicated by improved heart, kidney and endothelial function and reduced heart and kidney fibrosis in both models of chronic hypertension.
RESULTS: Long term treatment with SAR407899 has been well tolerated and dose-dependently reduced elevated blood pressure in both models with no signs of tachyphylaxia. Blood pressure lowering effects and protective effects on hypertension related end organ damage of SAR407899 were superior to ramipril and amlodipine in the DOCA rat. Typical end-organ damage was significantly reduced in the SAR407899-treated animals. Chronic administration of SAR407899 significantly reduced albuminuria in both models. The beneficial effect of SAR407899 was associated with a reduction in leukocyte/macrophage tissue infiltration. The overall protective effect of SAR407899 was superior or comparable to that of ACE-inhibition or calcium channel blockade. Chronic application of SAR407899 protects against hypertension and hypertension-induced end organ damage, regardless of the pathophysiological mechanism of hypertension.
CONCLUSION: Rho-kinases-inhibition by the SAR407899 represents a new therapeutic option for the treatment of hypertension and its complications.
PMCID: PMC4306204  PMID: 25632317
Hypertension; End organ damage; Rho-kinase; Angiotensin converting enzyme-inhibition
4.  Interest and Informational Preferences Regarding Genomic Testing for Modest Increases in Colorectal Cancer Risk 
Public health genomics  2014;17(1):48-60.
To explore interest in genomic testing for modest changes in colorectal cancer risk and preferences for receiving genomic risk communications among individuals with intermediate disease risk due to a family history of colorectal cancer.
Surveys were conducted on 278 men and women at intermediate risk for colorectal cancer enrolled in a randomized trial comparing a remote personalized risk communication intervention (TeleCARE) aimed at promoting colonoscopy to a generic print control condition. Guided by Leventhal’s Common Sense Model of Self-regulation, we examined demographic and psychosocial factors possibly associated with interest in SNP testing. Descriptive statistics and logistic regression models were used to identify factors associated with testing interest and preferences for receiving genomic risk communications.
Three-fourths of participants expressed interest in SNP testing for colorectal cancer risk. Testing interest did not markedly change across behavior modifier scenarios. Participants preferred to receive genomic risk communications from a variety of sources: printed materials, (69.1%), oncologists (59.5%), primary-care physicians (58.1%), and the web (57.9%). Overall, persons who were unmarried (p=0.029), younger (p=0.003), and with greater cancer-related fear (p=0.019) were more likely to express interest in predictive genomic testing for colorectal cancer risk. In a stratified analysis, cancer related fear was associated with interest in predictive genomic testing in the intervention group (p=0.017) but not the control group.
Individuals with intermediate familial risk for colorectal cancer are highly interested in genomic testing for modest increases in disease risk, specifically unmarried persons, younger age groups, and those with greater cancer fear.
PMCID: PMC3992284  PMID: 24435063
SNP (single nucleotide polymorphism); genomic; colorectal cancer; behavior change; cancer risk; first-degree relatives; direct-to-consumer
5.  Hare-to-Human Transmission of Francisella tularensis subsp. holarctica, Germany 
Emerging Infectious Diseases  2015;21(1):153-155.
In November 2012, a group of 7 persons who participated in a hare hunt in North Rhine-Westphalia, Germany, acquired tularemia. Two F. tularensis subsp. holarctica isolates were cultivated from human and hare biopsy material. Both isolates belonged to the FTN002–00 genetic subclade (derived for single nucleotide polymorphisms B.10 and B.18), thus indicating likely hare-to-human transmission.
PMCID: PMC4285259  PMID: 25531286
Tularemia; Francisella; Francisella tularensis subsp. holarctica; hare; European brown hare; Lepus europaeus; zoonoses; North Rhine-Westphalia; Germany
6.  Serrated polyposis: Colonic phenotype, extra-colonic features and familial risk in a large cohort 
Diseases of the colon and rectum  2013;56(11):10.1097/DCR.0b013e3182a11cca.
Serrated polyposis is a poorly understood and likely under-diagnosed condition. Little is known regarding the colorectal cancer risk, extra-colonic phenotype, and etiology of serrated polyposis.
The aim of this study is to describe the clinical and family history features of a large cohort of individuals with serrated polyposis.
This is a retrospective cohort study from two prospectively collected registries.
Patients meeting the updated 2010 World Health Organization criteria for serrated polyposis.
We report descriptive statistics for clinical and family history factors.
A total of 52 individuals met criteria for serrated polyposis. Of these, one had Lynch syndrome and was not included in the statistical analyses. Median age at serrated polyposis diagnosis was 51 years (range 18–77). Twenty four (47%) were male and 25 (49%) had a history of smoking. Two-hundred sixty-eight lower endoscopic procedures were performed; 42 (82%) had colorectal adenomas, 8 (16%) had a personal history of colorectal cancer (only one was diagnosed during follow-up), 12 (24%) had extra-colonic tumors (4 had more than one primary tumor), and 19 (37%) reported a family history of colorectal cancer. Esophagogastroduodenoscopy in 30 individuals revealed only one (3%) with unexplained gastroduodenal polyps. No association was found between colorectal cancer diagnosis and sex, age at serrated polyposis diagnosis, extra-colonic tumor, history of adenoma, or smoking status.
This was a retrospective study with no comparison groups.
Gastroduodenal polyps are uncommon and likely not associated with serrated polyposis. Although extra-colonic tumors were common in our cohort, it is still unclear whether these are associated with serrated polyposis. Our data, along with previous studies, support an association between serrated polyposis and smoking. Further work is still needed to clarify the effect of smoking on polyp development/progression in serrated polyposis.
PMCID: PMC3832143  PMID: 24104994
Serrated polyposis; hyperplastic polyposis; sessile serrated adenoma; colon polyps; colorectal cancer
7.  Melanoma genetic counseling and test reporting improve screening adherence among unaffected carriers 2 years later 
A major goal of predictive genetic testing for melanoma is to promote early detection to reduce mortality. This study evaluated the long-term impact of melanoma genetic test reporting and counseling on screening adherence.
This study assessed adherence to recommendations for annual total body skin examinations (TBSEs) and monthly skin self-examinations (SSEs) among 37 members of Utah CDKN2A/p16 kindreds (10 unaffected carriers, 11 affected carriers, 16 unaffected noncarriers; response rate=64.9% of eligible participants).
Two years following test reporting, adherence to annual TBSE among unaffected carriers increased from 40% to 70%. However, unaffected noncarriers’ adherence decreased from 56% to 13%. Affected carriers reported TBSEs at both assessments (91% and 82%, respectively). Monthly SSE frequency remained highly variable in all patient groups: at 2 years, 29.7% reported monthly SSEs, 27.0% reported more frequent self-examinations, and 43.2% reported underscreening. However, SSE quality improved significantly: participants checked more body sites at 2 years than at baseline, especially feet, shoulders, legs, and genitals. Perceived logistic barriers to TBSEs (e.g., expensive, inconvenient) and SSEs (hard to remember, time-consuming) predicted lower adherence.
Unaffected carriers reported increased TBSE adherence and thoroughness of SSEs 2 years following melanoma genetic test reporting, suggesting clinical benefit in this modest sample. Unaffected noncarriers reported comparable gains in SSE thoroughness, but decreased TBSEs.
Melanoma genetic counseling and test reporting may improve adherence among unaffected carrier members of p16 families. Further interventions to reduce logistic barriers and to promote continued screening adherence among unaffected noncarrier family members may be needed.
PMCID: PMC3837428  PMID: 23950214
melanoma; genetic testing; total body skin examinations; skin self-examinations; screening
8.  Virtual Exertions: a user interface combining visual information, kinesthetics and biofeedback for virtual object manipulation 
Virtual Reality environments have the ability to present users with rich visual representations of simulated environments. However, means to interact with these types of illusions are generally unnatural in the sense that they do not match the methods humans use to grasp and move objects in the physical world. We demonstrate a system that enables users to interact with virtual objects with natural body movements by combining visual information, kinesthetics and biofeedback from electromyograms (EMG). Our method allows virtual objects to be grasped, moved and dropped through muscle exertion classification based on physical world masses. We show that users can consistently reproduce these calibrated exertions, allowing them to interface with objects in a novel way.
PMCID: PMC4181385  PMID: 25285327
H.5.1 [Information Interfaces and Presentation]: Multimedia Information Systems—Artificial, augmented and virtual realities; H.5.2 [Information Interfaces and Presentation]: User Interfaces—Input devices and strategies
9.  Familial risk of childhood cancer and tumors in the Li-Fraumeni spectrum in the Utah Population Database: Implications for genetic evaluation in pediatric practice 
We used the Utah Population Database to examine risk of cancer in relatives of 4,482 pediatric cancer cases (≤ 18 years old) diagnosed from 1966 to 2009 compared to matched population controls. We quantified cancer risk in relatives of children with cancer to determine evidence of familial aggregation and to inform risk assessment and counseling for families. Odds ratios that reflect risk were obtained using conditional logistic regression models adjusting for number of biological relatives, their degree of genetic relatedness and their person-years at risk. First-degree relatives (primarily siblings) of pediatric cases faced a twofold increased risk of a cancer diagnosis before age 19, which extended to their second-degree relatives (p < 10–, respectively). Furthermore, first-degree relatives of children diagnosed before age 5 had a 3.6-fold increased risk of developing pediatric cancer (p < 10–), second-degree relatives of very young (under age 5) cases were at 2.5-fold risk (p < 10–) and third-degree relatives were at twofold risk (P < 1023) of childhood cancer. Although first-degree relatives of pediatric cases have a slight increased risk of adult tumors, when they do develop cancer they have a 1.7-fold risk of developing a tumor in the Li-Fraumeni spectrum. Our findings support the hypothesis of familial aggregation in pediatric cancer and suggest that a higher percent of childhood cancers may be related to hereditary syndromes than are adult cancers. We encourage the collection of a family medical history that is routinely updated for all pediatric cancer patients, and that families with early-onset adult cancers or clusters of several cancers are referred for genetic counseling.
PMCID: PMC4058884  PMID: 23661176
pediatric cancers; Li-Fraumeni; familial risk; family history; genetic counseling
10.  Population differentiation of zander (Sander lucioperca) across native and newly colonized ranges suggests increasing admixture in the course of an invasion 
Evolutionary Applications  2014;7(5):555-568.
In addition to ecological factors, evolutionary processes can determine the invasion success of a species. In particular, genetic admixture has the potential to induce rapid evolutionary change, which can result from natural or human-assisted secondary contact between differentiated populations. We studied the recent range expansion of zander in Germany focusing on the interplay between invasion and genetic admixture. Historically, the rivers Elbe and Danube harboured the most north-western source populations from which a north-westward range expansion occurred. This was initiated by introducing zander outside its native range into rivers and lakes, and was fostered by migration through artificial canals and stocking from various sources. We analysed zander populations of the native and invaded ranges using nuclear and mitochondrial genetic markers. Three genetic lineages were identified, which were traced to ancestral ranges. Increased genetic diversity and admixture in the invaded region highlighted asymmetric gene flow towards this area. We suppose that the adaptive potential of the invading populations was promoted by genetic admixture, whereas competitive exclusion in the native areas provided a buffer against introgression by novel genotypes. These explanations would be in line with evidence that hybridization can drive evolutionary change under conditions when new niches can be exploited.
PMCID: PMC4055177  PMID: 24944569
competitive exclusion; gene flow; hybridization; local adaptation; pike-perch; secondary contact
11.  Systematic literature review and validity evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) in patients with multiple sclerosis 
BMC Neurology  2014;14:58.
There are a number of instruments that describe severity and progression of multiple sclerosis and they are increasingly used as endpoints to assess the effectiveness of therapeutic interventions. We examined to what extent the psychometric properties of two accepted instruments – EDSS and MSFC – meet methodological standards and the value they have in clinical trials.
We conducted a systematic literature search in relevant databases [MEDLINE (PubMed), ISI Web of Science, EMBASE, PsycINFO & PSYNDEX, CINAHL] yielding 3,860 results. Relevant full-text publications were identified using abstract and then full-text reviews, and the literature was reviewed.
For evaluation of psychometric properties (validity, reliability, sensitivity of change) of EDSS and MSFC, 120 relevant full-text publications were identified, 54 of them assessed the EDSS, 26 the MSFC and 40 included both instruments. The EDSS has some documented weaknesses in reliability and sensitivity to change. The main limitations of the MSFC are learning effects and the z-scores method used to calculate the total score. However, the methodological criterion of validity applies sufficiently for both instruments.
For use in clinical studies, we found the EDSS to be preferred as a primary and secondary outcome measure in recent studies (50 EDSS, 9 MSFC).
Recognizing their strengths and weaknesses, both EDSS and MSFC are suitable to detect the effectiveness of clinical interventions and to monitor disease progression. Almost all publications identify the EDSS as the most widely used tool to measure disease outcomes in clinical trials. Despite some limitations, both instruments are accepted as endpoints and neither are discussed as surrogate parameters in identified publications. A great advantage of the EDSS is its international acceptance (e.g. by EMA) as a primary endpoint in clinical trials and its broad use in trials, enabling cross-study comparisons.
PMCID: PMC3986942  PMID: 24666846
Multiple sclerosis; Expanded Disability Status Scale (EDSS); Multiple Sclerosis Functional Composite (MSFC); Psychometric properties; Validity; Reliability; Sensitivity of change
12.  TET2 Overexpression in Chronic Lymphocytic Leukemia Is Unrelated to the Presence of TET2 Variations 
BioMed Research International  2014;2014:814294.
TET2 is involved in a variety of hematopoietic malignancies, mainly in myeloid malignancies. Most mutations of TET2 have been identified in myeloid disorders, but some have also recently been described in mature lymphoid neoplasms. In contrast to the large amount of data about mutations of TET2, some data are available for gene expression. Moreover, the role of TET2 in chronic lymphocytic leukemia (CLL) is unknown. This study analyzes both TET2 expression and mutations in 48 CLL patients. TET2 expression was analyzed by exon arrays and quantitative real-time polymerase chain reaction (qRT-PCR). Next-generation sequencing (NGS) technology was applied to investigate the presence of TET2 variations. Overexpression of TET2 was observed in B-cell lymphocytes from CLL patients compared with healthy donors (P = 0.004). In addition, in CLL patients, an overexpression of TET2 was also observed in the clonal B cells compared with the nontumoral cells (P = 0.002). However, no novel mutations were observed. Therefore, overexpression of TET2 in CLL seems to be unrelated to the presence of genomic TET2 variations.
PMCID: PMC3947698  PMID: 24693539
13.  BAALC expression: a suitable marker for prognostic risk stratification and detection of residual disease in cytogenetically normal acute myeloid leukemia 
Blood Cancer Journal  2014;4(1):e173-.
High brain and acute leukemia, cytoplasmic (BAALC) expression defines an important risk factor in cytogenetically normal acute myeloid leukemia (CN-AML). The prognostic value of BAALC expression in relation to other molecular prognosticators was analyzed in 326 CN-AML patients (<65 years). At diagnosis, high BAALC expression was associated with prognostically adverse mutations: FLT3 internal tandem duplication (FLT3-ITD) with an FLT3-ITD/FLT3 wild-type (wt) ratio of ⩾0.5 (P=0.001), partial tandem duplications within the MLL gene (MLL-PTD) (P=0.002), RUNX1 mutations (mut) (P<0.001) and WT1mut (P=0.001), while it was negatively associated with NPM1mut (P<0.001). However, high BAALC expression was also associated with prognostically favorable biallelic CEBPA (P=0.001). Survival analysis revealed an independent adverse prognostic impact of high BAALC expression on overall survival (OS) and event-free survival (EFS), and also on OS when eliminating the effect of allogeneic stem cell transplantation (SCT) (OSTXcens). Furthermore, we analyzed BAALC expression in 416 diagnostic and follow-up samples of 66 patients. During follow-up, BAALC expression correlated with mutational load or expression levels, respectively, of other minimal residual disease markers: FLT3-ITD (r=0.650, P<0.001), MLL-PTD (r=0.728, P<0.001), NPM1mut (r=0.599, P<0.001) and RUNX1mut (r=0.889, P<0.001). Moreover, a reduction in BAALC expression after the second cycle of induction chemotherapy was associated with improved EFS. Thus, our data underline the utility of BAALC expression as a marker for prognostic risk stratification and detection of residual disease in CN-AML.
PMCID: PMC3913940  PMID: 24413067
BAALC expression; CN-AML; prognosis; MRD
14.  Impact of genetic testing on endometrial cancer risk-reducing practices in women at risk for Lynch syndrome 
Gynecologic oncology  2012;127(3):544-551.
Due to the increased lifetime risk of endometrial cancer (EC), guidelines recommend that women with Lynch syndrome (LS) age ≥35 undergo annual EC surveillance or prophylactic hysterectomy (PH). The aim of this study was to examine the uptake of these risk-reducing strategies.
The study population included women meeting clinical criteria for genetic evaluation for LS. Data on cancer risk-reducing behaviors were collected from subjects enrolled in two distinct studies: (1) a multicenter cross-sectional study involving completion of a one-time questionnaire, or (2) a single-center longitudinal study in which subjects completed questionnaires before and after undergoing genetic testing. The main outcome was uptake of EC risk-reducing practices.
In the cross-sectional cohort, 58/77 (75%) women at risk for LS-associated EC reported engaging in EC risk-reduction. Personal history of genetic testing was associated with uptake of EC surveillance or PH (OR 17.1; 95% CI 4.1–70.9). Prior to genetic testing for LS, 26/40 (65%) women in the longitudinal cohort reported engaging in EC risk-reduction. At one-year follow-up, 16/16 (100%) mismatch repair (MMR) gene mutation carriers were adherent to guidelines for EC risk-reduction, 9 (56%) of whom had undergone PH. By three-year follow-up, 11/16 (69%) MMR mutation carriers had undergone PH. Among women with negative or uninformative genetic test results, none underwent PH after testing.
Genetic testing for LS is strongly associated with uptake of EC risk-reducing practices. Women found to have LS in this study underwent prophylactic gynecologic surgery at rates comparable to those published for BRCA1/2 mutation carriers.
PMCID: PMC3496001  PMID: 22940489
15.  Prevalence of hypopituitarism after intracranial operations not directly associated with the pituitary gland 
Over the last few years, awareness and detection rates of hypopituitarism following traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) has steadily increased. Moreover, recent studies have found that a clinically relevant number of patients develop pituitary insufficiency after intracranial operations and radiation treatment for non-pituitary tumors. But, in a substantial portion of more than 40%, the hypopituitarism already exists before surgery. We sought to determine the frequency, pattern, and severity of endocrine disturbances using basal and advanced dynamic pituitary testing following non-pituitary intracranial procedures.
51 patients (29 women, 22 men) with a mean age of 55 years (range of 20 to 75 years) underwent prospective evaluation of basal parameters and pituitary function testing (combined growth hormone releasing hormone (GHRH)/arginine test, insulin tolerance test (ITT), low dose adrenocorticotropic hormone (ACTH) test), performed 5 to 168 months (median 47.2 months) after intracranial operation (4 patients had additional radiation and 2 patients received additional radiation combined with chemotherapy).
We discovered an overall rate of hypopituitarism with distinct magnitude in 64.7% (solitary in 45.1%, multiple in 19.6%, complete in 0%). Adrenocorticotropic hormone insufficiency was found in 51.0% (partial in 41.2%, complete in 9.8%) and growth hormone deficiency (GHD) occurred in 31.4% (partial in 25.5%, severe in 5.9%). Thyrotropic hormone deficiency was not identified. The frequency of hypogonadism was 9.1% in men. Pituitary deficits were associated with operations both in close proximity to the sella turcica and more distant regions (p = 0.91). Age (p = 0.76) and gender (p = 0.24) did not significantly differ across patients with versus those without hormonal deficiencies. Groups did not significantly differ across pathology and operation type (p = 0.07).
Hypopituitarism occurs more frequently than expected in patients who have undergone neurosurgical intracranial procedures for conditions other then pituitary tumors or may already exists in a neurosurgical population before surgery. Pituitary function testing and adequate substitution may be warranted for neurosurgical patients with intracranial pathologies at least if unexplained symptoms like fatigue, weakness, altered mental activity, and decreased exercise tolerance are present.
PMCID: PMC4175102  PMID: 24188166
Hypopituitarism; Pituitary deficiency; Intracranial operation; Neurosurgery
16.  Online Real-Time Presentation of Virtual Experiences for External Viewers 
Externally observing the experience of a participant in a virtual environment is generally accomplished by viewing an egocentric perspective. Monitoring this view can often be difficult for others to watch due to unwanted camera motions that appear unnatural and unmotivated. We present a novel method for reducing the unnaturalness of these camera motions by minimizing camera movement while maintaining the context of the participant’s observations. For each time-step, we compare the parts of the scene viewed by the virtual participant to the parts of the scene viewed by the camera. Based on the similarity of these two viewpoints we next determine how the camera should be adjusted. We present two means of adjustment, one which continuously adjusts the camera and a second which attempts to stop camera movement when possible. Empirical evaluation shows that our method can produce paths that have substantially shorter travel distances, are easier to watch and maintain the original observations of the participant’s virtual experience.
PMCID: PMC3810348  PMID: 24172709
Virtual Reality; Viewpoint Similarity; Camera Motion; Stabilization; Observation
17.  Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration 
BMC Neuroscience  2013;14:108.
Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties. One of these modifications is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization of truncated Aβ(3-x), generating pE3-Aβ. Compared to unmodified Aβ, pE3-Aβ is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other Aβ species. To directly investigate pE3-Aβ formation and toxicity in vivo, transgenic (tg) ETNA (E at the truncated N-terminus of Aβ) mice expressing truncated human Aβ(3–42) were generated and comprehensively characterized. To further investigate the role of QC in pE3-Aβ formation in vivo, ETNA mice were intercrossed with tg mice overexpressing human QC (hQC) to generate double tg ETNA-hQC mice.
Expression of truncated Aβ(3–42) was detected mainly in the lateral striatum of ETNA mice, leading to progressive accumulation of pE3-Aβ. This ultimately resulted in astrocytosis, loss of DARPP-32 immunoreactivity, and neuronal loss at the sites of pE3-Aβ formation. Neuropathology in ETNA mice was associated with behavioral alterations. In particular, hyperactivity and impaired acoustic sensorimotor gating were detected. Double tg ETNA-hQC mice showed similar Aβ levels and expression sites, while pE3-Aβ were significantly increased, entailing increased astrocytosis and neuronal loss.
ETNA and ETNA-hQC mice represent novel mouse models for QC-mediated toxicity of truncated and pE-modified Aβ. Due to their significant striatal neurodegeneration these mice can also be used for analysis of striatal regulation of basal locomotor activity and sensorimotor gating, and possibly for DARPP-32-dependent neurophysiology and neuropathology. The spatio-temporal correlation of pE3-Aβ and neuropathology strongly argues for an important role of this Aβ species in neurodegenerative processes in these models.
PMCID: PMC3850634  PMID: 24083638
ETNA; Pyroglutamate Aβ; Glutaminyl cyclase; Alzheimer’s disease; TBA; Neurodegeneration; Neuroinflammation; Striatum
18.  Patient and provider attitudes toward genomic testing for prostate cancer susceptibility: a mixed method study 
The strong association between family history and prostate cancer (PCa) suggests a significant genetic contribution, yet specific highly penetrant PCa susceptibility genes have not been identified. Certain single-nucleotide-polymorphisms have been found to correlate with PCa risk; however uncertainty remains regarding their clinical utility and how to best incorporate this information into clinical decision-making. Genetic testing is available directly to consumers and both patients and healthcare providers are becoming more aware of this technology. Purchasing online allows patients to bypass their healthcare provider yet patients may have difficulty interpreting test results and providers may be called upon to interpret results. Determining optimal ways to educate both patients and providers, and strategies for appropriately incorporating this information into clinical decision-making are needed.
A mixed-method study was conducted in Utah between October 2011 and December 2011. Eleven focus group discussions were held and surveys were administered to 23 first-degree relatives of PCa patients living in Utah and 24 primary-care physicians and urologists practicing in Utah to present specific information about these assessments and determine knowledge and attitudes regarding health implications of using these assessments.
Data was independently coded by two researchers (relative Kappa = .88; provider Kappa = .77) and analyzed using a grounded theory approach. Results indicated differences in attitudes and behavioral intentions between patient and provider. Despite the test’s limitations relatives indicated interest in genetic testing (52%) while most providers indicated they would not recommend the test for their patients (79%). Relatives expected providers to interpret genetic test results and use results to provide personalized healthcare recommendations while the majority of providers did not think the information would be useful in patient care (92%) and indicated low-levels of genetic self-efficacy.
Although similarities exist, discordance between provider and patient attitudes may influence the effective translation of novel genomic tests into clinical practice suggesting both patient and provider perceptions and expectations be considered in development of clinical decision-support tools.
PMCID: PMC3750463  PMID: 23870420
Genomics; Prostate cancer; Cancer screening; Attitudes; Providers
19.  Effective Replays and Summarization of Virtual Experiences 
Direct replays of the experience of a user in a virtual environment are difficult for others to watch due to unnatural camera motions. We present methods for replaying and summarizing these egocentric experiences that effectively communicate the users observations while reducing unwanted camera movements. Our approach summarizes the viewpoint path as a concise sequence of viewpoints that cover the same parts of the scene. The core of our approach is a novel content dependent metric that can be used to identify similarities between viewpoints. This enables viewpoints to be grouped by similar contextual view information and provides a means to generate novel viewpoints that can encapsulate a series of views. These resulting encapsulated viewpoints are used to synthesize new camera paths that convey the content of the original viewers experience. Projecting the initial movement of the user back on the scene can be used to convey the details of their observations, and the extracted viewpoints can serve as bookmarks for control or analysis. Finally we present performance analysis along with two forms of validation to test whether the extracted viewpoints are representative of the viewers original observations and to test for the overall effectiveness of the presented replay methods.
PMCID: PMC3354691  PMID: 22402688
Virtual Reality; Viewpoint Similarity; Summarization; GPU; Bookmarking
20.  Application of MM-GB/SA and WaterMap to SRC Kinase Inhibitor Potency Prediction 
WaterMap and MM-GB/SA scoring methods were applied to an extensive congeneric series of small-molecule SRC inhibitors with high-quality enzyme data and well characterized binding modes to compare the performance of these scoring methods in this data set and to provide insight into the relative strengths of each method. Only minor conformational changes in SRC bound with representative DFG-in class of inhibitors were demonstrated in previous studies; thus, the protein flexibility that normally presents a challenge to pose and potency predictions was minimized in this model system. While WaterMap correctly recognized major trends in the SAR of this series, MM-GB/SA performed better in ranking the relative ligand affinities. The different scoring methods were further analyzed to determine which aspects of series SAR were more amenable to MM-GB/SA than WaterMap scoring.
PMCID: PMC4025851  PMID: 24900440
WaterMap; MM-GB/SA; SRC tyrosine kinase; free energy of binding
21.  Frequency and Prognostic Impact of CEBPA Proximal, Distal and Core Promoter Methylation in Normal Karyotype AML: A Study on 623 Cases 
PLoS ONE  2013;8(2):e54365.
The clinical impact of aberrant CEBPA promoter methylation (PM) in AML is controversially discussed. The aim of this study was to clarify the significance of aberrant CEBPA PM with regard to clinical features in a cohort of 623 cytogenetically normal (CN) de novo AML. 555 cases had wild-type CEBPA, 68 cases harbored CEBPA mutations. The distal promoter was methylated in 238/623 cases (38.2%), the core promoter in 8 of 326 cases (2.5%), whereas proximal PM was never detected. CEBPA PM and CEBPA mutations were mutually exclusive. CEBPA distal PM positive cases were characterized by reduced CEBPA mRNA expression levels and elevated white blood cell counts. CEBPA distal PM was less frequent in patients with mutations in FLT3, NPM1 and TET2 and more frequent in cases with RUNX1 and IDH2R140 mutations. Overall, no association of methylation to prognosis was seen. However CEBPA distal PM was associated with inferior outcome in cases with low FLT3-ITD ratio or TET2 mutations. A distinct gene expression profile of CEBPA distal PM positive cases compared to CEBPA mutated and CEBPA distal PM negative cases was observed. In conclusion, the presence of aberrant CEBPA PM is associated with distinct biological features but impact on outcome is weak.
PMCID: PMC3562230  PMID: 23383300
22.  Pre-Study protocol MagPEP: a multicentre randomized controlled trial of magnesium sulphate in the prevention of post-ERCP pancreatitis 
BMC Gastroenterology  2013;13:11.
Acute pancreatitis is the most common complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In spite of continuing research, no pharmacologic agent capable of effectively reducing the incidence of ERCP-induced pancreatitis has found its way into clinical practise. A number of experimental studies suggest that intrapancreatic calcium concentrations play an important role in the initiation of intracellular protease activation, an initiating step in the course of acute pancreatitis. Magnesium can act as a calcium-antagonist and counteracts effects in calcium signalling. It can thereby attenuate the intracellular activation of proteolytic digestive enzymes in the pancreas and reduces the severity of experimental pancreatitis when administered either intravenously or as a food supplement.
We designed a randomized, double-blind, placebo-controlled phase III study to test whether the administration of intravenous magnesium sulphate before and after ERCP reduces the incidence and the severity of post-ERCP pancreatitis. A total of 502 adult patients with a medical indication for ERCP are to be randomized to receive either 4930 mg magnesium sulphate (= 20 mmol magnesium) or placebo 60 min before and 6 hours after ERCP. The incidence of clinical post-ERCP pancreatitis, hyperlipasemia, pain levels, use of analgetics and length of hospital stay will be evaluated.
If magnesium sulphate is found to be effective in preventing post-ERCP pancreatitis, this inexpensive agent with limited adverse effects could be used as a routine pharmacological prophylaxis.
Trial registration
Current Controlled Trials ISRCTN46556454
PMCID: PMC3599317  PMID: 23320650
23.  Protein Kinase C-β-Dependent Activation of NF-κB in Stromal Cells Is Indispensable for the Survival of Chronic Lymphocytic Leukemia B Cells In Vivo 
Cancer Cell  2013;23(1):77-92.
Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here, we describe a survival signaling pathway activated in stromal cells by contact to B cells from patients with chronic lymphocytic leukemia (CLL). The expression of protein kinase C (PKC)-βII and the subsequent activation of NF-κB in bone marrow stromal cells are prerequisites to support the survival of malignant B cells. PKC-β knockout mice are insusceptible to CLL transplantations, underscoring the in vivo significance of the PKC-βII-NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from patients with CLL, acute lymphoblastic leukemia, and mantle cell lymphoma suggests that this pathway may commonly be activated in a variety of hematological malignancies.
► Malignant B cells induce the expression of PKC-βII in bone marrow stromal cells ► The activation of NF-κB in tumor stromal cells strictly depends on PKC-βII ► The PKC-βII-NF-κB pathway is indispensable for survival of malignant B cells in vivo ► The PKC-βII-NF-κB pathway is activated by ALL and mantle cell lymphoma cells
PMCID: PMC3546417  PMID: 23328482
24.  Survey of unaffected BRCA and mismatch repair (MMR) mutation positive individuals 
Familial cancer  2009;8(4):363-369.
Many individuals do not proceed with cancer predisposition testing due to fears of genetic discrimination (GD). We report the results of a survey of 47 unaffected, mutation positive individuals regarding insurance outcomes. Participants recruited from six different Cancer Risk Programs across the country were queried about their experiences with health, life, and disability insurance, as well as employment issues. Eighty-seven percent of participants carried a BRCA mutation and 87% were part of a group insurance plan at the time of testing. Forty-seven percent of participants self-paid for testing. Less than 10% of participants reported that their results were placed in the general medical record, while 43% did not know where their results were placed. Due to concerns about GD, 13% of participants stated they avoided changing jobs. Thirteen percent stated that their at-risk relatives had not undergone testing for the familial mutation due to fears about GD. Adverse events following genetic testing included two denials from private health insurers, one denial for average life insurance coverage and one denial for additional disability insurance. There were no reports of job discrimination. Results suggest fear of GD is prevalent, yet data do not support evidence that GD exists.
PMCID: PMC3528358  PMID: 19466581
Genetic discrimination; Genetic counseling; Insurance
25.  Implementation of the quality management system improves postoperative pain treatment: a prospective pre-/post-interventional questionnaire study 
An organizational approach is proposed as an immediate solution for improving postoperative pain (POP) management. The aim was to evaluate the clinical effectiveness of a quality management system (QMS), based on procedure-specific, multimodal analgesic protocols, modified to meet the individual patients’ requirements.
Patients from the orthopaedic, gynaecological, visceral, and trauma surgery departments of the university hospital were involved in two prospective surveys. Survey 1 was performed at baseline and survey 2 was performed after the implementation of QMS within an interval of 1 year. The patients were asked to report pain intensity on the visual rating scale, incidence of analgesia-related side-effects, and incidence of pain interference with the items of life quality and their satisfaction with the treatment of POP.
Patients from Survey 2 (n=251) reported 25–30% less pain than those from Survey 1 (n=269) (P<0.0001). Nausea was reported by 40% of the patients from Survey 1 vs 17% from Survey 2, vomiting by 25 vs 11% and fatigue by 76% in Survey 1 vs 30% in Survey 2 (P<0.0001). Life quality and patients’ satisfaction improved in Survey 2 vs Survey 1 (P<0.001).
The implementation of QMS allowed the reduction in POP intensity with a simultaneous decrease in analgesia-related side-effects. This has led to an increased quality of life and patient satisfaction.
PMCID: PMC3520148  PMID: 23048069
adverse effects; analgesia; pain, postoperative; quality management

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