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author:("rogawski, A")
1.  Influence of baseline left ventricular function on the clinical outcome of surgical ventricular reconstruction in patients with ischaemic cardiomyopathy 
European Heart Journal  2012;34(1):39-47.
The Surgical Treatment for Ischemic Heart Failure (STICH) trial demonstrated no overall benefit when surgical ventricular reconstruction (SVR) was added to coronary artery bypass grafting (CABG) in patients with ischaemic cardiomyopathy. The present analysis was to determine whether, based on baseline left ventricular (LV) function parameters, any subgroups could be identified that benefited from SVR.
Methods and results
Among the 1000 patients enrolled, Core Lab measures of baseline LV function with adequate quality were obtained in 710 patients using echocardiography, in 352 using cardiovascular magnetic resonance, and in 344 using radionuclide imaging. The relationship between LV end-systolic volume index (ESVI), end-diastolic volume index, ejection fraction (EF), regional wall motion abnormalities, and outcome were first assessed only by echocardiographic measures, and then by 13 algorithms using a different hierarchy of imaging modalities and their quality. The median ESVI and EF were 78.0 (range: 22.8–283.8) mL/m2 and 28.0%, respectively. Hazard ratios comparing the randomized arms by subgroups of LVESVI and LVEF measured by echocardiography found that patients with smaller ventricles (LVESVI <60 mL/m2) and better LVEF (≥33%) may have benefitted by SVR, while those with larger ventricles (LVESVI >90 mL/m2) and lower LVEF (≤25%) did worse with SVR. Algorithms using all three imaging modalities found a weaker relationship between LV global function and the effects of SVR. The extent of regional wall motion abnormality did not influence the effects of SVR.
Subgroup analyses of the STICH trial suggest that patients with less dilated LV and better LVEF may benefit from SVR, while those with larger LV and poorer LVEF may do worse.
Clinical Trial Registration #: NCT00023595.
PMCID: PMC3533917  PMID: 22584648
STICH; Surgical ventricular reconstruction; Coronary disease; Heart failure
2.  What is personalized medicine: sharpening a vague term based on a systematic literature review 
BMC Medical Ethics  2013;14:55.
Recently, individualized or personalized medicine (PM) has become a buzz word in the academic as well as public debate surrounding health care. However, PM lacks a clear definition and is open to interpretation. This conceptual vagueness complicates public discourse on chances, risks and limits of PM. Furthermore, stakeholders might use it to further their respective interests and preferences. For these reasons it is important to have a shared understanding of PM. In this paper, we present a sufficiently precise as well as adequate definition of PM with the potential of wide acceptance.
For this purpose, in a first step a systematic literature review was conducted to understand how PM is actually used in scientific practice. PubMed was searched using the keywords “individualized medicine”, “individualised medicine”, “personalized medicine” and “personalised medicine” connected by the Boolean operator OR. A data extraction tabloid was developed putting forward a means/ends-division. Full-texts of articles containing the search terms in title or abstract were screened for definitions. Definitions were extracted; according to the means/ends distinction their elements were assigned to the corresponding category. To reduce complexity of the resulting list, summary categories were developed inductively from the data using thematic analysis. In a second step, six well-known criteria for adequate definitions were applied to these categories to derive a so-called precising definition.
We identified 2457 articles containing the terms PM in title or abstract. Of those 683 contained a definition of PM and were thus included in our review. 1459 ends and 1025 means were found in the definitions. From these we derived the precising definition: PM seeks to improve stratification and timing of health care by utilizing biological information and biomarkers on the level of molecular disease pathways, genetics, proteomics as well as metabolomics.
Our definition includes the aspects that are specific for developments labeled as PM while, on the other hand, recognizing the limits of these developments. Furthermore, it is supported by the quantitative analysis of PM definitions in the literature, which suggests that it it is widely acceptable and thus has the potential to avoid the above mentioned issues.
PMCID: PMC3878093  PMID: 24359531
Biomarkers; Conceptual vagueness; Definition; Individualized medicine; Stratification; Timing
3.  Evidence That GH115 α-Glucuronidase Activity, Which Is Required to Degrade Plant Biomass, Is Dependent on Conformational Flexibility* 
Background: The structure of GH115 glucuronidases that remove glucuronic acid from xylan chains is unknown.
Results: Bacteroides ovatus GH115 glucuronidase is a dimeric enzyme that contains a flexible active site pocket.
Conclusion: The assembly of the catalytic apparatus of the glucuronidase requires substantial conformational changes.
Significance: Conformational changes are highly unusual in glycoside hydrolases.
The microbial degradation of the plant cell wall is an important biological process that is highly relevant to environmentally significant industries such as the bioenergy and biorefining sectors. A major component of the wall is glucuronoxylan, a β1,4-linked xylose polysaccharide that is decorated with α-linked glucuronic and/or methylglucuronic acid (GlcA/MeGlcA). Recently three members of a glycoside hydrolase family, GH115, were shown to hydrolyze MeGlcA side chains from the internal regions of xylan, an activity that has not previously been described. Here we show that a dominant member of the human microbiota, Bacteroides ovatus, contains a GH115 enzyme, BoAgu115A, which displays glucuronoxylan α-(4-O-methyl)-glucuronidase activity. The enzyme is significantly more active against substrates in which the xylose decorated with GlcA/MeGlcA is flanked by one or more xylose residues. The crystal structure of BoAgu115A revealed a four-domain protein in which the active site, comprising a pocket that abuts a cleft-like structure, is housed in the second domain that adopts a TIM barrel-fold. The third domain, a five-helical bundle, and the C-terminal β-sandwich domain make inter-chain contacts leading to protein dimerization. Informed by the structure of the enzyme in complex with GlcA in its open ring form, in conjunction with mutagenesis studies, the potential substrate binding and catalytically significant amino acids were identified. Based on the catalytic importance of residues located on a highly flexible loop, the enzyme is required to undergo a substantial conformational change to form a productive Michaelis complex with glucuronoxylan.
PMCID: PMC3879575  PMID: 24214982
Bioenergy; Enzyme Structure; Glycoside Hydrolases; Plant Cell Wall; X-ray Crystallography
4.  Prognostic indicators of survival in patients with compensated and decompensated cirrhosis 
Patients with cirrhosis are classified in a compensated and a decompensated stage. Portal hypertension is responsible for most of the complications of cirrhosis that mark the transition from compensated to decompensated cirrhosis. The objectives of this study were (a) to analyse survival of the different stages and substages of cirrhosis and (b) to examine the prognostic value of the hepatic venous pressure gradient (HVPG) at each of the stages.
A total of 729 patients with suspected cirrhosis underwent routine measurement of portal pressure and systemic haemodynamics between 11/1995 and 12/2004. The primary end-point of the study was death, collected until November 30th, 2006. Multivariable analysis was performed using two models to determine predictors of death at each stage.
A total of 443 patients were included in the study. The 1-year mortality was 5.4% in compensated and 20.2% in decompensated patients. Compensated patients in stage 1 (no varices) had a longer survival than stage 2 patients (varices present) (P = 0.015). In decompensated patients, survival was not different between stage 3 (ascites, with or without varices) and stage 4 (variceal haemorrhage, with or without ascites). Age and HVPG (cut-off 10 mmHg) were independent predictors of death in compensated patients, whereas MELD was in decompensated patients.
Survival rates and predictors of death are different between patients with compensated and decompensated cirrhosis. Unlike the Italian cohort staging system, ascites is a better stratifying clinical event than variceal haemorrhage in patients with decompensated cirrhosis. The presence of clinically significant portal hyper-tension has prognostic value in compensated cirrhosis.
PMCID: PMC3713489  PMID: 22679906
ascites; cirrhosis; oesophageal varices; variceal haemorrhage
5.  Association of Angiotensin-Converting Enzyme Inhibitor Therapy Initiation With a Reduction in Hemoglobin Levels in Patients Without Renal Failure 
Mayo Clinic Proceedings  2012;87(12):1189-1195.
To investigate whether treatment initiated with an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin II receptor blocker (ARB) for patients with ischemic heart disease, hypertension, or diabetes causes a reduction in hemoglobin (Hb) levels.
Patients and Methods
This was a retrospective cohort analysis using the computerized database of a large health maintenance organization. Included were all adults with a first purchase of an ACE-I, an ARB, or a calcium channel blocker (CCB) between January 1, 2004, and December 31, 2009, defined as the index date. Measures of Hb levels before and 1 year after the index date were reviewed, and the change was calculated. All the analyses were stratified by pharmaceutical class. The main exposure variables were the proportion of days covered (PDC) by these drugs and the mean enalapril dosage (for enalapril users only).
Levels of Hb before and after treatment were available for 14,754 patients taking ACE-Is, 751 taking ARBs, and 3087 taking CCBs. A high PDC was significantly associated with greater yearly reductions in Hb levels compared with a low PDC for CCB use, but was more pronounced for ACE-I and ARB use. A high PDC was also associated with a higher odds of developing anemia in ACE-I users (odds ratio [OR], 1.59; P<.001) and ARB users (OR, 2.21; P=.05). In nonanemic enalapril users, every 10-mg increment in daily dose was associated with an OR of 1.45 for the development of anemia (P<.001). The association remained after excluding nonadherent patients.
Levels of Hb are reduced during the first year of use of ACE-Is and to a lesser extent with use of ARBs. This association is dose dependent and is not explained by patient adherence.
PMCID: PMC3547548  PMID: 23141116
ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; Hb, hemoglobin; IHD, ischemic heart disease; MHS, Maccabi Healthcare Services; OR, odds ratio; PDC, proportion of days covered; WHO, World Health Organization
6.  Motor Imagery and Tennis Serve Performance: The External Focus Efficacy 
There is now ample evidence that motor imagery (MI) contributes to enhance motor performance. Previous research also demonstrated that directing athletes’ attention to the effects of their movements on the environment is more effective than focusing on the action per se. The present study aimed therefore at evaluating whether adopting an external focus during MI contributes to enhance tennis serve performance. Twelve high-level young tennis players were included in a test-retest procedure. The effects of regular training were first evaluated. Then, players were subjected to a MI intervention during which they mentally focused on ball trajectory and specifically visualized the space above the net where the serve can be successfully hit. Serve performance was evaluated during both a validated serve test and a real match. The main results showed a significant increase in accuracy and velocity during the ecological serve test after MI practice, as well as a significant improvement in successful first serves and won points during the match. Present data therefore confirmed the efficacy of MI in combination of physical practice to improve tennis serve performance, and further provided evidence that it is feasible to adopt external attentional focus during MI. Practical applications are discussed.
Key PointsMotor imagery contributes to enhance tennis serve performance.Data provided evidence of the benefits of adopting an external focus of attention during imagery.Results showed significant improvement in successful first serves and won points during a real match.
PMCID: PMC3761826  PMID: 24149813
Movement imagery; motor performance; focus of attention; safety window
7.  Joint Kinetics to Assess the Influence of the Racket on a Tennis Player’s Shoulder 
This study aimed at investigating the influence of three rackets on shoulder net joint moments, power and muscle activity during the flat tennis serve under field- conditions. A 6-camera Eagle® motion analysis system, operating at 256 Hz, captured racket and dominant upper limb kinematics of the serve in five tennis players under three racket conditions (A: low mass, high balance and polar moment, B: low three moments of inertia, and C: high mass, swingweight and twistweight). The electromyographic activity of six trunk and arm muscles was simultaneously recorded. Shoulder net joint moments and power were computed by 3D inverse dynamics. The results showed that greater shoulder joint power and internal/external rotation peak moments were found to accelerate and decelerate racket A in comparison with the racket C. Moreover, serving with the racket A resulted in less activity in latissimus dorsi muscle during the acceleration phase, and biceps brachii muscle during the follow-through phase when compared with racket C. These initial findings encourage studying the biomechanical measurements to quantify the loads on the body during play in order to reduce them, and then prevent shoulder injuries. Racket specifications may be a critical point for coaches who train players suffering from shoulder pain and chronic upper limb injuries should be considered in relation to the racket specifications of the players.
Key PointsLight racket required more joint power than heavy one to achieve similar post impact ball velocity.Serving with a light racket resulted in higher shoulder internal and external rotation moments than using a heavy one for similar performance.Chronic shoulder pain should encourage coaches to check for potentially inappropriate racket specifications of their players.
PMCID: PMC3761829  PMID: 24149804
EMG; inverse dynamics; joint power; joint moment; tennis serve
8.  Operative field temperature during transnasal endoscopic cranial base procedures 
Acta Neurochirurgica  2013;155(5):903-908.
Data regarding the safety of endoscopic skull base exploration are very scarce. With this method, fragile vital structures (cranial nerves, the optic complex, brainstem, hypothalamus or cerebral ventricles) are exposed to direct illumination within a closed space. Also, high-speed drills, cauterization and ultrasonic aspiration deliver a significant load of thermal energy. The aim of this study was to record the temperature close to the structures of the skull base and in the intradural space during the procedures performed using extended endoscopic transnasal approaches.
The temperature of the skull base was continuously recorded during six transnasal endoscopic procedures. Implantable copper-constantan thermocouples were inserted: one into the esophagus and another through the nostril to reach the operative field at the skull base.
At the beginning of the procedure, the temperature of the operative field was on average 36.8 °C ± 0.80 °C, i.e. only 1 °C higher than the esophageal temperature. Then it grew continuously during the whole procedure, to eventually reach a level of 42–43 °C at the final stage, whereas the esophageal temperature remained stable. Occasionally, the temperature increased up to 45 °C during cauterization and ultrasonic aspiration, and even up to 62 °C during high-speed drilling.
Endoscopic skull base surgery is associated with an incessant increase of the temperature of the intraoperative field. The temperature can peak suddenly to levels which can potentially harm neural structures and influence the rate of postoperative complications.
PMCID: PMC3627044  PMID: 23494137
Endoscopy; Transnasal; Extended approach; Cranial base; Temperature
9.  A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma 
British Journal of Cancer  2013;108(3):503-511.
This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer.
Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2 : 1 to also receive intravenous trebananib 10 mg kg−1 once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS).
One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81–1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53–1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade ⩾3 adverse events was similar between treatment arms (Arm A, 61% Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%).
Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.
PMCID: PMC3593550  PMID: 23361051
AMG 386; trebananib; angiopoietin inhibitor; metastatic colorectal carcinoma
10.  Efficacy and safety of ipilimumab therapy in patients with metastatic melanoma: a retrospective multicenter analysis 
Contemporary Oncology  2013;17(3):257-262.
Aim of the study
The Patient Assistance Program, a type of expanded access program, was initiated for compassionate purposes to provide ipilimumab to patients with unresectable stage III or IV melanoma with failed previous treatment. The aim of this analysis is to evaluate efficacy, safety, and tolerability of ipilimumab therapy in daily clinical practice.
Material and methods
We analyzed 50 patients (29 males, 21 females) aged 21 to 76 years (median: 49 years). An ipilimumab dose of 3 mg/kg was administered intravenously every 3 weeks for a total of 4 doses. Patients were assessed for response rate, progression-free survival and overall survival, and monitored for adverse events.
The objective response (complete or partial response) rate was 12%. Median overall survival was 8 months and median progression-free survival was 3 months. In patients with ECOG-PS 0, the median overall survival was 16 months. Immune-related adverse events (irAEs) occurred in 48% of the patients, grade 3 or 4 irAEs were reported in 8% of the patients, and there were no toxic deaths.
Ipilimumab demonstrated clinical benefit in previously treated advanced melanoma patients. Although clinical benefit is limited to a minority of the patients, there is a benefit in terms of overall survival in this group of patients.
PMCID: PMC3934064  PMID: 24596511
melanoma; ipilimumab; CTLA-4; immunotherapy; outcome
11.  Understanding How Noncatalytic Carbohydrate Binding Modules Can Display Specificity for Xyloglucan* 
The Journal of Biological Chemistry  2012;288(7):4799-4809.
Background: Carbohydrate binding modules (CBMs) contribute to the enzymatic degradation of complex polysaccharide structures.
Results: New CBMs display specificity for decorated glucans through an extensive hydrophobic platform that interacts with both backbone and side chain structures.
Conclusion: CBMs that bind to complex β-glucans exploit different components of these ligands as specificity determinants.
Significance: CBMs can utilize the side chains of decorated glucans as specificity determinants.
Plant biomass is central to the carbon cycle and to environmentally sustainable industries exemplified by the biofuel sector. Plant cell wall degrading enzymes generally contain noncatalytic carbohydrate binding modules (CBMs) that fulfil a targeting function, which enhances catalysis. CBMs that bind β-glucan chains often display broad specificity recognizing β1,4-glucans (cellulose), β1,3-β1,4-mixed linked glucans and xyloglucan, a β1,4-glucan decorated with α1,6-xylose residues, by targeting structures common to the three polysaccharides. Thus, CBMs that recognize xyloglucan target the β1,4-glucan backbone and only accommodate the xylose decorations. Here we show that two closely related CBMs, CBM65A and CBM65B, derived from EcCel5A, a Eubacterium cellulosolvens endoglucanase, bind to a range of β-glucans but, uniquely, display significant preference for xyloglucan. The structures of the two CBMs reveal a β-sandwich fold. The ligand binding site comprises the β-sheet that forms the concave surface of the proteins. Binding to the backbone chains of β-glucans is mediated primarily by five aromatic residues that also make hydrophobic interactions with the xylose side chains of xyloglucan, conferring the distinctive specificity of the CBMs for the decorated polysaccharide. Significantly, and in contrast to other CBMs that recognize β-glucans, CBM65A utilizes different polar residues to bind cellulose and mixed linked glucans. Thus, Gln106 is central to cellulose recognition, but is not required for binding to mixed linked glucans. This report reveals the mechanism by which β-glucan-specific CBMs can distinguish between linear and mixed linked glucans, and show how these CBMs can exploit an extensive hydrophobic platform to target the side chains of decorated β-glucans.
PMCID: PMC3576085  PMID: 23229556
Carbohydrate-binding Protein; Isothermal Titration Calorimetry; Plant Cell Wall; Protein Structure; X-ray Crystallography
14.  Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence 
British Journal of Cancer  2011;105(6):796-806.
We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer.
We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo.
Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours.
Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.
PMCID: PMC3171020  PMID: 21847123
ErbB-2; trastuzumab; Notch-1; GSI; recurrence; resistance
15.  Conversion of epidermal growth factor receptor 2 and hormone receptor expression in breast cancer metastases to the brain 
Breast Cancer Research : BCR  2012;14(4):R119.
We investigated the status of estrogen receptor alpha (ERα), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) in primary tumor and in the corresponding brain metastases in a consecutive series of breast cancer patients. Additionally, we studied factors potentially influencing conversion and evaluated its association with survival.
The study group included 120 breast cancer patients. ERα, PR, and HER2 status in primary tumors and in matched brain metastases was determined centrally by immunohistochemistry and/or fluorescence in situ hybridization.
Using the Allred score of ≥ 3 as a threshold, conversion of ERα and PR in brain metastases occurred in 29% of cases for both receptors, mostly from positive to negative. Conversion of HER2 occurred in 14% of patients and was more balanced either way. Time to brain relapse and the use of chemotherapy or trastuzumab did not influence conversion, whereas endocrine therapy induced conversion of ERα (P = 0.021) and PR (P = 0.001), mainly towards their loss. Receptor conversion had no significant impact on survival.
Receptor conversion, particularly loss of hormone receptors, is a common event in brain metastases from breast cancer, and endocrine therapy may increase its incidence. Receptor conversion does not significantly affect survival.
PMCID: PMC3680944  PMID: 22898337
16.  C. elegans PAT-9 is a nuclear zinc finger protein critical for the assembly of muscle attachments 
Cell & Bioscience  2012;2:18.
Caenorhabditis elegans sarcomeres have been studied extensively utilizing both forward and reverse genetic techniques to provide insight into muscle development and the mechanisms behind muscle contraction. A previous genetic screen investigating early muscle development produced 13 independent mutant genes exhibiting a Pat (paralyzed and arrested elongation at the two-fold length of embryonic development) muscle phenotype. This study reports the identification and characterization of one of those genes, pat-9.
Positional cloning, reverse genetics, and plasmid rescue experiments were used to identify the predicted C. elegans gene T27B1.2 (recently named ztf-19) as the pat-9 gene. Analysis of pat-9 showed it is expressed early in development and within body wall muscle lineages, consistent with a role in muscle development and producing a Pat phenotype. However, unlike most of the other known Pat gene family members, which encode structural components of muscle attachment sites, PAT-9 is an exclusively nuclear protein. Analysis of the predicted PAT-9 amino acid sequence identified one putative nuclear localization domain and three C2H2 zinc finger domains. Both immunocytochemistry and PAT-9::GFP fusion expression confirm that PAT-9 is primarily a nuclear protein and chromatin immunoprecipitation (ChIP) experiments showed that PAT-9 is present on certain gene promoters.
We have shown that the T27B1.2 gene is pat-9. Considering the Pat-9 mutant phenotype shows severely disrupted muscle attachment sites despite PAT-9 being a nuclear zinc finger protein and not a structural component of muscle attachment sites, we propose that PAT-9 likely functions in the regulation of gene expression for some necessary structural or regulatory component(s) of the muscle attachment sites.
PMCID: PMC3419604  PMID: 22616817
Sarcomere; Muscle; Zinc finger; Pat
17.  Comparison of Different Anthropometric Measurements and Inflammatory Biomarkers 
Introduction. Different anthropometric variables have been shown to be related to cardiovascular morbidity and mortality. Our aim was to compare the association between different anthropometric measurements and inflammatory status. Methods and results. A cross-sectional study design in which we analyzed the data collected during a five-year period in the Tel Aviv Medical Center Inflammation Survey (TAMCIS). Included in the study were 13,033 apparently healthy individuals at a mean (SD) age of 43. Of these, 8,292 were male and 4,741 female. A significant age-adjusted and multiple-adjusted partial correlation was noted between all anthropometric measurements and all inflammatory biomarkers. There was no significant difference in the correlation coefficients between different biomarkers and anthropometric variables. Conclusion. Most of the common used anthropometric variables are similarly correlated with inflammatory variables. The clinician can choose the variable that he/she finds easiest to use.
PMCID: PMC3362833  PMID: 22675656
18.  Definitions of genetic testing in European legal documents 
Journal of Community Genetics  2012;3(2):125-141.
The definition of “genetic testing” is not a simple matter, and the term is often used with different meanings. The purpose of this work was the collection and analysis of European (and other) legislation and policy instruments regarding genetic testing, to scrutinise the definitions of genetic testing therewith contained the following: 60 legal documents were identified and examined—55 national and five international ones. Documents were analysed for the type (context) of testing and the material tested and compared by legal fields (privacy and confidentiality, data protection, biobanks, insurance and labour law, forensic medicine); some instruments are very complex and deal with various legal fields at the same time. There was no standard for the definitions used, and different approaches were identified (from wide general, to some very specific and technically based). Often, legal documents did not contain any definitions, and many did not distinguish between genetic testing and genetic information. Genetic testing was more often defined in non-binding legal documents than in binding ones. Definitions are core elements of legal documents, and their accuracy and harmonisation (particularly within a particular legal field) is critical, not to compromise their enforcement. We believe to have gathered now the evidence for adopting the much needed differentiation between (a) “clinical genetics testing”, (b) “genetics laboratory-based genetic testing” and (c) “genetic information”, as proposed before.
Electronic supplementary material
The online version of this article (doi:10.1007/s12687-012-0077-1) contains supplementary material, which is available to authorized users.
PMCID: PMC3312943  PMID: 22278813
Legislation; Definition; Genetic test; Genetic information; EuroGentest
19.  Neighborhoods and Chronic Disease Onset in Later Life 
To strengthen existing evidence on the role of neighborhoods in chronic disease onset in later life, we investigated associations between multiple neighborhood features and 2-year onset of 6 common conditions using a national sample of older adults.
Neighborhood features for adults aged 55 years or older in the 2002 Health and Retirement Study were measured by use of previously validated scales reflecting the built, social, and economic environment. Two-level random-intercept logistic models predicting the onset of heart problems, hypertension, stroke, diabetes, cancer, and arthritis by 2004 were estimated.
In adjusted models, living in more economically disadvantaged areas predicted the onset of heart problems for women (odds ratio [OR]=1.20; P<.05). Living in more highly segregated, higher-crime areas was associated with greater chances of developing cancer for men (OR=1.31; P<.05) and women (OR=1.25; P<.05).
The neighborhood economic environment is associated with heart disease onset for women, and neighborhood-level social stressors are associated with cancer onset for men and women. The social and biological mechanisms that underlie these associations require further investigation.
PMCID: PMC2912970  PMID: 20299643
20.  Selected surgical managements in snoring and obstructive sleep apnea patients 
The diagnostic process and the surgical procedures in patients with snoring and obstructive sleep apnea syndrome (OSAS) are crucial. The aim of this study was to assess the efficacy of surgical treatment in snoring and OSAS patients.
A precise laryngological examination and screening polysomnography (Poly-Mesam) were performed in all patients with mild, moderate and severe OSAS before and 6 months after surgery. The patients completed questionnaires concerning their complaints. We included patients qualified to septoplasty, laser-assisted uvulopalatoplasty (LAUP), uvulopalatopharyngoplasty (UPPP) and radiofrequency-induced thermotherapy of the tongue base (RITT). Outcome evaluation of surgery was performed on the basis of data received from follow-up laryngological examinations, selected parameters obtained from the Poly-Mesam test and follow-up questionnaires.
In most cases we observed improvement, defined as decreasing some sleep parameters, such as a respiratory disturbance index (RDI), by more than 50%, decreasing the loudness of snoring, decreasing the number of hypopneas, and obtaining better blood saturation values. After UPPP we noticed changes in retropalatal space, soft palate dimensions and uvula-posterior pharyngeal wall distance. In the postoperative period we did not observe severe complications. In some cases we found short-lived palatal deficiency after UPPP. Patients after RITT experienced discomfort and throat pain lasting from 2 to 4 days. In 2 patients we observed swelling of the tongue base, which decreased after few days.
Surgery in OSAS contributes to normalization of some sleep parameters. The majority of patients experienced improvement after surgery.
PMCID: PMC3560687  PMID: 22207114
snoring; sleep apnea syndrome; septoplasty; uvulopalatoplasty; uvulopalatopharyngoplasty; radiofrequency-induced thermotherapy
21.  Possible role of α-mannosidase and β-galactosidase in larynx cancer 
Contemporary Oncology  2012;16(2):154-158.
Lysosomal exoglycosidases, such as α-mannosidases (MAN) and β-galactosidases (GAL), are found in different glycoside hydrolase sequence-based families. Considerable research has proved plays the role of MAN, which play a key role in the modification and diversification of hybrid N-glycans, processes with strong cellular links to cancer. Therefore the study aim was to investigate the activities of MAN and GAL in larynx cancer compared to controls.
Material and methods
Larynx cancer (n = 21) and normal healthy tissue (n = 21) were collected from patients during total laryngectomy. A biopsy of macroscopically healthy tissue in the area of the lower 1/3 of omohyoid muscle was taken for frozen sections in each case and these served as controls. The release of p-nitrophenol from p-nitrophenol derivatives of MAN and GAL was used.
In all specimens we observed significantly higher activity of investigated enzymes in larynx cancer compared with controls. The mean release of MAN from activated cells was 3.702 ±1.3245 nkat/g wet tissue compared to controls (1.614 ±0.8220 nkat/g wet tissue). The mean release of GAL from the activated cells was 3.383 ±2.1980 nkat/g wet tissue compared to controls (2.137 ±1.3685 nkat/g wet tissue). Differences in observed activity were statistically significant.
The present data indicate that MAN and GAL are significantly and consistently elevated in larynx cancer growth. It also means that catabolic reactions involving glycoproteins, glycolipids and proteoglycans may play a role in larynx cancer. Further research should also evaluate the relative importance of these particular exoglycosidases in indicating the progress of the disease in considering the spectrum of identified marker mediators.
PMCID: PMC3687398  PMID: 23788869
α-mannosidase; β-galactosidase; laryngeal cancer; exoglycosidase activity
22.  Community Demographics and Access to Health Care among U.S. Hispanics 
Health Services Research  2009;44(5 Pt 1):1542-1562.
To explore the influence of the communities in which Hispanics live on their access to health care.
1996–2002 Medical Expenditure Panel Survey data, linked to secondary data sources and including 14,504 observations from 8,371 Mexican American respondents living in metropolitan areas.
Study Design
We use multivariate probit regression models, stratified by individuals' insurance status, for analyses of four dependent variables measuring access to health care. We measure community characteristics at the zip code tabulation area level, and key independent variables of interest are the percentage of the population that speaks Spanish and percentage of the population that is immigrant Hispanic. Each of these measures is interacted with individual-level measures of nativity and length of U.S. residency.
Principal Findings
For Mexican American immigrants, living in an area populated by relatively more Spanish speakers or more Hispanic immigrants is associated with better access to care. The associations are generally stronger for more recent immigrants compared with those who are better established. Among U.S.-born Mexican Americans who are uninsured, living in areas more heavily populated with Spanish-speaking immigrants is negatively associated with access to care.
The results suggest that characteristics of the local population, including language and nativity, play an important role in access to health care among U.S. Hispanics, and point to the need for further study, including analyses of other racial and ethnic groups, using different geographic constructs for describing the local population, and, to the extent possible, more specific exploration of the mechanisms through which these characteristics may influence access to care.
PMCID: PMC2754547  PMID: 19619247
Access; insurance; immigrant; Hispanic; community
23.  NOTCH-1 and NOTCH-4 are novel gene targets of PEA3 in breast cancer: novel therapeutic implications 
Women with triple-negative breast cancer have the worst prognosis, frequently present with metastatic tumors and have few targeted therapy options. Notch-1 and Notch-4 are potent breast oncogenes that are overexpressed in triple-negative and other subtypes of breast cancer. PEA3, an ETS transcription factor, is also overexpressed in triple-negative and other breast cancer subtypes. We investigated whether PEA3 could be the critical transcriptional activator of Notch receptors in MDA-MB-231 and other breast cancer cells.
Real-time PCR and Western blot analysis were performed to detect Notch-1, Notch-2, Notch-3 and Notch-4 receptor expression in breast cancer cells when PEA3 was knocked down by siRNA. Chromatin immunoprecipitation was performed to identify promoter regions for Notch genes that recruited PEA3. TAM-67 and c-Jun siRNA were used to identify that c-Jun was necessary for PEA3 enrichment on the Notch-4 promoter. A Notch-4 luciferase reporter was used to confirm that endogenous PEA3 or AP-1 activated the Notch-4 promoter region. Cell cycle analysis, trypan blue exclusion, annexin V flow cytometry, colony formation assay and an in vivo xenograft study were performed to determine the biological significance of targeting PEA3 via siRNA, Notch signaling via a γ-secretase inhibitor, or both.
Herein we provide new evidence for transcriptional regulation of Notch by PEA3 in breast cancer. PEA3 activates Notch-1 transcription in MCF-7, MDA-MB-231 and SKBr3 breast cancer cells. PEA3 activates Notch-4 transcription in MDA-MB-231 cells where PEA3 levels are endogenously high. In SKBr3 and BT474 breast cancer cells where PEA3 levels are low, overexpression of PEA3 increases Notch-4 transcripts. Chromatin immunoprecipitation confirmed the enrichment of PEA3 on Notch-1 and Notch-4 promoters in MDA-MB-231 cells. PEA3 recruitment to Notch-1 was AP-1-independent, whereas PEA3 recruitment to Notch-4 was c-JUN-dependent. Importantly, the combined inhibition of Notch signaling via a γ-secretase inhibitor (MRK-003 GSI) and knockdown of PEA3 arrested growth in the G1 phase, decreased both anchorage-dependent and anchorage-independent growth and significantly increased apoptotic cells in vitro. Moreover, either PEA3 knockdown or MRK-003 GSI treatment significantly reduced tumor growth of MDA-MB-231 xenografts in vivo.
Taken together, the results from this study demonstrate for the first time that Notch-1 and Notch-4 are novel transcriptional targets of PEA3 in breast cancer cells. Targeting of PEA3 and/or Notch pathways might provide a new therapeutic strategy for triple-negative and possibly other breast cancer subtypes.
PMCID: PMC3218952  PMID: 21679465
24.  The Health Effects of Medicare for the Near-Elderly Uninsured 
Health Services Research  2009;44(3):926-945.
To determine whether Medicare enrollment at age 65 has an effect on the health trajectory of the near-elderly uninsured.
Data Sources
Eight biennial waves (1992–2006) of the Health and Retirement Study, a nationally representative panel survey of noninstitutionalized 51–61 year olds and their spouses.
Study Design
We use a quasi-experimental approach to compare the health effects of insurance for the near-elderly uninsured with previously insured contemporaneous controls. The primary outcome measure is overall self-reported health status combined with mortality (i.e., excellent to very good, good, fair to poor, dead).
The change in the trajectory of overall health status for the previously uninsured that can be attributed to Medicare is small and not statistically significant. For every 100 persons in the previously uninsured group, joining Medicare is associated with 0.6 fewer in excellent or very good health (95 percent CI: −4.8, 3.3), 0.3 more in good health (95 percent CI: −3.8, 4.1), 2.5 fewer in fair or poor health (95 percent CI: −7.4, 2.3), and 2.8 more dead (−4.0, 10.0) by age 73. The health trajectory patterns from physician objective health measures are similarly small and not statistically significant.
Medicare coverage at age 65 for the previously uninsured is not linked to improvements in overall health status.
PMCID: PMC2699915  PMID: 19674430
Uninsured; Medicare; health insurance; health status
25.  Isolated sphenoid sinus pathologies – the problem of delayed diagnosis 
Isolated sphenoid sinus pathologies are relatively rare. In the majority of cases, symptoms do not arise in the early stages of the disease or are non-specific, therefore making diagnosis difficult. The aim of this study was to investigate the diagnostic process and the reasons for development of complications in patients with isolated sphenoid sinus pathology.
The clinical data and observation charts of 32 patients were investigated to determine how long the main symptoms of sphenoid pathology had been present before the patients were referred for medical treatment, and the time that elapsed from the first ambulatory medical assessment to the initial diagnosis.
Complaints and symptoms of sphenoid sinus pathology had been present for 10.2 months before the diagnosis was established. Although the duration of complaints in “ORL” (diagnosed by otorhinolaryngologist) and “non-ORL” (diagnosed by other specialists) group of patients was similar (10.8 and 9.5 months on average, respectively), unexpectedly, in the “non-ORL” group of patients, the time necessary for making the initial diagnosis was actually shorter than in the “ORL” group (1.8 vs 4.1 months). At the time of hospital admission, endoscopic examination revealed no abnormalities in 31.2% of patients. In 28.1% of patients the pathological process in the sphenoid sinus was diagnosed only after the onset of complications.
The occult character of the disease and the lack of severe and specific symptoms, rather than the delay in getting extensive diagnostic tests, are responsible for the delayed diagnosis and treatment.
PMCID: PMC3524726
sphenoiditis; isolated lesion; complications

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