No association between the lipoprotein lipase S447X polymorphism and Alzheimer's disease

Results from various genetic association studies of the lipoprotein lipase (LPL) S447X polymorphism and Alzheimer's disease (AD), range from a statistically significant negative association of clinically examined patients to a non-significant but consistent trend for under-representation of the X447 allele in neuropathologically confirmed subjects. In this report we have compared the distribution of the above polymorphism in an independent group of clinically diagnosed AD patients, including a subgroup where the disease was pathologically confirmed, and a spousal control group. No statistically significant differences emerged from this comparison. We conclude that LPL cannot be a major factor in pathogenesis of AD.     

Greek McGill Pain Questionnaire: validation and utility in cancer patients

In 1968, Melzack and Casey suggested that there are three major psychological dimensions of pain: sensory, affect, evaluative. These categories interact with one another to provide quantitative and qualitative information on the components of pain. In 1975, Melzack developed the McGill Pain Questionnaire, which is composed of four major parts and evaluates the qualities of pain. The aim of this study was to assess the applicability, reliability, and validity of the McGill Pain Questionnaire on a sample of Greek cancer patients receiving palliative treatment. It was administered to 114 cancer patients before the initiation of the palliative treatment, and then to 80 cancer patients during the treatment 7 days later. The results indicated that scale reliability was very good (0.95-0.97). During the pretreatment period, correlations between Present Rating Index (PRI), Present Pain Intensity (PPI), and Number of Words Chosen (NWC) ranged between 0.42 and 0.92. During the post-treatment time, the correlations ranged between 0.28 and 0.91. Only 21.8% of the words met a criterion of 30% for representativeness on the first administration of the questionnaire, and 9% met this criterion on the second. Validity was satisfactory (P < 0.005) according to "responsiveness to changes in time", as there was a statistical difference between the pretreatment and post-treatment time. Patients presented a desirable level of convergent construct validity (P < 0.05) concerning their performance status. Exploratory factor analysis was examined and two factors with eigenvalue over 1 were extracted, and they accounted for 95.2% of the variance. These results support the Greek-MPQ as a reliable and valid measure for evaluating the qualities of cancer pain in patients receiving palliative care.     

Identification of the polycomb group protein SU(Z)12 as a potential molecular target for human cancer therapy

We have previously identified SU(Z)12 as an E2F target gene. Because many E2F target genes encode proteins that are critical for the control of cell proliferation, we have further characterized the regulation and expression of SU(Z)12. To understand the molecular mechanisms responsible for expression of SU(Z)12 mRNA, we have analyzed the promoter region. We found that the SU(Z)12 gene is controlled by dual promoters, one of which functions bidirectionally. In addition to the E2F binding site, we have identified two binding sites for T cell factor (TCF)/beta-catenin complexes. Using gel mobility shift assays, we demonstrated that both TCF sites can be bound by TCF4. TCF/beta-catenin complexes have been shown to be a critical regulator of gene expression in tumors of the colon, breast, and liver. Accordingly, we have used chromatin immunoprecipitation assays to confirm that TCF4/beta-catenin complexes are bound to the SU(Z)12 promoter in colon cancer cells but not in HeLa cells. We next adapted the chromatin immunoprecipitation assay for use with primary colon tumor samples, and, using matched pairs of normal and tumor tissue obtained from several different colon cancer patients, we demonstrate that levels of beta-catenin bound to the SU(Z)12 promoter are increased in colon tumors. Finally, we show that the SU(Z)12 mRNA is up-regulated in a number of different human tumors, including tumors of the colon, breast, and liver. Recent studies have found that SU(Z)12 is a component of the Drosophila ESC-E(Z) and the human EED-EZH2 Polycomb chromatin remodeling complexes. Therefore, we suggest that SU(Z)12, which may modulate the tumor phenotype by changing gene expression profiles, may be a logical target for the design of a new antitumor agent     

Adeno-associated virus serotype 2-mediated gene transfer to the parotid glands of nonhuman primates

Salivary glands (SGs) are promising gene transfer targets with potential clinical applicability. Previous experiments in rodents using recombinant serotype 2 adeno-associated viral (rAAV2) vectors have demonstrated relatively stable transgene-encoded protein levels after SG gene transfer. In the present study, we examine direct SG administration of rAAV2 vectors encoding rhesus macaque erythropoietin (RhEPO) to the parotid glands of nonhuman primates using two different doses (n = 3 per group; 1 x 10(10) or 3 x 10(11) particles/gland, respectively). Gene transfer had no negative effects on general macaque physiology (e.g., weight, complete blood count, and serum chemistry). Macaques were euthanized 6 months after vector administration and complete necropsy and pathology assessments were performed, revealing no vector-related pathological lesions in any of the examined organs. In the high-dose group, RhEPO expression increased quickly (i.e., by week 1) and levels remained relatively stable both in serum and saliva until the end of the study. Serum-to-saliva ratios of RhEPO revealed secretion of the transgene product into the bloodstream, but not to the extent previously observed in mice. Furthermore, the kinetic results were not predicted by those observed in murine SGs. With respect to viral biodistribution, at necropsy vector was found overwhelmingly in the targeted parotid gland ( approximately 100 times more than levels in other tissues, most of which were similar to tissue levels in nontreated animals). We conclude that administration of modest doses of rAAV2 vectors to SGs for therapeutic purposes can be accomplished without significant or permanent injury to the targeted gland or to distant organs of nonhuman primates.     

The average cumulative risks of breast and ovarian cancer for carriers of mutations in BRCA1 and BRCA2 attending genetic counseling units in Spain.

PURPOSE: It is not clear that the published estimates of the breast and ovarian cancer penetrances of mutations in BRCA1 and BRCA2 can be used in genetic counseling in countries such as Spain, where the incidence of breast cancer in the general population is considerably lower, the prevalence of BRCA2 mutations seems to be higher, and a distinct spectrum of recurrent mutations exists for both genes. We aimed to estimate these penetrances for women attending genetic counseling units in Spain. EXPERIMENTAL DESIGN: We collected phenotype and genotype data on 155 BRCA1 and 164 BRCA2 mutation carrier families from 12 centers across the country. Average age-specific cumulative risks of breast cancer and ovarian cancer were estimated using a modified segregation analysis method. RESULTS: The estimated average cumulative risk of breast cancer to age 70 years was estimated to be 52% [95% confidence interval (95% CI), 26-69%] for BRCA1 mutation carriers and 47% (95% CI, 29-60%) for BRCA2 mutation carriers. The corresponding estimates for ovarian cancer were 22% (95% CI, 0-40%) and 18% (95% CI, 0-35%), respectively. There was some evidence (two-sided P = 0.09) that 330A>G (R71G) in BRCA1 may have lower breast cancer penetrance. CONCLUSIONS: These results are consistent with those from a recent meta-analysis of practically all previous penetrance studies, suggesting that women with BRCA1 and BRCA2 mutations attending genetic counseling services in Spain have similar risks of breast and ovarian cancer to those published for other Caucasian populations. Carriers should be fully informed of their mutation- and age-specific risks to make appropriate decisions regarding prophylactic interventions such as oophorectomy.     

The Application of Science- and Risk-Based Concepts to Drug Substance Stability Strategies

The International Conference on Harmonization (ICH) has provided practical guidance on the amount and type of drug substance stability data needed to support marketing applications (International Conference on Harmonization 2001, 2002, 2003a, b). Additional guidance has been issued by the World Health Organization (WHO 2009). Recent scientific advances and practices have resulted in improved scientific understanding of the chemical and physical attributes that contribute directly or indirectly to drug substance stability. Combining this improved understanding with the science- and risk-based approaches detailed in ICH Q8, Q9, and Q10 allows for alternative and more scientifically driven approaches to meet the scientific and regulatory objectives for drug substance stability (International Conference on Harmonization 2005, 2008, 2009). In this paper, proposals are presented to more fully leverage enhanced product knowledge to design improved stability strategies. The chemical and physical attributes that potentially impact drug substance stability are discussed, and strategies that leverage accelerated stability studies are presented.     

Early biomechanical markers of postural instability in Parkinson's disease

Current clinical assessments do not adequately detect the onset of postural instability in the early stages of Parkinson's disease (PD). The aim of this study was to identify biomechanical variables that are sensitive to the effects of early Parkinson's disease on the ability to recovery from a balance disturbance. Ten adults diagnosed with idiopathic PD and no clinically detectable postural instability, and ten healthy age-range matched controls (HC) completed the study. The first step in the response to a backwards waist pull was quantified in terms of strategy, temporal, kinematic, kinetic, and center of pressure (COP) variables. People with PD, compared to HC, tended to be less consistent in the choice of stepping limb, utilized more time for weight shift, used a modified ankle joint motion prior to liftoff, and the COP was further posterior at landing. The study results demonstrate that PD changes the response to a balance disturbance which can be quantified using biomechanical variables even before the presence of clinically detectable postural instability. Further studies are required to determine if these variables are sensitive and specific to postural instability.     

Traumatic tricuspid insufficiency: a case report with a review of the literature.

Traumatic tricuspid insufficiency, a rare complication of blunt chest trauma, has been reported with increasing frequency during the last 40 years. Automobile accidents are the leading cause of traumatic tricuspid valve regurgitation. The most frequently reported injury is chordal rupture, followed by rupture of the anterior papillary muscle and leaflet tear, primarily of the anterior leaflet. In the acute phase of the injury, the traumatic lesion may go undetected. In the chronic phase many patients remain asymptomatic and others exhibit symptoms and signs of moderate to severe right heart failure. Clinically overt right heart failure has been the traditional indication for surgery, which usually consisted of tricuspid valve replacement. More recently, a more aggressive strategy, with surgical repair of the valve performed before deterioration of the right ventricular function occurs, has been advocated.     

The Hospital Anxiety and Depression Scale in Greek cancer patients: psychometric analyses and applicability

Goals of work The aim of the present study was to validate the Greek version of the Hospital Anxiety and Depression Scale (HAD) in a palliative care unit.Patients and methods The scale was translated with the forward-backward procedure to Greek. It was administered twice, with a 1-week interval, to 120 patients with advanced cancer. Together with the HAD scale, the patients also completed the Spielberger State-Anxiety Scale (STAI-S).Main results Factor analyses identified a two-factor solution corresponding to the original two subscales of the HAD, which were found to be correlated. The Greek version of the HAD had Cronbachs alphas for the anxiety and depression scales of 0.887 and 0.703, respectively. Validity as performed using known-group analysis showed good results. Both anxiety and depression subscales discriminated well between subgroups of patients differing in disease severity as defined by ECOG performance status. Correlations between the HAD scale and the STAI-S was 0.681 for the anxiety subscale and 0.485 for the depression subscale.Conclusions These psychometric properties of the Greek version of the HAD scale confirm it as a valid and reliable measure when administered to patients with advanced cancer.     

Age and education adjusted normative data and discriminative validity for Rey’s Auditory Verbal Learning Test in the elderly Greek population

Rey’s Auditory Verbal Learning Test (RAVLT) is a widely used neuropsychological test to assess episodic memory. In the present study we sought to establish normative and discriminative validity data for the RAVLT in the elderly population using previously adapted learning lists for the Greek adult population. We administered the test to 258 cognitively healthy elderly participants, aged 60–89 years, and two patient groups (192 with amnestic mild cognitive impairment, aMCI, and 65 with Alzheimer’s disease, AD). From the statistical analyses, we found that age and education contributed significantly to most trials of the RAVLT, whereas the influence of gender was not significant. Younger elderly participants with higher education outperformed the older elderly with lower education levels. Moreover, both clinical groups performed significantly worse on most RAVLT trials and composite measures than matched cognitively healthy controls. Furthermore, the AD group performed more poorly than the aMCI group on most RAVLT variables. Receiver operating characteristic (ROC) analysis was used to examine the utility of the RAVLT trials to discriminate cognitively healthy controls from aMCI and AD patients. Area under the curve (AUC), an index of effect size, showed that most of the RAVLT measures (individual and composite) included in this study adequately differentiated between the performance of healthy elders and aMCI/AD patients. We also provide cutoff scores in discriminating cognitively healthy controls from aMCI and AD patients, based on the sensitivity and specificity of the prescribed scores. Moreover, we present age- and education-specific normative data for individual and composite scores for the Greek adapted RAVLT in elderly subjects aged between 60 and 89 years for use in clinical and research settings.