Definitive Linkage Research Articles

Establishing the Institute of Independent Evaluation of Higher Education in the Russian Federation

The paper presents the results of the search, systematization and analysis of independent higher education evaluation systems that have been developed in the country in the recent decade. The research has been carried out using standardised evaluation mechanisms that adhere to the criteria of mass scale, openness, and stability. The analysis of the independent evaluation of higher education’s present situation revealed certain inconsistencies between the legislative and regulatory framework and real practice. It should be emphasised that, while different processes have now been developed for this type of evaluation, they still require enhancement. The assessment mechanisms themselves need to undergo an external, independent evaluation to ensure their reliability, integrity, and trustworthy evidence. It has been indicated that independent evaluation procedures have jointly developed into a system: the institution of independent evaluation. This system is characterised by integrity, orderliness, and definite linkages. One may consider the aggregating technology of the aforementioned evalu-ations to be the synergistic outcome of the system’s establishment. In order to achieve a synergistic effect on the evaluation of all higher education institutions and educational programmes in the country, the authors suggest a method for aggregating the outcomes of the described evaluation procedures. The obtained research outcomes prove their applicability to the internal and external evaluation of a higher education institution’s performance and to the strategic planning of the development of both the institution and the higher education system.

The Tetraspanin CD9 Shapes Glucocorticoid Sensitivity in Pediatric B-Precursor Acute Lymphoblastic Leukemia

Background: De novo or acquired resistance to glucocorticoids (GCs), the common therapeutic regimens for remission-induction in pediatric B-precursor acute lymphoblastic leukemia, confronts treatment success and is a strong predictor for disease relapse. Discovery of predictive markers and underlying mechanisms of GC resistance could lead to new treatment and prognostic modalities. Aims: This study aims: (1) to demonstrate the association between CD9 expression and GC sensitivity in childhood BCP-ALL; (2) to dissect the underlying mechanisms driving GC resistance; and (3) to discover the possible therapeutic modalities for restoring GC susceptibility. Methods: Ex vivo drug sensitivity profiling to prednisone (Pred) and dexamethasone (Dex) was performed on 6 BCP-ALL cell lines and 18 patient samples with differential CD9 expression. Association of CD9 expression with patient responses to Pred prophase was analyzed in a pediatric BCP-ALL cohort (n=182). Functional impact of CD9 on GC susceptibility was dissected by gain- and loss-of-function experiments in BCP-ALL cells. Mechanistic basis of CD9-driven GC response was investigated through genomics, transcriptomics, and proteomics. Reversal of GC resistance by pathway-targeted agents were explored on BCP-ALL cells and xenograft models. Results: Distinctive differences in the drug sensitivity pattern were found between CD9- and CD9+ BCP-ALL cell lines, with the former showing resistance to GCs but not other chemotherapeutic agents. Concurrently, CD9- primary lymphoblasts exhibited resistance to Dex (IC50s: 2,761 vs. 31 nM) and Pred (IC50s: 8,185 vs. 268 nM) compared with CD9+ samples (positivity defined by the presence of ≥ 20% CD9+ blasts). More Pred poor responders (defined by the presence of ≥ 1×10 9/L circulating lymphoblasts on day 8) were found in CD9- than CD9+ patients (19.4% vs. 6.2%, P=0.018). Subgroup analyses revealed more poor responders with CD9- phenotype were enriched in patients with older age (60% vs. 3.7%, P=0.008), male gender (21.7% vs. 6.7%, P=0.045), higher white blood cell count (66.7% vs. 15.4%, P=0.004), and in those with BCR-ABL1 translocation (100% vs. 12.5%, P=0.024), or not otherwise cytogenetically specified BCP-ALL (30.8% vs. 5.8%, P=0.019). Univariate and multivariate analyses further confirmed CD9 negativity as an independent predictor for GC resistance (OR=5.1, P=0.009). Overexpression of CD9 in CD9- cells (SEM, KOPN-8) by lentiviral transduction significantly enhanced GC sensitivity by 2.8-62.3-fold ( P<0.024), whereas CD9 knockout in CD9+ cells (697) using CRISPR-Cas9 decreased GC susceptibility ( P<0.003). No significant differences in mRNA or protein expression of the GC receptor NR3C1 were identified between CD9+ and CD9- cells, as well as its isoforms or mutants. The cytoplasm-to-nucleus translocation of GC receptor was consistent among cell lines regardless of CD9 expression status, but CD9 was physically interacted with NR3C1. Upon GC stimulation, the presence of CD9 increased the number of DEGs (110 vs. 82 DEGs) and magnitude of GC-responsive genes exclusively detected in the background of CD9 (1.3-18.6-fold; e.g. AKAP13, STAT5A, EZR). CD9- cells showed constitutive activation of the MAPK pathway and could be preferentially restored for GC susceptibility by the MEK1/2 inhibitor trametinib in vitro. BCP-ALL xenograft modeling revealed that, compared to single agent Dex treatment, combination with trametinib significantly reduced the leukemic load in animal transplanted with CD9- SEM but not CD9+ BV-173 cell lines. Ex vivo drug testing further showed that the resistance to GCs in some CD9+ cases could be partially reversed by combination of trametinib and the JAK inhibitor ruxolitinib due to the activation of STAT5. Conclusions: This study provides a definitive linkage of CD9 with GC sensitivity in childhood BCP-ALL mediated through a NR3C1-independent mechanism. CD9- cases could be prone to trametinib combination therapy, whereas CD9+ cases might need a third drug such as ruxolitinib to counteract GC resistance.

Exploring Information communication Technology-enabled travel Pattern in a city region of India

ABSTRACTInformation and Communication Technology (ICT) is advocated to contribute to sustainable transportation by prompting a change in travel patterns. Therefore, using an ICT-enabled city region in India as the study context, the objectives of the study were to examine the influence of ICT on travel patterns in city regions and explore the strategies to enhance ICT usage for positively changed travel patterns. Findings suggest that definite linkages between ICT usage and travel patterns exist. An increase in ICT usage in daily activities of people will enable a significant reduction in trip generation, travel distance and travel time. Strategic interventions including enhancing networking and ICT connectivity, provisioning free Wi-Fi hot spots at important nodal points, and enabling the availability of real-time road transportation-related information can enhance ICT usage leading to a positively changed travel pattern. This is likely to improve traffic movement and reduce congestion contributing to sustainable urban road transportation.

Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 virus and Staphylococcus aureus infections

BackgroundEarly studies indicated that vitamin D (VD) exerted pleiotropic extra-skeletal effects in the airway, but the definite linkage between VD deficiency and airway host responses remains unclear.Methods142 cases of clinical data from Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, were collected to characterize the relationship between VD deficiency and chronic rhinosinusitis (CRS). Based on the clinical observations, 2.5-D airway epithelial organoids cultured at the air–liquid interface (ALI) were used to simulate the effects of VD treatment in the development of airway epithelium and the modulation of the host responses against influenza H1N1 virus (representing viral infections) and Staphylococcus aureus (representing bacterial infections) infections in the airway. The intrinsic mechanisms of VD deficiency underlying epithelial remodeling were mapped by transcriptomic as well as proteomic analyses.ResultsIn this study we observed prevailing VD deficiency among inpatients suffering from CRS, a common disease predominantly characterized by epithelial impairment and remodeling. Relative to control organoids cultured without VD, long-term incubation with VD accelerated basal cell proliferation during nasal epithelial development. Under infectious conditions, VD treatment protected the organoids against influenza H1N1 virus and Staphylococcus aureus invasions by reinforcing the respiratory host defenses, including upregulation of LL37, suppression (or inhibition) of proinflammatory cytokines, strengthening of epithelial integrity, and mucociliary clearance. In silico analysis of transcriptomics and proteomics suggested that VD modulated the epithelial development and remodeling, involving epithelial cell proliferation/differentiation, epithelial–mesenchymal transition (EMT), and cytokine signaling in the immune system, as well as responses to microbe, cell junction organization, and extracellular matrix organization via PTEN signaling, independent of TGF-β signaling.ConclusionsOur findings emphasize the importance of managing VD deficiency in clinical settings for the sake of alleviating pathological epithelial remodeling. Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 and Staphylococcus aureus infections.

KRAS Mutation in Endometriosis-Associated Ovarian Borderline and Malignant Epithelial Tumors

Background: Endometriosis is a common disease among women with the capacity to transform into ovarian neoplasms. KRAS mutation is a keystone in tumor-genesis of many malignant neoplasms. Objectives: In the current study, we investigated KRAS mutations in endometriosis-associated ovarian borderline and malignant epithelial tumors. Methods: The specimens of 42 consecutive patients undergoing a surgical procedure whose final diagnosis comprised endometriosis-associated borderline and malignant epithelial ovarian tumors including 12 borderline epithelial tumors and 30 ovarian epithelial carcinomas were histopathologically reviewed. All cases were evaluated regarding the type of tumor, differentiation and simultaneous presence of endometriosis or atypical endometriosis. DNA extraction from the selected paraffin block was done and mutation of codons 12 and 13 was assessed. Results: Due to the quality of genomic DNA for PCR study was not acceptable in 6 out of 42 cases, among remaining 36 cases, KRAS mutation was observed in 6 cases including 2 cases with mutations in 2nd base of 12th codon (G→T), 3 cases with substitution of G→A in the 2nd base of 12th codon, and one with substitution of G→T in the 1st base of 12th codon. Conclusions: We evaluated the KRAS mutation in the spectrum of ovarian epithelial tumors associated with endometriosis for treatment approaches including targeted therapies. Our results suggested a possible link between KRAS mutation and endometriosis-associated ovarian borderline and malignant tumors but there was no convincing evidence to prove a definite linkage.

Evolution of the Late Cretaceous Nanaimo Basin, British Columbia, Canada: Definitive provenance links to northern latitudes

AbstractAccurate reconstruction of the Late Cretaceous paleogeography and tectonic evolution of the western North American Cordilleran margin is required to resolve the long-standing debate over proposed large-scale, orogen-parallel terrane translation. The Nanaimo Basin (British Columbia, Canada) contains a high-fidelity record of orogenic exhumation and basin subsidence in the southwestern Canadian Cordillera that constrains the tectonic evolution of the region. Integration of detrital zircon U-Pb geochronology, conglomerate clast U-Pb geochronology, detrital muscovite 40Ar/39Ar thermochronology, and Lu-Hf isotopic analysis of detrital zircon defines a multidisciplinary provenance signature that provides a definitive linkage with sediment source regions north of the Sierra Nevada arc system (western United States).Analysis of spatial and temporal provenance variations within Nanaimo Group strata documents a bimodal sediment supply with a local source derived from the adjacent magmatic arc in the southern Coast Mountains batholith and an extra-regional source from the Mesoproterozoic Belt Supergroup and the Late Cretaceous Atlanta lobe of the Idaho batholith. Particularly robust linkages include: (1) juvenile (εHf >+10) Late Cretaceous zircon derived from the southern Coast Mountains batholith; (2) a bimodal Proterozoic detrital zircon signature consistent with derivation from Belt Supergroup (1700–1720 Ma) and ca. 1380 Ma plutonic rocks intruding the Lemhi subbasin of central Idaho (northwestern United States); (3) quartzite clasts that are statistical matches for Mesoproterozoic and Cambrian strata in Montana and Idaho (northwestern United States) and southern British Columbia; and (4) syndepositional evolved (εHf >−10) Late Cretaceous zircon and muscovite derived from the Atlanta lobe of the Idaho batholith. These provenance constraints support a tectonic restoration of the Nanaimo Basin, the southern Coast Mountains batholith, and Wrangellia to a position outboard of the Idaho batholith in Late Cretaceous time, consistent with proposed minimal- fault- offset models (<~1000 km).

The application of forensic geomorphology in rhinoceros poaching investigations in Africa

ABSTRACT South Africa experienced since 2008 high escalations in rhinoceros poaching. It is essential to protect southern Africa’s heritage by developing/adapting new research methods and techniques that can assist prosecutors to improve their successes in achieving convictions. The paper aimed to investigate the use of forensic geomorphology in the context of a poached rhino to assist in the prosecution of suspected poachers in the absence of any DNA linkages. Two experimental study sites mimicked the aspects of the landscape in which rhinoceros normally occur. Trace evidence was removed from the suspects that moved through the landscape in order to verify if any significant similarities could be identified against control samples collected at poaching sites and at locations based on the terrain utilized by the poachers during the simulated poaching incident. The paper concluded that a linkage could be recognized between the selected landscape and the collected trace evidence. The results indicate that the first experimental study site illustrated a definite linkage between the suspects and the poaching site, whereas the second experimental study site suggested that there was a possibility that a linkage could be made. This study only used inorganic material such as sand grains to link suspects to scenes.

Does adding claims to EMR data improve comorbidity burden capture? A Concerto Health AI Definitive Oncology Dataset and Symphony Linkage Study.

e18186 Background: Current commercially available oncology electronic medical record (EMR) databases typically have limited data on patient comorbidities which may limit the ability to accurately include/exclude these patients or adjust for these factors in health outcomes research. The objective of this study was to investigate the impact of identifying comorbidities using both EMR and claims data. Methods: The Concerto Health AI Definitive Oncology Dataset is a deeply curated cohort of patients (pts) derived from a wide range of oncology practices throughout the United States. Concerto Health AI has a co-exclusive partnership with ASCO CancerLinQ and collects data from multiple other sources. These data were deterministically linked to US Symphony Health’s (SH) Integrated Dataverse, an anonymized, HIPAA-compliant data set. Advanced (stage IIIb/IV) non-small cell lung cancer (aNSCLC) pts with data curated via manual review by nurse practitioners and diagnosed after 2011 were included. Comorbidities within 1 year prior to advanced diagnosis were categorized using the Charlson Comorbidity Index (CCI). The impact of the claims linkage on inclusion/exclusion (I/E) criteria was assessed by applying criteria from the IMpower150 clinical study and exploring changes to survival estimates, as calculated using Kaplan-Meier method. Results: A total of 11,373 aNSCLC pts were identified, of which 7,887 pts were linked to SH. Using only Concerto, 278 pts (3.5%) had a CCI score ≥1, whereas 3,033 pts (38.4%) had a CCI score ≥1 using linked Concerto and SH. After applying I/E criteria from IMpower150 using available data elements from Concerto only, 88 pts were identified matching the trial criteria, with a median survival of 15.8 mths (95% CI: 14.4, 21.0). When leveraging Concerto and SH, 8 (9.1%) more patients were excluded (n = 80) based on comorbidities (6 pts) and oral medications (2 pts), with a median survival of 16.6 mths (95% CI: 14.6, 23.4). Conclusions: The addition of claims to EMR enhanced the ability to identify patient comorbidities given the longer history and broader physician specialty of claims data. Future real-world studies should explore linkages across datasets to better capture comorbidities for patient selection and adjustment.

Environmental sources of community-acquired legionnaires' disease: A review.

Most Legionnaires' disease in the US and abroad is community-acquired and believed to be sporadic, or non-outbreak associated. Most patients are exposed to numerous water sources, thus making it difficult to focus environmental investigations. Identifying known sources of sporadic community-acquired Legionnaires' disease will inform future sporadic Legionnaires' disease investigations as well as highlight directions for research. The objective is to summarize and rank sporadic Legionnaires' disease sources based on the level of linkage between the environmental source and cases. A PubMed search was conducted using the search terms legion* and (origins or source or transmission) and (sporadic or community-acquired). Studies of nosocomial and/or outbreak-associated disease were excluded from this review. Definite, probable, possible and suspect ranks were assigned to sources based on evidence of linkage to sporadic Legionnaires' disease. The search yielded 196 articles and 47 articles were included in the final review after application of exclusion criteria. A total of 28 sources were identified. Of these, eight were assigned definite rank including residential potable water and car air-conditioner water leakage. Probable rank was assigned to five sources including solar-heated potable water and soil. Possible rank was assigned to nine sources including residential potable water and cooling towers. Suspect rank was assigned to 20 sources including large building water systems and cooling towers. Residential potable water, large building water systems and car travel appear to contribute to a substantial proportion of sporadic Legionnaires' disease. Cooling towers are also a potentially significant source; however, definitive linkage to sporadic cases proves difficult. The sources of sporadic Legionnaires' disease cannot be definitively identified for most cases.

Examining the Relationship Between Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome in Nondiabetic Subjects

ABSTRACTObjective: Nonalcoholic fatty liver disease (NAFLD) is considered by some to be the hepatic manifestation of the metabolic syndrome (MS). However, others believe NAFLD is a distinct entity that actually initiates MS. Whichever is true, a definite linkage exists between both is generally accepted based upon the frequency of common occurrence and realization that insulin resistance (IR) is and realization that. The objective is to better understand the relationship between NAFLD and MS. Specifically, is there any concrete evidence that development of NAFLD precedes MS or vice versa? Another goal was to better comprehend capabilities of circulating aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and their ratio used commonly for diagnosis of NAFLD.Methods: Data from 288 participants with fasting blood glucose (FBG) levels below the diabetic level (<125 mg/dL) and AST and ALT values in the normal range (<40 U/L) were examined. Correlations between ALT and AST and their ratio as independent variables with a variety of metabolic parameter were evaluated and compared.Results: Like FBG, many significant positive correlations among glucose–insulin indices, body composition, blood pressure, dyslipidemias, and inflammation were discovered using ALT, and less so with AST, as the independent variable. In some cases, even stronger correlations in a negative direction with IR and MS were found with the ratio AST/ALT. Corroboration occurred when values in the lowest and highest quartiles of ALT and AST/ALT readings showed appropriate statistically significant differences. Conclusions: The findings here suggest that both NAFLD and the MS very early in development have a common inciting mechanism(s)—most likely IR. Accordingly, the early concurrent temporal results are consistent with the concept that NAFLD is a hepatic manifestation of the IR associated with the MS. They do not exclude the possibility that once some liver functional adjustments take place, several aspects of the MS are bolstered further, perhaps via intensified heightening of IR.

2013 multistate outbreaks of Cyclospora cayetanensis infections associated with fresh produce: focus on the Texas investigations.

The 2013 multistate outbreaks contributed to the largest annual number of reported US cases of cyclosporiasis since 1997. In this paper we focus on investigations in Texas. We defined an outbreak-associated case as laboratory-confirmed cyclosporiasis in a person with illness onset between 1 June and 31 August 2013, with no history of international travel in the previous 14 days. Epidemiological, environmental, and traceback investigations were conducted. Of the 631 cases reported in the multistate outbreaks, Texas reported the greatest number of cases, 270 (43%). More than 70 clusters were identified in Texas, four of which were further investigated. One restaurant-associated cluster of 25 case-patients was selected for a case-control study. Consumption of cilantro was most strongly associated with illness on meal date-matched analysis (matched odds ratio 19·8, 95% confidence interval 4·0-∞). All case-patients in the other three clusters investigated also ate cilantro. Traceback investigations converged on three suppliers in Puebla, Mexico. Cilantro was the vehicle of infection in the four clusters investigated; the temporal association of these clusters with the large overall increase in cyclosporiasis cases in Texas suggests cilantro was the vehicle of infection for many other cases. However, the paucity of epidemiological and traceback information does not allow for a conclusive determination; moreover, molecular epidemiological tools for cyclosporiasis that could provide more definitive linkage between case clusters are needed.

Brief Report on the Effect of Environment on Prevalence of Auto Immune Diseases in Veterans

The role of environment has been widely speculated to play a role in the pathogenesis of auto-immune diseases such as Lupus, Rheumatoid Arthritis, Psoriasis, etc. However, no definitive linkage has been found so far. In order to explore this possible association, a retrospective study was undertaken in veterans who had fought in various wars ranging from WWII to Gulf War and the prevalence of auto-immune diseases ascertained. This was compared to the prevalence in civilian populations. Except for auto-immune thyroiditis, no difference was found in veterans who had been exposed to different environments and between them and civilians in the US. A larger study will be needed to explore this lack of association.

In Vivo Occupancy of Dopamine D3 Receptors by Antagonists Produces Neurochemical and Behavioral Effects of Potential Relevance to Attention-Deficit–Hyperactivity Disorder

Dopamine D(3) receptors have eluded definitive linkage to neurologic and psychiatric disorders since their cloning over 20 years ago. We report a new method that does not employ a radiolabel for simultaneously defining in vivo receptor occupancy of D(3) and D(2) receptors in rat brain after systemic dosing using the tracer epidepride (N-[[(2S)-1-ethylpyrrolidin-2-yl]methyl]-5-iodo-2,3-dimethoxybenzamide). Decreases in epidepride binding in lobule 9 of cerebellum (rich in D(3) receptors) were compared with nonspecific binding in the lateral cerebellum. The in vivo occupancy of the dopamine D(3) receptors was dose dependently increased by SB-277011A (trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide) and U99194 (2,3-dihydro-5,6-dimethoxy- N,N-dipropyl-1H-inden-2-amine). Both antagonists increased extracellular levels of acetylcholine (ACh) in the medial prefrontal cortex of rats and modified brain-tissue levels of ACh and choline. Consistent with these findings, the D(3) receptor antagonists enhanced the acquisition of learning of rats either alone or in the presence of the norepinephrine uptake blocker reboxetine as with the attention-deficit-hyperactivity disorder (ADHD) drug methylphenidate. Like reboxetine, the D(3) receptor antagonists also prevented deficits induced by scopolamine in object recognition memory of rats. Mice in which the dopamine transporter (DAT) has been deleted exhibit hyperactivity that is normalized by compounds that are effective in the treatment of ADHD. Both D(3) receptor antagonists decreased the hyperactivity of DAT(-/-) mice without affecting the activity of wild type controls. The present findings indicate that dopamine D(3) receptor antagonists engender cognition-enhancing and hyperactivity-dampening effects. Thus, D(3) receptor blockade could be considered as a novel treatment approach for cognitive deficits and hyperactivity syndromes, including those observed in ADHD.

Identification of Tool Marks of a Sickle on a Telephone Cable

Linkage of a cutting tool (a sickle) with a telephone cable of 100 pairs of copper wires is reported in a case of theft of a telephone cable. Telephone cables contain numerous insulated copper wires of small diameter inside an outer covering and are stolen for the relatively precious copper. The cutting pattern of the cable can only point to the type of the tool but because of the large number of copper wires, it is practically difficult to make a definite linkage with the tool used to cut the cable by comparing the tool marks. The present work reports the successful attempt of the authors in establishing a definite linkage of a stolen telephone cable with a sickle recovered from the suspects. Spot microchemical test was performed for detection of copper on the blade of the sickle, and then tool mark comparison was performed to link the tool marks on the metal strip inside the outer covering of the cable to the blade of the sickle.

Re–Os isotope and highly siderophile element systematics of the Paraná continental flood basalts (Brazil)

Basalts of the Paraná continental flood basalt (PCFB) province erupted through dominantly Proterozoic continental crust during the Cretaceous. In order to examine the mantle source(s) of this major flood basalt province, we studied Os, Sr, Nd, and Pb isotope systematics, and highly siderophile element (HSE) abundances in tholeiitic basalts that were carefully chosen to show the minimal effects of crustal contamination. These basalts define a precise Re–Os isochron with an age of 131.6±2.3Ma and an initial 187Os/188Os of 0.1295±0.0018 (γ187Os=+2.7±1.4). This initial Os isotopic composition is considerably more radiogenic than estimates of the contemporary Depleted Mantle (DM). The fact that the Re–Os data define a well constrained isochron with an age similar to 40Ar/39Ar age determinations, despite generally low Os concentrations, is consistent with closed-system behavior for the HSE. Neodymium, Sr, and Pb isotopic data suggest that the mantle source of the basalts had been variably hybridized by melts derived from enriched mantle components. To account for the combined Os, Nd, Sr, and Pb isotopic characteristics of these rocks, we propose that the primary melts formed from metasomatized asthenospheric mantle (represented by arc-mantle peridotite) that underwent mixing with two enriched components, EM-I and EM-II. The different enriched components are reflected in minor isotopic differences between basalts from southern and northern portions of the province.The Tristan da Cunha hotspot has been previously suggested to be the cause of the Parana continental flood basalt magmatism. However, present-day Tristan da Cunha lavas have much higher 187Os/188Os isotopic compositions than the source of the PCFB. These data, together with other isotopic and elemental data, preclude making a definitive linkage between the Tristan plume and the PCFB.

The challenges of finding the gene responsible for a rare, autosomal dominant gastric cancer susceptibility syndrome

Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS) is a newly described, rare autosomal dominant syndrome, characterized by fundic gland polyposis with occasional hyperplastic and adenomatous polyps. We diagnosed GAPPS in a large Australian (Family 1) and two smaller North American families (Family 2 and 3). Mutations in APC, MUTYH, CDH1, SMAD4, BMPR1A, STK11 and PTEN were excluded in all families by sequence analysis of exons and flanking regions, as well as by assays for deletion or duplication of exons. We mapped the GAPPS gene in Family 1 by linkage analysis (LOD score 4.21) to a 20Mb region which contains about 60 genes. Short tandem repeat genotyping showed that the affected members of Family 2 share a haplotype in this 20Mb region, but analysis of Affymetrix SNP 6.0 data from three affected members of Family 2 showed that they also shared several other regions of the genome. However, both Family 2 and 3 are too small for definitive linkage analysis. We have carried out full exome sequencing for three affected individuals in Family 1 (and targeted sequencing of the linked region in another individual), and of three affected members of Family 2. We did not find any rare coding or splice site variants in the linked region that were shared by all affected members of Family 1; nor any from the same region in both affected members of Family 2. All coding exons and miR genes in the linked region have been sequenced at least 30X at every base, or by Sanger sequencing, except for seven exons for which Sanger sequencing is yet to be completed. We will also use Sanger sequencing to improve the coverage of exons in the linked region in Family 2. However, our current hypothesis is that non-coding mutations in the linked region are responsible for the GAPPS syndrome in both Families 1 and 2 and so whole genome sequence analysis for two affected members in Family 1 has been performed and analysis is underway.

Pathogens and Chronic or Long-Term Neurologic Disorders

Infections of the central nervous system may provoke glial and autoimmune responses but a definitive linkage between these infections and the pathogenesis of chronic neurologic disorders is still elusive. There are controversial reports implicating infectious agents in the pathogenetic mechanisms of chronic or long-term neurologic disorders, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and autistic spectrum disorders, but the specific role of bacterial or viral infections in the pathogenesis of these medical entities has not been fully elucidated. Up till now, the evidence is distant from definite, but certain cases may be attributed to infections in the millieu of multiple toxic events such as trauma, nutritional deficits, immune dysregulation and excitotoxicity in genetically vulnerable indiniduals. There is an ongoing debate concering the direct involvement of various infectious agents in the neurodegenerative and neurobehavioral diseases pathogenesis and/or their contribution to the deterioration of the disease or co-morbidity in these patients. These patients are exceptionally difficult to be treated by using single therapeutic modalities, because their disese is multifocal and treatment is aimed to control signs and symptoms rather than the true causes of the disease and its progressive course. Furthermore, even if these causative links were indetifiable, our therapeutic interventions would come too late due to the irreversible damages at the time of the initiation of treatment. Our aim is to comprehensively review all available data suggesting that infections could be common antecedent events of progressive neurologic degenerative or behavioural diseases.

An Analysis of 20 Years of Radiation-Related Health Care Complaints in Texas for the Purposes of Quality Improvement

In an effort to reveal the possible underlying causes of radiation-related health care complaints in the State of Texas, complaint data were evaluated using historical Texas Department of Health-Bureau of Radiation Control (TDH-BRC) reports. A major aim of the study was to generate a summary of the most commonly reported complaints that might be generalized to health care providers using sources of radiation across Texas. A generalizable list of common complaints would be a valuable tool for education and prevention programs, serving to possibly reduce the overall incidence of radiation-related medical complaints. Descriptive text summary reports of complaints were obtained from the TDH-BRC for the 20-y period inclusive of 1981 to 2001. The information was systematically coded into a computerized database. During the 20-y period of study, 481 health care-related complaints were identified, with approximately 74% consisting of claims of an "uncredentialed technician" (39%), "overexposure" (21%), or "regulatory violation" (14%). The most common categories of complaints imply some patient understanding or knowledge of the credentialing requirements of workers, the applicable dose limits, or the regulatory requirements associated with medical procedures. Since it is unlikely that an average patient would be aware of such issues, the findings suggest the complaints are not actually indications of the inappropriate uses of radiation, but are rather based on the patient's broader perception of services rendered. Most of the complaints levied during the period of study were done so anonymously (58%) and were levied against a generic facility (61%) rather than a specific technician (5%), doctor (4%), or student (1%). Approximately 61% of the complaints resulted in the issuance of a notice of violation upon investigation by the TDH-BRC, but the available data did not permit definitive linkage between the initial complaint and the violation issued. Taken in aggregate, the analysis suggests that improved communications between health care providers and the patients they serve could possibly serve to prevent future complaints. Although the analysis was limited to the data from a single state, the results may be of use to quality assurance programs on a broader scale because of the objective identification of likely common issues. Possible options for improving the means of systematically collecting initial compliant data in the future are also discussed.

Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia

Autosomal dominant hereditary spastic paraplegia (AD HSP) linked to chromosome 12q (SPG10) is caused by mutations in the neuronal kinesin heavy-chain KIF5A gene. This is a rare cause of AD HSP, and only two disease-causing mutations have been reported thus far. In both instances, affected individuals harboring mutations in the KIF5A gene displayed symptom onset at a very early age. Here we present the results of clinical and genetic analyses of a large kindred with uncomplicated AD HSP. We were able to establish a definitive linkage to the SPG10 locus, and sequencing of the KIF5A gene revealed a heterozygous missense mutation 1,035 A>G in exon 10, resulting in tyrosine-to-cysteine substitution. This mutation is located in a highly conserved kinesin motor domain of the neuronal kinesin heavy-chain protein, but in contrast to two previously reported missense mutations, the age of symptom onset in our family was much later, with an average age of 36.1+/-4 years. Our results demonstrate that mutations in the KIF5A gene can also be associated with an adult age of onset of AD HSP.

A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17

Over 30 different mutations have now been identified in MAPt that cause frontotemporal dementia (FTD). However, there are several families with FTD that show definite linkage to the region on chromosome 17 that contains MAPt, in which no mutation(s) has been identified. Although these families could have a complex mutation of the MAPt locus that has evaded detection it is also possible that another gene in this region is associated with FTD. This possibility is supported by neuropathological findings in these families, which consist of neuronal inclusions that are immunoreactive for ubiquitin (ub-ir) but not for tau. In addition to neuronal cytoplasmic inclusions, several chromosome 17-linked families are reported to have ub-ir neuronal intranuclear inclusions (NII); a finding which is uncommon in sporadic FTD. Here, we describe detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions. We have demonstrated that this family is linked to a 19.06 cM region of chromosome 17q21 with a maximum multipoint LOD score of 3.911 containing MAPt. By combining the results of our genetic analysis with those previously published for other families with similar pathology, we have further refined the minimal region to a 3.53 cM region of chromosome 17q21. We did not identify point mutations in MAPt by direct sequencing or any gross MAPt gene alterations using fluorescent in situ hybridization. In addition, tau protein extracted from members of this family was unremarkable in size and quantity as assessed by western blotting. Neuropathological characterization of the ub-ir NII in this family shows that they are positive for promyelocytic leukaemia protein (PML) and SUMO-1 that suggests that these inclusions form in the nuclear body and suggests a possible mechanism of neurodegeneration in tau-negative FTD linked to chromosome 17q21.