A specific allele of the histidine-rich glycoprotein (HRG) locus is linked with elevated plasma levels of HRG in a Dutch family with thrombosis

Recent studies describe families with both elevated plasma HRG levels and thrombosis. In order to study the possibility that allelic variants of the HRG locus are associated with differences in HRG level, we studied linkage between HRG levels and a dinucleotide repeat polymorphism in a Dutch family which was selected on the presence of both thrombosis and elevated plasma HRG levels. No other known risk factors from thrombosis were found in this family. Linkage was calculated between the dinucleotide repeat and the HRG level considering the HRG level as a quantitative phenotype assuming a population prevalence of elevated HRG of 5%. Two classes of HRG levels were defined by a mean and a variance: one class with normal HRG levels and a second class with high HRG levels. Using a mean HRG level of 99% for individuals with a normal HRG level and 145% for individuals with high HRG, a maximum lod score of 4.17 (odds in favour of linkage of 22 000:1) was found at a recombination fraction of 0, indicating linkage. Considering the pedigree, an association was found between the presence of a specific allele (no. 6) of the dinucleotide repeat polymorphism and plasma HRG levels. Family members carrying allele 6 were found to have higher HRG plasma levels compared with family members lacking allele 6 (149% v 109% respectively). We conclude that in this family, linkage is found between the HRG locus and the HRG level, and that a HRG gene coupled to allele 6 of the dinucleotide polymorphism is associated with elevated plasma HRG levels. No evidence was found for a causal relationship between elevated plasma HRG levels and thrombosis in this family.     

Cell-autonomous induction of functional tumor suppressor 15-lipoxygenase 2 (15-LOX2) contributes to replicative senescence of human prostate progenitor cells

Normal human prostatic (NHP) epithelial cells undergo senescence in vitro and in vivo, but little is known about the tissue-specific molecular mechanisms. Here we first characterize young primary NHP cells as CK5(+)/CK18(+) intermediate basal cells that also express several other putative stem/progenitor cell markers including p63, CD44, alpha2beta1, and hTERT. When cultured in serum- and androgen-free medium, NHP cells gradually lose the expression of these markers, slow down in proliferation, and enter senescence. Several pieces of evidence implicate 15-lipoxygenase 2 (15-LOX2), a molecule with a restricted tissue expression and most abundantly expressed in adult human prostate, in the replicative senescence of NHP cells. First, the 15-LOX2 promoter activity and the mRNA and protein levels of 15-LOX2 and its multiple splice variants are upregulated in serially passaged NHP cells, which precede replicative senescence and occur in a cell-autonomous manner. Second, all immortalized prostate epithelial cells and prostate cancer cells do not express 15-LOX2. Third, PCa cells stably transfected with 15-LOX2 or 15-LOX2sv-b, a splice variant that does not possess arachidonate-metabolizing activity, show a passage-related senescence-like phenotype. Fourth, infection of early-passage NHP cells with retroviral vectors encoding 15-LOX2 or 15-LOX2sv-b induces partial cell-cycle arrest and big and flat senescence-like phenotype. Finally, 15-LOX2 protein expression in human prostate correlates with age. Together, these data suggest that 15-LOX2 may represent an endogenous prostate senescence gene and its tumor-suppressing functions might be associated with its ability to induce cell senescence.     

A validated patient reported measure of urinary urgency severity in overactive bladder for use in clinical trials

PURPOSE: Overactive bladder (OAB) is a syndrome consisting of urinary urgency with or without urge incontinence, usually with increased urinary frequency and nocturia. In response to current limitations in OAB clinical research a new patient reported measure of urgency severity associated with OAB has been developed, namely the Indevus Urgency Severity Scale (IUSS). We report the measurement properties of the IUSS. MATERIALS AND METHODS: Validation study data were collected alongside a phase III clinical trial of 20 mg trospium chloride twice daily vs placebo in patients with OAB associated with urge incontinence. We evaluated IUSS item variability, known group, content, criterion and construct validity, test-retest reliability, responsiveness and respondent burden. RESULTS: A total of 658 patients were evaluated at baseline and 579 were reevaluated at week 12. IUSS demonstrated good item variability. Greater urgency severity was associated with increased symptom bother and worse health related quality of life, as measured by the OAB QOL questionnaire. IUSS had a significant positive association with essential clinical and quality of life outcomes, demonstrating content validity. IUSS was highly responsive to a decrease in the average number of patient toilet voids per 24 hours to 7 or fewer toilet voids and average urge incontinence episodes per 24 hours to zero. It discriminated between patients who had above and below the median number of toilet voids and urge incontinence episodes per 24 hours. IUSS also had good test-retest reliability and content validity, and it created minimal respondent burden. CONCLUSIONS: IUSS is a validated patient reported measure of urgency severity for collecting event specific information in the context of a clinical trial.     

Promoting health, building community

As part of its mission to honor human dignity and to care for the poor and vulnerable, Catholic Healthcare Partners (CHP), Cincinnati, has made a systemwide commitment to address housing needs in the communities it serves. A priority for the system is providing safe, affordable housing options for the low-income elderly. CHP's approach goes beyond "bricks and mortar," however. The system aims not only to provide a home for senior adults but also to enrich their lives. Through various activities and support services, CHP's senior living complexes in Kentucky, Ohio, Pennsylvania, and Tennessee offer residents an opportunity to live in a vibrant community. CHP facilities have developed a variety of initiatives to enhance residents' lives. Among these are: spiritual care services, nurses who serve as a resource to low-income elders, a short-stay shelter for seniors in transition, a service referral program, and therapy to help elders remain independent. In order to offer these comprehensive services to senior adults, CHP relies on partnerships with a variety of organizations and on funding from both the federal government and private investors. Especially as the nation's population ages, CHP continues to make its housing ministry a strategic priority.     

The efficacy of different commercially available demineralized bone matrix substances in an athymic rat model

OBJECTIVE: Bone graft substitutes have been developed because there is a limited supply of autogenous graft and the harvesting of iliac crest bone graft is associated with significant morbidity. Currently, there are a number of different commercially available demineralized bone matrix (DBM) products available that have been prepared by different methods and have different carriers. The objective of this study was to compare eight different commercially available DBM products. METHODS: Eight different DBMs were used to attempt a spinal fusion between the L4-L5 transverse processes in athymic rats. There were 10 rats in each group, and 5 rats were killed at both 4 and 8 weeks. Radiographic and histologic analyses were performed. Manual palpation testing was also performed. RESULTS: At 4 weeks, Osteofil Paste had the highest radiographic scores, whereas Grafton Putty had the best radiographic scores at 8 weeks. Conversely, the spines implanted with Allomatrix had the lowest radiographic scores at both 4 and 8 weeks. In regard to forming a spinal fusion confirmed by manual palpation, Osteofil Paste was the most effective at 4 weeks, whereas Grafton Flex and Grafton Putty had the highest rate of fusion at 8 weeks. Conversely, the lowest rates of fusion were seen in the Allomatrix and Grafton Crunch groups. Statistical analysis showed that there were significant differences among the groups seen on radiographs and by manual palpation. Qualitative differences could be appreciated between the groups histologically. CONCLUSION: Significant differences exist among commercially available DBMs in forming a spinal fusion in an athymic rat.     

Breathing and swallowing dynamics across the adult lifespan

BACKGROUND: Aberrations in the physiologic components of normal oropharyngeal swallowing have been linked to aspiration events and to predisposition to aspiration pneumonia, a common, deadly disease in elderly persons. Studies have demonstrated a temporal, physiologic link between breathing and the principal physiologic swallowing components involved in airway protection during swallowing. We developed a normative model of integrated breathing and swallowing patterns using concomitant videofluoroscopic images and nasal respiratory airflow recordings. OBJECTIVES: To establish normative temporal and respiratory-phase pattern relationships between breathing and swallowing in adult human beings across the aging continuum; to relate any alterations in these patterns to swallowing abnormality, an aspiration event during swallowing, and predisposition to aspiration pneumonia; and to develop clinically practical evaluation methods for identifying breathing and swallowing discoordination. SETTING: Fluoroscopy suite in an acute care hospital. PARTICIPANTS: Eighty-two healthy adult volunteers gave informed consent. All eligible healthy volunteers were welcome and were screened for age, race, and sex for equal distribution of each. INTERVENTION: Respiratory-phase patterns and the onset and duration of 11 predetermined swallowing events and associated respiratory activities were studied. All participants' single-liquid barium swallow examinations were studied with simultaneous videofluoroscopy and respiratory recordings. MAIN OUTCOME MEASURES: Onset of each of the 11 predetermined breathing and swallowing events was digitally recorded and analyzed. The phases of breathing before and after swallowing were identified. The presence, depth, and response to airway penetration were recorded and related to respiratory pattern. RESULTS: Four respiratory-phase patterns were identified that changed with advanced age. The correlation analyses of the temporal breathing and swallowing events revealed a normal pattern of 4 clearly distinguishable functional units. Differences in apnea duration and apnea offset occurred with advanced age. CONCLUSION: This research provides evidence for clearly distinguishable patterns and functional groupings of breathing and swallowing events, a necessary first step toward determining whether abnormal breathing and swallowing patterns in patients with dysphagia are associated with health outcome.     

Burkholderia gladioli osteomyelitis in association with chronic granulomatous disease: case report and review

We describe a case of insidious small bone osteomyelitis and soft tissue abscess with Burkholderia gladioli in a 6-year-old Caucasian boy with chronic granulomatous disease. DNA sequencing of the 16S ribosomal RNA gene confirmed the bacterial identification. Clinical cure was achieved with a combination of antimicrobial therapy and surgical debridement. A review of infections caused by Burkholderia spp., other than Burkholderia cepacia complex, in pediatric patients with chronic granulomatous disease is provided.