Effects of age-based movement on the estimation of growth assuming random-at-age or random-at-length data.

Simulation methods were used to generate paired data from a simulated population that included the age-based process of movement and the length-based process of gear selection. The age-based process caused bias in the estimates of growth parameters assuming random at length, even when relatively few age classes were affected. Methods that assumed random at age were biased by the subsequent inclusion of the length-based process of gear selection. Additional knowledge of the age structure of the sampled area is needed to ensure an unbiased estimate of the growth parameters when using the length-conditional approach in the presence of age-based movement. Estimates of the variability in the length-at-age relationship were better estimated with the length-conditional than the traditional method even when the assumptions of random at length were violated. Inclusion of paired observations of length and associated age inside the population dynamics model may be the most appropriate way of estimating growth.

Quantitation OF ARGS aggrecan fragments in synovial fluid, serum and urine from osteoarthritis patients.

OBJECTIVE: To characterise ARGS neoepitope concentrations in various matrices from patients with knee osteoarthritis (OA) and assess performance of an immunoassay to facilitate clinical development of therapeutics affecting the A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) pathway. DESIGN: Matched sera, urine, and synovial fluid (SF) (surgical subjects only) were collected from healthy subjects, subjects with knee OA (non-surgical OA), and OA subjects undergoing total knee replacement (OA-TKR; n = 20 per group). Diurnal and inter-day variation was evaluated in the non-surgical OA group over 3 separate visits. Serum and urine samples were collected on two visits for the OA-TKR group with SF taken only at the time of surgery. ARGS neoepitope was quantitated using an optimized immunoassay. RESULTS: Serum ARGS neoepitope concentrations were elevated in OA-TKR subjects compared to non-surgical OA subjects (P = 0.005) and healthy subjects (P = 0.0002). Creatinine corrected urinary ARGS neoepitope concentrations were more variable, but were also elevated in the OA-TKR subjects compared to healthy subjects (P = 0.008). No significant diurnal effect or inter-day variance was observed in serum or urine. Serum ARGS neoepitope concentrations correlated with age (P = 0.0252) but not with total number of joints with OA involvement. SF ARGS neoepitope concentrations correlated with Western Ontario and MacMaster OA Index (WOMAC) stiffness score (P = 0.04) whereas a weaker, non-significant trend towards positive correlation with combined WOMAC score and the number of concurrent joints was observed. CONCLUSIONS: This study utilized a sensitive and robust assay to evaluate ARGS neoepitope concentrations in various matrices in OA patients and healthy volunteers. ARGS neoepitope appears promising as a prognostic/stratification marker to facilitate patient selection and as an early pharmacodynamic marker for OA therapeutic trials.

Design and Characterisation of Titanium Nitride Subarrays of Kinetic Inductance Detectors for Passive Terahertz Imaging.

We report on the investigation of titanium nitride (TiN) thin films deposited via atomic layer deposition (ALD) for microwave kinetic inductance detectors (MKID). Using our in-house ALD process, we have grown a sequence of TiN thin films (thickness 15, 30, 60 nm). The films have been characterised in terms of superconducting transition temperature T c , sheet resistance R s and microstructure. We have fabricated test resonator structures and characterised them at a temperature of 300 mK. At 350 GHz, we report an optical noise equivalent power NEP opt ≈ 2.3 × 10 - 15 W / Hz , which is promising for passive terahertz imaging applications.

The adaptor protein TRADD activates distinct mechanisms of apoptosis from the nucleus and the cytoplasm.

TNFR1 associated death domain protein (TRADD) contains an N-terminal TRAF binding domain and a C-terminal death domain along with nuclear import and export sequences that cause shuttling between the cytoplasm and nucleus. The death domain of TRADD contains the nuclear import sequence and expression of the core death domain (nuclear TRADD) results in exclusive nuclear localization and activation of a distinct apoptotic pathway. Cytoplasmic TRADD activates apoptosis through Fas-associated death domain protein (FADD) and caspase-8 activation that was blocked by caspase inhibitors or dominant-negative FADD. These inhibitors did not inhibit death induced by nuclear TRADD, which could only be inhibited by combining caspase inhibitors and a serine protease inhibitor. The pathway activated by nuclear TRADD requires caspase-9 catalytic activity. However, apoptosis activating factor deficiency confers only partial protection from death. This pathway represents an alternate means by which TRADD can regulate cell death independently of FADD and caspase-8 that occurs from the nucleus rather than the cytoplasm.

Interaction of MYC with host cell factor-1 is mediated by the evolutionarily conserved Myc box IV motif.

The MYC family of oncogenes encodes a set of three related transcription factors that are overexpressed in many human tumors and contribute to the cancer-related deaths of more than 70,000 Americans every year. MYC proteins drive tumorigenesis by interacting with co-factors that enable them to regulate the expression of thousands of genes linked to cell growth, proliferation, metabolism and genome stability. One effective way to identify critical co-factors required for MYC function has been to focus on sequence motifs within MYC that are conserved throughout evolution, on the assumption that their conservation is driven by protein-protein interactions that are vital for MYC activity. In addition to their DNA-binding domains, MYC proteins carry five regions of high sequence conservation known as Myc boxes (Mb). To date, four of the Mb motifs (MbI, MbII, MbIIIa and MbIIIb) have had a molecular function assigned to them, but the precise role of the remaining Mb, MbIV, and the reason for its preservation in vertebrate Myc proteins, is unknown. Here, we show that MbIV is required for the association of MYC with the abundant transcriptional coregulator host cell factor-1 (HCF-1). We show that the invariant core of MbIV resembles the tetrapeptide HCF-binding motif (HBM) found in many HCF-interaction partners, and demonstrate that MYC interacts with HCF-1 in a manner indistinguishable from the prototypical HBM-containing protein VP16. Finally, we show that rationalized point mutations in MYC that disrupt interaction with HCF-1 attenuate the ability of MYC to drive tumorigenesis in mice. Together, these data expose a molecular function for MbIV and indicate that HCF-1 is an important co-factor for MYC.

A common functional consequence of tumor-derived mutations within c-MYC.

The relevance of changes to the coding sequence of the c-MYC oncogene to malignancy is controversial. Overexpression of a pristine form of MYC is observed in many cancers and is sufficient to drive tumorigenesis in most contexts. Yet missense changes to MYC are found in ~50% of Burkitt's lymphomas, aggregate within an amino-terminal degron important for proteasomal destruction of MYC, and where examined profoundly enhance the tumorigenic properties of MYC in vitro and in vivo. Much of the controversy surrounding these mutants stems from the limited number of mutations that have been evaluated and their clustering within a single region of the MYC protein; the highly-conserved Myc box I (MbI) element. Here, by analysis of extant genomic data sets, we identify a previously unrecognized hotspot for tumor-associated MYC mutations, located in a conserved central portion of the protein. We show that, despite their distal location in MYC, mutations in this region precisely phenocopy those in MbI in terms of stability, in vitro transformation, growth-promoting properties, in vivo tumorigenesis and ability to escape p53-dependent tumor surveillance mechanisms. The striking parallels between the behavior of tumor-derived mutations in disparate regions of the MYC protein reveals that a common molecular process is disrupted by these mutations, implying an active role for these mutations in tumorigenesis and suggesting that different therapeutic strategies may be needed for treatment of lymphomas expressing wild type versus mutant forms of MYC protein.

Early cardioversion of atrial fibrillation facilitated by transesophageal echocardiography: short-term safety and impact on maintenance of sinus rhythm at 1 year.

BACKGROUND: For patients presenting with atrial fibrillation of only a few weeks duration, the use of transesophageal echocardiography offers the opportunity to markedly abbreviate the duration of atrial fibrillation before cardioversion. We sought to determine if the shorter duration of atrial fibrillation allowed by a transesophageal echocardiography strategy had an impact on the recurrence of atrial fibrillation and prevalence of sinus rhythm during the first year following cardioversion. METHODS: Transesophageal echocardiography was attempted in 539 patients (292 men, 247 women; 71.6 +/- 13.0 years.) with atrial fibrillation > or =2 days (66.1% <3 weeks) or of unknown duration before elective cardioversion of atrial fibrillation. Therapeutic anticoagulation at the time of transesophageal echocardiography was present in 94.6% of patients, and 73.4% of subjects were discharged on warfarin. RESULTS: Atrial thrombi were identified in 70 (13.1%) patients. Successful cardioversion in 413 patients without evidence of atrial thrombi was associated with clinical thromboembolism in 1 patient (0.24%, 95% confidence interval: 0.0--0.8%). In patients with atrial fibrillation <3 weeks at the time of cardioversion (a duration incompatible with conventional therapy of 3 to 4 weeks of warfarin before cardioversion), the 1-year atrial fibrillation recurrence rate was lower (41.1% vs. 57.9%, P <0.01), and the prevalence of sinus rhythm at 1 year was increased (65.8% vs. 51.3%, P <0.03). No other clinical or echocardiographic index was associated with recurrence of atrial fibrillation or sinus rhythm at 1 year. CONCLUSIONS: Early cardioversion facilitated by transesophageal echocardiography has a favorable safety profile and provides the associated benefit of reduced recurrence of atrial fibrillation for patients in whom the duration of atrial fibrillation is <3 weeks.

Advanced squamous cell carcinoma of the maxillary sinus. Results of combined regional infusion chemotherapy, radiation therapy and surgery.

Sequential intraarterial chemotherapy using bleomycin and methotrexate followed by high dose radiation and surgery was evaluated in 10 patients with stage III and IV squamous carcinomas of the maxillary sinus. Seven of 10 patients had extensive tumor necrosis in the surgical specimen, and no evidence of residual tumor was found in 4 of these patients. After a median follow up period of 24 months, there has been only one local recurrence in resected patients. Three patients died from pulmonary metastases. Although many unanswered questions remain regarding the efficacy of triple therapy for maxillary sinus malignancy, these results are encouraging and establish that surgical resection and healing are not compromised by preoperative chemotherapy and radiation.

Indirect immunofluorescence technique to detect monoclonal antinuclear antibody.

Monoclonal proteins directed against nuclear antigens are extremely rare. We describe the use of a double antibody immunofluorescence technique to document the existence of a monoclonal antibody with nuclear antigen activity. The patient was an elderly woman with a small monoclonal protein, but no evidence of a lymphoproliferative or autoimmune disorder. A homogeneous antinuclear antibody (ANA) prompted further studies to determine whether the monoclonal protein was related to the ANA activity. A double-antibody immunofluorescence procedure is described by which the ANA positivity was shown to be entirely due to a monoclonal IgMK protein. It consists of using fluorescein anti-kappa and rhodamine anti-lambda applied to a section of mouse kidney treated with the patient's serum. Documentation of antigenic specificity of monoclonal antibodies by double antibody fluorescence provides a straightforward method that can be utilized by routine clinical laboratories.

Renal oncocytoma: report of a case with bilateral multifocal oncocytomas.

Renal oncocytomas are uncommon, benign tumors that classically are treated by local excision or heminephrectomy. Preoperative differentiation from renal cell carcinoma is invaluable in the planning of treatment. Cases of renal oncocytoma treated conservatively have been reported. This is a case report of bilateral multifocal renal oncocytomas of which only three previous cases have been reported. Diagnosis was made from multiple fine needle biopsies and present treatment consists only of conservative observation.

Insights into the pathophysiology of iron metabolism in Pythium insidiosum infections.

Pythium insidiosum causes life-threatening disease in mammals. Animals with pythiosis usually develop anemia, and most human patients are reported to have thalassemia and the major consequence of thalassemia, iron overload. Therefore, this study evaluated the iron metabolism in rabbits experimentally infected with P. insidiosum. Ten infected rabbits were divided into two groups: one groups received a placebo, and the other was treated with immunotherapy. Five rabbits were used as negative controls. The hematological and biochemical parameters, including the iron profile, were evaluated. Microcytic hypochromic anemia was observed in the infected animals, and this condition was more accentuated in the untreated group. The serum iron level was decreased, whereas the transferrin level was increased, resulting in low saturation. The level of stainable iron in hepatocytes was markedly decreased in the untreated group. A high correlation was observed between the total iron binding capacity and the lesion size, and this correlation likely confirms the affinity of P. insidiosum for iron. The data from this study corroborate the previous implications of iron in the pathogenesis of pythiosis in humans and animals.

Area variation in recreational cycling in Melbourne: a compositional or contextual effect?

OBJECTIVE: To examine whether compositional and/or contextual area characteristics are associated with area socioeconomic inequalities and between-area differences in recreational cycling. SETTING: The city of Melbourne, Australia. PARTICIPANTS: 2349 men and women residing in 50 areas (58.7% response rate). MAIN OUTCOME MEASURE: Cycling for recreational purposes (at least once a month vs never). DESIGN: In a cross-sectional survey participants reported their frequency of recreational cycling. Objective area characteristics were collected for their residential area by environmental audits or calculated with Geographic Information Systems software. Multilevel logistic regression models were performed to examine associations between recreational cycling, area socioeconomic level, compositional characteristics (age, sex, education, occupation) and area characteristics (design, safety, destinations or aesthetics). RESULTS: After adjustment for compositional characteristics, residents of deprived areas were less likely to cycle for recreation (OR 0.66; 95% CI 0.43 to 1.00), and significant between-area differences in recreational cycling were found (median odds ratio 1.48 (95% credibility interval 1.24 to 1.78). Aesthetic characteristics tended to be worse in deprived areas and were the only group of area characteristics that explained some of the area deprivation differences. Safety characteristics explained the largest proportion of between-area variation in recreational cycling. CONCLUSION: Creating supportive environments with respect to safety and aesthetic area characteristics may decrease between-area differences and area deprivation inequalities in recreational cycling, respectively.

The significance of secretory IgA in middle ear fluid.

Studies of immunoglobulin levels in middle ear fluid in children with chronic otitis media show that MEF (middle ear fluid) IgA levels are proportionately higher than serum levels. Disproportionately elevated MEF IgA levels may be due to secretory IgA. Finding secretory IgA in MEF suggests the presence of a secretory epithelium and may define the etiology of chronic inflammation. Resolution of the secretory epithelium may be hastened with adequate ventilation of the middle ear space.

The effects of health beliefs on screening mammography utilization among a diverse sample of older women.

Screening mammography is particularly effective in detecting breast cancer in elderly women. Yet, although half of all breast cancers are diagnosed in older women, statistics show that women aged 65 and over tend to underutilize screening mammography. Prior research has used the constructs of the Health Belief Model to explore attitudes and beliefs relative to breast cancer screening. Prior studies have also identified health beliefs and concerns relative to screening mammography and race/ethnicity as some of the patient-related predictors of screening mammography utilization among younger women. This study uses the theoretical framework of the Health Belief Model to explore the effects of these variables on utilization in a multiracial, multiethnic, random sample of 1011 women, aged 65 and over. Race/ethnicity, belief that mammograms detect cancer, ease the mind, and provide accurate results; concern over the radiation, pain, and cost associated with receiving a mammogram; and other independent variables were tested as predictors of screening mammography utilization. Regression analysis identified that the belief that having a mammogram eases recipients minds was the most significant predictor of screening mammography utilization. None of the other health beliefs or health concerns were significant predictors. Race/ethnicity had no direct effects on utilization nor was it a confounder in the relationship between health beliefs, concerns and utilization. These results indicate that, along with emphasizing the importance of mammograms in early detection of breast cancer, stressing the reassurance that mammography brings recipients may be an effective health education strategy for elderly women of different racial/ethnic backgrounds.

Characteristics of metachronous colorectal carcinoma occurring despite colonoscopic surveillance.

PURPOSE: Metachronous colorectal cancer still occurs in a small percentage of patients, despite colonoscopic surveillance. Cancers in hereditary nonpolyposis colorectal cancer for which there is a high risk of metachronous cancer show distinctive DNA changes termed replication errors (RER+). Ten to 20 percent of sporadic colorectal cancers are also RER+. The aim of this study was to identify factors predictive of metachronous colorectal cancer, despite colonoscopic surveillance. Clinicopathologic characteristics and RER status of cancers were examined. METHODS: Colorectal cancer patients, who entered into a surveillance program of being examined with colonoscopy within six months of surgery and then at intervals of three years thereafter, were reviewed. The 433 patients compliant with the protocol who had had more than one colonoscopy had been followed up for a mean of 3.8 +/- 2.2 years. DNA was extracted from archival paraffin-embedded cancer tissue for determination of RER status. RESULTS: Ten cases of metachronous cancer were identified, giving a rate of 0.61 percent per year. The site of the index cancer in patients who later developed metachronous cancer was predominantly proximal (P = 0.0007), and these cancers were more likely to have mucinous histology (P < 0.0005). Three of 10 (30 percent) index cancers were RER+, which was not significantly different from unselected series of control colorectal cancers in which 20 of 108 (18.5 percent) were RER+. DISCUSSION: This study documents the rate of metachronous cancer among patients compliant with a defined colonoscopic screening program and suggests that the risk is highest in patients with a proximal mucinous cancer. RER status does not appear to be a very strong predictive factor, and this study does not support its use as a guide to the frequency of surveillance colonoscopy. More data would be required to determine if RER positivity conferred a relative risk of 3.3 or less.

Exclusion of APC and MCC as the gene defect in one family with familial juvenile polyposis.

BACKGROUND: In familial juvenile polyposis, multiple juvenile polyps occur throughout the colon. The genetic defect has not been characterized. The risk of colon cancer is increased, although the magnitude of the increased risk is controversial. The hypothesis of this study was that the genetic defect is within a tumor suppressor gene, possibly one already known to be inactivated in colorectal neoplasia. METHODS: Linkage analysis using the short tandem repeat polymorphism D5S346 was performed to determine if juvenile polyposis was linked to either APC (adenomatous polyposis coli) or MCC (mutated in colorectal carcinoma) genes within a single large family. RESULTS: A family in which eight subjects have been affected by juvenile polyposis over three generations is described. Six affected subjects had colectomies in childhood, but the two who have so far survived beyond 35 years of age have developed adenocarcinoma of the jejunum. Within this family, linkage analysis excluded linkage of the juvenile polyposis trait to either APC or MCC. CONCLUSIONS: In a family with juvenile polyposis with a clear predisposition to malignancy, including carcinoma of the jejunum, APC and MCC were not the defective genes causing the condition.