Renal artery reconstruction for the preservation of renal function

AbstractPurpose: We reviewed a 13-year experience with an emphasis on long-term survival and renal function response when renal artery reconstruction (RAR) was performed primarily for the preservation or restoration of renal function in patients who had atherosclerotic renovascular disease.Methods: From January 1, 1980, to June 30, 1993, 139 patients underwent RAR for renal function salvage and were retrospectively reviewed. Inclusion criteria were either preoperative serum creatinine level >2.0 mg/dl (67% of patients) or RAR to the entire functioning renal mass irrespective of baseline renal function. Patient survival was calculated by life-table methods. Cox regression analysis was used to determine relative risk (RR) estimates for the late outcomes of continued deterioration of renal function and late survival after RAR. A logistic regression model was used to evaluate variables associated with perioperative complications.Results: Clinical characteristics of the cohort were notable for advanced cardiac (history of congestive heart failure, 27%; angina, 22%; previous myocardial infarction, 19%) and renal disease (serum creatinine level <2.0 mg/dl, 33%; 2.0 mg/dl to 3.0 mg/dl, 40%, >3.0 mg/dl, 27%). Cardiac disease was the principle cause of early (6 of 11 operative deaths) and late death. Operative management consisted of aortorenal bypass in 47%, extraanatomic bypass in 45%, and endarterectomy in 8%; 45% of patients required combined aortic and RAR. The operative mortality rate was 8%; significant perioperative renal dysfunction occurred in 10%. Major operative morbidity was associated with increasing azotemia (RR = 2.1; p = 0.001; 95% confidence interval [CI], 1.3 to 4.7 for each 1.0 mg/dl increase in baseline creatinine level). Of those patients who had a baseline creatinine level ≥2.0 mg/dl, 54% had ≥20% reduction in creatinine level after RAR. Late follow-up data were available for 87% of operative survivors at a mean duration of 4 years (range, 6 weeks to 12.6 years). Actuarial survival at 5 years was 52% ± 5%. Continued deterioration in renal function occurred in 24% of patients who survived operation, and eventual dialysis was required in 15%. Deterioration of renal function after RAR was associated with increasing levels of preoperative creatinine (RR = 1.6; 95% CI, 1.2 to 1.8; p = 0.001 for each 1.0 mg/dl increment in baseline creatinine level), and inversely related to early postoperative improvement in creatinine level (RR = 0.41; 95% CI, 0.2 to 0.9; p = 0.04).Conclusions: Intervention before major deterioration in renal function and an aggressive posture toward the frequently associated coronary artery disease are necessary to improve long-term results when RAR is performed for renal function salvage. (J Vasc Surg 1996;24:371-82.

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

The extramural metastasis might be categorized in lymph node staging for colorectal cancer

<p>Abstract</p> <p>Background</p> <p>The objective of this study is to assess the clinical significance and prognostic impact of extramural metastasis in colorectal carcinoma and establish an optimal categorization in the staging system.</p> <p>Methods</p> <p>To determine the frequency and prognostic significance of extramural metastasis, from 2000 to 2005, a total of 1,215 patients with colorectal cancer who underwent surgical resection were recruited into this study. Individual demographic and clinicopathologic data were collected including tumor stage, nodal stage, tumor histology, degree of tumor differentiation, and presence of lymphovascular invasion. After surgery, all patients received standard treatments and follow-up, which were closed in April 2010.</p> <p>Results</p> <p>EM was detected in 167 (13.7%) patients and in 230 (1.8%) of the 12,534 nodules retrieved as 'lymph nodes'. The incidence of extramural metastasis was significantly higher in patients with large tumors, deeper invasive depth and more lymph node metastasis (P < 0.001). After curative operation, overall survival was significantly worse for patients with extramural metastasis than those without (P < 0.001). Multivariate analysis identified extramural metastasis as an independent prognostic factor (RR = 2.1, 95%CI:1.5-3.0). By using the Akaike information criterion (AIC), N staging was capable of predicting survival outcome with the highest accuracy when both nodal involvement and extramural metastasis were treated together as N factors(AIC = 1025.3).</p> <p>Conclusion</p> <p>Extramural metastasis might be diagnosed as replaced lymph nodes in the process of classification, thus forming a new categorization.</p

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Mechanisms of ring chromosome formation, ring instability and clinical consequences

<p>Abstract</p> <p>Background</p> <p>The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients.</p> <p>Methods</p> <p>Several techniques were performed such as genome-wide array, MLPA (Multiplex Ligation-Dependent Probe Amplification) and FISH (Fluorescent <it>in situ </it>Hybridization).</p> <p>Results</p> <p>The ring chromosomes of patients I to XIV were determined to be, respectively: r(3)(p26.1q29), r(4)(p16.3q35.2), r(10)(p15.3q26.2), r(10)(p15.3q26.13), r(13)(p13q31.1), r(13)(p13q34), r(14)(p13q32.33), r(15)(p13q26.2), r(18)(p11.32q22.2), r(18)(p11.32q21.33), r(18)(p11.21q23), r(22)(p13q13.33), r(22)(p13q13.2), and r(22)(p13q13.2). These rings were found to have been formed by different mechanisms, such as: breaks in both chromosome arms followed by end-to-end reunion (patients IV, VIII, IX, XI, XIII and XIV); a break in one chromosome arm followed by fusion with the subtelomeric region of the other (patients I and II); a break in one chromosome arm followed by fusion with the opposite telomeric region (patients III and X); fusion of two subtelomeric regions (patient VII); and telomere-telomere fusion (patient XII). Thus, the r(14) and one r(22) can be considered complete rings, since there was no loss of relevant genetic material. Two patients (V and VI) with r(13) showed duplication along with terminal deletion of 13q, one of them proved to be inverted, a mechanism known as inv-dup-del. Ring instability was detected by ring loss and secondary aberrations in all but three patients, who presented stable ring chromosomes (II, XIII and XIV).</p> <p>Conclusions</p> <p>We concluded that the clinical phenotype of patients with ring chromosomes may be related with different factors, including gene haploinsufficiency, gene duplications and ring instability. Epigenetic factors due to the circular architecture of ring chromosomes must also be considered, since even complete ring chromosomes can result in phenotypic alterations, as observed in our patients with complete r(14) and r(22).</p

Conditions for the occurrence of acicular ferrite transformation in HSLA steels

For the class of steels collectively known as high strength low alloy (HSLA), an acicular ferrite (AF) microstructure produces an excellent combination of strength and toughness. The conditions for the occurrence of the AF transformation are, however, still unclear, especially the effects of austenite deformation and continuous cooling. In this research, a commercial HSLA steel was used and subjected to deformation via plane strain compression with strains ranging from 0 to 0.5 and continuous cooling at rates between 5 and 50 °C s −1 . Based on the results obtained from optical microscopy, scanning electron microscopy and electron backscattering diffraction mapping, the introduction of intragranular nucleation sites and the suppression of bainitic ferrite (BF) laths lengthening were identified as the two key requirements for the occurrence of AF transformation. Austenite deformation is critical to meet these two conditions as it introduces a high density of dislocations that act as intragranular nucleation sites and deformation substructures, which suppress the lengthening of BF laths through the mechanism of mechanical stabilisation of austenite. However, the suppression effect of austenite deformation is only observed under relatively slow cooling rates or high transformation temperatures, i.e., conditions where the driving force for advancing the transformation interface is not sufficient to overcome the austenite deformation substructures

International comparisons of behavioral and emotional problems in preschool children: parents’ reports from 24 societies

International comparisons were conducted of preschool children’s behavioral and emotional problems as reported on the Child Behavior Checklist for Ages 1½–5 by parents in 24 societies (N¼19,850). Item ratings were aggregated into scores on syndromes; Diagnostic and Statistical Manual of Mental Disorders–oriented scales; a Stress Problems scale; and Internalizing, Externalizing, and Total Problems scales. Effect sizes for scale score differences among the 24 societies ranged from small to medium (3–12%). Although societies differed greatly in language, culture, and other characteristics, Total Problems scores for 18 of the 24 societies were within 7.1 points of the omnicultural mean of 33.3 (on a scale of 0–198). Gender and age differences, as well as gender and age interactions with society, were all very small (effect sizes<1%). Across all pairs of societies, correlations between mean item ratings averaged .78, and correlations between internal consistency alphas for the scales averaged .92, indicating that the rank orders of mean item ratings and internal consistencies of scales were very similar across diverse societies

Anti-calmodulins and Tricyclic Adjuvants in Pain Therapy Block the TRPV1 Channel

Ca2+-loaded calmodulin normally inhibits multiple Ca2+-channels upon dangerous elevation of intracellular Ca2+ and protects cells from Ca2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca2+-uptake via the vanilloid inducible Ca2+-channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced 45Ca2+-uptake at µM concentrations: calmidazolium (broad range)≥trifluoperazine (narrow range)>chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially). Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca2+ or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca2+-uptake in intact TRPV1+ cells, and suggests an extracellular site of inhibition. TRPV1+, inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca2+-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca2+-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca2+-channels but not affecting motoneurons

Enhanced Immunogenicity, Mortality Protection, and Reduced Viral Brain Invasion by Alum Adjuvant with an H5N1 Split-Virion Vaccine in the Ferret

Pre-pandemic development of an inactivated, split-virion avian influenza vaccine is challenged by the lack of pre-existing immunity and the reduced immunogenicity of some H5 hemagglutinins compared to that of seasonal influenza vaccines. Identification of an acceptable effective adjuvant is needed to improve immunogenicity of a split-virion avian influenza vaccine.No serum antibodies were detected after vaccination with unadjuvanted vaccine, whereas alum-adjuvanted vaccination induced a robust antibody response. Survival after unadjuvanted dose regimens of 30 µg, 7.5 µg and 1.9 µg (21-day intervals) was 64%, 43%, and 43%, respectively, yet survivors experienced weight loss, fever and thrombocytopenia. Survival after unadjuvanted dose regimen of 22.5 µg (28-day intervals) was 0%, suggesting important differences in intervals in this model. In contrast to unadjuvanted survivors, either dose of alum-adjuvanted vaccine resulted in 93% survival with minimal morbidity and without fever or weight loss. The rarity of brain inflammation in alum-adjuvanted survivors, compared to high levels in unadjuvanted vaccine survivors, suggested that improved protection associated with the alum adjuvant was due to markedly reduced early viral invasion of the ferret brain.Alum adjuvant significantly improves efficacy of an H5N1 split-virion vaccine in the ferret model as measured by immunogenicity, mortality, morbidity, and brain invasion