The RAGE axis and endothelial dysfunction: maladaptive roles in the diabetic vasculature and beyond

Receptor for advanced glycation end product (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. The ligand-RAGE axis is emerging as a central mechanism linked to vascular injury and atherosclerosis in diabetes and in euglycemia. The repertoire of RAGE ligands, including advanced glycation end products, S100/calgranulins, high-mobility group box 1, amyloid-beta peptide, and Mac-1, transcends RAGE biology from specifically the science of diabetic complications to central aspects of the inflammatory response and oxidative stress. Experiments in cell culture and in vivo support the notion that interaction of RAGE ligands with RAGE activates key signal transduction pathways that modulate fundamental cellular properties, thereby leading to vascular and inflammatory cell perturbation. These considerations support the premise that the ligand-RAGE axis may be an important target for therapeutic intervention in cardiovascular disease and, fundamentally, in initiation and amplification of inflammatory responses.     

Prevalence of essential tremor in Singapore: a study on three races in an Asian country

To investigate the prevalence of Essential Tremor (ET) in Singapore and compare the rates between Singaporean Chinese, Malays, and Indians, a community-based survey among a disproportionate random sample of 15,000 individuals (9000 Chinese, 3000 Malays, 3000 Indians) aged 50 years and above was conducted. In phase 1, trained interviewers conducted a door-to-door survey using a screening questionnaire for Parkinson's disease. In phase 2, medical specialists examined participants who screened positive to evaluate for the presence of postural or kinetic tremor of the upper limbs, or head tremor. Participants with suspected ET had their diagnosis confirmed in phase 3 by a movement disorders specialist and fellow based on the latest core diagnostic criteria. Forty participants with classic ET were identified. The prevalence rate (PR) of ET was 2.37 per 1000 (95% CI: 1.65-3.32), age-adjusted to UICC world standard population. The PR was significantly higher in males (p=0.01) and increased significantly with age (p<0.001). Indians (PR=4.94 per 1000, 95% CI: 2.63-9.04) were 1.8 times more likely to have ET than Chinese (PR=2.77 per 1000, 95% CI: 1.78-4.17) (p=0.08). No Malays with ET were identified. The data suggest that the prevalence of ET increases with age, is higher in males and may be higher amongst Indians.     

Assessment of capacity to consent to research among older persons with schizophrenia, Alzheimer disease, or diabetes mellitus: comparison of a 3-item questionnaire with a comprehensive standardized capacity instrument

CONTEXT: Considerable discussion surrounds issues related to the capacities of neuropsychiatric patients to consent to research, yet few empirical investigations have directly compared decisional capacity among patients with a serious mental illness with that among patients with neurologic or medical conditions. Also, as requirements for formal assessment of decisional capacity are becoming more common, there is a clear need to identify efficient screening methods. OBJECTIVES: To compare decisional capacity among 3 diagnostic groups, and to examine the degree to which impaired understanding can be detected with a brief set of screening questions. SETTING: Outpatient veterans hospital clinic and university-based neuropsychiatric research centers. DESIGN/ PARTICIPANTS: Cross-sectional comparison of decisional capacity among older (>/=60 years) outpatients with schizophrenia (n = 35), mild to moderate Alzheimer disease (n = 30), and type 2 diabetes mellitus (n = 36), and determination of sensitivity and specificity of a screening measure. MAIN OUTCOME MEASURES: Three-item decisional capacity questionnaire and the MacArthur Competence Assessment Tool for Clinical Research. RESULTS: Patients with diabetes mellitus performed the best on the capacity instruments, patients with Alzheimer disease had the worst performance, and patients with schizophrenia were intermediate. However, there was considerable heterogeneity within each group. Even within diagnostic groups, the level of cognitive functioning (measured with the Mini-Mental State Examination) was generally the best predictor of decisional capacity (particularly in the understanding component). The 3-item questionnaire was sensitive to impaired understanding as measured with the MacArthur Competence Assessment Tool for Clinical Research understanding subscale. CONCLUSIONS: Decisional capacity differed among the 3 groups; there was considerable heterogeneity even within each diagnostic group, so individualized consideration of capacity may be warranted. The level of cognitive deficits is 1 potential marker of which participants should receive comprehensive capacity evaluations, but sensitive brief questionnaires targeting key aspects of disclosed information may also provide an effective means of screening for participants warranting comprehensive capacity evaluations.     

Depleted uranium dust from fired munitions: physical, chemical and biological properties

This paper reports physical, chemical and biological analyses of samples of dust resulting from munitions containing depleted uranium (DU) that had been live-fired and had impacted an armored target. Mass spectroscopic analysis indicated that the average atom% of U was 0.198 +/- 0.10, consistent with depleted uranium. Other major elements present were iron, aluminum, and silicon. About 47% of the total mass was particles with diameters <300 microm, of which about 14% was <10 microm. X-ray diffraction analysis indicated that the uranium was present in the sample as uranium oxides-mainly U3O7 (47%), U3O8 (44%) and UO2 (9%). Depleted uranium dust, instilled into the lungs or implanted into the muscle of rats, contained a rapidly soluble uranium component and a more slowly soluble uranium component. The fraction that underwent dissolution in 7 d declined exponentially with increasing initial burden. At the lower lung burdens tested (<15 microg DU dust/lung) about 14% of the uranium appeared in urine within 7 d. At the higher lung burdens tested (~80-200 microg DU dust/lung) about 5% of the DU appeared in urine within 7 d. In both cases about 50% of that total appeared in urine within the first day. DU implanted in muscle similarly showed that about half of the total excreted within 7 d appeared in the first day. At the lower muscle burdens tested (<15 microg DU dust/injection site) about 9% was solubilized within 7 d. At muscle burdens >35 microg DU dust/injection site about 2% appeared in urine within 7 d. Natural uranium (NU) ore dust was instilled into rat lungs for comparison. The fraction dissolving in lung showed a pattern of exponential decline with increasing initial burden similar to DU. However, the decline was less steep, with about 14% appearing in urine for lung burdens up to about 200 microg NU dust/lung and 5% at lung burdens >1,100 microg NU dust/lung. NU also showed both a fast and a more slowly dissolving component. At the higher lung burdens of both DU and NU that showed lowered urine excretion rates, histological evidence of kidney damage was seen. Kidney damage was not seen with the muscle burdens tested. DU dust produced kidney damage at lower lung burdens and lower urine uranium levels than NU dust, suggesting that other toxic metals in DU dust may contribute to the damage.     

Postpartum depression recurrence versus discontinuation syndrome: observations from a randomized controlled trial

OBJECTIVE: To differentiate characteristics of a discontinuation syndrome from a recurrence of major depressive disorder in the context of a randomized trial. METHOD: We performed a randomized clinical trial to compare the efficacy of sertraline versus placebo for the prevention of recurrent postpartum DSM-IV major depressive disorder. Women whose depression did not recur in the initial 17-week active treatment trial were followed through the taper phase (weeks 18-20). At week 17, 3 women assigned to placebo and 8 assigned to sertraline remained in the trial. Nine symptoms that characterize discontinuation syndrome were extracted from the 25-item Asberg Rating Scale for Side Effects (ASE) and assessed weekly during the taper phase. The 21-item Hamilton Rating Scale for Depression was used to evaluate depressive symptoms. RESULTS: In the taper phase, there were no significant differences between the sertraline- and placebo-treated women on the sum of the ASE-derived symptoms. Both groups had low levels of symptoms on the ASE during the weeks of taper. None of the 3 women assigned to placebo and 2 of the 8 women assigned to sertraline suffered a depressive recurrence within 6 weeks of the end of the study. CONCLUSIONS: A gradual taper of sertraline (75 mg) over 3 weeks did not lead to discontinuation syndrome; however, the systematic dissection of symptoms resulted in our conclusion that the duration of preventive therapy should be extended to 26 weeks (about 6 months) in subsequent randomized trials, consistent with the treatment guidelines for a single episode of depression.     

Problems in reporting doses and volumes during multiple high-dose-rate intracavitary brachytherapy for carcinoma cervix as per ICRU Report 38: a comparative study using flexible and rigid applicators

OBJECTIVE: The objective was to evaluate the extent of geometric and positional variations of two different applicators during multiple high-dose-rate (HDR) intracavitary brachytherapy (ICBT) in carcinoma cervix and its implication on reporting as per International Commission on Radiation Units and Measurement (ICRU) Report 38. METHODS: Fifty patients, following teletherapy, were randomly allocated to two groups of 25 each. They received a dose of 6 Gy to point A during each of the three HDR ICBT applications by either a flexible Ralstron or a rigid geometry Rotterdam applicator. The various applicator components related to its geometry and their Cartesian coordinates were evaluated from orthogonal films. The doses to ICRU bladder, rectal, pelvic, lymphatic trapezoid points, and dimensions of 6-Gy ICRU height, width, thickness, and volume were estimated for each application. RESULTS: Significant variation was observed with the three HDR ICBT applications for each group, for all components and for both applicators, although it was relatively more with the flexible Ralstron applicator. The average shift in each of the coordinates of os, uterine tip, and ovoids was around 10 mm for both groups. These resulted in significant variations in all the ICRU Report 38 reporting parameters for three insertions in any given patient and across 25 patients of both groups. CONCLUSIONS: Multiple HDR ICBT applications led to significant variation in the applicator geometry and its positions in pelvis, irrespective of the applicator rigidity. This results in uncertainties in reporting as per ICRU Report 38 guidelines, and thus calls for its revision.     

Familial exudative vitreoretinopathy (FEVR). Clinical profile and management

PURPOSE: To report our experience with the diagnosis and management of Familial Exudative Vitreoretinopathy (FEVR) in a predominantly older Indian population.. METHODS: This prospective interventional non-comparative case series included 38 patients of FEVR and their 23 family members. The diagnosis was established by clinical examination, fluorescein angiography and family screening. Prophylactic photocoagulation/cryotherapy or surgical treatment was done depending on the severity of the disease. RESULTS: The mean age of the patients was 23.6 years. The fundus/fluorescein angiographic findings in 116 eyes of our 61 patients (6 eyes phthisical) were as follows: forty eight (41.4%) eyes had only peripheral avascular zone, 8 (6.9%) eyes had peripheral new vessels, and 35 (30.1%) eyes had retinal detachments (RD)--10 (8.6%) exudative, 5 (4.3%) tractional and 20 (17.2%) rhegmatogenous. Prophylactic photocoagulation or cryotherapy was done in 34 eyes for retinal holes, local exudative detachments and bleeding new vessels. All the eyes retained stable vision over a mean follow-up of 16 months. Only 14 RDs were suitable for surgery: scleral buckling, vitrectomy or both. The reattachment rate was 85.7% (12 of 14) and the best-corrected visual acuity (BCVA) improved to 5/60 or better in 50% of these eyes over a 2-year follow-up. CONCLUSIONS: FEVR appears to be more common than reported. Timely diagnosis and intervention is essential in view of the lifelong progression of the disease, late exacerbations, frequent involvement of family members, and poor surgical results. A high index of suspicion, family screening and early prophylaxis are recommended to prevent avoidable blindness from this underdiagnosed disease.     

Cystoenteric conversion and reduction cystoplasty for treatment of bladder dysfunction after pancreas transplantation

PURPOSE: Bladder drainage of pancreatic exocrine secretions during pancreas transplantation can lead to significant urological complications. Our experience with cystoenteric conversion (CEC) is reviewed with respect to safety and efficacy. Select patients underwent concurrent reduction cystoplasty. MATERIALS AND METHODS: A total of 255 pancreas transplantations were performed at the University of Washington between 1990 and 2001, of which 236 were bladder drained and 33 required enteric conversion of bladder drainage. An additional patient from an outside institution required conversion. These cases were reviewed retrospectively. Of the patients 21 with large capacity (greater than 500 ml) bladders underwent concurrent reduction cystoplasty. RESULTS: Mean age of the 20 male and 14 female patients was 44 years (range 33 to 60) and mean interval between transplantation and CEC was 4.3 years (0.6 to 9). The most frequent indication for CEC was recurrent urinary tract infections (15 of 34 cases, 44%). Mean followup after CEC was 2.5 years (range 0.3 to 6.5). Six complications requiring reoperation were seen in 5 of the 34 patients (15%), one of which led to death (3%). Normal pancreatic graft function persisted in 30 of the 34 cases (88%). After reduction cystoplasty mean bladder capacity in all 34 cases decreased from 900 to 465 ml intraoperatively (p <0.0001) and from 650 to 362 ml in 9 according to urodynamics (p <0.015). Of the patients 30 (88%) experienced resolution of symptoms, while 3 (9%) experienced improvement and 1 (3%) continued to have recurrent infections. CONCLUSIONS: Although we advocate maximal conservative treatment of the urological complications of pancreas transplantation, CEC offers safe and effective management of these complications, and can easily be combined with reduction cystoplasty in select cases to optimize postoperative voiding function.