Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate ...(GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease.
In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m
of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed.
A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m
in the allopurinol group and 67.3 ml per minute per 1.73 m
in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m
(95% confidence interval CI, -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m
per year with allopurinol and -2.5 ml per minute per 1.73 m
per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m
per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups.
We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).
•Brain dynamics depicts a complex energy landscape that changes over time.•We approximate the energy landscape of brain dynamics underlying different states.•Measure of consciousness through ...variability of attractors of human fMRI signals.•A new tool, the Model transform, applies simple models to complex systems.
Brain dynamics depicts an extremely complex energy landscape that changes over time, and its characterisation is a central unsolved problem in neuroscience. We approximate the non-stationary landscape sustained by the human brain through a novel mathematical formalism that allows us characterise the attractor structure, i.e. the stationary points and their connections. Due to its time-varying nature, the structure of the global attractor and the corresponding number of energy levels changes over time. We apply this formalism to distinguish quantitatively between the different human brain states of wakefulness and different stages of sleep, as a step towards future clinical applications.
Excessive daytime sleepiness and sleep disorders, including sleep apnea syndrome, restless legs syndrome, and periodic limb movement disorder, occur with increased frequency in patients with ...end-stage renal disease (ESRD). The detection and management of sleep disorders in ESRD patients is often challenging but may have significant clinical benefits. Some of the poor quality of life in ESRD may be attributed to the presence of concomitant sleep disorders, yet the classical symptoms of sleep disorders (poor concentration, daytime sleepiness, and insomnia) are often ascribed to the uremic syndrome itself. Conventional risk factors and screening tools used in the diagnosis of sleep disorders seem to have limited applicability in dialysis patients implicating the unique pathophysiology of sleep disorders in ESRD. Emerging evidence suggests that sleep apnea may contribute to the augmented cardiovascular event rates and to the accelerated development of atherosclerosis in ESRD. Whether treatment of sleep disorders in ESRD patients can affect the high morbidity and mortality of ESRD patients has yet to be elucidated. To date, conventional renal replacement therapies do not appear to have a significant impact on the treatment of sleep disorders in ESRD. The promising therapeutic effects of optimal uremia control in the forms of nocturnal hemodialysis and renal transplantation on sleep disorders require further mechanistic and clinical studies.
At the beginning of autumn, 1996, fish with “punched-out” skin lesions and erratic behaviour associated with exposure to toxins produced by
Pfiesteria piscicida or
Pfiesteria-like dinoflagellate ...species were seen in the Pocomoke River and adjacent waterways on the eastern shore of the Chesapeake Bay in Maryland, USA. In August, 1997, fish kills associated with
Pfiesteria occurred in these same areas. People who had had contact with affected waterways reported symptoms, including memory difficulties, which raises questions about the human-health impact of environmental exposure to
Pfiesteria toxins.
We assessed 24 people who had been exposed. We collected data on exposure history and symptoms, did a complete medical and laboratory assessment (13 people), and carried out a neuropsychological screening battery. Performance on neuropsychological measures was compared with a matched control group.
People with high exposure were significantly more likely than occupationally matched controls to complain of neuropsychological symptoms (including new or increased forgetfulness); headache; and skin lesions or a burning sensation of skin on contact with water. No consistent physical or laboratory abnormalities were found. However, exposed people had significantly reduced scores on the Rey Auditory Verbal Learning and Stroop Color-Word tests (indicative of difficulties with learning and higher cognitive function), and the Grooved Pegboard task. There was a dose-response effect with the lowest scores among people with the highest exposure. By 3–6 months after cessation of exposure, all those assessed had test scores that had returned to within normal ranges.
People with environmental exposure to waterways in which
Pfiesteria toxins are present are at risk of developing a reversible clinical syndrome characterised by difficulties with learning and higher cognitive functions. Risk of illness is directly related to degree of exposure, with the most prominent symptoms and signs occurring among people with chronic daily exposure to affected waterways.
Cholinergic markers, neuropeptides, and amines and their metabolites were sampled from identical specimens across 10 neocortical regions in a large sample of Alzheimer's disease (AD) cases and ...controls. Levels of choline acetyltransferase, acetylcholinesterase, somatostatin, corticotropin-releasing factor, serotonin, and 5-hydroxyindoleacetic acid were significantly reduced in AD versus controls. After data reduction, the most descriptive neurochemical indices were used to examine the relationship of neurochemical measures and dementia severity within the AD sample, controlling for age effects. Dementia severity ratings were based on antemortem assessments (46.9% of AD sample) and postmortem chart review (53.1% of the AD sample). Choline acetyltransferase activity was highly correlated with clinical dementia ratings across the neocortex of the AD cases. Somatostatin and corticotropin-releasing factor levels were correlated with dementia severity only when control cases were included in the analyses. None of the amines, their metabolites, or the neuropeptides quantified related significantly to dementia severity in the AD cohort. These data (a) confirm the strong association of cholinergic deficits with functional impairment in AD and show that this association is independent of age and (b) suggest that of all the neurochemical species quantified, the cholinergic indices may be unique in their association with dementia severity.
Starting with the 1975 discovery of the tau lepton, I look back on the last three decades of change in the substance and style of experimental and theoretical research in elementary particle physics. ...I recount the major accomplishments of those decades and predict a bright future for particle physics in the next two decades. Turning to three problems, I lament the change in theoretical style and taste, I discuss the growth in the complexity, size, and cost of particle physics experiments, and I conclude with a pessimistic comment on the size of particle physics collaborations.
Background. The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from ...single-institution retrospective studies. Methods. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. Results. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versushost disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelvemonth cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matchedrelated allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. Conclusions. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.
The total selenium content of various foods produced and/or consumed in two rural regions of eastern Croatia was determined using the AAS hydride generation technique. The samples were previously ...digested in a mixture of perchloric, sulfuric, and nitric acids (1:1:5). As expected, rich sources of protein like fish, meat, eggs, etc., were also rich in selenium. The lowest selenium levels were found in fruits and vegetables. Significant differences were noted for some foods grown on two separate locations around Rivers Drava and Sava in eastern Croatia with higher concentrations in samples from the Sava basin. The mean content of selenium in foods (on the wet weight) was compared with the levels reported from other countries. On the basis of this, the dietary Se intake in both areas is likely to be between suboptimal or adequate supply of this element.
We use 429 fb$^{-1}$ of $e^+e^-$ collision data collected at the $\Upsilon(4S)$ resonance with the BABAR detector to measure the radiative transition rate of $b\rightarrow s\gamma$ with a sum of 38 ...exclusive final states. The inclusive branching fraction with a minimum photon energy of 1.9 GeV is found to be $\mathcal{B}(\bar B \rightarrow X_{s}\gamma)=(3.29\pm 0.19\pm 0.48)\times 10^{-4}$ where the first uncertainty is statistical and the second is systematic. We also measure the first and second moments of the photon energy spectrum and extract the best fit values for the heavy-quark parameters, $m_{b}$ and $\mu_{\pi}^{2}$, in the kinetic and shape function models.
We report the results of an examination of the elemental content of neurofibrillary tangle-bearing and neurofibrillary tangle-free neurons identified within the hippocampus of 10 subjects with ...Alzheimer's disease and 4 neuropathologically intact age-matched control subjects. The study employed laser microprobe mass analysis (LAMMA), a technique that provides extremely sensitive multielement detection in plastic-embedded, semithin-sectioned tissues. Evidence for the selective accumulation of aluminum within the neurofibrillary tangle-bearing neurons was obtained in all 10 subjects with Alzheimer's disease. The site of aluminum deposition within these cells was the neurofibrillary tangle itself, and not the "nuclear region," as we previously reported. Iron accumulation was also detected within neurofibrillary tangles. Evaluation for the accumulation of other elements within the tangle-bearing neurons failed to reveal any other metallic element as being consistently present. In addition, probe sites directed to neurons identified in snap-frozen cryostat sections from 2 subjects with Alzheimer's disease revealed similar spectra with prominent aluminum-related peaks, confirming that our findings are not related to exogenous contamination through fixation, embedding, or other procedures prior to analysis. This study further confirms the association of aluminum and neurofibrillary tangle formation in Alzheimer's disease.
PDF
