Five year mortality and direct costs of care for people with diabetic foot complications are comparable to cancer.

BackgroundIn 2007, we reported a summary of data comparing diabetic foot complications to cancer. The purpose of this brief report was to refresh this with the best available data as they currently exist. Since that time, more reports have emerged both on cancer mortality and mortality associated with diabetic foot ulcer (DFU), Charcot arthropathy, and diabetes-associated lower extremity amputation.MethodsWe collected data reporting 5-year mortality from studies published following 2007 and calculated a pooled mean. We evaluated data from DFU, Charcot arthropathy and lower extremity amputation. We dichotomized high and low amputation as proximal and distal to the ankle, respectively. This was compared with cancer mortality as reported by the American Cancer Society and the National Cancer Institute.ResultsFive year mortality for Charcot, DFU, minor and major amputations were 29.0, 30.5, 46.2 and 56.6%, respectively. This is compared to 9.0% for breast cancer and 80.0% for lung cancer. 5 year pooled mortality for all reported cancer was 31.0%. Direct costs of care for diabetes in general was $237 billion in 2017. This is compared to$80 billion for cancer in 2015. As up to one-third of the direct costs of care for diabetes may be attributed to the lower extremity, these are also readily comparable.ConclusionDiabetic lower extremity complications remain enormously burdensome. Most notably, DFU and LEA appear to be more than just a marker of poor health. They are independent risk factors associated with premature death. While advances continue to improve outcomes of care for people with DFU and amputation, efforts should be directed at primary prevention as well as those for patients in diabetic foot ulcer remission to maximize ulcer-free, hospital-free and activity-rich days

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia.

BackgroundEndophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed.MethodsParticipants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year.ResultsMost neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria.ConclusionsThe majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the "gene-to-phene gap" in schizophrenia research

Reduced Lean Mass in Early Alzheimer Disease and Its Association With Brain Atrophy

This is the published version. Copyright American Medical AssociationObjective: To examine body composition in individuals with early AD and without dementia and its relation to cognition and brain volume. Design: Cross-sectional case-control study. Participants: Individuals without dementia (Clinical Dementia Rating, 0; n=70) and with early-stage AD (Clinical Dementia Rating, 0.5 or 1; n=70) in the Alzheimer and Memory Program at the University of Kansas School of Medicine. Main Outcome Measures: Participants were evaluated with brain magnetic resonance imaging (MRI), neuropsychological testing, and dual-energy x-ray absorptiometry to determine whole-body fat and lean masses. Body mass index was calculated as weight in kilograms divided by height in meters squared. Results: Lean mass was reduced in persons with early AD compared with controls without dementia (F=7.73; P=.006) after controlling for sex. Whole-brain volume (=.20; P.001), white matter volume (=.19; P.001), and global cognitive performance (=.12; P=.007) were associated with lean mass (dependent variable) when controlling for age and sex. The total body fat and percentage of body fat values were not different across groups or related to cognition and brain volume. Conclusion: Loss of lean mass is accelerated in AD and is associated with brain atrophy and cognitive performance, perhaps as a direct or indirect consequence of AD pathophysiology or through shared mechanisms common to both AD and sarcopenia

Trends in Cancer Mortality in 15 Industrialized Countries, 1969-1986

Background: Assessing trends in cancer provides a means for gauging progress against the disease, estimating future demands for care and treatment, and suggesting clues about shifting causal factors that may account for the more recent changes. Purpose: This study was designed to evaluate trends in the major sites of cancer associated with high mortality rates in 15 industrialized countries. To highlight differences among regions, we grouped these countries into six geographic areas: United States, Eastern Europe, Western Europe, East Asia, Oceania, and Nordic countries. In addition, cancer mortality trends in these regions were compared with incidence patterns in the United States. Methods: Data provided by the World Health Organization were used to evaluate age-specific mortality trends from 1969 through 1986 for lung, breast, prostate, stomach, and colorectal cancers and for all other sites considered as a group. We also assembled and analyzed data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute for the same sites and age groups from 1973 through 1986. Results: Over the period 1969 through 1986, recorded cancer mortality in persons aged 45 years and older in the six regions studied has increased for lung, breast, and prostate cancers in most age groups, while the decline in stomach cancer mortality is substantial. The increase in lung cancer deaths in men aged 45-54 years has slowed greatly or reversed in all areas except Eastern Europe and East Asia. Trends for intestinal cancer vary by age and region. For all other sites considered as a group, increases have occurred for persons older than 64 years in most regions. In Eastern Europe, there are disturbingly high rates and rapid increases for several of the major forms of cancer in persons aged 45-54 years. In general, trends for cancer incidence in the United States parallel those for mortality. For intestinal cancer, however, incidence has increased while mortality has declined. Conclusions: The trends we report cannot be explained solely by changes in cigarette smoking or aging. Other causes of changes in cancer incidence and mortality need to be determined. Implications: The increasing and decreasing trends in mortality from and incidence of cancer that we found are important for health care planning and may also suggest opportunities for research in cancer prevention. [J Natl Cancer Inst 84: 313-320, 1992

Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague–Dawley and Long–Evans rats

Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is heritable and deficient in certain psychiatric disorders, including schizophrenia. Sprague–Dawley (SD) rats are more sensitive to PPI disruptive effects of dopamine (DA) agonists at long interstimulus intervals (60–120 ms) and less sensitive to their PPI-enhancing effects at short (10–30 ms), compared with Long–Evans (LE) rats. These heritable strain differences in sensitivity to the PPI disruptive effects of DA agonists must ultimately reflect neural changes "downstream" from forebrain DA receptors. The current study evaluated the effects of the DA agonist, apomorphine (APO), on ventral pallidal (VP) gamma-aminobutyric acid (GABA) and glutamate efflux and PPI in SD and LE rats. PPI was tested in SD and LE rats after vehicle or APO (0.5 mg/kg, subcutaneously (s.c.)) in a within-subject design. In different SD and LE rats, VP dialysate was collected every 10 min for 120 min after vehicle or APO (0.5 mg/kg, s.c.) and analyzed for GABA and glutamate content by capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF). As predicted, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared to LE rats. APO significantly reduced VP GABA efflux in SD but not in LE rats; glutamate efflux was unaffected in both strains. Heritable strain differences in PPI APO sensitivity in SD vs LE rats parallel, and may be mediated by, strain differences in the VP GABA efflux

Mobile Phones, Brain Tumors, and the Interphone Study: Where Are We Now?

Background: In the past 15 years, mobile telephone use has evolved from an uncommon activity to one with > 4.6 billion subscriptions worldwide. However, there is public concern about the possibility that mobile phones might cause cancer, especially brain tumors

Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc − Activity in the Medial Prefrontal Cortex

Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc −, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Objectives: Our goal was to determine whether increased system xc − activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating. Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc −, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3–3 mg/kg, sc). N-Acetylcysteine (10–100 μM) and the system xc − inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc − activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc − activity. Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10–100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc −. Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc − independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine

Review of the Epidemiologic Literature on EMF and Health

Exposures to extremely low-frequency electric and magnetic fields (EMF) emanating from the generation, transmission, and use of electricity are a ubiquitous part of modern life. Concern about potential adverse health effects was initially brought to prominence by an epidemiologic report two decades ago from Denver on childhood cancer. We reviewed the now voluminous epidemiologic literature on EMF and risks of chronic disease and conclude the following: a) The quality of epidemiologic studies on this topic has improved over time and several of the recent studies on childhood leukemia and on cancer associated with occupational exposure are close to the limit of what can realistically be achieved in terms of size of study and methodological rigor. b) Exposure assessment is a particular difficulty of EMF epidemiology, in several respects: i) The exposure is imperceptible, ubiquitous, has multiple sources, and can vary greatly over time and short distances. ii) The exposure period of relevance is before the date at which measurements can realistically be obtained and of unknown duration and induction period. iii) The appropriate exposure metric is not known and there are no biological data from which to impute it. c) In the absence of experimental evidence and given the methodological uncertainties in the epidemiologic literature, there is no chronic disease for which an etiological relation to EMF can be regarded as established. d) There has been a large body of high quality data for childhood cancer, and also for adult leukemia and brain tumor in relation to occupational exposure. Among all the outcomes evaluated in epidemiologic studies of EMF, childhood leukemia in relation to postnatal exposures above 0.4 microT is the one for which there is most evidence of an association. The relative risk has been estimated at 2.0 (95% confidence limit: 1.27-3.13) in a large pooled analysis. This is unlikely to be due to chance but, may be, in part, due to bias. This is difficult to interpret in the absence of a known mechanism or reproducible experimental support. In the large pooled analysis only 0.8% of all children were exposed above 0.4 microT. Further studies need to be designed to test specific hypotheses such as aspects of selection bias or exposure. On the basis of epidemiologic findings, evidence shows an association of amyotrophic lateral sclerosis with occupational EMF exposure although confounding is a potential explanation. Breast cancer, cardiovascular disease, and suicide and depression remain unresolved

Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's disease

AbstractThe dopaminergic neurotoxin N-methyl,4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) causes a syndrome in primates and humans which mimics Parkinson's disease (PD) in clinical, pathological, and biochemical findings, including diminished activity of complex I in the mitochondrial electron transport chain. Reduced complex I activity is found in sporadic PD and can be transferred through mitochondrial DNA, suggesting a mitochondrial genetic etiology. We now show that MPTP treatment of mice and N-methylpyridinium (MPP+) exposure of human SH-SY5Y neuroblastoma cells increases oxygen free radical production and antioxidant enzyme activities. Cybrid cells created by transfer of PD mitochondria exhibit similar characteristics; however, PD cybrids' antioxidant enzyme activities are not further increased by MPP+ exposure, as are the activities in control cybrids. PD mitochondrial cybrids are subject to metabolic and oxidative stresses similar to MPTP parkinsonism and provide a model to determine mechanisms of oxidative damage and cell death in PD