Evaluation of the poly(ADP‐ribose) polymerase‐1 gene variants in Alzheimer's disease

Amyloid peptide is thought to play a critical role in neuronal death in Alzheimer's disease (AD), most likely through oxidative stress. Free radical‐related injury leads to DNA breaks, which subsequently activates the repair enzyme poly(ADP‐ribose) polymerase‐1 (PARP‐1). In this study, the relationship between genetic variants situated at the PARP‐1 gene and AD development was investigated. We performed a case and control study from a Taiwanese population enrolled 120 AD patients and 111 healthy controls by using a polymerase chain reaction restriction fragment length polymorphism approach for two PARP‐1 exonic polymorphisms, 414C/T (rs1805404) and 2456T/C (rs1136410), corresponding to protein residues at positions 81Asp/Asp and762Val/Ala. There were no significant differences in allele or genotype frequencies for either PARP‐1 gene variant between the case and control groups; however, upon analysis of the haplotype distribution, four haplotypes (Hts) were identified. We found that the distributions of Ht3‐TT and Ht4‐CC were significantly associated with an increased risk of AD (P<0.0001), whereas the Ht1‐TC haplotype showed a protective effect for cases compared with the control group (P<0.05). These results reveal that the PARP‐1 gene is highly associated with AD susceptibility and might contribute to a critical mechanism that mediates cell survival or death as a response to cytotoxic stress. J. Clin. Lab. Anal. 24:182–186, 2010. © 2010 Wiley‐Liss, Inc.     

Cardiac surgery in the elderly.

OBJECTIVE: There has been a gradual increase in the number of elderly patients referred for cardiac surgery. These patients present a difficult challenge, they are usually symptomatic yet at high risk for intervention. The aim of this study is to review our experience with cardiac surgery in patients aged 80 years or older. PATIENTS AND METHODS: Between January 1981 and October 1997, 242 patients; 135 female, 107 male, mean age 82.8 years (range 80-95) underwent surgery on cardiopulmonary bypass in our unit. Surgery was performed on 14 as an emergency and 136 on an urgent (patient restricted to a hospital bed due to symptoms) basis. Pre-operatively 182 (75.2%) were in NYHA functional class 3 or 4. RESULTS: Early mortality was 14 (5.7%). A mitral valve procedure and emergency surgery were significantly associated (P < 0.05) with an increased risk of operative mortality. Median ITU and in-hospital stay was 1 day (range 0-33) and 10 (range 6-49) days, respectively. Ninety-three percent of patients were living independently at home 2 months post-operatively. Survival (+/-SEM) is 98% complete (totals 557 patient years) and including early mortality at 1 and 5 years was 85.5+/-2.4% (n = 154), and 67.7+/-4.3% (n = 33). Survival for patients undergoing isolated aortic valve replacement (AVR) and coronary artery bypass grafting (CABG) at 5 years was 64.8+/-7.8% and 79.7+/-7.4%, respectively. Survival was significantly worse in patients undergoing a mitral procedure. Using Cox's proportional hazards model only type of operation (mitral surgery) was significantly associated with worse survival. CONCLUSION: Cardiac surgery can be performed in a selected elderly population with a low operative mortality. Post-operatively elderly patients attain an excellent quality of life and survival. Emergency and mitral surgery in this group of patients is less rewarding.     

Analgesic Nephropathy and Renal Replacement Therapy in Australia: Trends,Comorbidities and Outcomes

Background and objectives: This study examined age-specific incidence and prevalence of renal replacement therapy attributed to analgesic nephropathy from 1971 through 2005 and adjusted comorbidity prevalence and survival of patients who had analgesic nephropathy and were on renal replacement therapy (compared with control subjects without diabetes).Design, setting, participants, & measurements: This retrospective cohort study, using data from the Australia and New Zealand Dialysis and Transplant registry, included all patients who were aged 35 to 84 yr and started long-term renal replacement therapy in Australia from 1971 through 2006.Results: Of 31,654 incident renal replacement therapy patients, 10.2% had analgesic nephropathy. Incidence and prevalence of renal replacement therapy attributed to analgesic nephropathy decreased earlier and faster among younger (age <55 yr) patients. Prevalence of analgesic nephropathy among 75- to 84-yr-old renal replacement therapy patients is still increasing. Compared with control subjects without diabetes, comorbidities (coronary artery, cerebrovascular, peripheral vascular, and chronic lung diseases) were more prevalent among patients with analgesic nephropathy at renal replacement therapy start. All-cause, cardiovascular, infection, and cancer mortality were higher among patients who had analgesic nephropathy and were on renal replacement therapy. For both comorbidities and mortality, the associations were stronger in younger patients.Conclusions: Trends in renal replacement therapy attributed to analgesic nephropathy differed by age. Patients with analgesic nephropathy have more comorbidities and poorer survival on renal replacement therapy, especially among younger patients.Classical analgesic nephropathy (AN) is characterized by reduced GFR, pyuria, hematuria, proteinuria, tubular dysfunction, hypertension, and papillary necrosis (1). Associated features include urinary tract transitional cell carcinomas (TCC) (2), accelerated atherosclerosis, peptic ulcer disease, and pigmentation and premature aging of the skin.AN is caused by long-term ingestion of combination analgesics that contain phenacetin or its main metabolite, paracetamol, in combination with aspirin, caffeine, or codeine (3,4). Combination analgesic use was prevalent in the 1960s and 1970s in Australia, parts of Europe (Scandinavia, Belgium, and Switzerland), and Canada. In Australia, combination analgesics were easily available as Vincent''s or Bex powders (phenacetin with aspirin and caffeine). Regular use exceeded 10% of the population in some states (5), especially among middle-aged women with chronic headache (2,6–8). Phenacetin was removed from combination analgesic powders in 1967 (Vincent''s) and 1975 (Bex), respectively and totally banned in 1977. Over-the-counter sales of all combination analgesics were banned in 1979 (9).Although a Swiss cohort study documented higher risks for cardiovascular morbidity and mortality in combination analgesic users (10), it is uncertain whether this was due to their chronic kidney disease. The impact on the survival of patients who have AN and are on renal replacement therapy (RRT) is also unclear. In this study, we used data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry to examine for (1) trends in the incidence and prevalence of RRT attributed to AN during the period 1971 through 2005; (2) comorbidity prevalence at RRT start, comparing patients with and without AN; and (3) survival on RRT, comparing patients with AN and other nondiabetic nephropathy.     

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin‐1c

Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin‐1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)‐induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c‐deficient (Fbln1c^–/–) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild‐type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c^–/– mice with AAD also had reduced numbers of α‐smooth muscle actin‐positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)‐5, IL‐13, IL‐33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL‐5, IL‐33 and TNF levels in lung‐draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3‐positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL‐5 and IL‐13 from co‐cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium‐treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Asymptomatic chronic hepatitis B virus infection does not increase the risk of diabetes mellitus: A ten‐year observation

Background and Aim: Chronic hepatitis C virus infection has been known to increase the risk of diabetes. Whether this association holds true for chronic hepatitis B virus (HBV) infection remains unclear. We thus conducted this study to investigate the influence of asymptomatic chronic HBV infection on the incidence of diabetes in a longitudinal cohort. Methods: A total of 1233 adults who received health examinations in 1997–1998 and in 2000–2001 were enrolled. Among them, 483 subjects who received a third health examination in 2006–2008 were further sampled. The prevalence and incidence of diabetes between asymptomatic HBV carriers and non‐HBV controls were compared using the χ²‐test and logistic regression. Results: In 1997–1998, the prevalence rates of diabetes (9.49 and 12.0%) and glucose intolerance (28.5 and 25.4%) in HBV carriers and non‐HBV controls were comparable (P > 0.05). There was no significant correlation between asymptomatic HBV infection and the presence of diabetes in subjects examined in 1997–1998, 2000–2001, or 2006–2008 when adjusted for age, gender, and body mass index (P > 0.05). In 296 non‐diabetic subjects during 1997–1998, the ten‐year incidence of diabetes/glucose intolerance was similar between HBV carriers and non‐HBV controls (40.0 and 38.7%, P > 0.05). Moreover, no significant correlation was found between asymptomatic HBV infection and the incidence of diabetes/glucose intolerance in 2006–2008 (P = 0.775). Conclusions: Compared to non‐HBV controls, subjects with asymptomatic chronic HBV infection do not have an increased risk of diabetes, and thus HBV itself is not pro‐diabetic.     

Excessive synchronization of basal ganglia neurons at 20 Hz slows movement in Parkinson's disease

Excessive synchronization of neuronal activity at around 20 Hz is a common finding in the basal ganglia of patients with untreated Parkinson's disease (PD). Correlative evidence suggests, but does not prove, that this spontaneous activity may contribute to slowness of movement in this condition. Here we investigate whether externally imposed synchronization through direct stimulation of the region of the subthalamic nucleus at 20 Hz can slow motor performance in a simple unimanual tapping task and whether this effect is frequency selective. Tapping rates were recorded on 42 sides in 22 patients with PD after overnight withdrawal of medication. Tapping was performed without stimulation and during bilateral stimulation at 20 Hz, 50 Hz and 130 Hz. We found that tapping rates were slowed by 8.2+/-3.2% (p=0.014) during 20-Hz stimulation in subjects with relatively preserved baseline function in the task. This effect was frequency selective. The current data provide proof of the principle that excessive beta synchrony within the basal ganglia-cortical loop may contribute to the slowing of movements in Parkinson's disease.