Long-lasting stress, quantitative changes in nitric oxide concentration and functional state of brain mitochondria

We have studied biochemical changes occurring in brain cell mitochondria of white rats on the background of stress induced by 30-day isolation and disruption of circadian rhythms. It was ascertained that due to long-lasting stress, there occurs activation of oxidative processes in mitochondria as well as inhibition of anti-oxidant system activity, causing development of energy deficiency in brain cells. The above-mentioned biochemical processes become the reason for activation and opening of the mitochondrial permeability transition pore (MPTP), which, in its turn, signals the start of neuroapoptosis and various neurodegenerative processes.     

Genetic, biochemical, and crystallographic characterization of Fhit–substrate complexes as the active signaling form of Fhit

Alterations in the FHIT gene at 3p14.2 occur as early and frequent events in the development of several common human cancers. The ability of human Fhit-negative cells to form tumors in nude mice is suppressed by stable reexpression of Fhit protein. Fhit protein is a diadenosine P¹,P³-triphosphate (ApppA) hydrolase whose fungal and animal homologs form a branch of the histidine triad (HIT) superfamily of nucleotide-binding proteins. Because the His-96 → Asn substitution of Fhit, which retards ApppA hydrolase activity by seven orders of magnitude, did not block tumor-suppressor activity in vivo, we determined whether this mutation affected ApppA binding or particular steps in the ApppA catalytic cycle. Evidence is presented that His-96 → Asn protein binds ApppA well and forms an enzyme-AMP intermediate extremely poorly, suggesting that Fhit–substrate complexes are the likely signaling form of the enzyme. The cocrystal structure of Fhit bound to Ado-p-CH₂-p-p_s-Ado (IB2), a nonhydrolyzable ApppA analog, was refined to 3.1 Å, and the structure of His-96 → Asn Fhit with IB2 was refined to 2.6 Å, revealing that two ApppA molecules bind per Fhit dimer; identifying two additional adenosine-binding sites on the dimer surface; and illustrating that His-98 is positioned to donate a hydrogen bond to the scissile bridging oxygen of ApppA substrates. The form of Fhit bound to two ApppA substrates would present to the cell a dramatically phosphorylated surface, prominently displaying six phosphate groups and two adenosine moieties in place of a deep cavity lined with histidines, arginines, and glutamines.     

Cardiovascular,rheumatologic, and pharmacologic predictors of stroke in patients with rheumatoid arthritis: A nested,case–control study

Objective

To determine the risk of stroke in patients with rheumatoid arthritis (RA) and risk factors associated with stroke.

Methods

We performed nested case–control analyses within a longitudinal databank, matching up to 20 controls for age, sex, and time of cohort entry to each patient with stroke. Conditional logistic regression was performed as an estimate of the relative risk of stroke in RA patients compared with those with noninflammatory rheumatic disorders, and to examine severity and anti–tumor necrosis factor (anti‐TNF) treatment effects in RA.

Results

We identified 269 patients with first‐ever all‐category strokes and 67 with ischemic stroke, including 41 in RA patients. The odds ratio (OR) for the risk of all‐category stroke in RA was 1.64 (95% confidence interval [95% CI] 1.16–2.30, P = 0.005), and for ischemic stroke was 2.66 (95% CI 1.24–5.70, P = 0.012). Ischemic stroke was predicted by hypertension, myocardial infarction, low‐dose aspirin, comorbidity score, Health Assessment Questionnaire score, and presence of total joint replacement, but not by diabetes, smoking, exercise, or body mass index. Adjusted for cardiovascular and RA risk factors, ischemic stroke was associated with rofecoxib (P = 0.060, OR 2.27 [95% CI 0.97–5.28]), and possibly with corticosteroid use. Anti‐TNF therapy was not associated with ischemic stroke (P = 0.584, OR 0.80 [95% CI 0.34–1.82]).

Conclusion

RA is associated with increased risk of stroke, particularly ischemic stroke. Stroke is predicted by RA severity, certain cardiovascular risk factors, and comorbidity. Except for rofecoxib, RA treatment does not appear to be associated with stroke, although the effect of corticosteroids remains uncertain.     

Long-term risk of stroke and other vascular events in patients with asymptomatic carotid artery stenosis

CONTEXT: The annual risk of ischemic stroke in patients with asymptomatic carotid artery stenosis is about 2% during the short-term (2-3 years), but the long-term risks of stroke and other vascular events are unknown, although they may affect surgical decision making. OBJECTIVE: To evaluate the long-term risk of stroke and other vascular events in patients with asymptomatic carotid artery stenosis. DESIGN: Cohort study with a median follow-up of 10 years (range, 5-18 years). SETTING: The teaching hospital of the University of Toronto, Toronto, Ontario. PATIENTS: From the initial cohort of 500 patients, 106 patients with asymptomatic carotid artery stenosis were selected because they had completed at least 5 years of follow-up. MAIN OUTCOME MEASURES: Ipsilateral stroke, myocardial infarction, and nonstroke vascular death. RESULTS: The 10- and 15-year actuarial risks of ipsilateral stroke were 5.7% (95% confidence interval [CI], 0%-12%) and 8.7% (95% CI, 1%-17%), respectively, in patients with 0% to 49% internal carotid artery stenosis, and 9.3% (95% CI, 1%-18%) and 16.6% (95% CI, 1%-32%) in patients with 50% to 99% internal carotid artery stenosis. The 10- and 15-year risks of myocardial infarction and nonstroke vascular death were 10.1% (95% CI, 4%-16%) and 24.0% (95% CI, 14%-34%). Age (P =.02), diabetes mellitus (P =.02), and internal carotid artery stenosis of 50% or more (P =.04) were predictive of increased risks of myocardial infarction and nonstroke vascular death. Internal carotid artery stenosis of 50% or more did predict the risk of ipsilateral stroke (P =.003) when all 181 asymptomatic carotid arteries were included. CONCLUSIONS: The annual stroke risk in patients with asymptomatic carotid artery stenosis was low and remained stable during long-term follow-up. Any benefit from carotid surgery is therefore unlikely to increase significantly with long-term follow-up. The high long-term risks of myocardial infarction and nonstroke vascular death suggest that prevention strategies should concentrate on coronary risk more than stroke risk.     

Georgia mental health country profile

This article is on the mental health of the population of Georgia describing context and mental health needs, extrinsic and intrinsic influences on mental health in the country, and health and social services for people with mental health problems and mental illnesses. The mental health profile of Georgia has been compiled with the help of an instrument developed by the International Consortium on Mental Health. Georgia is one of the former republics of the USSR with a population of about 4.5 million people. Political, social and economic changes have led to wide scale social stress in Georgia in recent years and to related psychosocial and behavioural problems. Difficult economic conditions and internal displacement are thought to be key contributory factors to the three-fold increase in suicide experienced during the decade following independence. Georgia has produced a written mental health policy. However, its implementation is hampered by the lack of resources, training and community awareness. The Government has passed a Mental Health Act, but this is also ineffective at present due to a lack of staff, financing and appropriate facilities.     

Visualization of stimulation patterns in cochlear implants: application to event-related potentials (P300) in cochlear implant users

Auditory P300 potentials obtained in cochlear implant users were evoked with tone bursts designed to reflect the frequency stimulation patterns of intracochlear electrodes. To visualize these stimulation patterns in MED-EL COMBI 40+ cochlear implants, we calculated color-coded plots of the charge of each stimulus pulse as a function of time and stimulation channel (stimulograms). The aim of this study was to investigate the effect of stimulation patterns on event-related potentials, such as the P300. The influence of electrode separation on the P300 response in postlingually deaf adults using a cochlear implant is demonstrated in two examples.     

Monitoring radiofrequency renal lesions in real time using contrast-enhanced ultrasonography: a porcine model

BACKGROUND AND PURPOSE: Ablation by cold (cryoablation) or radiofrequency energy (RFA), has been popularized for the treatment of small renal tumors. Regrettably, there currently is no reliable method of radiologically monitoring the propagation of RF lesions in real time. Ultrasonography enhanced by gas-filled microbubble contrast agents allows depiction of regions of tissue perfusion and has been described as a useful adjunct in diagnosing renal pseudotumors, improving prostate biopsy results, and confirming successful ablation of liver tumors. We hypothesized that contrast-enhanced ultrasonography (CEUS) would allow us to define, in real time, areas of cell death secondary to RFA and thus determine successful treatment. MATERIALS AND METHODS: Five female swine underwent initial laparoscopic exploration and creation of ipsilateral upper- and lower-pole renal RFA lesions. Lesion size was measured with standard gray-scale, Doppler, and microbubble CEUS. After 2 weeks, an identical procedure was performed on the contralateral kidney, including repeat sonographic measurements on the first kidney. All swine were then immediately sacrificed, and both kidneys (20 lesions) were harvested for pathologic analysis (hematoxylin-eosin and nicotinamide adenine dinucleotide stains). Radiographic lesion size was then compared with the gross and microscopic findings. RESULTS: The RFA lesions could not be imaged accurately in real time with standard gray-scale or Doppler sonography. However, microbubble CEUS was able to monitor parenchymal blood flow and, thus, the lesions (no blood flow) in real time. Hypoechoic lesions (no bubble enhancement) imaged during contrast sonography corresponded with regions of cell death as demonstrated on pathologic analysis. CONCLUSIONS: Microbubble CEUS is can monitor RFA lesions in real time. This novel imaging modality should allow more effective renal tumor ablation.