Systematic review and meta-analysis of the prevalence of neuropathic-like pain and/or pain sensitization in people with knee and hip osteoarthritis.

OBJECTIVE: To determine the prevalence of neuropathic-like pain (NP) and pain sensitization (PS) defined by self-report questionnaires in knee and hip osteoarthritis, and whether prevalence is potentially explained by disease-severity or affected joint. DESIGN: MEDLINE, EMBASE, CINAHL were systematically searched (1990-April 2020) for studies describing the prevalence of NP and PS in knee and hip osteoarthritis using self-report questionnaires. Random-effects meta-analysis was performed. Statistical heterogeneity between studies and sub-groups (affected joint and population source as a proxy for disease severity) was assessed (I2 statistic and the Chi-squared test). RESULTS: From 2,706 non-duplicated references, 39 studies were included (2011-2020). Thirty-six studies reported on knee pain and six on hip pain. For knee osteoarthritis, the pooled prevalence of NP was: using PainDETECT, possible NP(score ≥13) 40% (95%CI 32-48%); probable NP(score >18) 20% (95%CI 15-24%); using Self-Report Leeds Assessment of Neuropathic Symptoms and Signs, 32% (95%CI 26-38%); using Douleur Neuropathique (DN4) 41% (95% CI 24-59%). The prevalence of PS using Central Sensitization Inventory (CSI) was 36% (95% CI 12-59%). For hip osteoarthritis, the pooled prevalence of NP was: using PainDETECT, possible NP 29% (95%CI 22-37%%); probable NP 9% (95%CI 6-13%); using DN4 22% (95%CI 12-31%) in one study. The prevalence of possible NP pain was higher at the knee (40%) than the hip (29%) (difference 11% (95% CI 0-22%), P = 0.05). CONCLUSIONS: Using self-report questionnaire tools, NP was more prevalent in knee than hip osteoarthritis. The prevalence of NP in knee and hip osteoarthritis were similar for each joint regardless of study population source or tool used. Whether defining NP using self-report questionnaires enables more effective targeted therapy in osteoarthritis requires investigation.

Iron deficiency and risk factors for lower iron stores in 6-24-month-old New Zealanders.

OBJECTIVES: To determine the prevalence of biochemical iron deficiency and identify factors associated with ferritin levels among 6-24-month-old urban South Island New Zealand children. DESIGN: Cross-sectional survey conducted from May 1998 to March 1999. SETTING: The cities of Christchurch, Dunedin and Invercargill. SUBJECTS: A total of 323 randomly selected 6-24-month-old children participated (response rate 61%) of which 263 provided a blood sample. METHODS: A complete blood cell count, zinc protoporphyrin, serum ferritin and C-reactive protein were measured on nonfasting venipuncture blood samples, 3-day weighed food records and general questionnaire data were collected. RESULTS: Among children with C-reactive protein<10 mg/l (n=231), 4.3% had iron deficiency anaemia, 5.6% had iron deficiency without anaemia, and 18.6% had depleted iron stores, when a ferritin cutoff of < or =12 g/l was used. Age (negative), sex (girls>boys), ethnicity (Caucasian>non-Caucasian), weight-for-age percentiles (negative) and birth weight (positive) were associated with ferritin after adjusting for infection and socioeconomic status. When current consumption of iron fortified formula and >500 ml of cows' milk per day were included, these were associated with a 22% increase and 25% decrease in ferritin, respectively (R2=0.28). CONCLUSIONS: The presence of suboptimal iron status (29%) among young New Zealand children is cause for concern, even though severe iron deficiency is rare, because children with marginal iron status are at risk of developing severe iron deficiency if exposed to a physiological challenge.

Lifestyle factors associated with glycaemic control and body mass index in older adults with diabetes.

OBJECTIVE: To investigate the relations between lifestyle factors (diet and exercise), glycated haemoglobin (HbA(1c)) and body mass index (BMI) in older adults with diabetes. DESIGN AND SETTING: A community hospital-based cross-sectional study of 150 noninstitutionalized, ambulatory adults (>/=65 y) with diabetes, residing within New Zealand's Kapiti region. SUBJECTS: Patients were recruited from all general practices; two diabetes clinics; local diabetes society and through advertisements in community newspapers. A total of 211 eligible people were identified, but 60 refused to participate and one withdrew. In all, 150 people completed the study (71% participation rate). METHODS: Nutrient intakes were calculated by a food-frequency questionnaire. Physical activity was assessed by interview using a validated questionnaire. Medical history and demographic data were obtained by interview or self-completed questionnaires; height, weight and HbA(1c) were measured. Multivariate models using bootstrapping and stepwise linear regression were used to select factors associated with HbA(1c) and BMI. RESULTS: Each five-unit increase in energy from dietary saturated fat and five-unit increase in BMI were associated with 6% (95% confidence interval=2-10%; P=0.004) and 4% (0.3-7%; P=0.031) increases in HbA(1c), respectively. For females with moderate, compared with low overall activity, there was a 14% (7-20%; P=0.000) reduction in BMI while for males the reduction was only 5% (-1-11%; P=0.116). BMI decreased 5% (2-9%; P=0.004) with each 10-y increase in age, while a five-unit increment in energy from dietary sucrose was associated with a 6% (1-11%; P=0.025) increase in BMI. CONCLUSIONS: Reducing dietary saturated fat and excess body weight may be useful means of improving glycaemic control in older adults with diabetes. Increasing physical activity and reducing energy from dietary sucrose may assist weight control, the former particularly in women.

Maximal response to a plasma cholesterol-lowering diet is achieved within two weeks.

BACKGROUND AND AIM: Replacing saturated fat with polyunsaturated fat reduces plasma cholesterol concentrations; however, it has not been well documented how rapidly the decline occurs nor how long is required to reach the maximum cholesterol-lowering effect. The aim of the present study was to determine the time course of change in plasma cholesterol concentrations when participants adopt a lipid-lowering diet. METHODS AND RESULTS: Participants (n = 19) were asked to follow for 19 days a diet high in saturated fat and then crossed over--without washout--for 19 days to a diet high in n-6 polyunsaturated fat. Participants were asked to maintain a total fat intake of 30-33% of total energy on both diets. Energy and nutrient intakes were assessed by self-reported food records covering 3 days. Plasma total cholesterol concentrations were measured on days 0, 1, 2, 5, 8, 12, and 19 of the n-6 polyunsaturated fat rich diet. Mean (95% CI) plasma total cholesterol concentration declined from 5.10 mmol/L (4.77, 5.46) at day 0 to 4.25 mmol/L (3.83, 4.67) on day 12 and remained unchanged at 4.23 mmol/L (3.85, 4.61) on day 19. A statistically significant decrease in plasma cholesterol concentration was achieved on day 2 of the intervention; by day 5, 59% (0.51 mmol/L) of the maximum reduction (0.87 mmol/L) had been reached. CONCLUSIONS: Adopting a lipid lowering diet initiates an immediate decline in plasma cholesterol concentration, the full effect of which is achieved within two weeks.

Selenium and zinc status are suboptimal in a sample of older New Zealand women in a community-based study.

The importance of selenium and zinc in the immune functioning of the aged is widely recognized. Seniors in New Zealand are at particularly high risk of low selenium status because of the low selenium soil environment. The zinc status of the New Zealand elderly has never been assessed. In this cross-sectional study, the biochemical selenium, zinc and lipid levels, physical functional capacity and dietary intakes of 103 randomly selected free-living New Zealand women (mean age +/- SD, 75 +/- 3 y) were assessed. Among nonusers of selenium supplements (n = 80), 80% [95% confidence interval (CI): 70; 88%] had plasma selenium levels (0.85 +/- 0.23 micromol/L) below 1.00 micromol/L [ approximately 10% below mean plasma selenium necessary for full expression of glutathione peroxidase (GPx) activity in New Zealand subjects]. Plasma selenium was strongly correlated with GPx: r = 0.56; P < 0.0001. For nonusers of zinc supplements (n = 88), serum zinc concentrations were 12.4 +/- 1.4 micromol/L, with 12% (95% CI: 6; 21%) having levels below the cut-off value (10.7 micromol/L). Estimated mean daily selenium and zinc intakes were 34 +/- 10 microg and 8.7 +/- 2.0 mg, respectively. Subjects in the highest tertile of a functional capacity index had higher biochemical zinc and selenium values than those in the lowest tertile (P < 0.05). The correlation between plasma selenium and GPx indicates that selenium intake in these women is still insufficient for full expression of GPx activity. Lower serum zinc levels also appear to be prevalent. Because a suboptimal trace element status may be more common among those with a poor physical functioning, promotion of the consumption of nutrient dense foods or supplements to improve selenium and zinc status of elderly women in New Zealand may be beneficial.

Axonal injury is accentuated in the caudal corpus callosum of head-injured patients.

Amyloid precursor protein (APP) accumulation is a sensitive marker for the axonal damage that is commonly seen in the brain as the result of head injury. This form of damage is particularly associated with midline structures such as the corpus callosum, although it is not clear whether some areas are more susceptible than others. The aim of this study was to determine if there was a differential distribution of axonal injury throughout the corpus callosum after head injury in an unselected group of cases. Coronal tissue sections from eight cases were taken at different levels through the corpus callosum, including the genu, body, and splenium. The sections were immunostained with an antibody to APP, and the amount of axonal damage at the different levels was quantified using computer image analysis to build up a rostro-caudal profile for each case. The profiles revealed a significantly higher APP load in caudal parts of the corpus callosum. This supports previous nonquantitative reports in the literature and has important implications in terms of choosing where tissue should be sampled to maximize the chance of detecting axonal injury post mortem.

Overexpression of s100beta in Down's syndrome: correlation with patient age and with beta-amyloid deposition.

S100beta is an astrocyte-derived uritotrophic' cytokine which has been implicated in the pathogenesis of Alzheimer's disease. S100beta overexpression by plaque-associated astrocytes correlates with growth of abnormal (strophic') neurites in beta-amyloid plaques, one of the major neuropathological hallmarks of Alzheimer's disease. As the characteristic neuropathological changes of Alzheimer's disease are virtually universal in middle-aged Down's syndrome patients, studies of Down's syndrome patients provide a unique opportunity to investigate the pathophysiological processes underlying the development of Alzheimer-type neuropathological changes. Computerized morphometric analysis was used to quantify astrocyte activation and astrocytic expression of S100beta, and to correlate these with beta-amyloid deposition, in a clinically well-characterized cohort of Down's syndrome subjects, aged 13-65 years. There were significant positive correlations between S100beta expression and patient age, and between S100beta expression and cerebral cortical beta-amyloid deposition. Moreover, the numbers of activated (enlarged) astrocytes overexpressing S100beta showed a significant correlation with the numeric density of beta-amyloid plaques, from the youngest to the oldest ages and within age ranges where pathology is most florid, while no such relationship was found between the numbers of small, non-activated S100beta-immunoreactive cells and numerical density of beta-amyloid plaques. These correlations, together with established functions of S100beta, are consistent with the idea that S100beta overexpression promotes beta-amyloid plaque formation and progression in Down's syndrome.

Effects of diaspirin crosslinked hemoglobin infusion in treadmill-exercised swine.

The hemodynamic and metabolic effects of diaspirin crosslinked hemoglobin (DCLHb) were investigated using graded treadmill exercise in swine (n = 5/group). Swine received DCLHb (10% solution, 5 ml/kg) or oncotically-matched human serum albumin (HSA, 5ml/kg). Baseline metabolic and hemodynamic data were similar. In both groups exercise increased hemodynamic parameters. Exercise increased heart rate (HR) from 139 +/- 12 to 293 +/- 28 bpm with DCLHb and from 136 +/- 13 to 314 +/- 13 bpm with HSA. Exercise increased cardiac output (CO) from 5.7 +/- 0.75 to 15.6 +/- 2.01/min in the DCLHb group and from 5.3 +/- 0.48 to 15.7 +/- 0.881/min in the HSA group. However, CO returned to baseline faster with DCLHb upon stopping exercise. The DCLHb-treated group demonstrated a significantly higher oxygen extraction during exercise (12.04 +/- 0.38 vs 9.48 +/- 0.99 ml O2/100 ml blood) and a lower oxygen delivery throughout recovery (74.6 +/- 6.6 vs 102.2 +/- 7.21 O2/min), indicating enhanced oxygen delivery during exercise in the treatment group. DCLHb infusion did not impair metabolic or hemodynamic functions. These data indicate that DCLHb may increase oxygen delivery to working tissue more efficiently than HSA during treadmill exercise in swine.

A comparison of manual and semi-automated methods in the assessment of axonal injury.

Diffuse axonal injury (DAI) in the central nervous system is a common cause of post-traumatic coma and may result in varying degrees of disability up to and including the vegetative state. Experimental studies in man and animals have previously relied upon semi-quantitative grading systems for determining the relationship between the extent of DAI and the clinical features of patients. Using beta-amyloid precursor protein immunocytochemistry for the detection of DAI in sections of corpus callosum from 15 cases of fatal head injury, we have developed a quantitative image analysis technique for the assessment of axonal injury. This new method is objective and reproducible and should allow better correlation with biomechanical, radiological, and clinical parameters to increase our understanding of DAI.

Is there a genetic basis for the deposition of beta-amyloid after fatal head injury?

1. Alzheimer's disease is a heterogeneous disorder that may be caused by genetic or environmental factors or by a combination of both. Abnormalities in chromosomes 1, 14, and 21 have all been implicated in the pathogenesis of the early-onset form of the disease, while the epsilon 4 allele of the apolipoprotein E gene (on chromosome 19) is now recognized as a risk factor for early- and late-onset sporadic and familial Alzheimer's disease. 2. The best-established environmental trigger for the disease is a head injury, based on epidemiological and neuropathological evidence. Approximately 30% of patients who die after a single episode of severe head injury show intracerebral deposition of beta-amyloid protein (A beta), a protein that is thought to be central to the pathogenesis of Alzheimer's disease. 3. Recent studies have revealed an over-representation of the apoE epsilon 4 allele in those head-injured patients displaying A beta pathology, thus providing the first evidence for a link between a genetic susceptibility (apoE epsilon 4) and an environmental trigger (head injury) in the development of Alzheimer-type pathology.

Nitric oxide modulation of retinal, choroidal, and anterior uveal blood flow in newborn piglets.

The purpose of the present study was to investigate the role of nitric oxide (NO) in modulating the resting vascular tone of the choroidal and anterior uveal circulations and the autoregulatory gain of the retina. Blood flow (ml/min/100 gm dry weight) to tissues was determined in 23 anesthetized piglets (3-4 kg) using radiolabelled microspheres. Ocular Perfusion Pressure (OPP) was defined as mean arterial pressure minus intraocular pressure (IOP) which was manipulated hydrostatically by cannulation of the anterior eye chamber. The OPP was decreased during intravenous infusion (30 mg/kg/hr) of either the NO-synthase inhibitor L-NAME or the inactive enantiomer D-NAME. Blood flows were determined at OPP of 60, 50, 40, 30, and 20 mmHg following initial ocular blood flow measurements. Mean initial choroidal and anterior uveal blood flows with L-NAME showed a 47+/-12% and a 43+/-6% reduction (p <.001), respectively. Mean choroidal blood flows were significantly reduced (p<.01) in the L-NAME treated animals at an OPP of 60 and 50 when compared to D-NAME. Uveal blood flows were linearly correlated with OPP in the L-NAME and D-NAME treated groups. Uveal blood flow was greater following exogenous administration of L-arginine (180 mg/kg). Mean initial retinal blood flow did not differ significantly in either group. Retinal blood flow with L-NAME was reduced at OPP of 60 mmHg and below compared to D-NAME (p<.05). The degree of compensation in the autoregulatory gain of the retinal vasculature was reduced in the presence of L-NAME at an OPP of 50 mmHg and below compared to D-NAME. These data support the hypothesis that NO may be a primary mediator in maintaining resting vascular tone to the choroid and anterior uvea in vivo and that NO blockade reduces the degree of compensation in the autoregulatory gain of the retinal vasculature within a specific range of ocular perfusion pressures.

Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression.

The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the beta-amyloid precursor protein, thus favoring continuing deposition of beta-amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100beta, is a neurite growth-promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine-induced neuronal insults can activate microglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.

Life-long overexpression of S100beta in Down's syndrome: implications for Alzheimer pathogenesis.

Chronic overexpression of the neurite growth-promoting factor S100beta has been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. Such plaques are virtually universal in middle-aged Down's syndrome, making Down's a natural model of Alzheimer's disease. We determined numbers of astrocytes overexpressing S100beta, and of neurons overexpressing beta-amyloid precursor protein (beta-APP), and assayed for neurofibrillary tangles in neocortex of 20 Down's syndrome patients (17 weeks gestation to 68 years). Compared to controls, there were twice as many S100beta-immunoreactive (S100beta+) astrocytes in Down's patients at all ages: fetal, young, and adult (p = 0.01, or better, in each age group). These were activated (i.e., enlarged), and intensely immunoreactive, even in the fetal group. There were no neurofibrillary changes in fetal or young Down's patients. The numbers of S100beta+ astrocytes in young and adult Down's patients correlated with the numbers of neurons overexpressing beta-APP (p < 0.05). Our findings are consistent with the idea that conditions--including Down's syndrome--that promote chronic overexpression of S100beta may confer increased risk for later development of Alzheimer's disease.

Relation between delayed impairment of cerebral energy metabolism and infarction following transient focal hypoxia-ischaemia in the developing brain.

Phosphorus magnetic resonance spectroscopy (31P MRS) was used to determine whether focal cerebral injury caused by unilateral carotid artery occlusion and graded hypoxia in developing rats led to a delayed impairment of cerebral energy metabolism and whether the impairment was related to the magnitude of cerebral infarction. Forty-two 14-day-old Wistar rats were subjected to right carotid artery ligation, followed by 8% oxygen for 90 min. Using a 7T MRS system. 31P brain spectra were collected during the period from before until 48 h after hypoxia-ischaemia. Twenty-eight control animals were studied similarly. In controls, the ratio of the concentration of phosphocreatine ([PCr]) to inorganic orthophosphate ([Pi]) was 1.75 (SD 0.34) and nucleotide triphosphate (NTP) to total exchangeable phosphate pool (EPP) was 0.20 (SD 0.04): both remained constant. In animals subjected to hypoxia-ischaemia, [PCr] to [Pi] and [NTP] to [EPP] were lower in the 0- to 3-h period immediately following the insult: 0.87 (0.48) and 0.13 (0.04), respectively. Values then returned to baseline level, but subsequently declined again: [PCr] to [Pi] at -0.02 h-1 (P < 0.0001). [PCr] to [Pi] attained a minimum of 1.00 (0.33) and [NTP] to [EPP] a minimum of 0.14 (0.05) at 30-40 h. Both ratios returned towards baseline between 40 and 48 h. The late declines in high-energy phosphates were not associated with a fall in pHi. There was a significant relation between the extent of the delayed impairment of energy metabolism and the magnitude of the cerebral infarction (P < 0.001). Transient focal hypoxia-ischaemia in the 14-day-old rat thus leads to a biphasic disruption of cerebral energy metabolism, with a period of recovery after the insult being followed by a secondary impairment some hours later.

Quantification of Alzheimer-type neurofibrillary lesions by automated image analysis.

Neurofibrillary pathology is seen in a wide variety of disorders such as Alzheimer's disease (AD), progressive supranuclear palsy and the Parkinsonism-dementia amyotrophic lateral sclerosis complex of Guam. To assess the pathological importance of these lesions quantitative studies need to be undertaken. To date, most neuropathological studies have been based on qualitative, or at best semi-quantitative, data reporting the presence or absence of specific lesion types. To obtain such data traditionally involves laborious manual measurements, which rely heavily on the skill of the investigator and tend to have low inter- and intra-rater reliabilities. We have developed a novel analysis technique, using colour image analysis, which can accurately quantify the total amount of neurofibrillary damage present. Furthermore we have developed a set of mathematically defined morphological criteria to allow objective discrimination between the three types of neurofibrillary damage seen in the cortex immunostained with Alz-50. Use of this novel technique provides a reliable, rational means for the classification of neurofibrillary lesions.

Comparative investigation of neurofibrillary damage in the temporal lobe in Alzheimer's disease, Down's syndrome and dementia pugilistica.

Neurofibrillary lesions such as neurofibrillary tangles, neurites and neuropil threads are used as neuropathological markers of Alzheimer's disease (AD). However these lesions are also seen in non-demented elderly cases as well as in several other disorders such as Down's syndrome (DS), dementia pugilistica (DP) and Parkinson's disease. Quantitative studies may therefore help in understanding the pathophysiological role of these lesions. Using a novel image analysis technique we have quantified the extent of neurofibrillary damage in AD, DS and DP. We have found that the extent of neurofibrillary change did not significantly differ between AD and DS, though there were also strong parallels between AD and DP. We conclude that both genetic (as in DS) and environmental (as in DP) risk factors for AD-type pathology provide a similar pattern of neurofibrillary degeneration to that in AD itself suggesting that similar degenerative mechanisms might be triggered in all three conditions.

Resuscitation from severe hemorrhage.

The potential to be successfully resuscitation from severe traumatic hemorrhagic shock is not only limited by the "golden 1 hr", but also by the "brass (or platinum) 10 mins" for combat casualties and civilian trauma victims with traumatic exsanguination. One research challenge is to determine how best to prevent cardiac arrest during severe hemorrhage, before control of bleeding is possible. Another research challenge is to determine the critical limits of, and optimal treatments for, protracted hemorrhagic hypotension, in order to prevent "delayed" multiple organ failure after hemostasis and all-out resuscitation. Animal research is shifting from the use of unrealistic, pressure-controlled, hemorrhagic shock models and partially realistic, volume-controlled hemorrhagic shock models to more realistic, uncontrolled hemorrhagic shock outcome models. Animal outcome models of combined trauma and shock are needed; a challenge is to find a humane and clinically realistic long-term method for analgesia that does not interfere with cardiovascular responses. Clinical potentials in need of research are shifting from normotensive to hypotensive (limited) fluid resuscitation with plasma substitutes. Topics include optimal temperature, fluid composition, analgesia, and pharmacotherapy. Hypotensive fluid resuscitation in uncontrolled hemorrhagic shock with the addition of moderate resuscitative (28 degrees to 32 degrees C) hypothermia looks promising in the laboratory. Regarding the composition of the resuscitation fluid, despite encouraging results with new preparations of stroma-free hemoglobin and hypertonic salt solutions with colloid, searches for the optimal combination of oxygen-carrying blood substitute, colloid, and electrolyte solution for limited fluid resuscitation with the smallest volume should continue. For titrating treatment of shock, blood lactate concentrations are of questionable value although metabolic acidemia seems helpful for prognostication. Development of devices for early noninvasive monitoring of multiple parameters in the field is indicated. Molecular research applies more to protracted hypovolemic shock followed by the systemic inflammatory response syndrome or septic shock, which were not the major topics of this discussion.

Effects of soman (pinacolyl methylphosphonofluoridate) on coronary blood flow and cardiac function in swine.

The effects of soman (pinacolyl methylphosphonofluoridate) on coronary blood flow, the electrocardiogram, and cardiac function were measured in alpha-chloralose-anesthetized swine. Coronary blood flow (CBF), mean arterial blood pressure (MAP), peak systolic left ventricular pressure (IVP), maximum rate of left ventricular pressure development (dP/dtmax), cardiac output, and the ECG were monitored continuously. A dose of 2X LD50 of soman (1 LD50 = 4.6 micrograms/kg) was given at 1 LD50/min in the femoral vein, which produced an increase in coronary sinus plasma acetylcholine (ACh) from a control of 0.7 +/- 0.01 nmol/ml to a maximum 314% of control at 15 min and a decrease in CBF from a control of 99 +/- 13 ml/min/100 g to a minimum 55% of control at 15 min. The increase in ACh in the coronary sinus was significantly correlated with a decrease in CBF (r = -0.87, p < 0.001). The fall in CBF was accompanied by concomitant decreases in IVP, MAP, and dP/dtmax, with S-T segment elevation and ventricular fibrillation. The increase in coronary sinus acetylcholine concentration was significantly correlated with a 10-fold fall in coronary sinus acetylcholinesterase levels from a control of 2.47 +/- 0.97 mol acetylcholine hydrolyzed/ml blood/min and was consistent with the time course for the reduced hemodynamic measurements. These studies support the hypothesis that acetylcholine increases following soman toxicity may decrease coronary blood flow, thereby initiating ischemic electrocardiographic changes and reducing cardiac function.

Altered beta-APP metabolism after head injury and its relationship to the aetiology of Alzheimer's disease.

There is increasing evidence of a link between head injury and the subsequent onset of Alzheimer's disease. Deposits of amyloid beta-protein (A beta) are found not only in cases of dementia pugilistica but in some 30% of patients dying after a single episode of severe head injury. Detailed clinicopathological studies have shown that A beta deposition is most likely, but not exclusively, to occur, the older the patient at the time of injury, and if the injury is the result of a fall. Distribution studies have shown that the A beta is widely deposited in the neocortex and there is no apparent association with any of the multiple primary or secondary pathologies of traumatic brain injury. There is an increased expression of beta-APP particularly in the pre-alpha cells of the entorhinal cortex and in areas of axonal damage. Recent molecular genetic studies have shown that there is a strong association between deposits of A beta and the apolipoprotein E genotype of the individual.

A quantitative comparison of plaque types in Alzheimer's disease and senile dementia of the Lewy body type.

In a previous study we reported no difference in the overall beta-amyloid protein (beta AP) load between Alzheimer's disease (AD) and senile dementia of the Lewy body type (SDLT). However, it is possible that differences in the morphology of beta AP plaque types exist, analogous to the differences in cytoskeletal pathology found in these two disorders. We have carried out a quantitative image analysis of plaque subtypes in the temporal lobe of AD (n = 8), SDLT (n = 9) and control (n = 11) cases. Measurements of beta AP load and plaque density were consistently higher in AD and SDLT than in controls. When AD and SDLT cases were compared no differences were seen in either the density or relative proportions of classic and diffuse plaques. Based on these results we suggest that the variation in the clinical course of these diseases reflects differences in the cytoskeletal pathology, whereas the final stages of profound dementia common to both disorders is associated with the deposition of beta AP.