Plasma haem oxygenase-1 may represent a first-in-class biomarker of oxidative stress in rheumatoid arthritis.

OBJECTIVES: This study explores the early identification of rheumatoid arthritis (RA) patients at elevated risk of progression. Haem-oxygenase-1 (HO-1) is a marker of oxidative stress in inflammation. Here, we investigate HO-1 as a biomarker of oxidative stress and its association with clinical disease activity and radiographic progression in RA. METHOD: Baseline HO-1 was measured sequentially in plasma samples from patients with early rheumatoid arthritis (eRA) (n = 80). Disease Activity Score based on 28-joint count-C-reactive protein, Clinical Disease Activity Index, and total Sharp score were used to evaluate the disease course serially over 2 years. Paired plasma and synovial fluid samples were examined for HO-1 in active established rheumatoid arthritis (esRA) (n = 20). Plasma from healthy control subjects was also included (n = 35). RESULTS: Plasma HO-1 levels were increased in eRA {1373 pg/mL [interquartile range (IQR) 1110-2050]} and esRA [2034 pg/mL (IQR 1630-2923)] compared with controls [1064 pg/mL (IQR 869.5-1378)]. HO-1 plasma levels decreased with treatment. Baseline HO-1 correlated with disease activity and radiographic progression. A strong, linear correlation was found between synovial and plasma HO-1 levels (r = 0.75, p < 0.001). CONCLUSION: In eRA, plasma levels of HO-1 were increased and correlated with disease and radiographic progression. A baseline measurement of plasma HO-1 levels demonstrated superior performance to currently used clinical and serological disease markers in the prediction of radiographic progression. Plasma HO-1 may function as a first-in-class biomarker of synovial oxidative stress in RA.

Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease.

Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat-primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD-ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72 related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.

Overdiagnosis of dementia in young patients - a nationwide register-based study.

BACKGROUND: Little is known about the quality of the diagnostic evaluation and the validity of dementia diagnoses in young patients established in routine clinical practice. The aim of this study was to investigate the validity of the diagnosis of dementia registered in the Danish nationwide hospital registers in young patients. METHODS: Two hundred patients were randomly selected from 891 patients <65 years registered with a dementia diagnosis for the first time in 2008. The patients' medical records were reviewed to evaluate if they fulfilled ICD-10 and/or DSM-IV criteria for dementia and current clinical criteria for specific dementia subtypes. RESULTS: A registered diagnosis was found to be correct in only 59%. A misdiagnosis of dementia occurred primarily in patients with depression or alcohol abuse. CONCLUSION: Our results suggest that dementia is overregistered and overdiagnosed in young patients. This may be due to a different symptom profile of dementia in young patients, lack of knowledge among clinical physicians and the wide range of conditions which may be misinterpreted as dementia.

Transthyretin as a potential CSF biomarker for Alzheimer's disease and dementia with Lewy bodies: effects of treatment with cholinesterase inhibitors.

BACKGROUND: Previous studies have indicated that transthyretin (TTR) levels in cerebrospinal fluid (CSF) are altered in depression and dementia. The present study aimed to investigate whether CSF TTR can be used to discriminate between patients with Alzheimer's disease (AD) and patients with dementia with Lewy bodies (DLB) with or without medication, as well as to reveal whether CSF TTR correlates with depression in dementia. METHODS: CSF samples from 59 patients with AD, 13 patients with DLB and 13 healthy controls were collected, and biochemical analysis was performed. Subjects were assessed for the presence of depression. RESULTS: No significant differences in CSF TTR were found between AD, DLB, and control subjects or between depressed and non-depressed dementia patients. Interestingly, we found a significant reduction in CSF TTR (14%) in AD patients who were medicated with cholinesterase inhibitors compared to those AD patients who were not. CONCLUSIONS: Significant reductions in CSF TTR were found after cholinesterase inhibitor treatment in patients with AD compared to untreated individuals. CSF TTR was unaltered in patients with DLB and had no relationship to depression in the present cohort with dementias.

A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment.

BACKGROUND: Mutations in the Presenilin 2 gene (PSEN2) are rare causes of Alzheimer's disease (AD). Pathogenic mutations in the genes associated with autosomal dominant inherited AD have been shown to alter processing of the amyloid precursor protein (APP) resulting in a relative increase of the amount of Abeta42 peptide. METHODS AND RESULTS: We present a patient with neuropathologically confirmed early-onset AD characterized by profound language impairment. The patient was heterozygous for a novel missense mutation in exon 11 of the PSEN2 gene leading to a predicted amino acid substitution from valine to methionine in position 393, a conserved residue. However, in vitro expression of PSEN2 V393M cDNA did not result in detectable increase of the secreted Abeta42/40 peptide ratio. The mutation was not found in 384 control individuals tested. CONCLUSIONS: The possible pathogenic nature of the mutation is not clarified. We discuss the limitations of functional PSEN2 studies and the challenges associated with genetic counselling of family members at risk.

No change in neuron numbers in the dentate nucleus of patients with schizophrenia estimated with a new stereological method--the smooth fractionator.

The dentate nucleus is phylogenetically the most recent nucleus in the cerebellum. Owing to its connections to the thalamus and the prefrontal cortex it may be involved in the symptomathology in schizophrenia and other psychiatric illnesses. In this stereological study we implemented the smooth fractionator, which combines the unbiased principles of the optical fractionator with a new and more efficient sampling strategy to the dentate nucleus. The smooth fractionator represents the most efficient sampling strategy described so far in stereology, in terms of reducing the sampling variance and thus increasing the efficiency. It is the first application of the smooth fractionator to human brain tissue and presents estimations of total number of neurons in the dentate nuclei of eight patients with schizophrenia compared to eight control persons. The total number of neurons in the dentate nucleus was estimated to 3.36 x 10(6) in subjects with schizophrenia, which was not statistically significant different from 3.65 x 10(6) in control subjects (P = 0.63). The advantages and disadvantages of the smooth fractionator method are discussed and its precision in practical application is estimated.

Pronounced loss of cell nuclei and anisotropic deformation of thick sections.

The local deformation and variations in section thickness are studied in 100-microm thick vibratome sections of well-fixed human brain tissue. During processing, including drying on glass slides, the section thickness is reduced to less than half, but close to the edges there is less shrinkage of the section thickness. Close to both surfaces there is a pronounced reduction in the number of neuronal nucleoli. At the scale of the original section, the upper 15 microm and the lower 10 microm are depleted. The loss is most pronounced at the upper surface, which is unprotected during processing. In the central 70% of the section height, where one would ordinarily use an optical disector for sampling, there is no indication of non-uniform shrinkage. The simplest explanation for the observed loss of nucleoli is that all cells opened by the knife may lose their nuclei across an unprotected section surface. The observations do not generalize to other tissues and other preparation techniques, but illustrate the magnitude of some of the problems for uniform sampling and unbiased estimation in very thick sections. The uniform optical disector sampling of nucleoli in thick sections, as opposed to that of cell nuclei, raises a special problem, which is discussed briefly.

Successful intrauterine term pregnancy after resection of corneal pregnancy.

A woman with previous bilateral salpingectomia, including wedge-formed corneal resection, became heterotopic pregnant after in-vitro-fertilization. Ultrasound revealed a twin corneal pregnancy and an intrauterine pregnancy. Undergoing laparotomy, the uterine corner with the ectopic pregnancy was resected. The intrauterine pregnancy proceeded uncomplicated. She delivered a healthy girl, at 38 weeks of gestation.

The distributions of Purkinje cell perikaryon and nuclear volume in human and rat cerebellum with the nucleator method.

The Purkinje cells are among the largest cells in the central nervous system and are the output cells of the cerebellar cortex. They are, therefore, of special interest in cerebellar diseases. The estimation of total number and mean perikaryon and nuclear volume of Purkinje cells in five normal human and nine rat cerebella were obtained using unbiased methods based on stereological principles. The average total number of Purkinje cells was 30.5 x 10(6) (Coefficient of variation, CD = S.D./mean = 0.13) in humans and 0.61 x 10(6) (0.21) in rats. Thus the total number of Purkinje cells was 50 times higher in the human cerebellum compared with rats, while numerical density (number/mm3) was 13 times lower in humans (0.81 x 10(3)) compared with rats (10.1 x 10(3)). An unbiased stereological principle, the nucleator, was applied to estimate the volume of Purkinje cell perikarya and nuclei. In humans the average geometric mean volume of Purkinje cell perikaryon is 12,400 microm3 (interindividual coefficient of variation = 0.08), which is about three times larger than in rats, 4900 microm3 (CVi = 0.09). The intraindividual distributional variation (CVd) in perikaryon volume is much larger in humans compared to rats (CVd = 0.72 vs 0.32). One of the differences between the two species is the simple proportionality between perikaryon and nucleus size i humans, whereas larger Purkinje cells have relatively larger nuclei in the rat.

A stereological study of substantia nigra in young and old rhesus monkeys.

The number of pigmented and non-pigmented neurons in the substantia nigra (SN) of 10 old and six young female Macaca mulatta monkeys and in three old alpha male monkeys were estimated using new stereological cell counting methods. No systematic right-left differences were noted, nor were old animals different from young ones with respect to SN volume (68.9 mm3 vs. 62.8 mm3) or absolute number of nerve cells (320,000 vs. 312,000). However, the total number of pigmented neurons was about eight times higher in old animals compared with young ones (166,000 vs. 21,400) while the total number of non-pigmented SN neurons was less than half in old animals compared with young ones (139,000 vs. 285,000). These differences create difficulties in generalizing experimental results from the rhesus animal model to man. It seems unlikely that a simple correlation can be made between pigmented and tyrosine hydroxylase (TH) positive neurons in SN in monkeys. Instead of estimating the total number of pigmented and non-pigmented cells, only SN neurons positive for TH using immunohistochemical techniques might be used an indicator of the total number of dopaminergic neurons in SN in monkeys.

Total numbers of various cell types in rat cerebellar cortex estimated using an unbiased stereological method.

A new and efficient stereological method for estimating the total number of the different cell types in rat cerebellar cortex is presented. The cells have been subdivided into the following categories: Purkinje cells, granule cells, Golgi cells, glial cells in the granular layer, Bergmann glial cells and neurons and glial cells in the molecular layer. The method has been used to estimate the total number of some of the cell types in rats exposed to orally administered toluene at doses of 200, 400 and 800 mg/kg/day for 12 weeks compared with a control group. No statistically significant differences were found between the exposed and non-exposed animals. The described method can be used in a number of both biological and experimental studies. With the use of new stereological methods it is possible to get precise estimates of total cell numbers in a much shorter time than earlier required. This makes it possible to improve the reliability of the final result by increasing the number of cases processed.

Cardiac activity, ventilation rate and acid-base regulation in rainbow trout exposed to hypoxia and combined hypoxia and hypercapnia.

A computerised system for non-invasive monitoring of heart and ventilation rates and the time intervals between heart beats and between breaths was developed and used to investigate cardio-respiratory changes in rainbow trout exposed to hypoxia and to combined hypoxia and hypercapnia. Upon exposure to hypoxia and hypoxia-hypercapnia the arterial O2 tension decreased from about 90 mmHg to about 30 mmHg. Acid-base changes were small in hypoxia whereas exposure to combined hypoxia-hypercapnia caused a large extracellular respiratory acidosis. This acidosis was completely compensated within 24h by accumulation of bicarbonate in plasma to concentrations twice the normoxic values. The ventilation rate was increased to higher values in hypoxic-hypercapnic trout than in hypoxic trout. In contrast to previous reports, the heart rate increased in hypoxia. On top of the tachycardia response to hypoxia, the heart rate was governed by circadian rhythms, with higher heart rates during the day than during the night. The time interval between heart beats varied considerably in normoxic fish. Hypoxia strongly reduced this variability, which may originate in a reduced cholinergic tone to the heart. The width of the frequency distribution of the time intervals between breaths was not affected by hypoxia. The degree of cardio-respiratory synchronization was low in both normoxic and in hypoxic and hypoxic-hypercapnic trout.

A quantitative study of the human cerebellum with unbiased stereological techniques.

Estimates of total number of different neuron and glial cell types in the dentate nuclei and the four major regions of the human cerebellum were obtained by new stereological methods. With the optical disector and Cavalieri methods, the total number of neurons and glial cells in the human cerebellum of five elderly men was estimated to be 105,000 x 10(6) (coefficient of variation, CV = 0.13). Of this total, the granule cells comprised 101,000 x 10(6) (CV = 0.13) and the Purkinje cells comprised 30.5 x 10(6) (CV = 0.13) of the neurons. The mean of the total number of neurons in the dentate nucleus was 5.01 x 10(6) (CV = 0.28). The average surface area of the human cerebellum was estimated to be 1160 cm2 (CV = 0.29). The rationale for the different sampling schemes used to quantify the various cell types is described.

Sural nerve conduction parameters in normal subjects related to age, gender, temperature, and height: a reappraisal.

Failure to take body height into considerations in the evaluation of nerve conduction velocities (CV) has recently been deemed unacceptable. This statement prompted the present study. Besides height, the influence of age, gender, and temperature was studied in 92 normal subjects, half of whom were females. The CV decreased 0.9 m/s per 10 years increase in age, the same in women and men aged 15 to 44 years. Mean temperature between distal and proximal ends of the nerve segment examined increased 6.1 +/- 0.3 degree C after heating followed by a CV increase of 7.0 +/- 0.5 m/s. The CV decreased 0.15 m/s per 100-mm increase in heights. When considering 37 individuals aged 25 to 34 years only, the CV increased 0.34 m/s per 1-m increase in height. In both instances, the changes were within the experimental error (2.3%) of the method.

[Warning bleedings prior to subarachnoid hemorrhage from intracranial, sacculate aneurysms. A consecutive, prospective study]. / Advarselsblødninger ved subaraknoidalblødninger fra intrakraniale, sakkulate aneurismer. En konsekutiv, prospektiv undersøgelse.

The incidence of warning leaks prior to subarachnoid hemorrhage was found to be 36.4% in 99 consecutive patients admitted consecutively to a neurosurgical department suffering from subarachnoid hemorrhage from ruptured intracranial, sacculate, arterial aneurysms. The durations of delays before admission to a neurosurgical department and the reasons for these, were analyzed. The patients who experienced a warning leak were in significantly poorer clinical condition than would have been the fact if they had been admitted at the time of the warning leak. It is important to bear the possibility of subarachnoid hemorrhage in mind, when a patient who has not previously complained of headache experiences violent sudden onset of headache. A program for investigation of suspected subarachnoid hemorrhage is suggested.

Phenytoin-loading: pharmacokinetic comparison between an intravenous bolus injection and a diluted standard solution.

Phenytoin (PHT) is considered a first or second choice in the treatment of status epilepticus that is refractory to benzodiazepines. The use of an intravenous bolus injection of PHT is hazardous due to the risk of cardiac conduction disturbances, dose-dependent side effects in general, as well as the possibility of severe necrotic lesions in case of extravasation. We compared the number and intensity of side effects and serum level profiles of a highly concentrated, non-dilutable bolus (46 mg/ml) of PHT [Fenytoin, DAK] with a dilutable standard solution (1.5 mg/ml) [Phenhydan] administered intravenously in 500 ml saline. Six healthy volunteers received both regiments (9.1 mg/kg). The diluted solution showed a curvilinear saturation curve with a lower concentration maximum (C-max) than the concentrated solution. Lower toxicity of the diluted solution was indicated by a clinical rating of side effects. Based on a higher incidence and degree of side effects following administration of the more concentrated formulation of PHT, compared with the more diluted preparation, we recommend the use of the less concentrated formulation.

Phenotypic and genetic relationships between residual energy intake and growth, feed intake, and carcass traits of young bulls.

Residual energy intake, defined as actual minus predicted energy intake during a production period, was estimated for each of 650 bull calves of 31 Holstein Friesian or Brown Swiss sires. Residual energy intake, measured under ad libitum feeding, had heritabilities similar to those of growth rate and energy conversion ratio with an estimate of approximately .3. Residual energy intake was related to average daily energy intake both phenotypically and genetically such that selection for decreased residual energy intake would lead to a decrease in daily feed intake. Such selection would also tend to increase carcass fatness (i.e., genetically fat animals are the most efficient). Residual energy intake estimated with and without correction for carcass composition were closely correlated. Thus, residual energy intake may be estimated without the knowledge of carcass composition in growing bulls of dual-purpose breeds.

No influence of the antidepressant paroxetine on carbamazepine, valproate and phenytoin.

A single-blind, placebo-controlled, cross-over trial investigating possible interactions between paroxetine, a serotonin re-uptake inhibitor, and carbamazepine (CBZ), valproate (VPA) and phenytoin (PHT) was carried out in 20 outpatients with epilepsy. Patients on long-term treatment with CBZ, VPA, or PHT were given a 7-day placebo treatment, followed by paroxetine co-treatment for 16 days. Side effects were infrequent and mild. Paroxetine caused no changes in the plasma concentrations and all values were within the recommended ranges. No changes in protein binding were found. Plasma concentrations of paroxetine at steady state (8-147 ng/ml) were in the normal range for a 30-mg daily dosing regimen. None of the patients experienced epileptic seizures during the study.

Genetic parameters of growth, feed intake, feed conversion and carcass composition of dual-purpose bulls in performance testing.

Genetic parameters for growth, total energy intake, feed conversion ratio, average daily energy intake and carcass composition were estimated in an experiment with 650 bull calves from 31 half-sib groups of Holstein Friesian or Brown Swiss sires. All traits analyzed had an amount of additive genetic variance that allows for considerable response to selection. No interaction between genotype (sire group) and proportion of roughage in the diet was found. Daily gain was strongly correlated negatively with feed conversion ratio but positively correlated with daily energy intake. Results indicate that genetic selection for either daily gain or average daily energy intake would decrease carcass fatness at a constant slaughter weight. However, the environmental correlation between daily energy intake and carcass fatness was positive.

Importance of the recognition of a warning leak as a sign of a ruptured intracranial aneurysm.

In the Danish Aneurysm Study 1076 patients (pts.) were admitted with an aneurysmal subarachnoid hemorrhage in the 5-year period 1978-83. A warning leak (WL), defined as a sudden episode of headache, vomiting, nuchal pain, dizziness or drowsiness, was identified in 166 pts. (15.4%). In 99 of these the episode was evaluated by a physician but misdiagnosed. A 2-year follow-up examination of the 99 pts. showed that 30 pts. had a normal mental outcome and 43 pts. were dead. If these patients were correctly diagnosed after the WL, when they were in Hunt grade 1-2, the outcome-figures would probably have been significantly better. A theoretical transfer of the outcome-probabilities for pts. in Hunt grade 1-2 to the above mentioned 99 pts. would result in 66 pts. with a normal mental outcome and 25 dead pts. This shows the importance of recognition of a WL episode.