Chromogranin A in cerebrospinal fluid: a biochemical marker for synaptic degeneration in Alzheimer''s disease?

OBJECTIVE: To describe the clinical, radiologic and histopathological features of two cases of carcinoma metastatic to the optic nerve with different pathways of spread. DESIGN: Chart review. SETTING: Oncology clinic in Montreal. PATIENTS: One patient previously treated for breast carcinoma and one patient previously treated for small-cell carcinoma of the lung. RESULTS: The patient with breast carcinoma was found to have an elevated mass involving her right optic nerve head. This finding was confirmed by B-scan ultrasonography. The other patient initially presented with left retinal metastasis and subsequently manifested massive secondary involvement of the ipsilateral optic nerve, documented by computed tomography. Both patients were initially treated with radiotherapy to the eye and orbit, but postmortem histopathological study showed that this treatment had little effect on the tumour. CONCLUSIONS: The histopathological observations suggest that if radiotherapy is to be used in the treatment of metastasis to the optic nerve, the dosage of radiation should be higher than that recommended for the treatment of choroidal metastasis.     

Distribution and characterization of enterostatin-like immunoreactivity in human cerebrospinal fluid

The effects of two highly fermentable dietary fibers (guar gum and pectin) on the type and concentrations of cecal polyamines as affected by the intestinal microflora were studied in groups of germ-free (n = 10/group) and conventional rats (n = 6/group). Both germ-free and conventional rats were randomly assigned to one of three treatments as follows: 1) fiber-free control diet, 2) control diet + 10% guar gum and 3) control diet + 10% pectin. In germ-free rats, guar gum and pectin had no effect on cecal polyamine concentrations. Putrescine was confirmed to be the major endogenous polyamine within the gut lumen. In cecal contents of conventional rats, both guar gum and pectin led to the appearance of cadaverine and to elevated putrescine concentrations in comparison with the fiber-free control diet (1.35 +/- 0.15 and 2.27 +/- 0.32, respectively, vs. 0.20 +/- 0.03 micromol/g dry weight, P < 0.05). The cecal cadaverine concentration was higher in pectin- than in guar-fed rats (8.20 +/- 0.89 vs. 1.92 +/- 0.27 micromol/g dry weight, P < 0.05). Counts of total bacteria, bacteroides, fusobacteria and enterobacteria were higher (P < 0.05) in rats fed guar gum and pectin. Bifidobacteria were found exclusively in guar-fed rats. In vitro studies on selected species representing the numerically dominant population groups of the human gut flora (bacteroides, fusobacteria, anaerobic cocci and bifidobacteria) were examined for their ability to synthesize intracellular polyamines. These experiments demonstrated the ability of bacteroides, fusobacteria and anaerobic cocci to synthesize high amounts of putrescine and spermidine. Calculations based on these results suggest that the intestinal microflora are a major source of polyamines in the contents of the large intestine.     

Concentration of neural thread protein in cerebrospinal fluid from progressive supranuclear palsy and Parkinson's disease

We measured the concentration of neural thread protein (NTP) in cerebrospinal fluid (CSF) by an automatized microparticle enzyme immunoassay from 11 progressive supranuclear palsy (PSP) patients and 11 Parkinson's disease (PD) patients and 7 patients with cervical spondylosis as controls. The mean levels did not differ significantly among the groups. In the PSP group, however, the levels correlated significantly with the severity of motor symptoms, signs and functional disability but not with dementia, while the opposite was true in the PD group. The elevated levels in PSP cases may reflect an increase with progression of the disease in such pathological structures as neurofibrillary tangles or neuropil threads, while in PD such levels may indicate associated Alzheimer-type pathology.     

Osteogenesis imperfecta: the distinction from child abuse and the recognition of a variant form

Inactivation of glutathione peroxidase correlates with the rate of hemoglobin chain oxidation. The enzyme inactivation is mainly present in those conditions where the autoxidation of the oxygenated chains is followed by transformation of the oxidized molecule into a hemichrome. Free hemoglobin chains have been encapsulated in human red blood cells by a dialysis technique that involves transient hypotonic hemolysis followed by isotonic resealing. Chain-loaded erythrocytes represent a good in vitro model of thalassemia. The presence of free human chains in the cell alters the intraerythrocytic glutathione peroxidase activity (alpha chains are more effective in the inactivation of the enzyme with respect to the beta chains).     

Mannan-binding lectin in human serum, cerebrospinal fluid and brain tissue and its role in Alzheimer's disease

Mannan-Binding lectin (MBL) is a serum lectin which can activate the classical complement pathway. Complement proteins of the classical pathway have been found in the brains of patients with Alzheimer's disease (AD) in association with AD brain pathology. To investigate the role for MBL in AD we have looked for its presence in the brain by immunohistochemistry and determined the levels of MBL in paired samples of cerebrospinal fluid and serum from AD patients and controls. MBL was detected in association with blood vessels in the brain tissue of both AD patients and control subjects. There was no apparent difference in the distribution of MBL in the brain tissue between the two groups. The mean concentration of MBL in the CSF was 44% lower in AD patients than in controls (AD 154 +/- 35 pg/ml, n = 19; non-AD 276 +/- 50 pg/ml, n = 15, p < 0.05). The levels of MBL in serum were not significantly different in the two groups. Thus, this study shows that MBL is associated with blood vessels in the brains of both AD and control subjects. Moreover, CSF levels of MBL appear to be lower in AD patients than in control subjects which may indicate a higher degree of MBL consumption connected with complement activation in the AD patients.     

Penetration of fusidic acid into human brain tissue and cerebrospinal fluid

Penetration of fusidic acid into brain tissue in six patients and cerebrospinal fluid in seven patients was determined. Tissue samples, taken during surgery revealed drug levels at about 7% of simultaneous serum concentrations. In contrast, cerebrospinal fluid concentrations were below 1% of serum levels. Since serum- and tissue levels of fusidic acid were far above the minimal inhibitory concentration (MICs) of staphylococci and streptococci, and since it has a long serum half-life of about 10 hours, it is a promising candidate for prophylaxis in neurosurgery.     

Monitoring frequency of occurrence without awareness: evidence from patients with Alzheimer''s disease

Mouse mammary tumor virus (MMTV) is a type B retrovirus that is transmitted as an infectious milk-borne particle and that causes mammary carcinomas by insertional activation of cellular protooncogenes. Germ line infections result in endogenous Mtv proviruses integrated in the genome of most mouse strains. These endogenous proviruses have been integrated into the genomes of mice for only the past 3-5 million years. The open reading frame present in the 3' long terminal repeat (LTR) of the provirus encodes a superantigen (SAg) which is able to stimulate a large proportion of T cells sharing a common T-cell receptor beta chain variable domain (v beta). Expression of this SAg is critical to the MMTV life cycle. After expression of the SAg in B cells a significant number of T cells are recruited to respond to these MMTV infected cells. As a consequence both the T cells expressing the relevant TCR V beta domain and the infected B cells become activated and start dividing. This would facilitate integration of MMTV and amplify the number of virus infected lymphocytes. Most likely during lactation the mammary glands become receptive to viral infection. The presence of endogenous Mtvs induces an early clonal deletion of reactive T cells. For this reason it has been argued that the presence of these proviruses confers a selective advantage to the mouse population by protecting the host from infection with an exogenous MMTV coding for a cross-reactive SAg. However, recent results discussed herein suggest that Mtv proviruses may also be detrimental to the mouse population by participating in recombinations with exogenous MMTVs, giving rise to highly tumorigenic recombinant particles. These results are discussed in the light of recent reports suggesting the involvement of viral sequences with a high homology to MMTV in human mammary tumorigenesis.     

Presenilins: detection and characterization of Alzheimer''s disease genes]

Melatonin's timekeeping function is undoubtedly related to the fact that it is primarily produced during nighttime darkness; that is, melatonin and light occur at opposite times. The human phase response curve (PRC) to melatonin appears to be about 12h out of phase with the PRC to light. These striking complementarities, together with light's acute suppressant effect on melatonin production, suggest that a function for endogenous melatonin is to augment entrainment of the circadian pacemaker by the light-dark cycle. The melatonin PRC also indicates correct administration times for using exogenous melatonin to treat circadian phase disorders.     

Dihydroergosine: anticonflict effect in rats and enhancing effects on [3H]muscimol binding in the human brain post mortem

The anticonflict activity of the ergot alkaloid, dihydroergosine, a drug which binds to 5-hydroxytryptamine1 (5-HT1) receptors and to gamma-aminobutyric acidA (GABAA) receptor-associated Cl- ionophore, was studied in water-deprived rats. In vitro effects of this drug on [3H]muscimol and [3H]flunitrazepam binding to the crude synaptosomal pellet of the human frontal cortex post-mortem were also investigated. Dihydroergosine, given 2 h prior to testing, enhanced drinking under punished (0.8 mA) conditions, and diminished it under unpunished conditions. The mechanism of this effect was (-)-propranolol- and pindolol-insensitive and picrotoxin-sensitive. Flumazenil either failed to affect, or at a higher dose (10 mg/kg), counteracted the dihydroergosine-induced enhancement of punished drinking. This dose of flumazenil was itself anxiogenic. Dihydroergosine had mild sedative and analgesic properties. Low concentrations of dihydroergosine (10 nM to 100 microM) enhanced the binding of [3H]muscimol but not of [3H]flunitrazepam. The results suggest that dihydroergosine may possess anxiolytic properties presumably mediated by its specific action at the GABA/benzodiazepine/chloride channel complex.     

Detection of staphylococcal genes directly from cerebrospinal and peritoneal fluid samples using a multiplex polymerase chain reaction

A 27-year-old woman receiving electroconvulsive therapy (ECT) for the treatment of depression developed post-ECT headaches refractory to treatment with acetaminophen and various nonsteroidal antiinflammatory drugs. The patient was then treated successfully with oral sumatriptan. This case suggests that sumatriptan may be a useful treatment of post-ECT headaches that are unresponsive to conventional analgesics.     

750 MHz 1H NMR spectroscopy characterisation of the complex metabolic pattern of urine from patients with inborn errors of metabolism: 2-hydroxyglutaric aciduria and maple syrup urine disease

750 MHz 1H NMR spectroscopy has been used to characterise in detail the abnormal low molecular weight metabolites of urine from two patients with inborn errors of metabolism. One case of the rare condition 2-hydroxyglutaric aciduria has been examined. There is at present no rapid routine method to detect this genetic defect, although NMR spectroscopy of urine is shown to provide a distinctive pattern of resonances. Assignment of a number of prominent urinary metabolites not normally seen in control urine could be made on the basis of their known NMR spectral parameters including the diagnostic marker 2-hydroxyglutaric acid, which served to confirm the condition. In addition, 750 MHz 1H NMR spectroscopy has been used to characterise further the abnormal metabolic profile of urine from a patient with maple syrup urine disease. This abnormality arises from a defect in branched chain keto-acid decarboxylase activity and results in a build up in the urine of high levels of branched chain oxo- and hydroxy-acids resulting from altered metabolism of the branched chain amino acids, valine, leucine and isoleucine. A number of previously undetected abnormal metabolites have been identified through the use of one-dimensional and two-dimensional J-resolved and COSY 750 MHz 1H NMR spectroscopy, including ethanol, 2-hydroxy-isovalerate, 2,3-dihydroxy-valerate, 2-oxo-3-methyl-n-valerate and 2-oxo-isocaproate. NMR spectroscopy of urine, particularly when combined with automatic data reduction and computer pattern recognition using a combination of biochemical markers, promises to provide an efficient alternative to other techniques for the diagnosis of inborn errors of metabolism.     

ECG pattern recognition and classification using non-linear transformations and neural networks: a review

The most widely used signal in clinical practice is the ECG. ECG conveys information regarding the electrical function of the heart, by altering the shape of its constituent waves, namely the P, QRS, and T waves. Thus, the required tasks of ECG processing are the reliable recognition of these waves, and the accurate measurement of clinically important parameters measured from the temporal distribution of the ECG constituent waves. In this paper, we shall review some current trends on ECG pattern recognition. In particular, we shall review non-linear transformations of the ECG, the use of principal component analysis (linear and non-linear), ways to map the transformed data into n-dimensional spaces, and the use of neural networks (NN) based techniques for ECG pattern recognition and classification. The problems we shall deal with are the QRS/PVC recognition and classification, the recognition of ischemic beats and episodes, and the detection of atrial fibrillation. Finally, a generalised approach to the classification problems in n-dimensional spaces will be presented using among others NN, radial basis function networks (RBFN) and non-linear principal component analysis (NLPCA) techniques. The performance measures of the sensitivity and specificity of these algorithms will also be presented using as training and testing data sets from the MIT-BIH and the European ST-T databases.     

1H NMR spectroscopy studies of Huntington's disease: correlations with CAG repeat numbers

Huntington's disease (HD) is the result of an expanded (CAG) repeat in a gene on chromosome 4. A consequence of the gene defect may be progressive impairment of energy metabolism. We previously showed increased occipital cortex lactate in HD using localized 1H spectroscopy. We have now extended these studies to show an almost threefold elevation in occipital cortex lactate in 31 HD patients as compared with 17 normal control subjects (p < 10(-11)). The spectra in three presymptomatic gene-positive patients were identical to normal control subjects in cortical regions, but three in eight showed elevated lactate in the striatum. Similar to recently reported increases in task-related activation of the striatum in the dominant hemisphere, we found that striatal lactate levels in HD patients were markedly asymmetric (higher on the left side). Markers of neuronal degeneration, decreased N-acetylaspartate (NAA)/creatine and increased choline/creatine levels, were symmetric. Both decreased NAA and increased lactate in the striatum significantly correlated with duration of symptoms. When divided by his or her age, an individual's striatal NAA loss and lactate increase were found to directly correlate with the subject's CAG repeat number, with correlation coefficients of 0.8 and 0.7, respectively. Similar correlations were noted between postmortem cell loss and age versus CAG repeat length. Together, these data provide further evidence for an interaction between neuronal activation and a defect in energy metabolism in HD that may extend to presymptomatic subjects.     

Detection of cytomegalovirus in plasma and cerebrospinal fluid specimens from human immunodeficiency virus-infected patients by the AMPLICOR CMV test

We have developed the AMPLICOR CMV Test, which is rapid and sensitive for the detection of cytomegalovirus (CMV) in plasma and cerebrospinal fluid (CSF) specimens. The test incorporated an internal control in the reaction mixture to monitor the amplification efficiency and the presence of inhibitors. The AMPLICOR CMV Test was very specific in detecting 12 clinical CMV isolates and four laboratory CMV strains tested. Cross-reactivity with 26 non-CMV pathogens was not observed. The AMPLICOR CMV Test requires only 50 microl of specimen (plasma or CSF) for processing. The performance of the AMPLICOR CMV Test was compared to those of the CMV antigenemia assay and the conventional tube culture method. Among 112 plasma specimens from 43 human immunodeficiency virus-infected patients, CMV was detected in 20 (18%) of the specimens by the AMPLICOR CMV Test, 21 (19%) of the specimens by the CMV antigenemia assay, and 10 (9%) of the specimens by culture. In CSF specimens from AIDS patients, CMV was detected in 10 of 58 (17%) specimens tested by the AMPLICOR CMV Test, 5 of 28 (18%) specimens tested by the antigen assay, and none of the 25 specimens tested by culture. While the performance of the AMPLICOR CMV Test in this study was comparable to that of the CMV antigen assay, processing of specimens by the AMPLICOR CMV Test was much simpler than that by the antigen assay; in addition, the antigen assay requires greater than 10(5) leukocytes from blood or 1 ml of CSF to perform the assay. Our study suggested that the AMPLICOR CMV Test could provide a rapid and sensitive assay for the detection of CMV in plasma and CSF specimens.     

Pattern recognition analysis of 1H NMR spectra from perchloric acid extracts of human brain tumor biopsies

Pattern recognition techniques (factor analysis and neural networks) were used to investigate and classify human brain tumors based on the 1H NMR spectra of chemically extracted biopsies (n = 118). After removing information from lactate (because of variable ischemia times), unsupervised learning suggested that the spectra separated naturally into two groups: meningiomas and other tumors. Principal component analysis reduced the dimensionality of the data. A back-propagation neural network using the first 30 principal components gave 85% correct classification of meningiomas and nonmeningiomas. Simplification by vector rotation gave vectors that could be assigned to various metabolites, making it possible to use or to reject their information for neural network classification. Using scores calculated from the four rotated vectors due to creatine and glutamine gave the best classification into meningiomas and nonmeningiomas (89% correct). Classification of gliomas (n = 47) gave 62% correct within one grade. Only inositol showed a significant correlation with glioma grade.     

Quantification of biomedical NMR data using artificial neural network analysis: lipoprotein lipid profiles from 1H NMR data of human plasma

Artificial neural network (ANN) analysis is a new technique in NMR spectroscopy. It is very often considered only as an efficient "black-box' tool for data classification, but we emphasize here that ANN analysis is also powerful for data quantification. The possibility of finding out the biochemical rationale controlling the ANN outputs is presented and discussed. Furthermore, the characteristics of ANN analysis, as applied to plasma lipoprotein lipid quantification, are compared to those of sophisticated lineshape fitting (LF) analysis. The performance of LF in this particular application is shown to be less satisfactory when compared to neural networks. The lipoprotein lipid quantification represents a regular clinical need and serves as a good example of an NMR spectroscopic case of extreme signal overlap. The ANN analysis enables quantification of lipids in very low, intermediate, low and high density lipoprotein (VLDL, IDL, LDL and HDL, respectively) fractions directly from a 1H NMR spectrum of a plasma sample in < 1 h. The ANN extension presented is believed to increase the value of the 1H NMR based lipoprotein quantification to the point that it could be the method of choice in some advanced research settings. Furthermore, the excellent quantification performance of the ANN analysis, demonstrated in this study, serves as an indication of the broad potential of neural networks in biomedical NMR.     

Differential expression of TGF-beta 1, 2 and 3 isotypes in Alzheimer''s disease: a comparative immunohistochemical study with cerebral infarction, aged human and mouse control brains

The Chinese version of the Dyadic Adjustment Scale (C-DAS) was administered to 1,501 married adults, along with other instruments that assessed their psychosocial adjustment. Factor analysis showed that four factors were abstracted from the C-DAS (Dyadic Consensus, Dyadic Cohesion, Dyadic Satisfaction, and Affectional Expression); the factors extracted could be reproduced reliably in two random subsamples, as well as in the male and female samples. Although some areas of refinement are suggested, the present data generally support the universality of the concept of dyadic adjustment as indexed by the Dyadic Adjustment Scale. Contrary to the data reported previously, the present factor structures based on the male and female samples were highly similar and stable.     

Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.