Search

The deposition of abnormal protein fibrils is a prominent pathological feature of many different 'protein conformational' diseases, including some important neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), motor neurone disease and the 'prion' dementias. Some of the fibril-forming proteins or peptides associated with these diseases have been shown to be toxic to cells in culture. A clear understanding of the molecular mechanisms responsible for this toxicity should shed light on the probable link between protein deposition and cell loss in these diseases. In the case of the beta-amyloid (Abeta), which accumulates in the brain in AD, there is good evidence that the toxic mechanism involves the production of reactive oxygen species (ROS). By means of an electron spin resonance (ESR) spin-trapping method, we have shown recently that solutions of Abeta liberate readily detectable amounts of hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). We have also obtained similar results with alpha-synuclein, which accumulates in Lewy bodies in PD. Our data suggest that hydrogen peroxide accumulates during Abeta or alpha-synuclein incubation and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, we now support the idea that one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD, PD, and possibly some other protein conformational diseases, could be the direct production of ROS during formation of the abnormal protein aggregates. This hypothesis suggests a novel approach to the therapy of this group of diseases.

Background: There is controversy as to whether PTSD can develop following a brain injury with a loss of consciousness. However, no studies have specifically examined the influence of the memories that the individuals may or may not have on the development of symptoms., Aims: To consider how amnesia for the traumatic event effects the development and profile of traumatic stress symptoms., Method: Fifteen hundred case records from an Accident and Emergency Unit were screened to identify 371 individuals with traumatic brain injury who were sent questionnaires by post. The 53 subsequent valid responses yielded three groups: those with no memory (n = 14), untraumatic memories (n = 13) and traumatic memories (n = 26) of the index event. The IES-R was used as a screening measure followed by a structured interview (CAPS-DX) to determine caseness and provide details of symptom profile., Results: Groups with no memories or traumatic memories of the index event reported higher levels of psychological distress than the group with untraumatic memories. Ratings of PTSD symptoms were less severe in the no memory groups compared to those with traumatic memories., Conclusions: Psychological distress was associated with having traumatic or no memories of an index event. Amnesia for the event did not protect against PTSD; however, it does appear to protect against the severity and presence of specific intrusive symptoms.

The cmc and IC50 values of the beta-amyloid (Abeta) aggregation inhibitors, 3-p-toluoyl-2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran 1, and 2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran 2 have been determined. After comparison of the cmc data and biological data (IC50 values), we conclude that these active benzofurans do not act as surfactants or micelles at the concentration required to inhibit beta-amyloid-peptide aggregation.

Objective: This study examined pretreatment variables to predict outcome in two treatments for bulimia nervosa., Method: Patients were offered either 16 weeks of cognitive-behavioral therapy (CBT) or a self-treatment manual followed by up to 8 weeks of CBT (sequential group). Using complete data, stepwise regression analyses were performed., Results: It was found that a longer duration of illness and lower binge frequency predicted a better outcome both at the end of treatment (p < .001) and at 18 months of follow-up (p < .005). In the sequential group, lower pretreatment binge frequency predicted better outcome at the end of treatment (p < .05) and at 18 months of follow-up (p < .05). In the CBT group, longer duration of illness predicted better outcome at the end of treatment (p < .02)., Discussion: It is concluded that (1) those with more frequent binging may require a more intense intervention and (2) those who have been ill longer may be more motivated to respond to treatment.

Rat monoclonal anti-idiotype antibodies (mAb2) were raised against two mouse monoclonal antibodies (mAb1), 1D10 and 2A6, with specificity for the M-like protein of Streptococcus equi. The capacity of the mAb2 to inhibit the binding between the corresponding mouse mAb1 against which the mAb2 were raised and the M-like protein was investigated in an inhibition EIA. One of the ten mAb2 examined, namely 5D1 (anti-mAb1 1D10), was able to inhibit this binding. The mAb2 5D1 bound to the mAb1 1D10 in such a way as to completely inhibit the subsequent binding of the M-like protein antigen to the paratope of the mAb1 1D10. The mAb2 5D1 is likely to represent a true image of the M-like protein antigen and may thus be described as an Ab2 beta anti-idiotype antibody.

Anti-idiotype antibodies that carry an internal image of an antigen epitope (Ab2 beta antibodies) can be used in vaccine preparations to favourably manipulate the immune network. These vaccines have been shown to induce protective immunity in animals that have not been intentionally exposed to the native antigen epitope. This review attempts to define certain theoretical and practical aspects of immunological network manipulations and their relevance to Ab2 beta internal image anti-idiotype antibody vaccine design.

Normal infants have been shown to respond to a relatively low concentration of inhaled histamine. However, those studies used partial maximal expiratory flow volume (PMEFV) curves to assess lung function. In order to directly compare responsiveness between infants and older children, we compared bronchial responsiveness to histamine between a group of 45 normal infants, median age 4 wk (range 2 to 6 wk) and a group of 30 nonasthmatic older children, median age 10 yr (range 5 to 15 yr) using PMEFV curves in both groups to assess lung function. In the infant group, PMEFV curves were generated using the forced expiratory flow volume technique. For the older children, PMEFV curves were generated by voluntary effort. The provocative concentration of histamine that produced a 40% fall (PC40) in maximum flow at functional residual capacity (VmaxFRC) was calculated from the PMEFV curves. The geometric mean PC40 of the infants (1.02 g/L) was lower than the geometric mean of the older children (3.4 g/L) (p less than 0.001). However, these results were then corrected for dilution of the aerosol due to air entrainment (AE). Corrected values of PC40 were not significantly different between infants and older children. These results demonstrate the importance of accounting for AE in the evaluation of histamine responsiveness and suggest that bronchial responsiveness may be similar in normal infants and older children.

A procedure by which crystalline sodium norcarnitine can be prepared in large quantities and high yields has been developed. Carnitine is selectively demethylated by thiophenoxide ion in N,N-dimethylethanolamine. The reactive thiophenoxide ion is generated in situ by addition of thiophenol to this basic reaction solvent. Hence, sodium thiophenoxide, which has been used in similar applications, but is difficult to prepare, can be avoided. Accordingly, reaction of (R,S)-carnitine followed by aqueous azeotropic distillation of byproducts as well as excess starting materials and then by neutralization with sodium hydroxide gave sodium norcarnitine in 89% yield. (R)-Carnitine gave 91% yield of (R)-norcarnitine zwitterion before neutralization. A method for the facile preparation of radiolabeled (R)-carnitine is also described. Thus, methylation of sodium norcarnitine with methyl iodide in methanolic acetone produced carnitine, which precipitated, and sodium iodide, which was soluble.

Advanced age is not, per se, an indication for a different treatment approach, although certain modifications in the treatment plan are required. Recognition and management of anxiety disorders in the elderly must be prompt to interrupt the vicious cycle of anxiety-depression, physical illness, and other stresses.