Demyelination and single-carbon transfer pathway metabolites during the treatment of acute lymphoblastic leukemia: CSF studies

PURPOSE: To investigate the hypothesis that methotrexate causes demyelination due to a deficiency in S-adenosylmethionine (SAM) during the treatment of acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Twenty-four patients treated on the Medical Research Council United Kingdom ALL trial no. 11 (MRC UKALL XI) were studied. The trial randomized patients at the presymptomatic CNS treatment (PCNS) phase to receive (1) intrathecal methotrexate and cranial radiotherapy (CRTX); (2) high-dose intravenous methotrexate with folinic acid rescue and continuing intrathecal methotrexate (HDMTX); and (3) continuing intrathecal methotrexate alone (ITMTX). Serial CSF samples were collected throughout treatment and concentrations of 5-methyltetrahydrofolate (MTF), methionine (MET), SAM, and myelin basic protein (MBP) were measured. The results were grouped into treatment milestones and compared with an age-matched reference population. RESULTS: There was a highly significant effect of both treatment milestones and trial arm on the metabolite and MBP concentrations. CSF MTF reached a nadir during the induction phase of treatment, while SAM and MET reached their nadir during the consolidation phase. CSF MBP mirrored SAM concentration and there was a significant inverse relationship between the two. MTF, SAM, and MBP returned to normal values by the end of treatment, while MET was increased significantly. The effect of treatment was decremental across the ITMTX, HDMTX, and CRTX groups. CONCLUSION: Treatment of ALL causes marked abnormalities in the single-carbon transfer pathway and subclinical demyelination. Methotrexate is one cause of this. Whether these abnormalities contribute to the late cognitive deficits requires further study.     

GTP cyclohydrolase deficiency; intrafamilial variation in clinical phenotype, including levodopa responsiveness

Traditional Chinese drugs (TCDs) have played a key role for Chinese people in the treatment of diseases since ancient times. The use of TCDs has generated a great amount of information in the past thousand years about the relationship between natural products and the human body. However, up to now, our understanding on the mode of action of the TCD is still limited. Considering that the basic mechanism of all drug function involves the interaction between the drug and biological receptors at the molecular level, we propose to connect TCDs with modern medicine theory through molecular structures. We propose to explain functions of TCDs by using the knowledge developed in modern molecular biology, pharmacology, computer chemistry, and biochemistry. We are working on a computer-aided Chinese drug study that is discussed in this paper. A short introduction on the progress of our research is also given.     

The application of direct search optimisation to structural design

Development of an optimisation method suited to structural engineering design applications is described briefly. The method is essentially a conventional direct-search technique with exterior penalty constraints but uses variable penalty factors during the search to improve mobility between feasible regions. The method is illustrated by application to design of a composite box-girder footbridge, employing eight design variables and nineteen constraints, and the results are used to demonstrate the importance of considering sub-optima as well as the global optimum. The usefulness of univariant parameter/cost relationships in the region of global and local optimum points, derived as an intrinsic part of the optimisation process, is also stressed.     

Potentiostatic cleaning and conditioning of the cathodes used in electrodeposition cells

A new technique for the automatically controlled removal of residual electrodeposits from the cathode is presented. The discussion is based on theoretical electrode processes and laboratory experiments. The technique essentially consists of an industrial process potential controller which maintains the cathode in a noncorroding state while forcing the removal of the more electroactive residual metal deposits. The technique is both time and labor saving, and eliminates the additional need for cathode treating chemicals.     

A comparison of the socio-demographic and clinical characteristics of private household and communal establishment residents in a multi-ethnic inner-city area

This study compares the socio-demographic, physical and psychiatric profiles of representative samples of adults resident in communal establishments (n = 170) with those living in private households (n = 544) in a deprived multi-ethnic inner-city health district. Respondents were interviewed about their psychiatric and physical health as well as their early life experiences, close personal relationships, experiences of police contact and episodes of deliberate self-harm. Communal establishment residents were more likely to be single, white men and to be out of work than those in the private household sample. They typically left school at an earlier age, had a more disrupted upbringing, were less likely to have close personal relationships and reported more contact with the police. Both physical and psychiatric morbidity were substantially higher in the communal establishment residents than among those living in private households (especially for psychotic disorders). In contrast to these findings, comparisons between communal establishment residents with and without mental health problems revealed few differences. Our data highlight the extensive needs of those living in communal establishments and the need for a wide range of agencies to co-ordinate their efforts effectively if services to this population are to be effective.     

Mastery, sense of coherence, and mortality: Evidence of independent associations from the epic-norfolk prospective cohort study.

This study investigated the association between 2 distinct personal coping resources (mastery and sense of coherence) and all-cause, cardiovascular, and cancer mortality. During follow-up (up to 6 years), 994 deaths were recorded among 20,323 participants, ages 41 to 80 years, in the European Prospective Investigation into Cancer Study in the United Kingdom. A strong sense of mastery was associated with lower rates of mortality from all causes, cardiovascular disease, and cancer, after adjusting for age, sex, and prevalent chronic physical disease. The association with all-cause mortality was observed for both men and women and remained following further adjustment for cigarette smoking, social class, hostility, neuroticism, and extroversion. Analysis of the joint association between mastery and sense of coherence revealed both personal coping dispositions to be independently associated with lower rates of all-cause mortality. In addition, these data suggested that the association for mastery was specific to cardiovascular mortality, whereas the association for sense of coherence was specific to cancer mortality. These results may aid future study of coping resources as determinants of persistent well-being. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mastery is associated with cardiovascular disease mortality in men and women at apparently low risk.

Objective: We examine the prospective relationship between mastery, where limited mastery is defined as the inability to control negative emotions (and perceiving stressful experiences as beyond personal control), and cardiovascular disease (CVD) mortality particularly among individuals at apparently low CVD risk. Design: Prospective population-based study of 19,067 men and women, aged 41–80 years with no previous heart disease or stroke at baseline assessment. Main Outcome Measures: Primary outcome measure CVD mortality. Results: A total of 791 CVD deaths were recorded up to June 2009 during a median 11.3 person-years of follow-up. Limited perceived mastery over life circumstances was associated with an increased risk of CVD mortality, independently of biological, lifestyle, and socioeconomic risk factors (hazard ratio 1.11 per SD decrease in mastery score, 95% confidence interval 1.01–1.21). This association was more pronounced among those participants apparently at low CVD risk (p = .01 for test of interaction according to the number of CVD risk factors at baseline). Conclusions: Limited perceived control over life circumstances is associated with an increased risk of CVD mortality, independently of classical cardiovascular risk factors, and particularly among those at apparently low risk. Future attention should be given to this potentially modifiable personal characteristic, through the design of preliminary intervention studies, to reduce cardiovascular risk. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cerebrospinal fluid investigations for neurometabolic disorders

Strong acoustic pressure was applied to submitochondrial particles (SMP) from bovine heart in order to drive ATP synthesis by F1-F0 complex for the account of sound waves. We observed a net ATP production at two narrow frequency ranges, about 170 Hz and about 340 Hz, that corresponds to the resonance oscillations of experimental cuvette when the acoustic pressure had a magnitude of 100 kPa. The results can be explained quantitatively by contractive conformational changes of F1-F0 complex during catalytic turnover. Negative staining electron microscopy of SMP preparations was used to visualize the ADP(Mg2+)-induced conformational changes of F1-F0 complex. In the particles with high ATPase activity in the presence of phosphate the factors F1 and F0 formed a congregated domain plunged into the membrane without any observable stalk in between. The presence of ADP(Mg2+) caused a structural rearrangement of F1-F0 to the essentially different conformation: the domains F1 and F0 were dislodged distinctly from each other and connected by a long thin stalk. The latter conformation resembled well the usual bipartite profile of ATPase. The data indicate that besides rotation, the catalytic turnover of ATP synthase is also accompanied by stretch transitions of F1-F0 complex.