The APPLE Tree programme: Active Prevention in People at risk of dementia through Lifestyle, bEhaviour change and Technology to build REsiliEnce-randomised controlled trial.

BACKGROUND: Large-scale trials of multidomain interventions show that modifying lifestyle and psychological risk factors can slow cognitive decline. We aim to determine if a lower intensity, personally tailored secondary dementia prevention programme for older people with subjective or mild objective memory decline, informed by behaviour change theory, reduces cognitive decline over 2 years. METHODS: A multi-site, single-blind randomised controlled trial recruiting 704 older adults at high dementia risk due to mild cognitive impairment (MCI) or subjective cognitive decline (SCD). Participants are randomised using 1:1 allocation ratio to the APPLE Tree intervention versus control arm (dementia prevention information), stratified by site. The intervention explores and implements strategies to promote healthy lifestyle, increase pleasurable activities and social connections and improve long-term condition self-management. Two facilitators trained and supervised by a clinical psychologist deliver ten, 1-h group video call sessions over 6 months (approximately every fortnight), video-call 'tea breaks' (less structured, facilitated social sessions) in intervening weeks and individual goal-setting phone calls every 2 weeks. From 6 to 12 months, participants meet monthly for 'tea breaks', with those not attending receiving monthly goal-setting phone calls. Participants receive a food delivery, pedometer and website access to cognitive training and information about lifestyle modification. Follow-ups for all outcome measures are at 12 and 24 months. The primary outcome is cognition (Neuropsychological Test Battery (NTB) score) at 24 months. Secondary outcomes are quality of life, cost per quality-adjusted life year (QALY) and wellbeing and lifestyle factors the intervention targets (diet, vascular risk, body weight, activity, sleep, anxiety, depression, social networks and loneliness, alcohol intake and smoking). Participants from purposively selected sites participate in qualitative process evaluation interviews, which will be analysed using thematic analytic methods. DISCUSSION: If effective, the intervention design, involving remote delivery and non-clinical facilitators, would facilitate intervention roll-out to older people with memory concerns. TRIAL REGISTRATION: ISRCTN17325135 . Registration date 27 November 2019.

Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study.

Interest in lycopene has focused primarily on its use in the chemoprevention of prostate cancer (CaP); there are few clinical trials involving men with established disease. In addition, most data examining its mechanism of action have been obtained from experiments using immortal cell lines. We report the inhibitory effect(s) of lycopene in primary prostate epithelial cell (PEC) cultures, and the results of a pilot phase II clinical study investigating whole-tomato lycopene supplementation on the behavior of established CaP, demonstrating a significant and maintained effect on prostate-specific antigen velocity over 1 year. These data reinforce the justification for a large, randomized, placebo-controlled study.

Lycopene and prostate cancer.

The role of diet and dietary supplements in the development and progression of prostate cancer represents an increasingly frequent topic of discussion in the urologist's office. As access to information becomes forever easier, patients are more aware and educated about this subject than ever before. The role of antioxidants including carotenoids in all this has been the subject of great interest for some time. Lycopene, the carotenoid that gives tomatoes and other fruits and vegetables their red colour, has been of particular interest recently as regards its role in prostate cancer. The aim of this review is to briefly outline the biology and chemistry of lycopene, the scientific basis for its proposed anticancer properties and evaluate what conclusions the practicing urologist may draw from the data thus far. The media and industry have raced to encourage not only diets high in lycopene but also dietary lycopene supplements but there is probably only sufficient evidence to recommend to patients a diet rich in all vegetables and fruits of which tomatoes and tomato based products should certainly be a part.

Freedom from smoking: integrating hypnotic methods and rapid smoking to facilitate smoking cessation.

Hypnotic intervention can be integrated with a Rapid Smoking treatment protocol for smoking cessation. Reported here is a demonstration of such an integrated approach, including a detailed description of treatment rationale and procedures for such a short-term intervention. Of 43 consecutive patients undergoing this treatment protocol, 39 reported remaining abstinent at follow-up (6 months to 3 years posttreatment).

Detection of individual differences in radiation-induced apoptosis of peripheral blood lymphocytes in normal individuals, ataxia telangiectasia homozygotes and heterozygotes, and breast cancer patients after radiotherapy.

Quantification of radiation-induced apoptosis in peripheral blood lymphocytes (PBLs) has been proposed as a possible screening test for cancer-prone individuals and also for the prediction of normal tissue responses after radiotherapy. We have used the TUNEL assay (terminal transferase nick-end labeling) 24 h after irradiation with 4 Gy at high dose rate to assess interindividual differences in radiation-induced apoptosis between (1) a panel of normal individuals, (2) ataxia telangiectasia (AT) homozygotes and heterozygotes, and (3) breast cancer patients who had received radiotherapy 8-13 years ago, including a number of patients who had suffered adverse responses to radiation. With this protocol, we show clear differences in radiation-induced apoptosis between individuals, and good reproducibility in the assay. In agreement with previous reports using EBV-transformed lymphoblasts, we show a very poor induction of apoptosis in AT homozygotes and a reduced level in AT heterozygotes compared to normal individuals. A similar reduced level compared to normal individuals was seen in the breast cancer patients. Despite a wide range of values in the breast cancer patients and good reproducibility on repeat samples, there was no correlation of rates of apoptosis with the severity of breast fibrosis, retraction or telangiectasia. The reduced rate of apoptosis observed in the breast cancer cases may be associated with genetic predisposition to breast cancer; however, we conclude that assays of lymphocyte apoptosis are unlikely to be of use in predicting normal tissue tolerance to radiotherapy.

Analysis and interpretation of cost data in randomised controlled trials: review of published studies.

OBJECTIVE: To review critically the statistical methods used for health economic evaluations in randomised controlled trials where an estimate of cost is available for each patient in the study. DESIGN: Survey of published randomised trials including an economic evaluation with cost values suitable for statistical analysis; 45 such trials published in 1995 were identified from Medline. MAIN OUTCOME MEASURES: The use of statistical methods for cost data was assessed in terms of the descriptive statistics reported, use of statistical inference, and whether the reported conclusions were justified. RESULTS: Although all 45 trials reviewed apparently had cost data for each patient, only 9 (20%) reported adequate measures of variability for these data and only 25 (56%) gave results of statistical tests or a measure of precision for the comparison of costs between the randomised groups. Only 16 (36%) of the articles gave conclusions which were justified on the basis of results presented in the paper. No paper reported sample size calculations for costs. CONCLUSIONS: The analysis and interpretation of cost data from published trials reveal a lack of statistical awareness. Strong and potentially misleading conclusions about the relative costs of alternative therapies have often been reported in the absence of supporting statistical evidence. Improvements in the analysis and reporting of health economic assessments are urgently required. Health economic guidelines need to be revised to incorporate more detailed statistical advice.

When hypnosis causes trouble.

Like any other effective intervention, hypnotic treatment can occasionally cause harmful effects as well as beneficial ones. The first step in avoiding clinical complications is recognizing that they can occur. A review of the literature, however, suggests a long-standing inattention to the potential harmfulness of hypnotic interventions, including patients' unexpected reactions, leading to clinical complications, including amnesia, catharsis, paralysis, disorientation, literalness of response, accelerated transference, and memory contamination. In addition to these unexpected reactions by patients, complications can also arise from a practitioner's need for power and by the inappropriately narrow focus on the hypnotic process itself, leading to distraction from the more fundamental clinical process.

Naturally occurring vertical transmission of Neospora caninum in dogs.

Vertical transmission of Neospora caninum was studied in naturally infected, privately owned dogs, using antibody detection by IFAT to identify infected individuals. Retrospective studies were undertaken in litters from six bitches of the Hamiltonstövare breed, and on litters from seven bitches of other breeds--in both cases following diagnosis of clinical disease in puppies--and prospective studies were carried out on 17 seropositive bitches of other breeds. Puppies were classified as infected if either pre-colostral sera, or serum taken at > or = 5 weeks, had a titre of > or = 1:50 in the IFAT. The frequency of putative congenital transmission was variable; three seropositive dams produced successive litters, each containing seropositive puppies; four other seropositive bitches, which each whelped twice, produced six litters in which all pups were seronegative. Bitches born to seropositive dams themselves produced litters containing seropositive pups. In the retrospective studies, 32/61 (52%) of pups tested born to 13 seropositive dams were themselves seropositive and 22/88 (25%) of all pups born developed clinical signs compatible with a diagnosis of neosporosis. However, in the prospective study, only 4/118 (3%) pups tested from 17 seropositive dams were seropositive and 4/122 (3%) of all pups born developed signs consistent with neosporosis. This difference reflected levels of IFAT titre in the two groups of bitches and overall the proportion of pups seropositive was strongly and positively correlated (r = 0.980, P < 0.05) with bitch IFAT titre. Overall, 80% of pups born to seropositive dams were not infected as determined serologically. This study shows that the frequency of vertical transmission of naturally acquired Neospora infection in dogs is variable, but much too low to sustain infection alone. Post-natal infection must occur to maintain infection at seroprevalence rates reported in dog populations.

The mysterious persistence of hypnotic analgesia.

Hypnotic treatment of pain has a long history and, among hypnotic phenomena, pain relief is a relatively commonplace focus for intervention, yet we lack a conceptual explanation for this treatment. Hilgard's neodissociation theory accounts for the phenomenon of acute hypnotic analgesia, but not of persistent pain relief. Perhaps the enduring effect of hypnotic treatment can be explained at either of two levels: a neurophysiological model or a learning model. This explanation leads to the further question: How does hypnotic treatment of recurring pain achieve enduring relief? Clinical experience suggests a two-component model. First, the clinician communicates specific ideas that strengthen the patient's ability to derive therapeutic support and to develop a sense of openness to the unexplored possibilities for pain relief within the security of nurturing therapeutic relationship. Second, the clinician employs posthypnotic suggestions that capitalize on the patient's particular pain experiences, which simultaneously ameliorate the pain experience, and which, in small, repetitive increments, tend to maintain persistent pain relief over increasing periods of time.

Developing a rural primary care practice network.

Establishing and managing a primary care practice in rural communities is particularly challenging. Many rural practices are closing, and relatively few new practices are initiated independently. The integrated health system can provide at least part of the solution to the lack of physicians in the rural setting. The following article describes the objectives, methods, and results of an integrated health system's development of a rural primary care provider network.

A study of uranium lung clearance at a uranium processing plant.

A study has been made of the retention of uranium in the lungs of persons exposed chronically to low levels of uranium aerosols at the Y-12 Plant. A new characterization of the workplace aerosols shows an activity median aerodynamic diameter of 8 microns to be representative of the uranium oxides handled at the Y-12 Plant. The usual ICRP respiratory-system model is employed in conjunction with bioassay data from worker exposures to deduce a new set of parameters to describe lung clearance of these aerosols. This new assessment leads to good agreement between in vivo estimates of uranium lung burdens.

Isolated photosynthetic reaction center of photosystem II as a sensitizer for the formation of singlet oxygen. Detection and quantum yield determination using a chemical trapping technique.

Singlet oxygen formation by photosystem II reaction centers isolated from Pisum sativum has been detected by two chemical trapping techniques: histidine-dependent oxygen uptake and bleaching of p-nitrosodimethyl-aniline by the intermediary endoperoxide of histidine. The quantum yield of singlet oxygen formation determined by these methods was estimated to be 0.16 by comparison with the known quantum yields of standard singlet oxygen sensitizers. Singlet oxygen was formed on illumination of reaction centers under conditions that lead to formation of the triplet state of the primary electron donor, P680. Experiments with deuterated buffer and active oxygen scavengers indicated that singlet oxygen was the only active oxygen species produced by this reaction. Neither azide nor histidine, which are scavengers of singlet oxygen, protected against photobleaching of the chlorophyll of reaction centers that occurs concomitantly with singlet oxygen formation, suggesting that bleaching involves singlet oxygen generated within the protein matrix of the complex. Singlet oxygen sensitized exogenously by rose bengal (when excited specifically at 550 nm) was also found to bleach reaction center chlorophyll in a manner similar to the intrinsic mechanism. We conclude that singlet oxygen formed within the hydrophobic interior of the reaction center attacks the chlorophylls of P680, and presumably also amino acids in the vicinity, and that only the singlet oxygen that escapes to the medium is affected by added scavengers or deuterated medium. These experiments extend our earlier report of the detection of singlet oxygen by its luminescence at 1270 nm when isolated photosystem II reaction centers are illuminated (Macpherson, A. N., Telfer, A., Barber, J., and Truscott, T. G. (1993) Biochim. Biophys. Acta 1143, 301-309). Moreover, our results support the hypothesis that production of singlet oxygen underlies the vulnerability of photosystem II to photodamage and hence necessitates the rapid turnover of the D1 protein of the reaction center.

In vivo and in vitro photoinhibition reactions generate similar degradation fragments of D1 and D2 photosystem-II reaction-centre proteins.

Isolation of photosystem-II reaction centres from pea leaves after photoinhibitory treatment at low temperature (0-1 degrees C) has provided evidence for the mechanism of degradation of the D1 protein in vivo. These isolated reaction centres did not appear to be spectrally distinct from preparations obtained from control leaves that had not been photoinhibited. Breakdown fragments of both the D1 and D2 proteins were, however, found in preparations isolated from photoinhibited leaves, and showed similarities with those detected when isolated reaction centres were exposed to acceptor-side photoinhibition. Analyses of the origin of D1 fragments indicated that the primary cleavage site of this protein was between transmembrane helices IV and V indicative of the acceptor-side mechanism for photoinhibition. The origins of other D1 protein fragments indicate that some donor-side photoinhibition may also have occurred in vivo under the conditions employed. We have shown that the spectral and functional integrating of the isolated photosystem II reaction centre complex is resistant to proteolytic cleavage by trypsin. Use of a more non-specific protease (subtilisin), however, caused significant destabilisation of the special pair of chlorophylls constituting the primary electron donor, P680, with a consequential loss of functional activity. Thus, it is possible that specific cleavage of photosystem-II reaction-centre proteins may occur in vivo following photoinhibitory damage without a significant change in structural integrity, a conclusion supported by the finding that photodamaged and normal reaction centres were isolated together.

A functional model for the role of cytochrome b559 in the protection against donor and acceptor side photoinhibition.

A quinone-independent photoreduction of the low potential form of cytochrome b559 has been studied using isolated reaction centers of photosystem II. Under anaerobic conditions, the cytochrome can be fully reduced by exposure to strong illumination without the addition of any redox mediators. Under high light conditions, the extent and rate of the reduction is unaffected by addition of the exogenous electron donor Mn2+ and, during this process, no irreversible damage occurs to the reaction center. However, prolonged illumination in strong light brings about irreversible bleaching of chlorophyll, indicative of photoinhibitory damage. When the cytochrome is fully reduced and excess Mn2+ is present, the effect of moderate light is to facilitate the photoaccumulation of reduced pheophytin. The dark reoxidation of the reduced cytochrome is very slow under anaerobic conditions but significantly speeded up on addition of oxidized 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone. From these results it is suggested that the low potential form of cytochrome b559 can accept electrons directly from reduced pheophytin and in so doing help to protect the reaction center against acceptor side photoinhibition as suggested by Nedbal et al. [Nedbal, J., Samson, G. & Whitmarsh, J. (1992) Proc. Natl. Acad. Sci. USA 89, 7929-7933]. This conclusion has been incorporated into a model that further suggests that in its high potential form the cytochrome primarily acts to protect against donor side photoinhibition due to increased lifetime of highly oxidized species as previously proposed by Thompson and Brudvig [Thompson, L. & Brudvig, G. W. (1988) Biochemistry 27, 6653-6658]. The particular feature of our scheme is that it incorporates reversible interconversion between the two redox forms so as to protect against either type of photoinhibition.

Rate of oxidation of P680 in isolated photosystem 2 reaction centers monitored by loss of chlorophyll stimulated emission.

We have continued our studies of the primary photochemistry of isolated photosystem 2 reaction centers using femtosecond transient absorption spectroscopy. Experiments were performed over a wide range of excitation and probe wavelengths, using several data collection time scales. This has enabled us to resolve five different lifetimes ranging between 100 fs and 200 ps plus a nanosecond component. We demonstrate here and elsewhere [e.g., Durrant, J.R., Hastings, G., Joseph, D. M., Barber, J., Porter, G., & Klug, D. R. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 11632-11636] that the kinetic spectra associated with all but two of these lifetimes are clearly distinguishable. We have previously reported that a 21-ps lifetime is associated with pheophytin reduction [Hastings, G., Durrant, J. R., Hong, Q., Barber, J., Porter, G., & Klug, D. R. (1992) Biochemistry 31, 7638-7647]. In this paper, we show that it is possible to spectrally and temporally resolve stimulated emission from PS2 reaction centers with great accuracy and that this stimulated emission is largely unaffected by those kinetic components which are faster than 21 ps. The observation of a distinct stimulated emission band allows us to distinguish charge-separated states from chlorin singlet states. In this way, we are able to show that the proportion of charge-separated states prior to the 21-ps component is between 0% and 25%. We also show that the shape of the spectrum which we obtain for the state P680+Ph- is essentially invariant between 100 ps and 9 ns, and is the same as that previously reported for P680+Ph- by other researchers.(ABSTRACT TRUNCATED AT 250 WORDS)

Subpicosecond equilibration of excitation energy in isolated photosystem II reaction centers.

Photosystem II reaction centers have been studied by femtosecond transient absorption spectroscopy. We demonstrate that it is possible to achieve good photoselectivity between the primary electron donor P680 and the majority of the accessory chlorins. Energy transfer can be observed in both directions between P680 and these accessory chlorins depending on which is initially excited. After excitation of either P680 or the other chlorins, the excitation energy is observed to equilibrate between the majority of these pigments at a rate of 100 +/- 50 fs-1. This energy-transfer equilibration takes place before any electron-transfer reactions and must therefore be taken into account in studies of primary electron-transfer reactions in photosystem II. We also show further evidence that the initially excited P680 excited singlet state is delocalized over at least two chlorins and that this delocalization lasts for at least 200 fs.

Observation of pheophytin reduction in photosystem two reaction centers using femtosecond transient absorption spectroscopy.

Photosystem two reaction centers have been studied using a sensitive femtosecond transient absorption spectrometer. Measurements were performed at 295 K using different excitation wavelengths and excitation intensities which are shown to avoid multiphoton absorption by the reaction centers. Analyses of results collected over a range of time scales and probe wavelengths allowed the resolution of two exponential components in addition to those previously reported [Durrant, J. R., Hastings, G., Hong, Q., Barber, J., Porter, G., & Klug, D. R. (1992) Chem. Phys. Lett. 188, 54-60], plus the long-lived radical pair itself. A 21-ps component was observed. The process(es) responsible for this component was (were) found to produce bleaching of a pheophytin ground-state absorption band at 545 nm and the simultaneous appearance of a pheophytin anion absorption band at 460 nm resulting in a transient spectrum which was that of the radical pair P680+Ph-. This component is assigned to the production of reduced pheophytin. A lower limit of 60% of the final pheophytin reduction was found to occur at this rate. Despite subtle differences in transient spectra, the lifetime and yield of this pheophytin reduction are essentially independent of excitation wavelength within the signal to noise limitations of these experiments. A long-lived species was also observed. This species is produced by those processes which result in the 21-ps component, and it has a spectrum which is found to be independent of excitation wavelength. This spectrum is characteristic of the primary radical pair state P680+Ph-. In addition, a 200-ps component was found which is tentatively assigned to a slow energy-transfer/trapping process. This component was absent if P680 was excited directly and is therefore not integral to primary radical pair formation. Overall, it is concluded that the rate of pheophytin reduction is limited to (21 ps)-1, even when P680 is directly excited.