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By E. Dudley. Pace University.

Pa- tients with AD who carry PS1 or PS2 mutations have signifi- Localization cant increase of plasma A 42 levels (145) together with deposition of A 42 in the brain (146 cheap 20 gm cleocin gel with amex skin care for pregnancy,147) generic cleocin gel 20gm online acne breakouts. In fibroblasts Endogenous presenilins have a relatively limited subcellular from such patients, the APP metabolism is shifted toward distribution; they are found in the early compartments of an increase of A 42 production. Presenilin proteins have been local- mutated PS1 increases A 42 in transfected cells (148–151), ized to the endoplasmic reticulum (ER) and the Golgi sub- as well as in transgenic mice (148–150). Confocal and electron micros- PS influences the production of A 42 peptides remains un- copy, combined with subcellular fractionation experiments, certain, but these PS mutations appear to cause aberrant show that presenilins in neurons reside in the smooth and gain, rather than loss, of function. In neurons of PS1-knock- rough ER, the ER Golgi intermediate compartments, and, out mice, secretion of A is drastically reduced, leading to to a limited extent, in the cis-Golgi, but not beyond (139). This gives evidence that PS1 is obligatory Golgi compartments should, however, be interpreted with for proteolysis of APP at the -secretase cleavage site. Either mutation, when expressed in various mamma- (140). Studies provide convincing evidence that some mam- lian cell types, prevented both the normal endoproteolysis malian PS1 can be found at the cell surface, where it can be biotinylated (141). Conservative substitution of aspartate by glutamate still abrogated the -secretase Interaction with APP cleavage of APP, a finding indicating a specific requirement There is strong evidence that presenilins are able to interact for the two TM aspartates. These results are consistent with directly with APP. Complex formation between APP and one of two mechanisms: a role for presenilin as a unique presenilins has been demonstrated by coimmunoprecipita- cofactor for -secretase that could play a role in protein tion of both proteins in cells either transfected or with en- trafficking or a role as a functional -secretase, making it an dogenous proteins as well as with the yeast two-hybrid sys- unprecedented intramembranous aspartyl protease. Thinakaran and colleagues, in contrast to evidence for and against both possibilities. Presenilin proteins 1206 Neuropsychopharmacology: The Fifth Generation of Progress have been localized to early transport compartments, of PS1 not only prevented APP processing by -secretase, whereas abundant -secretase activity is restricted to late but also prevented the cleavage of the Notch C-terminus transport compartments and the endosomal pathway (55, in the membrane. The same holds true for the release of the Notch intra- either presenilins are directly involved in cleaving both cellular domain (see later), which occurs after ligand binding Notch and APP or mediate both cleavages in a more indirect by Notch at the cell surface (154,155). Processing of Notch resembles in some aspects the cellular localization of presenilin proteins in ER and early processing of APP. Notch is processed by a furin-mediated Golgi overlaps to some degree with the intracellular site of cleavage during its passage through the Golgi system. An addi- resultant two fragments remain in the same protein complex tional concern is that the presenilin sequences have no ho- and localize in the cellular membrane to form the functional mology to any of the proteases identified so far. The binding of the ligand to the receptor stimu- tion that PS is -secretase will require reconstitution of the lates the cleavage of one of the subunits at a specific extracel- -secretase/presenilinase activities in artificial lipid bilayers lular site close to the membrane. A subsequent intramem- using appropriate substrates and cellular factors. Partial branous cleavage liberates an intracellular fragment that characterization of detergent-solubilized -secretase activity translocates into the nucleus. This peptide forms an active shows that -secretase activity is catalyzed by PS1-contain- transcription complex, which activates transcription of ing macromolecular complex (156). The last of these proteolytic cleavage The alternate hypothesis holds that PS1 influences endo- steps of Notch resembles -secretase cleavage of APP. There are also data showing that presenilins elusive protease. It was demonstrated that CTF derived are functionally implicated in the Notch signaling pathway. Because APP and APLP1 trans- (159) consists of a severe impairment of the development membrane domains have very limited homology, it may be more difficult to envision that PS1 plays a role as a specific of the axial skeleton. The origin of these skeleton abnormali- -secretase involved in the cleavage of APP, Notch (see ties lies in the impairment of the segmentation of the so- later), and APLP1. Interestingly, Notch-1 (160) knockout animals suf- ing membrane-bound CTFs derived from APP family fered from similar abnormal skeleton deformations, a members or other transmembrane proteins to appropriate finding consistent with interaction of presenilins with cleavage or degradation compartments may be considered. The authors provide evidence strongly suggesting transcription factor essential for cholesterol biosynthesis. Notch function is in- nematode homologue of presenilin, was identified by volved in various signaling pathways, and Notch is crucial screening for suppressors of lin-12 (C. A similar pathway is used in Caenorhabditis elegans at multiple steps in development, including singling out to facilitate the signaling of transmembrane receptors of precursor cells involved in vulva differentiation (158). For the lin-12/Notch family, and human presenilins have been this purpose, two cells that are initially functionally identical shown to complement for Sel-12 function effectively (163).

My experience and comments on the Patient Centred Assessment Method process; by patient representative 2 As a sufferer from a sluggish (not to say absent) NHS protocol in dealing with anxiety issues caused by the diagnosis of a cardiac problem buy cleocin gel 20 gm with amex acne skin care, I joined the Living Better Project Steering Committee which was an RCGP-led study aiming to improve the care of people with LTCs in primary care order cleocin gel 20gm overnight delivery acne skin care, hoping for procedural improvement. Unfortunately the results of the research resulting from the Living Better project did not translate into the hoped for improved protocol to establish a route to identify co-lateral problems which frequently resulted alongside a chronic disease diagnosis. But, in PCAM, I saw an opportunity to introduce a method to improve this situation within the existing structure. Encouraged to be involved from the start in discussing the initial documentation and to join the Steering Committee by the key researchers it has been a pleasure to be involved with and to follow the development of this ambitious project. Always encouraged to participate fully in committee discussions and to contribute ideas throughout, and to feel free to criticise, my lay colleague and I were kept involved in all of the developing problems by the project leaders as well as in the successes. Our involvement in the discussion of the final report has also been thorough. The infectious enthusiasm of the researchers and their stoicism when things were difficult have been singular. There is no doubt in my mind that, in PCAM, there is the germ of an idea which will become part of NHS protocol in the years to come. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 75 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. DISCUSSION Strengths and limitations The strength of this study is that it was designed as a feasibility study that has fully tested practice, nurse and patient recruitment and retention. The combination of the five studies, which all contribute to the overall aims of the study, means that, often, multiple sources of information could be used to contribute to overall study findings. For example, studies A, C and D contributed to the acceptability and feasibility of using the PCAM in primary care nurse-led annual reviews, as well as the overall process evaluation (study E). Practices were recruited from very different areas of Scotland, for example from NHS GGC, which has the highest proportion of deprived practices in Scotland, and from NHS Grampian, which has small urban towns and rural areas. There is no doubt that the recruitment and retention figures are a big limitation for this study; however, this was what the study was designed to test, so it is a finding rather than a limitation in this case. The lack of nurse participation in study C is probably one of the most disappointing aspects, because it resulted in very few consultation recordings, and yet, these showed great promise in demonstrating that the PCAM may actually achieve its goals of changing nurse behaviour in consultations. The fact that researchers delivered training as well as being involved in study data collection may have introduced some bias into practices allocated to the PCAM arm; nurses may have felt that they had to be positive about the PCAM with the researcher with whom they had developed a relationship over time. However, interviews with PCAM PNs at the end of the study were conducted by the researcher with whom practices had had the least or no contact. Some differences between phases 1 and 2, and between the PCAM and CAU patient populations, may indicate that there is some nurse bias in selection of patients for inclusion in the study. This may have been as a result of learning which patients were more likely to accept or decline to complete questionnaires. Conclusions The PCAM has been uniquely adapted for use in primary care and there are no other directly comparable assessment tools that have been developed for and tested in primary care. The PCAM provides a comprehensive and practical approach to assessing biopsychosocial needs in patients with LTCs, including multimorbidity. The PCAM intervention consists of three components: a tailored and flexibly delivered training package; the PCAM tool; and a locally based resource toolkit. The PCAM has been shown to be feasible and acceptable for use in primary care in the UK, and shows that it does indeed have the potential to change the ways in which nurses engage with patients with LTCs, in the context of LTC reviews, which results in more attention to the mental well-being and social care needs of patients. The PCAM is more likely to be feasible when nurses see the asking of these questions as part of the role of nursing, view their role as facilitating links to information or resources that can address concerns (rather than feeling that they have to address the concerns themselves) and have the information about resources available to them, and there is a whole-practice commitment to the approach. Any future study of implementing or testing the PCAM in primary care would require these conditions to be met. Training in the use of the PCAM has to be flexible to fit in with limited practice time, and also requires the inclusion of reflective practice. The resource toolkit is also an integral part of the PCAM intervention and practices need to find dedicated time to keep this resource live, potentially reinforcing local connections at the same time. Recommendations The PCAM intervention warrants further exploration as an effective mechanism for improving the quality of care for people with LTCs in primary care, particularly in the holistic review of patient needs by primary care nurses.

Sleep sleep latency 20gm cleocin gel sale skin care nz, that is discount 20gm cleocin gel fast delivery acne x soap, the time from lights out to the onset disruption is the single most common complaint of patients of electrophysiologically defined sleep, and underestimate in a major depressive episode (9). Some have speculated that chronic insomnia may mised sleep efficiencies and intermittent waking time (13), contribute to the development of major depressions (10, it is not clear that sleep is significantly disparate from that 11); however, prospective controlled studies are needed to of noncomplaining sleepers in the majority of insomniacs. Kales and associates (5) found that Second, studies consistently find that insomniacs do not insomniacs also exhibited symptoms mood changes, such demonstrate daytime sleepiness, as measured by the Multi­ as dysphoric mood, worry, tension, anxiety, and irritability. These results must physiologically aroused, but rather passive and calm. Inability to to hypothesize that there may be different types of insom­ initiate sleep may be a characteristic of insomniacs both niacs: (a) hypoactive, as described; and (b) hyperactive, who during the day and night. This measure is of dubious utility in the evaluation of sleepi­ The causal direction of the relationship between insom­ ness in those who cannot initiate sleep. We cannot To circumvent this measurement difficulty, Lichstein readily assume that psychiatric symptoms are merely se­ and colleagues have used an index of sleepiness that does quelae of insomnia, nor can we definitively assume that not depend on sleep ability, but rather diameter of the pupil insomnia is always a consequence of psychopathology. Although there is some evidence Clearly, we need to attend to the relationship between mood to suggest that insomniacs differ from noninsomniacs on and insomnia. Even if criteria for a diagnostic disorder are sleepiness as measured by pupillometry (19,20), the effects not met, the interplay between moods and insomnia need were marginal. The technique may be promising, but the to be examined in order to increase our knowledge of the results are inconclusive. One would expect that concentration and memory difficulties (4). Compared to a worsening of nighttime sleep would exacerbate daytime noninsomniacs, insomniacs also rate their attention, mem­ impairment. Although there is some evidence that insomniacs 15,20) do not always directly relate to measures of daytime have difficulty with semantic memory (13), reaction time, functioning. Interestingly, Sugerman and asso­ both insomniacs and noninsomniacs. What, then, could boration), displayed cognitive deficits. Thus, there may be account for the decrements in daytime functioning? First, these data lead one to question whether Hypothesized Mechanisms or not insomniacs are indeed sleep deprived; and second, to hypothesize what could account for these reported symp­ Several studies support the notion that insomniacs are not toms if not sleep deprivation. This chronic activa­ tion may account for the inability to fall asleep at night and Are Insomniacs Sleep Deprived? Bonnet Daytime symptoms may not solely be attributable to sleep and Arand (22) 'yoked' the sleep of controls to that of loss. First, for the majority of insomniacs it is questionable insomniacs. Insomniacs demonstrated a pattern of hyper- time performance is markedly impaired. Studies demon­ arousal inconsistent with sleep deprivation (increased meta­ strate impaired vigilance, reduced reaction times, daytime bolic rate, body temperature, tension, and decreased vigor); microsleeps, memory impairment, and depressive symp­ therefore, daytime symptoms may be the result of hyper- toms (28–30). Findley and associates (31) found that per- arousal, not sleep deprivation. For example, anxi­ and simple reaction times—than did age-matched control ety could account for sleep onset difficulties at night and participants. The outcomes of these problems include im­ symptoms of fatigue during the day (23). Likewise, Coyle pairment in work efficiency, increased automobile accident (24) found that insomniacs with negative affect perceived rates, and decrements in quality of life. In the case of truck impaired daytime cognitive functioning and motivation, drivers, pilots, and other operators of heavy machinery, whereas insomniacs with positive affect perceived better these consequences of sleep-disordered breathing can be cat­ cognitive and motivational functioning. How an insomniac reacts to his or her sleep disruption Maintenance of respiration during sleep is dependent on may also predict his or her experience of daytime function­ intact central nervous system centers controlling respiration, ing. Several hypotheses related to this notion are offered. The emphasis of clinical and re- about it during the day (20,25).