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‘Historically informed performance’ (HIP) has become standard practice for the performance of ‘early music’ composed before 1800 and is increasingly applied to more recent compositions. The approac...

Background The high burden of infectious disease and associated antimicrobial use likely contribute to the emergence of antimicrobial resistance in remote Australian Aboriginal communities. We aimed to develop and apply context-specific tools to audit antimicrobial use in the remote primary healthcare setting. Methods We adapted the General Practice version of the National Antimicrobial Prescribing Survey (GP NAPS) tool to audit antimicrobial use over 2–3 weeks in 15 remote primary healthcare clinics across the Kimberley region of Western Australia (03/2018–06/2018), Top End of the Northern Territory (08/2017–09/2017) and far north Queensland (05/2018–06/2018). At each clinic we reviewed consecutive clinic presentations until 30 presentations where antimicrobials had been used were included in the audit. Data recorded included the antimicrobials used, indications and treating health professional. We assessed the appropriateness of antimicrobial use and functionality of the tool. Results We audited the use of 668 antimicrobials. Skin and soft tissue infections were the dominant treatment indications (WA: 35%; NT: 29%; QLD: 40%). Compared with other settings in Australia, narrow spectrum antimicrobials like benzathine benzylpenicillin were commonly given and the appropriateness of use was high (WA: 91%; NT: 82%; QLD: 65%). While the audit was informative, non-integration with practice software made the process manually intensive. Conclusions Patterns of antimicrobial use in remote primary care are different from other settings in Australia. The adapted GP NAPS tool functioned well in this pilot study and has the potential for integration into clinical care. Regular stewardship audits would be facilitated by improved data extraction systems.

The proposal that microtubule dynamic instability results from stabilization of microtubule ends by tubulin-GDP-Pi subunits (where Pi is inorganic phosphate) [Melki et al. (1996) Biochemistry 35, 12038] was based on studies of GTP hydrolysis and microtubule assembly that showed that tubulin-GDP-Pi subunits can transiently accumulate at microtubule ends. There is no direct evidence that GDP-Pi-subunits can stabilize microtubules under conditions where dynamic instability is observed and this has been inferred from the observation that tubulin-GDP-BeFn subunits stabilize microtubules. To test if tubulin-GDP-Pi stabilizes microtubules we sought evidence for a synergism between the effect of Pi and BeFn. We found, however, that Pi antagonizes the effect of BeFn by displacing it from tubulin subunits. The alternate mechanism in which Pi inhibits BeFn stabilization of microtubules by displacing fluoride from beryllium was ruled out from the 9Be and 19F NMR spectra in the presence and absence of Pi. Further evidence that tubulin-GDP-BeFn is not an analogue of tubulin-GDP-Pi and that tubulin-GDP-Pi is not responsible for maintaining the growth phase in microtubules manifesting dynamic instability was provided by our observation that Pi did not decrease the disassembly rate under conditions where tubulin-GDP-Pi subunits are expected to have formed. Results showing that BeFn binds randomly to subunits in microtubules provided evidence that Pi dissociation from the tubulin-GDP-Pi intermediate formed during GTP hydrolysis occurs randomly rather than processively starting at the growing microtubule tip.

The recent discovery that GTP linked to latex beads binds to microtubule ends suggested that nucleotide interactions at this site may play a role in regulating microtubule (MT) dynamics. Evidence for this was sought using DIC microscopy to analyze effects of the free GTP and GDP concentration on the rates of MT elongation and phase transition to rapid shortening (catastrophe, kc). That nucleotide can dissociate and thereby destabilize the plus end by forming nucleotide-free (apotubulin) subunits was indicated by an increase in kc from 0.001 to 0.05 s-1, when the free GTP concentration was reduced from 100 to 0.5 microM, during assembly with 15 microM tubulin--GTP subunits (TuT). That nucleotide can bind to the minus end was indicated by a nearly 5-fold decrease in the rate of elongation when the free GDP concentration was increased from 1.6 to 175 microM, during assembly with a mixture of 36 microM TuT and 54 microM TuD. Further evidence that nucleotide can bind to both ends was provided by the observation that with a mixture of 36 microM TuT and 54 microM TuD, kc was increased from 0.0036 to 0.05 s-1 at the plus end, and from 0.0005 to 0.005 s-1 at the minus end, when the free GDP concentration was increased from 1.6 to 175 microM. Our evidence for destabilization of microtubules by formation of apotubulin and by nucleotide exchange to form terminal TuD subunits suggests that microtubule dynamics can be regulated in cells by an exchange factor that generates apotubulin subunits, or by a GTPase activating protein that forms TuD subunits at microtubule ends.

The standard free energy for hydrolysis of the GTP analogue guanylyl-(a,b)-methylene-diphosphonate (GMPCPP), which is -5.18 kcal in solution, was found to be -3.79 kcal in tubulin dimers, and only -0.90 kcal in tubulin subunits in microtubules. The near-zero change in standard free energy for GMPCPP hydrolysis in the microtubule indicates that the majority of the free energy potentially available from this reaction is stored in the microtubule lattice; this energy is available to do work, as in chromosome movement. The equilibrium constants described here were obtained from video microscopy measurements of the kinetics of assembly and disassembly of GMPCPP-microtubules and GMPCP-microtubules. It was possible to study GMPCPP-microtubules since GMPCPP is not hydrolyzed during assembly. Microtubules containing GMPCP were obtained by assembly of high concentrations of tubulin-GMPCP subunits, as well as by treating tubulin-GMPCPP-microtubules in sodium (but not potassium) Pipes buffer with glycerol, which reduced the half-time for GMPCPP hydrolysis from > 10 h to approximately 10 min. The rate for tubulin-GMPCPP and tubulin-GMPCP subunit dissociation from microtubule ends were found to be about 0.65 and 128 s-1, respectively. The much faster rate for tubulin-GMPCP subunit dissociation provides direct evidence that microtubule dynamics can be regulated by nucleotide triphosphate hydrolysis.

Measurement of the affinity of microtubules for the anti-cancer drug taxol is problematic, because microtubules are not stable at the very low concentrations required to detect taxol dissociation. We have circumvented this problem by using the GTP analogue GMP-CPP (guanylyl alpha, beta-methylenediphosphonate), which renders microtubules sufficiently stable to allow binding studies with nonsaturating concentrations of taxol. AKd value equal to about 10 nM was estimated from the effect of taxol concentration on the dilution-induced disassembly rate and on the binding of [3H]taxol. With GTP-microtubules the Kd value for taxol binding by tubulin-GDP subunits in the core of the microtubule appears to be comparable with that of GMPCPP-microtubules. However, the stabilizing effect of the drug bound to tubulin subunits that arrive at ends of disassembling microtubules is attenuated by a two-step reaction sequence in which taxol dissociates (k = 30 s-1), followed by rapid (k = 1000 s-1) loss of the taxol-free tubulin subunit. This sequential reaction can be disrupted by high (micromolar) concentrations of taxol, which react rapidly with tubulin subunits at the ends of microtubules (k = 2 x 10(9) M-1 s-1). The inhibitory effect of taxol on microtubule disassembly at concentrations a thousand-fold greater than the Kd value suggests the desirability of using high taxol concentrations in chemotherapy with this compound.

Abstract The design of rigid jumpers at the base of deepwater dynamic Free Standing Hybrid Risers (FSHRs) represents a complex engineering challenge. Design issues involve strength under extreme static loads including relative end displacements, strength and fatigue under forced dynamics due to riser vortex induced vibration (VIV), direct VIV due to seabed bottom currents, internal flow induced vibration, cyclic thermal loads, and installation. This paper considers design optimisation of the Cascade and Chinook Riser Base Jumpers (RBJs) in the Gulf of Mexico for strength and fatigue under static and VIV loads since these conditions are generally dimensioning. A distinguishing feature in the engineering of such jumpers is a balanced approach to reconcile requirements for strength with those for fatigue because these tend to drive the design in opposite directions. In particular, strength considerations dictate a low stiffness solution to avoid high stress under jumper end motions, while the avoidance of dynamic coupling with the riser, in order to reduce fatigue damage, generally requires a high stiffness design. These conflicting requirements were satisfied by parameterising a base case design geometry and performing an automated design optimisation to minimise the fatigue-producing dynamic stress range (object function) under defined dynamic end loads while subject to specified constraints arising from geometric and strength requirements. The resulting design geometry increased fatigue lives by approximately two orders of magnitude compared to an early configuration resulting from strength design only. Following the design optimisation, other less critical design conditions were checked and found to be satisfactory. Introduction Figure 1 illustrates the FSHR system employed on the Petrobras Cascade and Chinook Field Development in 2500m of water. The main vertical steel riser pipe is anchored at the bottom to a suction anchor foundation structure with a flexible Roto-latch connection and maintained in tension via a Buoyancy Can (BC) located at 200m depth. A flexible pipe jumper provides tieback to the disconnectable Floating Production Storage and Offloading (FPSO) vessel turret system while at the seabed a Riser Base Jumper connects the riser to the associated Pipe-Line End Termination (PLET) as indicated in Figure 2. Further details of the FSHRs can be found in related papers, References 1 and 2. Key design considerations for the RBJ structures include:Strength under extreme static loads including relative end displacements,Strength and fatigue under forced dynamics arising from riser VIV,Direct VIV due to bottom current conditions,Internal flow induced vibration,Cyclic thermal loads andFabrication, load-out, transportation and installation. When considered alongside the large number of possible design parameters associated with a typical RBJ structure, these numerous and varied design conditions have proven a significant challenge for several recent Projects involving deepwater FSHR systems. This paper addresses this challenge by presenting an automated design optimisation procedure for strength and fatigue of the Cascade and Chinook RBJ structures under static strength and dynamic riser VIV loads since these conditions are generally dimensioning. An alternative design solution for isolating the RBJ from riser VIV motion is the use of a rigid connection between vertical riser and foundation structure. However this approach introduces different challenges including more complex strength and fatigue design of the lower riser (possibly leading to impractical Taper Stress Joint requirement), increased foundation loading, increased risk of suction anchor pull-out and consequent need for heavier, more fatigue resistant, foundation structure.

This paper presents measurements of the wake field behind three riser models obtained by using a Digital Particle Image Velocimetry (DPIV). The three riser models were a circular rigid cylinder, a cylinder fitted with fairings and a cylinder fitted with strakes. The models were free to vibrate in the cross-flow direction when towed in a uniform flow. The range of tested Reynolds number based on the diameter of the cylinder was from 3×104 to 2.5×105 . The measurement results showed that the transverse vibration amplitudes for both the faired and straked cylinder were far less than those of the bare cylinder. Based on the wake flow field comparison between the models tested it was found that the modes of vortex shedding observed behind the bare cylinder did not occur behind either the faired or straked cylinder. This reveals that the vibrations responses of the cylinders are directly related to their wake modes. Strong, regularly shed vortices induce large amplitude vibration and weak, scattered vortices lead small amplitude or no vibration. The different wake patterns are presented for the three cylinders.Copyright © 2008 by ASME

The rate of GTP hydrolysis by microtubules has been measured at tubulin subunit concentrations where microtubules undergo net disassembly. This was made possible by using microtubules stabilized against disassembly by reaction with ethylene glycol bis-(succinimidylsuccinate) (EGS) as sites for the addition of tubulin-GTP subunits. The tubulin subunit concentration was varied from 25 to 90% of the steady state concentration, and there was no net elongation of stabilized microtubule seeds. The GTPase rate with EGS microtubules was linearly proportional to the tubulin-GTP subunit concentration when this concentration was varied by dilution and by using GDP to compete with GTP for the tubulin E-site. The linear dependence of the rate is consistent with a GTP mechanism in which hydrolysis is coupled to the tubulin-GTP subunit addition to microtubule ends. It is inconsistent with reaction schemes in which: microtubules are capped by a single tubulin-GTP subunit, which hydrolyzes GTP when a tubulin-GTP subunit adds to the end; hydrolysis occurs primarily in subunits at the interface of a tubulin-GTP cap and the tubulin-GDP microtubule core; hydrolysis is not coupled to subunit addition and occurs randomly in subunits in a tubulin-GTP cap. It was also found that GDP inhibition of the microtubule GTPase rate results from GDP competition for GTP at the tubulin subunit E-site. There is no additional effect of GDP on the GTPase rate resulting from exchange into tubulin subunits at microtubule ends.

Background and Purpose. The purpose of this study was to determine the effect of a swimming endurance training program on changes in percentages and sizes of fiber types in different regions of the hamster diaphragm. Methods. Adult male golden Syrian hamsters were randomly assigned to a control group (n=9) or a swimming group (n=10). Hamsters in the swimming group swam for 80 minutes per session, 5 days per week, for 13 weeks. Fiber-type percentages and sizes were determined for the costal region and for the abdominal and thoracic surfaces of the crural region of the diaphragm from cross sections processed for myofibrillar adenosine triphosphatase. Results. Muscle fibers in the thoracic surface of the crural region were smaller in the swimming group than in the control group. Fiber-type percentages in the diaphragm, however, were not different between groups. Conclusion and Discussion. Swim training may have improved the endurance of the thoracic/crural region by decreasing cross-sectional area and thus decreasing the distance for oxygen to diffuse to the internal regions of the muscle fibers.

Evidence that 13 or 14 contiguous tubulin-GTP subunits are sufficient to cap and stabilize a microtubule end and that loss of only one of these subunits results in the transition to rapid disassembly(catastrophe) was obtained using the slowly hydrolyzable GTP analogue guanylyl-(a,b)-methylene-diphosphonate (GMPCPP). The minus end of microtubules assembled with GTP was transiently stabilized against dilution-induced disassembly by reaction with tubulin-GMPCPP subunits for a time sufficient to cap the end with an average 40 subunits. The minimum size of a tubulin-GMPCPP cap sufficient to prevent disassembly was estimated from an observed 25- to 2000-s lifetime of the GMPCPP-stabilized microtubules following dilution with buffer and from the time required for loss of a single tubulin-GMPCPP subunit from the microtubule end (found to be 15 s). Rather than assuming that the 25- to 2000-s dispersion in cap lifetime results from an unlikely 80-fold range in the number of tubulin-GMPCpP subunits added in the 25-s incubation, it is proposed that this results because the minimum stable cap contains 13 to 14 tubulin-GMPCPP subunits. As a consequence, a microtubule capped with 13-14 tubulin-GMPCPP subunits switches to disassembly after only one dissociation event (in about 15 s), whereas the time required for catastrophe of a microtubule with only six times as many subunits (84 subunits) corresponds to 71 dissociation events (84-13). The minimum size of a tubulin-GMPCPP cap sufficient to prevent disassembly was also estimated with microtubules in which a GMPCPP-cap was formed by allowing chance to result in the accumulation of multiple contiguous tubulin-GMPCPP subunits at the end, during the disassembly of microtubules containing both GDP and GMPCPP. Our observation that the disassembly rate was inhibited in proportion to the 13-14th power of the fraction of subunits containing GMPCPP again suggests that a minimum cap contains 13-14 tubulin-GMPCPP subunits. A remeasurement of the rate constant for dissociation of a tubulin-GMPCPP subunit from the plus-end of GMPCPP microtubules, now found to be 0.118 s-1, has allowed a better estimate of the standard free energy for hydrolysis of GMPCPP in a microtubule and release of Pi: this is +0.7 kcal/mol, rather than -0.9 kcal/mol, as previously reported.

EDITOR,--We are impressed with the move to evidence based medicine and clinical effectiveness. We strongly urge that the concept of clinical effectiveness1 should be broad enough to include the alleviation of …

Commissioning authorities increasingly attempt to base their purchasing decisions on systematic, epidemiologically informed assessment of the health needs of their local populations. General practitioners as purchasers usually rely on their own judgment. No one knows which method works better, but a combined approach may capture some of the advantages of both. One of the more widely welcomed aspects of the NHS reforms was the requirement that health authorities' decisions on how to use NHS resources should in future be based on a systematic assessment of each local population's needs for health care. This is meant to take account of local demography, the epidemiology of health problems, evidence on the effectiveness of treatments, and the preferences of local people.1 Needs assessment has become an important task for public health doctors and others working in commissioning authorities. This more rational and scientific method is put forward as an improvement over the former approach to allocating health funding, caricatured as “same as last year, plus or minus five per cent for pressure groups.”2 The most obvious way in which general practitioners can shape decisions on the pattern of purchasing for hospital and community health services is by becoming fundholders. Non-fundholding general …

Dampened oscillations of microtubule assembly can accompany polymerization at high tubulin subunit concentrations. This presumably results from a synchronization of dynamic instability behavior, which generates a large population of rapidly disassembling microtubules, that liberate tubulin-GDP oligomers. Subunits in oligomers cannot assemble until they dissociate, to allow GDP-GTP exchange. To determine whether rapidly disassembling microtubules generate oligomers directly, we measured the rate of dilution-induced disassembly of tubulin-GDP microtubules and the rate of dissociation of GDP from the so-formed tubulin-GDP subunits. The rate of GDP dissociation from liberated subunits was found to correspond to that of tubulin-GDP subunits (t1/2 = 5 s), rather than tubulin-GDP oligomers. This indicates that tubulin-GDP subunits are released from microtubules undergoing rapid disassembly. Oligomers apparently form in a side reaction from the high concentration of tubulin-GDP subunits liberated from the synchronously disassembling microtubule population. The rate of subunit dissociation is 0.11 s-1 with oligomers formed by concentrating tubulin-GDP subunits and 0.045 s-1 with oligomers formed by cold-induced microtubule disassembly. This difference provides evidence that the conformation of tubulin-GDP subunits released from rapidly disassembling microtubules differs from tubulin-GDP subunits that were not recently in the microtubule lattice.

EDITOR,--We endorse Barbara Ghodse's recommendation that extracontractual referrals could be handled more efficiently.1 We would emphasise more strongly the central importance of involving general practitioners both in assessing the justification for extracontractual referrals and through giving them feedback on decisions made. In Lambeth, Southwark, and Lewisham extracontractual referrals are considered by a …

Short microtubules can be formed by shearing a sample at polymerization steady state of microtubules formed by glycerol-induced assembly of pure tubulin dimer. Such short microtubules show a rapid increase in mean length. The rate of this increase is too fast to be accounted for by statistical redistribution of subunits between microtubules. We propose that the fast length changes are a result of the end-to-end annealing of microtubules demonstrated by Rothwell et al. (Rothwell, S. W., Grasser, W. A., and Murphy, D. B. (1986) J. Cell Biol. 102, 619-627). This proposal has been tested by measuring the rate of annealing of free microtubules to Tetrahymena axonemes under conditions identical to those used for the lengthening of sheared microtubules. That free microtubules anneal to axonemal microtubules is indicated by the following observations. Axonemes elongate at both ends in the presence of steady state microtubules, as predicted for a symmetrical annealing process; under conditions where the microtubule number concentration is greater than that for axonemes, the initial rate of axoneme elongation is more rapid with a low concentration of long microtubules at steady state than with a high number concentration of short microtubules at steady state. These observations are inconsistent with the predictions of a model based on microtubule dynamic instability (Mitchison, T., and Kirschner, M. (1984) Nature 312, 237-242). The annealing rate observed with axonemes can account for the rate of elongation of sheared steady state microtubules.

Microtubule dynamic instability has been accounted for by assuming that tubulin subunits at microtubule ends differ from the tubulin-GDP subunits that constitute the bulk of the microtubule. It has been suggested that this heterogeneity results because ends contain tubulin subunits that have not yet hydrolyzed an associated GTP molecule. Alternatively, in a recent model it was proposed that ends contain tubulin-GDP-Pi subunits from which Pi has not yet dissociated. The models differ in their predicted response to added ligands: because GDP in subunits in microtubules does not exchange with nucleotide in solution, the heterogeneity from a tubulin-GTP cap will not be eliminated by added GTP; however, the dissociability of Pi in tubulin-GDP-Pi subunits will allow a heterogeneity resulting from a tubulin-GDP-Pi cap to be eliminated by added excess Pi. Elimination of the heterogeneity is expected to be manifested by an elimination of dynamic instability behavior. Using video microscopy to study the kinetic behavior of individual microtubules under reaction conditions where dynamic instability is the dominant mechanism for microtubule length changes, we have determined the effects of 0.167 M Pi on the rate of subunit addition in the elongation phase, the rate of subunit dissociation in the rapid shortening phase, and the rates of the phase transitions from elongation to rapid shortening and from rapid shortening to growing. Since 0.167 M Pi did not decrease the subunit dissociation rate in the rapid shortening phase or the rate of the phase transition from growing to rapid shortening, our results provide no support for the hypothesis that tubulin-GDP-Pi subunits are responsible for dynamic instability behavior of microtubules.(ABSTRACT TRUNCATED AT 250 WORDS)

The kinetics for GTP hydrolysis associated with microtubule assembly with microtubular protein has been analyzed under reaction conditions where tubulin–GDP does not readily assemble into microtubules. The GTPase rate is only slightly faster during the time when net microtubule assembly occurs, as compared with steady state. The slightly slower steady-state GTPase rate apparently results from GDP product inhibition, since the progressive decrease in the rate can be quantitatively accounted for using the previously determined GTP dissociation constant and the Ki value for GDP. Since the GTPase rate is not a function of the rate for net microtubule assembly, it is concluded that GTP hydrolysis is not required for tubulin subunit incorporation into microtubules. The constancy of the rate indicates that the GTPase reaction occurs at a site, the concentration of which does not change during the assembly process. This result is consistent with a reaction scheme in which GTP hydrolysis occurs primarily at microtubule ends. We propose that hydrolysis occurs at microtubule ends, at the interface between a long core of tubulin–GDP subunits and a short cap of tubulin–GTP subunits.

Evidence for a slowly dissociating tubulin-GTP cap at microtubule ends was derived from observation of a delay for attaining a maximum disassembly rate, after the temperature of steady state microtubules was rapidly decreased from 36 to 34 degrees C. The possibility that the microtubules were capped by a single tubulin-GTP subunit on each subhelix was ruled out, by comparison of the disassembly kinetics following a temperature decrease and dilution. The existence of a subpopulation of microtubules that underwent irreversible or near irreversible disassembly was demonstrated by a 30-s lag for attainment of a maximum assembly rate, after steady state microtubules were shifted from 34 to 36 degrees C. A dynamic instability model predicts that a maximum assembly rate will be delayed until disappearance of a subpopulation of microtubules that disassemble before being recapped. Analysis indicates that the 30-s lag resulted because approximately 2% of the mass in the steady state microtubule population was uncapped and disassembling and not readily recapped. The half-time for recapping of disassembling microtubules, by addition of tubulin-GTP subunits to ends, was equal to or greater than 20 s. Since tubulin-GDP dissociated from microtubules at a rate of about 4500 s-1, slow recapping resulted in dramatic shortening of disassembling microtubules.

Coronary artery disease, also known as ischemic heart disease , is the leading killer of men and women worldwide. In 2004, coronary artery disease was responsible for 7.2 million deaths, or 12.2% of all deaths globally and 5.8% of all years of life lost (World Health Organization 2008). The disease is highly prevalent: at any given time, 54 million people in the world suffer from angina pectoris (the characteristic chest pain of ischemic heart disease), and 23.2 million people experience moderate to severe disability as a result of ischemic heart disease 2008). Thirty-day mortality after an acute heart attack is extremely high at 33%; even in a hospital with a coronary care unit where advanced care options are available, mortality is still 7%. Approximately 4% of patients who survive initial hospitalization die in the first year following a heart attack (Antman et al. 2004). Congestive heart failure , the end stage of many heart diseases, carries a 1-year mortality rate as high as 40% and a 5-year mortality between 26 and 75%; the prognosis for patients with congestive heart failure is worse than for those with most malignancies or AIDS (McMurray and Stewart 2000). Pharmacologic therapy, metallic stents, and coronary artery bypass grafts have been mainstays of treatment for ischemic heart disease. However, new biomaterial devices are on the horizon that will enable optimal treatment of coronary artery lesions, as well as regeneration of damaged cardiac tissue.

Microtubules at steady state were found to undergo dramatic changes in length, with only very little change in number concentration and mean length. This result is accounted for by a mechanism in which microtubules are capped at ends by tubulin-GTP subunits; loss of the tubulin-GTP cap at one end results in disassembly of all the tubulin-GDP subunits, so that the medial edge of the distal tubulin-GTP cap is exposed; the exposed tubulin-GTP cap is sufficiently stable, so that microtubule regrowth from the cap rather than loss of the cap occurs. This mechanism predicts that a bell-shaped length distribution of sheared microtubules will be transiently bimodal, with peaks of short and moderate length microtubules, in rearranging to an exponential length distribution. We have observed the predicted transient bimodal length distribution experimentally and in a Monte Carlo simulation. Dynamic instability has recently been accounted for by assuming that microtubule ends are capped with only a single tubulin-GTP subunit at each end of the five helices that serve as elongation sites. Such a minimal tubulin-GTP cap is apparently ruled out by our observations, which require that the remnant tubulin-GTP cap generated from disassembly be able to serve as nucleating site; we do not expect that a stable nucleating site can be generated from five tubulin-GTP subunits, oriented as the five helices that serve as elongation sites.

We have demonstrated that tubulin-GTP subunits can react with microtubule ends containing subunits with E-site-bound GDP. This observation can be taken to rule out a previous interpretation of a biphasic dependence of the rate for subunit flux into microtubules on the subunit concentration, which is based upon an assumption that GTP is required to be present in subunits at microtubule ends in order to allow addition of tubulin-GTP subunits. The nullified mechanism had been suggested to be the basis of the observation that growing and shrinking microtubules coexist as independent species. We have also confirmed previous studies indicating that the flux rate is nonlinearly dependent on the subunit concentration and account for this behavior by assuming that tubulin-GTP subunits reversibly add to microtubule ends by two paths. In one, tubulin-GTP subunits add nonproductively to generate an end which is unable to undergo further net microtubule elongation; however, this reaction can retard the rate for microtubule disassembly under conditions where the disassembly reaction predominates. In the other, tubulin-GTP subunits add productively to microtubule ends to generate ends which can undergo subsequent net elongation.

The evidence accumulating from these recent careful studies suggests that care in the community is likely to be less expensive and more beneficial than institution-based care for many people with chronic mental illness. The cost savings are likely to be greater for less severely disabled individuals. These findings are consistent with those of earlier studies conducted in the United States (5) and in Australia (6). The incorporation of cost-benefit analysis into the daily routine of service provision presents a major opportunity for using limited resources in a way that maximizes the benefit to patients. Clinical staff readily recognize the importance of balancing the costs and benefits of the services they provide. Their reservations and skepticism about cost-benefit analysis usually center on doubts about the reliability and validity of the means used to calculate the costs and benefits. Involving clinicians in developing measures of outcome offers an opportunity to secure their commitment to the value ...

SynopsisHealth care workers often advise patients with chronic psychiatric disability against marrying each other. A survey of a group of such marriages revealed no evidence of the predicted ill-effects, but rather a trend towards improvement after the marriage. There is a discrepancy between professional expectations and actual outcome of these marriages.

In discussing the selection of patients and operations for relief of coronary artery disease, we shall attempt to correlate clinical, laboratory, and pathological information; to show the evolution from a single internal mammary artery implant to our present concept of implant or implants combined with epicardiectomy and free omental graft; and to outline the place of multiple implants with and without free omental grafts, particularly in relation to previous myocardial infarctions. In our experience with well over 400 revascularization operations, followed up to 17 years, 75% of our patients have suffered from one to six previous myocardial infarctions. In addition, since 1962, patients with large left ventricles and ventricles in a state of failure have been successfully treated. In fact, 25% of our patients had chronic left ventricular failure at the time of operation, and 65% of these have returned to the community, no longer with this condition. The point