Wave-intensity analysis: a new approach to coronary hemodynamics.

In 10 anesthetized dogs, we measured high-fidelity left circumflex coronary (P(LCx)), aortic (P(Ao)), and left ventricular (P(LV)) pressures and left circumflex velocity (U(LCx); Doppler) and used wave-intensity analysis (WIA) to identify the determinants of P(LCx) and U(LCx). Dogs were paced from the right atrium (control 1) or right ventricle by use of single (control 2) and then paired pacing to evaluate the effects of left ventricular contraction on P(LCx) and U(LCx). During left ventricular isovolumic contraction, P(LCx) exceeded P(Ao), paired pacing increasing the difference. Paired pacing increased DeltaP(X) (the P(LCx)-P(Ao) difference at the P(Ao)-P(LV) crossover) and average dP(LCx)/dt (P < 0.0001 for both). During this time, WIA identified a backward-going compression wave (BCW) that increased P(LCx) and decreased U(LCx); the BCW increased during paired pacing (P < 0.0001). After the aortic valve opened, the increase in P(Ao) caused a forward-going compression wave that, when it exceeded the BCW, caused U(LCx) to increase, despite P(LV) and (presumably) elastance continuing to increase. Thus WIA identifies the contributions of upstream (aortic) and downstream (microcirculatory) effects on P(LCx) and U(LCx).     

Coincident sequence cloning: a new approach to genome analysis.

Many analytical molecular genetic techniques developed over the past decade have evolved primarily to tackle the problem of targeting or isolating sequences of interest in complex mixtures. A new approach to this problem, Coincident Sequence Cloning (CSC), involves integrating a pair of DNA mixtures in such a way as to isolate any shared sequence components.     

Low-tar medium-nicotine cigarettes: a new approach to safer smoking.

The logic of expecting people who cannot stop smoking to switch to cigarettes that have hardly any nicotine is questionable. Tar and nicotine yields of cigarettes available in Britain today correlate 0-93, and further reduction of tar intake is limited by the reluctance of smokers to tolerate similar reductions in nicotine. A new approach would be to aim at lowering tar yields of cigarettes from the present average of 18 mg to around 6 mg but maintaining nicotine yields at around 1-0 to 1-2 mg, which would be acceptable to most smokers. This approach requires that emphasis be placed on tar: nicotine ratios as well as on the absolute yields. These ratios for brands on sale in Britain today average 14-2 and range from 9-6 to 20-8. They provide an additional guide for comparing the relative harmfulness of different brands. For example, 35% of cigarette smokers in Britain smoke either Embassy Filter or Players No 6 Filter; by changing to John Player Carlton King Size they could reduce their tar intake by more than 20% without having to suffer any nicotine deprivation.     

Partial retraining: a new approach to input relevance determination.

In this article we introduce partial retraining, an algorithm to determine the relevance of the input variables of a trained neural network. We place this algorithm in the context of other approaches to relevance determination. Numerical experiments on both artificial and real-world problems show that partial retraining outperforms its competitors, which include methods based on constant substitution, analysis of weight magnitudes, and "optimal brain surgeon".     

Bacterial plasmid partition machinery: a minimalist approach to survival

The accurate segregation or partition of replicated DNA is essential for ensuring stable genome transmission. Partition of bacterial plasmids requires only three elements: a centromere-like DNA site and two proteins, a partition NTPase, and a centromere-binding protein (CBP). Because of this simplicity, partition systems have served as tractable model systems to study the fundamental molecular mechanisms required for DNA segregation at an atomic level. In the last few years, great progress has been made in this endeavor. Surprisingly, these studies have revealed that although the basic partition components are functionally conserved between three types of plasmid partition systems, these systems employ distinct mechanisms of DNA segregation. This review summarizes the molecular insights into plasmid segregation that have been achieved through these recent structural studies.     

Immunosuppression in cardiac graft rejection: a human in vitro model to study the potential use of new immunomodulatory drugs

CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFNgamma and TNFalphaalpha; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNFalpha-induced up-regulation of IFNgammaR. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFNgamma-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants.     

TMJ osteoarthritis: a new approach to diagnosis

Disorders of the temporomandibular joint (TMJ), including TMJ osteoarthritis (TMJ OA), are the topic of intensive clinical research; however, this is not the case in the archaeological literature, with the majority of work on the subject ceasing with the early 1990s. The methods employed in the diagnosis of TMJ OA within the archaeological work appear nonrepresentative of the disease and may have led to erroneous assumptions about the pattern and prevalence of OA. This current work presents a new method for evaluating OA specifically for the TMJ, considering both the biomechanics of the joint and the mechanisms of the disease. Totally, 496 specimens (including a group of modern documented specimens) were analyzed for the presence of TMJ OA using the following criteria: eburnation, osteophytes (marginal and new bone on joint surface), porosity, and alteration to joint contour. The results suggest that eburnation occurs rarely in the TMJ, so should not be used as an exclusive criterion. Rather a combination of at least two of the other criteria should be used, with osteophytes and porosity occurring the most frequently on both the mandibular condyle and articular eminence. Additionally, the prevalence of TMJ OA in the modern assemblage was similar to that observed in current clinical research, suggesting that the method employed here was able to produce a reasonable approximation of what is found in contemporary living populations.     

High-speed running performance: a new approach to assessment and prediction.

We hypothesized that all-out running speeds for efforts lasting from a few seconds to several minutes could be accurately predicted from two measurements: the maximum respective speeds supported by the anaerobic and aerobic powers of the runner. To evaluate our hypothesis, we recruited seven competitive runners of different event specialties and tested them during treadmill and overground running on level surfaces. The maximum speed supported by anaerobic power was determined from the fastest speed that subjects could attain for a burst of eight steps (approximately 3 s or less). The maximum speed supported by aerobic power, or the velocity at maximal oxygen uptake, was determined from a progressive, discontinuous treadmill test to failure. All-out running speeds for trials of 3-240 s were measured during 10-13 constant-speed treadmill runs to failure and 4 track runs at specified distances. Measured values of the maximum speeds supported by anaerobic and aerobic power, in conjunction with an exponential constant, allowed us to predict the speeds of all-out treadmill trials to within an average of 2.5% (R2 = 0.94; n = 84) and track trials to within 3.4% (R2 = 0.86; n = 28). An algorithm using this exponent and only two of the all-out treadmill runs to predict the remaining treadmill trials was nearly as accurate (average = 3.7%; R2 = 0.93; n = 77). We conclude that our technique 1) provides accurate predictions of high-speed running performance in trained runners and 2) offers a performance assessment alternative to existing tests of anaerobic power and capacity.     

Interstitial laser hyperthermia: a new approach to local destruction of tumours.

The use of local hyperthermia to treat cancer of the internal organs has been limited by the difficulty of controlling delivery of heat and limiting the effects to the tumour, but this can be overcome by using laser light transmitted through thin flexible fibres. Laser energy was delivered to tumours through fibres inserted percutaneously through needles directly into the centre of the tumour area. Ultrasound scanning was used to locate the tumour, position the fibres correctly within the tumour, and monitor the development of thermal necrosis in real time during laser exposure and through the subsequent period of healing. Five patients were treated (one with a tumour of the breast, one with a subcutaneous secondary tumour, one with a recurrent pancreatic tumour, and two with secondary tumours in the liver). Tumour necrosis was found on ultrasonography or computed tomography in all, and there were no immediate or delayed complications. In one patient the size of the isolated secondary tumour in the liver had not increased over 10 months, and he subsequently showed no other evidence of residual cancer. To develop this technique careful studies are essential to ensure that in every case the extent of thermal necrosis produced by absorption of the laser light can be matched to the full extent of the tumour being treated and that there is always sufficient adjacent normal tissue to ensure safe healing. These preliminary results suggest that this simple technique can be applied safely and effectively to common tumours in humans; more extensive trials in a range of cancers of solid organs are warranted.     

18F-fluorothiols: a new approach to label peptides chemoselectively as potential tracers for positron emission tomography

[(18)F]Fluorothiols are a new generation of peptide labeling reagents. This article describes the preparation of suitable methanesulfonyl precursors and their use in no-carrier-added radiosyntheses of (18)F-fluorothiols. The preparations of (3-[(18)F]fluoropropylsulfanyl)triphenylmethane, (2-[2-[2-(2-[(18)F]fluoroethoxy)ethoxy]ethoxy]ethylsulfanyl)triphenylmethane, and 4-[(18)F]fluoromethyl-N-[2-triphenylmethanesulfanyl)ethyl]benzamide starting from the corresponding methanesulfonyl precursors were investigated. Following the removal of the triphenylmethane protecting group, the (18)F-fluorothiols were reacted with the N-terminal chloroacetylated model peptide ClCH(2)C(O)-LysGlyPheGlyLys. The corresponding radiochemical yields of (18)F-labeled isolated model peptide, decay-corrected to (18)F fluoride, were 10%, 32%, and 1%, respectively. These results indicate a considerable potential of (18)F-fluorothiols for the chemoselective labeling of peptides as tracers for positron emission tomography (PET).     

Biosocial variances and infant survival: a path analysis approach.

This study used path analysis to assess the chances of survival of babies in a neonatal intensive care unit in Lansing, Michigan, USA. Two paths to neonatal survival were identified and the variables accounted for 20% of the variance in gestational age. The first path showed that prior infant losses were negatively correlated with gestational age while in the second path, gestational age showed negative relationships with pre-pregnancy weight and household job worries.     

Venous excess: a new approach to cardiovascular control and its teaching.

The circulatory control system is driven partly by factors relating to the arterial side and partly by factors relating to the venous side. Students are generally provided with a conceptually clear account of the arterial side, based on sound homeostatic mechanisms of negative feedback from a well-defined error signal, arterial pressure. However, on the venous side, teaching is often based on the notion of venous return, a concept that, as normally presented, is imprecise and intangible, a frequent cause of confusion that may lead to errors of clinical practice. Although one can trace these misconceptions back to some of Guyton's publications, Guyton himself was well aware of the complexities of venous resistance and capacitance but has not always been well served by subsequent misinterpretation. The fundamental problem with venous return that makes it inappropriate for controlling the circulation is that it lacks the essential requirement of being an error signal. We propose instead a new variable, venous excess, which represents the accumulation of any mismatch between the rate of blood entering the great veins and the rate of leaving, the cardiac output. As well as being directly observable without intervention (in a patient's jugular vein), it meets all of the requirements of an error signal: via the Starling mechanism it stimulates cardiac output, regulates venous compliance, and in the longer term is an important determinant of fluid intake and excretion, and these effects act to reduce the original perturbation. Based on this concept, we suggest a simple and secure basis for teaching the control of the circulation that avoids undue reliance on entities that are difficult to specify or measure and emphasizes the role of feedback and the similarities between the arterial and venous mechanisms.     

The L short-scar mammaplasty: a new approach.

An improved L mammaplasty technique was employed in 178 patients aged 13 to 55 years, with reductions of up to 1280 gm per breast, with small, well-positioned, and undistorted scars. I have obtained a satisfactory final shape of the breast with no major complications over a 3-year follow-up period. The markings are based on chest width and on the quantity of skin that will remain. The technique allows the surgeon to remove more skin, and it is indicated for minor, moderate, and large hypertrophies, as well as for ptotic and asymmetrical breasts. The resection comprises skin and mammary tissue from the inferior and middle portions of the breast, preserving the main lactiferous ducts. In case of hypertrophic breasts, the base is removed, preserving the branches of the lateral cutaneous nerves, which derive from the third, fourth, and fifth intercostal nerves.