The influence of vestibular stimulation on metabolism and body composition.

Obesity, diabetes and metabolic disease represent an ongoing and rapidly worsening public health issue in both the developed, and much of the developing world. Although there are many factors that influence fat storage, it has been clearly demonstrated that the homeostatic cornerstone of metabolism lies within the hypothalamus. Moreover, neuronal damage to vital areas of the hypothalamus can drive reregulation or dysregulation of endocrine function, energy expenditure and appetite, thereby promoting a shift in overall metabolic function towards a state of obesity. Therefore, identification of treatments that influence the hypothalamus to improve obesity and associated metabolic diseases has long been a medical goal. Interestingly, evidence from animal studies suggests that activating the vestibular system, specifically the macular gravity receptor, influences the hypothalamus in a way that decreases body fat storage and causes a metabolic shift towards a leaner state. Given that the macular element of the vestibular system has been shown to activate with transdermal electrical stimulation applied to the mastoids, this may be a potential therapeutic approach for obesity, diabetes or related metabolic diseases, whereby repetitive stimulation of the vestibular system influences hypothalamic control of metabolic homeostasis, thereby encouraging decreased fat storage. Here, we present an up-to-date review of the current literature surrounding the vestibular influence of the hypothalamus and associated homeostatic sites in the context of current and novel therapeutic approaches for improved clinical management of obesity and diabetes.

Electrostatic subframing and compressive-sensing video in transmission electron microscopy.

We present kilohertz-scale video capture rates in a transmission electron microscope, using a camera normally limited to hertz-scale acquisition. An electrostatic deflector rasters a discrete array of images over a large camera, decoupling the acquisition time per subframe from the camera readout time. Total-variation regularization allows features in overlapping subframes to be correctly placed in each frame. Moreover, the system can be operated in a compressive-sensing video mode, whereby the deflections are performed in a known pseudorandom sequence. Compressive sensing in effect performs data compression before the readout, such that the video resulting from the reconstruction can have substantially more total pixels than that were read from the camera. This allows, for example, 100 frames of video to be encoded and reconstructed using only 15 captured subframes in a single camera exposure. We demonstrate experimental tests including laser-driven melting/dewetting, sintering, and grain coarsening of nanostructured gold, with reconstructed video rates up to 10 kHz. The results exemplify the power of the technique by showing that it can be used to study the fundamentally different temporal behavior for the three different physical processes. Both sintering and coarsening exhibited self-limiting behavior, whereby the process essentially stopped even while the heating laser continued to strike the material. We attribute this to changes in laser absorption and to processes inherent to thin-film coarsening. In contrast, the dewetting proceeded at a relatively uniform rate after an initial incubation time consistent with the establishment of a steady-state temperature profile.

Towards ETEM serial crystallography: Electron diffraction from liquid jets.

A sufficiently thin column of liquid was produced to permit penetration with a 200 keV electron beam as evidenced by the observation of diffraction rings due to the intermolecular spacing of the liquid samples. For liquid thickness below 800 nm, the diffraction rings became visible above the inelastic background. Studies were carried out in the environmental chamber of a transmission electron microscope using water and isopropanol.

Blackawton bees.

BACKGROUND: Real science has the potential to not only amaze, but also transform the way one thinks of the world and oneself. This is because the process of science is little different from the deeply resonant, natural processes of play. Play enables humans (and other mammals) to discover (and create) relationships and patterns. When one adds rules to play, a game is created. THIS IS SCIENCE: the process of playing with rules that enables one to reveal previously unseen patterns of relationships that extend our collective understanding of nature and human nature. When thought of in this way, science education becomes a more enlightened and intuitive process of asking questions and devising games to address those questions. But, because the outcome of all game-playing is unpredictable, supporting this 'messyness', which is the engine of science, is critical to good science education (and indeed creative education generally). Indeed, we have learned that doing 'real' science in public spaces can stimulate tremendous interest in children and adults in understanding the processes by which we make sense of the world. The present study (on the vision of bumble-bees) goes even further, since it was not only performed outside my laboratory (in a Norman church in the southwest of England), but the 'games' were themselves devised in collaboration with 25 8- to 10-year-old children. They asked the questions, hypothesized the answers, designed the games (in other words, the experiments) to test these hypotheses and analysed the data. They also drew the figures (in coloured pencil) and wrote the paper. Their headteacher (Dave Strudwick) and I devised the educational programme (we call 'i,scientist'), and I trained the bees and transcribed the childrens' words into text (which was done with smaller groups of children at the school's local village pub). So what follows is a novel study (scientifically and conceptually) in 'kids speak' without references to past literature, which is a challenge. Although the historical context of any study is of course important, including references in this instance would be disingenuous for two reasons. First, given the way scientific data are naturally reported, the relevant information is simply inaccessible to the literate ability of 8- to 10-year-old children, and second, the true motivation for any scientific study (at least one of integrity) is one's own curiousity, which for the children was not inspired by the scientific literature, but their own observations of the world. This lack of historical, scientific context does not diminish the resulting data, scientific methodology or merit of the discovery for the scientific and 'non-scientific' audience. On the contrary, it reveals science in its truest (most naive) form, and in this way makes explicit the commonality between science, art and indeed all creative activities. PRINCIPAL FINDING: 'We discovered that bumble-bees can use a combination of colour and spatial relationships in deciding which colour of flower to forage from. We also discovered that science is cool and fun because you get to do stuff that no one has ever done before. (Children from Blackawton)'.

Medical complications of an aquatic innovation.

The sport of swimming has been affected by the innovations of technology with the evolution of the swimsuit. The health benefits of swimming are numerous and are well documented in the scientific literature. As swimming is a low-impact sport, injuries are relatively uncommon. As a direct result of the new swimsuits, team physicians have identified the emergence of a new trend in injury in the aquatic athlete. Extensive blistering and ulceration of the finger tips and distal interphalangeal joints in addition to ecchymoses of the lower limb are now common in the aquatic athlete wearing the new swimsuits. Team physicians working with elite swimmers should be aware of this phenomenon and institute preventive measures.

Localizable auditory warning pulses.

Three important forms of information available to the listener may be identified in any auditory warning: what (semantic), where (location) and when (perceived urgency). Each form is addressed in the present design study of auditory warning pulses. Recordings were made via a dummy head, and were presented dichotically to listeners in a left/right localization task. The first experiment identified a suitable notched noise component for providing location information in the pulse stimulus. The second experiment required participants to simultaneously identify a distinct tonal signature and the location of the sound when they were presented with one of three tonal types, or one of three compound (tone plus noise) stimuli. Response accuracy and response latency for this identification and localization task were significantly better with the compound than with tone alone stimuli. Perceived urgency of compound complex tone plus noise stimuli was investigated in the third experiment. While there may be a trade-off between localization acuity and perceived urgency, the addition of noise components to the auditory warning pulse was shown to enhance the location information available to the listener. It is suggested that some auditory warning designs will benefit from the simultaneous provision of what and where forms of information in the sounds.

Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure.

BACKGROUND: Pancreas transplantation improves quality of life and prevents the progression of secondary complications of diabetes. Whether these benefits translate into a long-term survival advantage is not entirely clear. METHODS: Using the United Network for Organ Sharing database, we analyzed long-term survival in 18,549 patients with type 1 diabetes and renal failure who received a kidney transplant between 1987 and 1996. Patient survival was calculated using the Kaplan-Meier method. Proportional hazards models were used to adjust for effects of differences in recipient and donor variables between simultaneous kidney-pancreas transplants (SKPTs) and kidney-alone transplants. RESULTS: SKPT and living donor kidney recipients had a significant crude survival distribution advantage over cadaver kidney transplant recipients (8-year survival rates: 72% for SKPT recipients, 72% for living donor kidney recipients, and 55% for cadaver kidney recipients). The survival advantage for SKPT recipients over cadaver kidney recipients diminished, but persisted after adjusting for donor and recipient variables and kidney graft function as time-varying covariates. SKPT recipients had a high mortality risk relative to living donor kidney recipients through 18 months posttransplantation (hazards ratio, 2.2; P < 0.001), but had a lower relative risk (hazard ratio, 0.86; P < 0.02) thereafter. In SKPT recipients, maintenance of a functioning pancreas graft was associated with a survival benefit. CONCLUSION: The long-term survival of SKPT recipients is superior to that of cadaver kidney transplant recipients with type 1 diabetes. There is no difference in survival of SKPT recipients and living donor kidney recipients with type 1 diabetes at up to 8 years' follow-up; the former have a greater early mortality risk and the latter have a greater late mortality risk. Results of this study suggest that successful simultaneous kidney-pancreas transplantation is not only life enhancing, but life saving.

Capture of attention in selective frequency listening.

Four signal-detection experiments demonstrated robust stimulus-driven, or exogenous, attentional processes in selective frequency listening. Detection of just-above-threshold signal tones was consistently better when the, signal matched the frequency of an uninformative cue tone, even with relatively long cue-signal delays (Experiment 1) or when as few as 1 in 8 signals were at the cued frequency (Experiment 2). Experiments 3 and 4 compared performance with informative and uninformative cues. The involvement of intentional, or endogenous, processes was found to only slightly increase the size of the cuing effect beyond that evident with solely exogenous processes, although the attention band, a measure of how narrowly attention is focused, was found to be wider when cues were informative. The implications for models of auditory attention are discussed.

Angiotensin in cardiac surgery: efficacy in patients on angiotensin converting enzyme inhibitors.

BACKGROUND: Patients presenting for cardiac surgery are often treated with angiotensin converting enzyme inhibitors (ACEIs), either for heart failure or hypertension. Control of systemic vascular resistance (SVR) during surgery can be difficult in such patients. Angiotensin II has been available as an unlicensed vasoconstrictor, but there is concern about renal damage and its use. AIM: This study compared a standard vasoconstrictor with angiotensin II and examined the effect on renal function after cardiac surgery. METHOD: Twenty consecutive, consenting patients scheduled for cardiac surgery that had been taking ACEIs for at least 6 months, were randomly assigned to receive either phenylephrine or angiotensin II for the control of SVR during and for 24 h after cardiac surgery. A pulmonary artery catheter was used to guide therapy. Creatinine clearance was measured before, 24 and 48 h after surgery. RESULTS: Low SVR and blood pressure requiring intervention was seen in all patients, particularly during cardiopulmonary bypass. One patient in the control group failed to respond to P, but responded normally to angiotensin II. Neither drug caused renal impairment. CONCLUSION: Angiotensin II is a safe alternative to phenylephrine in patients on ACEIs and should be considered in patients who fail to respond to conventional vasoconstrictors.

Induction immunotherapy in heart transplantation with T10B9.1A-31: a phase I study.

Cytolytic induction therapy of heart transplantation with OKT3 (immunoglobulin G2a isotype, anti CD3 idiotype) or T10B9.1A-31 (immunoglobulin MK isotype, anti-T-cell receptor alpha beta idiotype) was done in an open-label trial to determine the safety and efficacy of the latter monoclonal antibody. A total of nine patients undergoing orthotopic heart transplantation received a 10-day course of either T10B9.1A-31 (T10B9) (n = 4) 18 mg on bypass and 6 mg intravenously every 12 hours or OKT3 (n = 5) 10 mg on cardiopulmonary bypass and 5 mg intravenously daily. Endomyocardial biopsy surveillance revealed no rejection during induction therapy with T10B9, and one OKT3 induction failure was successfully treated with T10B9, all without significant side effects. T10B9 effectively prevented the onset of early acute rejection in heart transplantation with minimal side effects. T10B9 reversed rejection in one patient whose OKT3 induction failed. Results are encouraging and warrant further investigation.

HPLC determination of biologically active thiols using pre-column derivatisation with 5,5'-dithio-(bis-2-nitrobenzoic acid).

5,5'-Dithio-(bis-2-nitrobenzoic acid), Ellmans reagent (ESSE), is used as a pre-column derivatisation reagent for the determination of biologically active thiols by HPLC. D-penicillamine, N-acetyl-d-penicillamine, N-acetylcysteine, cysteine, captopril and thiomalic acid all give well resolved derivatives. The calibration graph and reproducibility (%R.S.D. +/- 1.3%) for the analysis of glutathione indicates that the method could be used for quantitative analysis. ESSE is widely used as a reagent in thiol determinations by electronic spectroscopy via the detection of the Ellmans anion (ES-) generated without any prior separation procedures. However, there are considerable reservations over its use for the spectrophotometric determination of thiols because of the possibility of side reactions which generate another Ellmans based species (ESO2-). The assay described determines the thiol as a derivatised mixed disulphide (ESSR) and since speciation between the anion ES- and the oxidation product ESO2- occurs it enables the process of oxidation to be monitored simultaneously.

Treatment of renal allograft rejection with T10B9.1A31 or OKT3: final analysis of a phase II clinical trial.

BACKGROUND: Treatment of acute renal allograft rejection with the monoclonal antibody (mAb) OKT3 has been shown to be superior to treatment with polyclonal antisera. To date, only OKT3 has demonstrated consistent efficacy in reversing rejection crisis. METHODS: From 1989 to 1993, a phase II trial comparing the mAb T10B9.1A31 (T10B9) with OKT3 for treatment of acute cellular rejection in renal allograft recipients was done at the University of Kentucky. We collected data from 178 patients potentially eligible to enter the study; 48 never rejected, 9 refused, 13 could not be biopsied, 16 received methylprednisolone, and 11 received antithymocyte globulin or OKT3. Altogether, 81 patients entered the study, 76 of whom were able to be evaluated. Patients with biopsy-confirmed acute rejection were randomly assigned to T10B9 or OKT3 for at least 10 days. RESULTS: Demographically, there was no difference between the T10B9 or OKT3 cohorts. Actuarial graft survival at 4 years was 87% for patients receiving T10B9, 79% for those receiving OKT3, and 89% for those receiving both mAbs (P=0.55). Patient survival at 4 years was 94% for T10B9, 100% for OKT3, and 89% for both mAbs (P=0.45). Mean creatinines of the cohorts were no different at 1, 6, 12, 24, and 36 months. There was less cytokine nephropathy (P<0.001) observed in patients receiving T10B9. Untoward gastrointestinal, neurological, respiratory, and febrile effects were significantly more frequent in the OKT3 cohort after the first dose (day 0) and with later (day 1-9) administration. Cytokine levels (tumor necrosis factor alpha and interferon gamma) measured 2 hr after the first dose were three to six times higher in patients treated with OKT3 than in those treated with T10B9 (P<0.005). Infectious complications were not significantly different, although serious infections occurred only in patients receiving OKT3. No cases of posttransplant lymphoproliferative disorder were seen in either cohort. Human anti-mouse antibody development was as follows: titer 1:100, 30% T10B9, 42% OKT3; titer 1:1000, 3% T10B9, 3% OKT3. There was no cross-reactivity with OKT3 in patients treated with T10B9, and there was only 9.7% cross-reactivity to T10B9 in patients treated with OKT3. CONCLUSIONS: T10B9 provides treatment for renal allograft acute cellular rejection as effective as that of OKT3 with fewer untoward effects, less cytokine release and nephropathy, fewer serious infections, and without increased development of human anti-mouse antibody. The lack of cross-reactivity offers an alternative therapy should the first mAb fail or re-rejection occur. A phase III trial should be initiated in renal allograft recipients, and phase I and phase II trials should be initiated in other solid-organ transplantations.

T10B9 (MEDI-500) mediated immunosuppression: studies on the mechanism of action.

The murine IgM anti-human CD3/TCR mAb T10B9 is an effective agent for the reversal of acute cellular renal allograft rejection which offers several advantages over conventional OKT3 therapy. These include reduced morbidity and a more rapid decrease in serum creatinine levels. In the studies presented here comparing T10B9 and OKT3, soluble T10B9 is shown to be a nonactivating anti-T cell mAb. Evidence for its lack of activating potential includes in vitro failure to stimulate PBMC proliferation either alone or in the presence of nonmitogenic doses of phorbol ester, failure to induce the expression of early and late activation antigens and failure to induce IFN-gamma, TNF-alpha, IL-6 or IL-2 release. Analysis of acute renal allograft rejection patient plasma cytokine levels 2 h after the first dose support the hypothesis that T10B9 has reduced immunoactivation activity in vivo. Both TNF alpha and IFN gamma patient plasma levels are significantly reduced in T10B9 as compared to OKT3 therapy. However, T10B9 is capable of cellular signaling as demonstrated by its ability to induce apoptosis and IL-2 release in the human T cell line Sup-T13. Thus T10B9 retains the potent immunosuppressive activity of OKT3 with reduced immunoactivation.

The time course of auditory segregation: concurrent vowels that vary in duration.

Human listeners perform well when identifying both members of simultaneous steady-state vowel pairs, even when the vowels start and stop at the same time, are presented monaurally, have approximately equal intensities, and have the same fundamental frequency (f0). The sensation described by listeners is of one dominant, vowel "colored" by the second, less easily identified, or nondominant vowel. Introducing a small separation in f0 between the vowels improves performance and listeners now report that there is a sensation of two voice sources rather than one. It has been suggested that listeners use an f0-guided segregation strategy in identifying two vowels that differ in f0. An experiment is reported in which four listeners attempted to identify both members of a pair of concurrent vowels which varied in duration from a single cycle of the stimulus waveform (one pitch period) up to eight cycles. A dominant vowel was identified with near 100% accuracy even in the single-cycle condition, whereas identification of the nondominant vowel showed a slow improvement up to eight cycles. A difference in f0 between the vowels improved identification of the nondominant vowel, but between three and four cycles of the vowels were necessary for this advantage. It is first concluded that the improvement in performance with stimulus duration is due to an improvement in identification of the nondominant vowel; and, second, a difference in f0 is not required for segregation of the dominant vowel which is available from stimuli which are too brief to provide a useful estimate of f0.

Acute effects of gentamicin on thick ascending limb function in the rat.

It is well established that the aminoglycoside antibiotics can adversely affect proximal tubule function. Predominantly indirect evidence suggests that aminoglycosides may also affect function of more distal nephron segments. The present study utilized whole kidney clearance, in vivo micropuncture and in vitro microperfusion to directly determine whether acute gentamicin treatment affects sodium chloride transport in the thick ascending limb of the loop of Henle. Gentamicin (25 mg/kg) significantly increased urine flow, as well as sodium, potassium and chloride excretion within 15 min of intravenous injection. Glomerular filtration rate and proximal tubule fluid reabsorption were not altered by acute gentamicin treatment. In contrast, both fractional and absolute loop chloride transport was significantly decreased. In the in vitro microperfused medullary thick ascending limb, luminal but not basolateral administration of gentamicin (1 mM) significantly decreased chloride reabsorption when compared to time controls. These data suggest that the increased urine and electrolyte excretion associated with acute gentamicin treatment is, at least in part, a consequence of decreased transport in the thick ascending limb of Henle's loop.

Effects of phase changes in low-numbered harmonics on the internal representation of complex sounds.

A series of experiments investigated the effect of phase changes in low-numbered single harmonics in target sounds that were either synthesized steady-state vowels fo periodic signals having only a single formant. A matching procedure was sued in which subjects selected a sound along a continuum differing in first formant frequency in order to get the best match with the target sound; perceptual effects of the phase manipulations in the target were detected as a change in the matched first formant frequency. Stimuli had to contain at least three harmonics to produce the effect, but id did not require a particular starting phase of the components. A suppression phenomenon is discussed, in which phase changes alter the phase-locking characteristics of auditory fibres tuned to low-numbered harmonics.