Covariates of vaginal microbiota and pro-inflammatory cytokine levels in women of reproductive age.

This study aimed to assess the correlation between covariates of the vaginal microbiota and local levels of proinflammatory cytokines in women of reproductive age presenting four molecularly defined bacterial community-state types (CSTs). We enrolled 133 non-pregnant women who attended primary care health clinics for routine Pap-testing. Molecular profiling of vaginal microbiota was performed by V3-V4 16S rRNA sequencing. The covariates of vaginal microbiota included were: vaginal pH, total bacterial cell count, diversity (Shannon index), -richness and dominant taxa abundances. Levels of interleukin (IL)-1ß, IL-6, IL-8, and tumour necrosis factor (TNF-α) were measured by enzyme-linked immunosorbent assays in supernatants of cervicovaginal fluids. Nonparametric Kruskal-Wallis test was used to compare microbiota covariates and cytokines among different CSTs. Spearman's tests were performed to assess correlations across the measured parameters. A total of 96 (72.2%) participants had CSTs dominated by Lactobacillus spp. (Lactobacillus crispatus CST I, n=38; Lactobacillus gasseri CST II, n=20; and Lactobacillus iners CST III, n=38). A total of 37 (27.8%) presented the Lactobacillus-depleted CST IV. Total bacterial count was higher in CST II (1.29E+05, 3.40E+04-6.69E+05) compared to other Lactobacillus-dominated CSTs (p=0.0003). The highest values of microbiota diversity (1.85; 0.23-2.68) and richness (27.0; 5.0-37.0) were observed in CST IV (P<0.0001). Lower levels of IL-1ß were observed in CST I (5.4; 0.0-3,256) when compared to CST III (51.7; 0.0-2,616) and to CST IV (56.2; 0.0-3,407) (P=0.008). Levels of IL-6 were higher in CST II (4.13; 0-131.4) than in CST IV (0.0-58.27) (P=0.02). Correlation tests showed an overall distinct profile of CST II when compared to other Lactobacillusdominated CSTs, particularly regarding the correlation between total bacterial load and cytokines (r>0.39). In conclusion, this study provides evidence of a single pro-inflammatory signature of L. gasseri-dominated microbiota in response to bacterial load. Further studies evaluating a broader range of inflammation markers are warranted.

The effectiveness of treating irrigation water using ultraviolet radiation or sulphuric acid fertilizer for reducing generic Escherichia coli on fresh produce-a controlled intervention trial.

AIMS: The aims of this study were to: (i) estimate the effectiveness of ultraviolet radiation (UV) and sulphuric acid-based fertilizer (SA), at reducing levels of generic Escherichia coli in surface irrigation water and on produce and surface soil in open produce fields; and (ii) describe the population dynamics of generic E. coli in produce fields. METHODS AND RESULTS: Spinach and cantaloupe plots were randomly assigned to control, UV or SA treatment groups. Irrigation water was inoculated with Rifampicin-resistant E. coli prior to treatment. More than 75% of UV- and SA-treated tank water samples had counts below the detection limit, compared to a mean count of 3·3 Log10 CFU per ml before treatment. Levels of Rifampicin-resistant E. coli in soil and produce both increased and decreased over 10-15 days after irrigation, depending on the plot and time-period. CONCLUSIONS: UV and SA treatments effectively reduce the levels of E. coli in surface irrigation water. Their effectiveness at reducing contamination on produce was dependent on environmental conditions. Applying wait-times after irrigation and prior to harvest is not a reliable means of mitigating against contaminated produce. SIGNIFICANCE AND IMPACT OF THE STUDY: The results are of timely importance for the agricultural industry as new FSMA guidelines require producers to demonstrate a low microbial load in irrigation water or allow producers to apply a wait-time to mitigate the risk of contaminated produce.

Synthesis and Characterization of Methylene Blue-Containing Silica-Coated Magnetic Nanoparticles for Photodynamic Therapy.

Superparamagnetic iron oxide nanoparticles (SPIONs), with appropriate surface coating, are commonly used for biomedical applications such as photodynamic therapy (PDT). This work describes the preparation and characterization of methylene blue (MB)-containing silica-coated SPIONs. Upon exposure to light, MB reacts with molecular oxygen and generates singlet oxygen (1O2) which is cytotoxic and causes irreversible damage to tumor tissues. In this work, SPIONs were synthesized by co-precipitation and coated with a single/double silica layer. The photoactive molecule MB was entrapped in the silica layer deposited on the surface of SPIONs, leading to the formation of hybrid nanomaterials composed of a magnetic core and silica layer. The nanocomposite exhibited magnetic behavior at room temperature due to the presence of its Fe3O4 core. Structural and morphological characterizations were performed by X-ray diffraction (XRD), Fourier transformed infrared (FTIR), SQUID magnetic measurements, ultraviolet-visible spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and dynamic light scattering. The results showed the presence of a crystalline Fe3O4 magnetic core and amorphous silica phases. Kinetic measurements revealed 1O2 generation by the nanoparticles upon irradiation with visible light (λ = 532 nm or λ = 633 nm). The results highlight the potential uses of SPIONs coated with MB-entrapped silica for PDT, whereby a sustained and localized generation of 1O2 was successfully achieved.

Increased vaginal pH in Ugandan women: what does it indicate?

Abnormal vaginal flora (AVF), indicative of bacterial vaginosis (BV) and/or aerobic vaginitis (AV), amongst other abnormalities, is a risk factor for multiple complications in pregnant as well as non-pregnant women. Screening for such conditions could help prevent these complications. Can self-testing for increased vaginal pH reliably detect BV and other high-risk microflora types, and is this more accurate than performing Gram stain-based Nugent score when screening for high-risk microflora? A total of 344 women presenting at different outpatient clinics in Mulago Hospital and Mbuikwe Outpatient clinics in Kampala, Uganda, were asked to test themselves by introducing a gloved finger into the vagina and smearing it on a microscopy slide, on which a pH strip was attached. Self-assessed categories of normal (pH 3.6-4.4), intermediate (4.5-4.7) or high pH (>4.7) were compared with demographic and with centralised microscopic data, both in air-dried rehydrated wet mounts (Femicare), as well as in Gram-stained specimens (Nugent). AVF was present in 38 %, BV in 25 % and AV in 11 % of patients. High pH and AVF is correlated with human immunodeficiency virus (HIV), infertility, frequent sex, but not vaginal douching. Screening for raised pH detects 90 % of AVF cases, but would require testing over half of the population. As AV and non-infectious conditions are frequent in women with AVF and high pH, Nugent score alone is an insufficient technique to screen women for a high-risk vaginal microflora, especially in infertile and HIV-infected women.

TNFα receptor1 drives hypoxia-promoted invasiveness of human melanoma cells.

AIM: Oxygen deprivation leading to hypoxia represents a common feature of advanced solid tumors, able to control several aspects of tumor progression. Indeed, ability to respond to changes in oxygen partial pressure represents a hallmark of malignant cells. Aim of this study is to disclose new pathway of hypoxia-induced tumor cell invasion. MATERIALS AND METHODS: Hs294T human melanoma cells were grown in a gas mixture containing 0.3% O2 and used to evaluate invasion on Matrigel-coated polycarbonate filters mounted in Boyden's chambers, MMP release and expression of inflammatory receptors and their ligands. RESULTS: We demonstrate that hypoxia promotes the expression of TNFα receptor 1 (TNFαR1) able to drive a higher ability to penetrate Matrigel-coated filters of Hs294T human melanoma cells, an effect does not mediated by hypoxia-inducible factor (HIF)-1α. CONCLUSION: Expression of inflammatory cytokine receptors in hypoxic human melanoma cells might provide a new target for improving strategies against local and distant tumor cell diffusion.

Sialidase activity in aerobic vaginitis is equal to levels during bacterial vaginosis.

OBJECTIVE: To evaluate levels of proinflammatory cytokines and sialidase activity in aerobic vaginitis (AV) in relation to normal vaginal flora and bacterial vaginosis (BV). STUDY DESIGN: In this cross-sectional study, a total of 682 consecutive non-pregnant women attending the gynecology service were assessed and 408 women were included. Vaginal rinsing samples were collected from 223 women with microscopic finding of BV (n=98), aerobic vaginitis (n=25) and normal flora (n=100). Samples were tested for interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, and sialidase activity. RESULTS: Compared to women with normal flora, vaginal levels of IL-1ß were highly increased in both BV and AV (p<0.0001). Significantly higher vaginal IL-6 was detected in AV (p<0.0001) but not in BV, in relation to normal flora. Women with AV also presented increased IL-8 levels (p<0.001), while those with BV presented levels similar to normal flora. Sialidase was increased in BV and AV compared with the normal group (p<0.0001) but no difference in sialidase activity was observed between BV and AV. CONCLUSION: A more intense inflammatory host response occurs for AV than for BV when compared with normal flora. Furthermore, the increased sialidase activity in AV and BV indicates that both abnormal vaginal flora types can be harmful to the maintenance of a healthy vaginal environment.

Handgrip impairment in Charcot-Marie-Tooth disease.

AIM: Charcot-Marie-Tooth disease (CMT) is a genetic neuropathy causing muscle weakening in the feet, legs and hands, with consequent impairment of ambulation and handgrip. For fast clinical evaluation and rehabilitation management of handgrip deficits, a functional classification in 4 stages or levels of clinical severity, based on the loss of handgrip types from the finest to the roughest, has been recently proposed. The aim of this study is to evaluate the prevalence of each level of handgrip impairment in a wide population of patients affected with demyelinating and axonal CMT. METHODS: Two-hundred and forty-eight non-operated hands were examined to evaluate if and how the pinch between the pulp of the thumb and the pulp of the second or third finger was made, starting from the palm-up position with the fingers abducted or, in case of impossibility to do so, if a lateral pinch or only a grasp was possible. Following to this observation, each hand was fitted in 1 of the 4 stages described in the above-mentioned classification and then the frequency of each stage was determined. RESULTS: As a whole, 75.4% hands were at stage 1; 9.7 were at stage 2; 10.9% at stage 3; 4% at stage 4. CONCLUSIONS: The results of this survey reveal that, in the majority of the CMT cases, handgrip is affected mildly so that only simple recommendations to prevent further muscle and joint damage are required; however, in more than 1 out 5 cases, the handrip impairment is quite severe and requires a detailed rehabilitative program with daily exercises, and, in a small number of cases, is so severe that independence in the daily living activities is lost or very reduced.

Standardization the PCR technique for the detection of delta toxin in Staphylococcus spp

Coagulase-negative staphylococci (CNS), components of the normal flora of neonates, have emerged as important opportunistic pathogens of nosocomial infections that occur in neonatal intensive care units. Some authors have reported the ability of some CNS strains, particularly Staphylococcus epidermidis, to produce a toxin similar to S. aureus delta toxin. This toxin is an exoprotein that has a detergent action on the membranes of various cell types resulting in rapid cell lysis. The objectives of the present study were to standardize the Polymerase Chain Reaction (PCR) technique for the detection of the gene responsible for the production of delta toxin (hld gene) in staphylococcal species isolated from catheters and blood cultures obtained from neonates, and to compare the results to those obtained with the phenotypic synergistic hemolysis method. Detection of delta toxin by the phenotypic and genotypic method yielded similar results for the S. aureus isolates. However, in S. epidermidis, a higher positivity was observed for PCR (97.4 por cento) compared to the synergistic hemolysis method (86.8 por cento). Among CNS, S. epidermidis was the most frequent islate and was a delta toxin producer. Staphylococcus simulans and S. warneri tested positive by the phenotypic method, but their positivity was not confirmed by PCR for the hld gene detection. These results indicate that different genes might be responsible for the production of this toxin in different CNS species, requiring highly specific primers for their detection. PCR was found to be rapid and reliable method for the detection of the hld gene in S. aureus and S. epidermidis

Power and peak blood lactate at 5050 m with 10 and 30 s 'all out' cycling.

Anecdotal observations suggest that the reduction in peak lactate accumulation in blood ([La]b peak) after exhausting exercise, in chronic hypoxia vs. normoxia, may be related to the duration of the exercise protocol, being less pronounced after short supramaximal exercise than after incremental exercise (IE) lasting several minutes. To test this hypothesis, six healthy male Caucasians (age 36.8 +/- 7.3, X +/- SD) underwent three exercise protocols on a cycle ergometer, at sea level (SL) and after 21 +/- 10 days at 5050 m altitude (ALT): (1) 10 s, (2) 30 s 'all out' exercise and (3) IE leading to exhaustion in approximately 20-25 min. 'Average' power output (P) was calculated for 10 or 30 s 'all out'; maximal power output (Pmax) was determined for IE. Lactate concentration in arterialized capillary blood ([La]b) was measured at rest and at different times during recovery; the highest [La]b during recovery was taken as [La]b peak. No significant differences in P were observed between SL and ALT, for either 10 or 30 s 'all out' exercise; Pmax during IE was significantly lower at ALT than at SL. [La]b peak after 10 s 'all out' was unaffected by chronic hypoxia (7.0 +/- 0.9 at ALT vs. 6.3 +/- 1.8 mmol x L(-1) at SL). After 30 s 'all out' the [La]b peak decrease, at ALT (10.6 +/- 0.6 mmol x L(-1)) vs. SL (12.9 +/- 1.4 mmol x L(-1)), was only approximately 50% of that observed for IE (6.7 +/- 1.6 mmol x L(-1) vs. 11.3 +/- 2.8 mmol x L(-1)). Muscle power output and blood lactate accumulation during short supramaximal exercise are substantially unaffected by chronic hypoxia.

Pathophysiology of cardiac transplantation and the challenge of exercise.

Heart transplantation is now currently performed in adult (A-HTR) as well as in pediatric cardiac patients (P-HTR). In A-HTR, heart denervation results in a delayed, blunted heart rate (HR) response to exercise onset, mainly sustained by the level of circulating catecholamines. At the offset of exercise HR resumes the pre-exercise level in 5-25 min, depending on the absolute work intensity. Peak HR is approximately 140 beats/min. Maximal aerobic power is 19 O2/kg x min, i.e., approximately 60% than that of healthy age-matched sedentary subjects and exercise tolerance is therefore reduced. A functional impairment at the muscle level may also be present, as suggested by the slow kinetics of the VO2 readjustment (phase II) at the onset of submaximal aerobic exercise. P-HTR generally behave as A-HTR. However, recently, in a few P-HTR a fast HR response to exercise and greater peak HR values (172 +/- 22 beats/min) were demonstrated. Maximal aerobic power of P-HTR was 32 +/- 7 ml O2/kg x min, greater than that of A-HTR, but yet approximately 60% of that of healthy age-matched controls. It may be concluded that occasionally P-HTR may resume an almost normal cardiovascular response to exercise; nevertheless, their exercise tolerance is limited, likely by functional impairment at the muscle level, whose origin is still unknown.

Blood lactate accumulation and muscle deoxygenation during incremental exercise.

Near-infrared spectroscopy (NIRS) could allow insights into controversial issues related to blood lactate concentration ([La](b)) increases at submaximal workloads (). We combined, on five well-trained subjects [mountain climbers; peak O(2) consumption (VO(2peak)), 51.0 +/- 4.2 (SD) ml. kg(-1). min(-1)] performing incremental exercise on a cycle ergometer (30 W added every 4 min up to voluntary exhaustion), measurements of pulmonary gas exchange and earlobe [La](b) with determinations of concentration changes of oxygenated Hb (Delta[O(2)Hb]) and deoxygenated Hb (Delta[HHb]) in the vastus lateralis muscle, by continuous-wave NIRS. A "point of inflection" of [La](b) vs. was arbitrarily identified at the lowest [La](b) value which was >0.5 mM lower than that obtained at the following. Total Hb volume (Delta[O(2)Hb + HHb]) in the muscle region of interest increased as a function of up to 60-65% of VO(2 peak), after which it remained unchanged. The oxygenation index (Delta[O(2)Hb - HHb]) showed an accelerated decrease from 60- 65% of VO(2 peak). In the presence of a constant total Hb volume, the observed Delta[O(2)Hb - HHb] decrease indicates muscle deoxygenation (i.e., mainly capillary-venular Hb desaturation). The onset of muscle deoxygenation was significantly correlated (r(2) = 0.95; P < 0.01) with the point of inflection of [La](b) vs., i.e., with the onset of blood lactate accumulation. Previous studies showed relatively constant femoral venous PO(2) levels at higher than approximately 60% of maximal O(2) consumption. Thus muscle deoxygenation observed in the present study from 60-65% of VO(2 peak) could be attributed to capillary-venular Hb desaturation in the presence of relatively constant capillary-venular PO(2) levels, as a consequence of a rightward shift of the O(2)Hb dissociation curve determined by the onset of lactic acidosis.

Is the heart preadapted to hypoxia? Evidence from fractal dynamics of heartbeat interval fluctuations at high altitude (5,050 m).

The dynamics of heartbeat interval time series over large time scales were studied by a modified random walk analysis introduced recently as Detrended Fluctuation Analysis. In this analysis, the intrinsic fractal long-range power-law correlation properties of beat-to-beat fluctuations generated by the dynamical system (i.e., cardiac rhythm generator), after decomposition from extrinsic uncorrelated sources, can be quantified by the scaling exponent (alpha) which, in healthy subjects, for time scales of approximately 10(4) beats is approximately 1.0. The effects of chronic hypoxia were determined from serial heartbeat interval time series of digitized twenty-four-hour ambulatory ECGs recorded in nine healthy subjects (mean age thirty-four years old) at sea level and during a sojourn at 5,050 m for thirty-four days (EvK2-CNR Pyramid Laboratory, Sagarmatha National Park, Nepal). The group averaged alpha exponent (+/- SD) was 0.99 +/- 0.04 (range 0.93-1.04). Longitudinal assessment of alpha in individual subjects did not reveal any effect of exposure to chronic high altitude hypoxia. The finding of alpha approximately 1 indicating scale-invariant long-range power-law correlations (1/f noise) of heartbeat fluctuations would reflect a genuinely self-similar fractal process that typically generates fluctuations on a wide range of time scales. Lack of a characteristic time scale along with the absence of any effect from exposure to chronic hypoxia on scaling properties suggests that the neuroautonomic cardiac control system is preadapted to hypoxia which helps prevent excessive mode-locking (error tolerance) that would restrict its functional responsiveness (plasticity) to hypoxic or other physiological stimuli.

Stability of heartbeat interval distributions in chronic high altitude hypoxia.

Recent studies of nonlinear dynamics of the long-term variability of heart rate have identified nontrivial long-range correlations and scale-invariant power-law characteristics (l/f noise) that were remarkably consistent between individuals and were unrelated to external or environmental stimuli (Meyer et al., 1998a). The present analysis of complex nonstationary heartbeat patterns is based on the sequential application of the wavelet transform for elimination of local polynomial nonstationary behavior and an analytic signal approach by use of the Hilbert transform (Cumulative Variation Amplitude Analysis). The effects of chronic high altitude hypoxia on the distributions and scaling functions of cardiac intervals over 24 hr epochs and 4 hr day/nighttime subepochs were determined from serial heartbeat interval time series of digitized 24 hr ambulatory ECGs recorded in 9 healthy subjects (mean age 34 yrs) at sea level and during a sojourn at high altitude (5,050 m) for 34 days (Ev-K2-CNR Pyramid Laboratory, Sagarmatha National Park, Nepal). The results suggest that there exists a hidden, potentially universal, common structure in the heterogeneous time series. A common scaling function with a stable Gamma distribution defines the probability density of the amplitudes of the fluctuations in the heartbeat interval time series of individual subjects. The appropriately rescaled distributions of normal subjects at sea level demonstrated stable Gamma scaling consistent with a single scaled plot (data collapse). Longitudinal assessment of the rescaled distributions of the 24 hr recordings of individual subjects showed that the stability of the distributions was unaffected by the subject's exposure to a hypobaric (hypoxic) environment. The rescaled distributions of 4 hr subepochs showed similar scaling behavior with a stable Gamma distribution indicating that the common structure was unequivocally applicable to both day and night phases and, furthermore, did not undergo systematic changes in response to high altitude. In contrast, a single function stable over a wide range of time scales was not observed in patients with congestive heart failure or patients after cardiac transplantation. The functional form of the scaling in normal subjects would seem to be attributable to the underlying nonlinear dynamics of cardiac control. The results suggest that the observed Gamma scaling of the distributions in healthy subjects constitutes an intrinsic dynamical property of normal heart function that would not undergo early readjustment or late acclimatization to extrinsic environmental physiological stress, e.g., chronic hypoxia.

Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients.

Metabolic and cardiovascular adjustments to various submaximal exercises were evaluated in 82 heart transplant recipients (HTR) and in 35 control subjects (C). HTR were tested 21.5 +/- 25.3 (SD) mo (range 1.0-137.1 mo) posttransplantation. Three protocols were used: protocol A consisted of 5 min of rectangular 50-W load repeated twice, 5 min apart [5 min rest, 5 min 50 W (Ex 1), 5 min recovery, 5 min 50 W (Ex 2)]; protocol B consisted of 5 min of rectangular load at 25, 50, or 75 W; protocol C consisted of 15 min of rectangular load at 25 W. Breath-by-breath pulmonary ventilation (VE), O2 uptake (VO2), and CO2 output (VCO2) were determined. During protocol A, beat-by-beat cardiac output (Q) was estimated by impedance cardiography. The half times (t1/2) of the on- and off-kinetics of the variables were calculated. In all protocols, t1/2 values for VO2 on-, VE on-, and VCO2 on-kinetics were higher (i.e., the kinetics were slower) in HTR than in C, independently of workload and of the time post-transplantation. Also, t1/2 Q on- was higher in HTR than in C. In protocol A, no significant difference of t1/2 VO2 on- was observed in HTR between Ex 1 (48 +/- 9 s) and Ex 2 (46 +/- 8 s), whereas t1/2 Q on- was higher during Ex 1 (55 +/- 24 s) than during Ex 2 (47 +/- 15 s). In all protocols and for all variables, the t1/2 off-values were higher in HTR than in C, In protocol C, no differences of steady-state VE, VO2, and VCO2 were observed in both groups between 5, 10, and 15 min of exercise. We conclude that 1) in HTR, a "priming" exercise, while effective in speeding up the adjustment of convective O2 flow to muscle fibers during a second on-transition, did not affect the VO2 on-kinetics, suggesting that the slower VO2 on- in HTR was attributable to peripheral (muscular) factors; 2) the dissociation between Q on- and VO2 on-kinetics in HTR indicates that an inertia of muscle metabolic machinery is the main factor dictating the VO2 on-kinetics; and 3) the VO2 off-kinetics was slower in HTR than in C, indicating a greater alactic O2 deficit in HTR and, therefore, a sluggish muscle VO2 adjustment.

Heart rate variability in the human transplanted heart: nonlinear dynamics and QT vs RR-QT alterations during exercise suggest a return of neurocardiac regulation in long-term recovery.

RATIONALE: Functional reinnervation of the transplanted human heart by the autonomic nervous system has not been demonstrated. A lack of autonomic control of the transplanted allograft is reflected by an increased resting heart rate, a sluggish heart rate response to dynamical exercise and a reduced heart rate variability. Recent evidence suggests that a measure of deterministic chaos in the heartbeat interval series (point correlation dimension, PD2i) is superior to the conventional power spectrum or other stochastic measures in detecting changes in the mechanism underlying heartbeat generation. METHODS: The PD2i is based on the presumption that the variability is determined and patterned, whereas the stochastic measures all assume that the variability is around a stationary mean and is noise. The PD2i reconstructs the degrees of freedom (number of independent variables) in the system that generates the time series examined, and does this irrespective of whether the system is stochastic or deterministic and is stationary in time. RESULTS: PD2i was determined for heartbeat intervals (RR, ECG digitized at 1200 Hz; supine posture) of 23 heart transplant recipients (HTR: 9 adults, 14 children; 0.04-7.7 years after transplantation) and 21 healthy control subjects (CTL; 13 adults, 8 children). The PD2i (+/-SD) averaged 5.4 +/- 0.7 for the CTL adults and 5.4 +/- 0.6 for the CTL children. Mean PD2i was reduced after transplantation to 1.1 +/- 0.1 in 6 HTRs recorded within 1 year after surgery; in one HTR recorded 2 weeks after surgery the mean PD2i was 3.7. Between 1 to 2 years PD2i was found increased in 2 of 3 subjects and between 2 to 8 years it was increased in 13 of 13, but not to control levels. In normal hearts the QT subinterval of each heartbeat cycle is associated with inotropy and the RR-QT remainder with chronotropy (i.e., the dyastolic interval during which RR is primarily regulated). To examine more closely the residual and returning heartbeat dynamics of the HTR subjects, these subinterval series were examined during mild exercise (40 to 90 Watts) and its recovery. In recent HTRs, resting QT and RR-QT were moderately reduced and modulated by exercise and recovery, but with an approximate 100 beat latency. In long-term (7-8 years) HTR subjects there was a rapid and larger response to exercise/recovery, but compared to normal the range was smaller and the complexity of the subinterval trajectories in time was simpler. CONCLUSIONS: Recurrence of low-dimensional deterministic dynamics after transplantation suggests recovery of neurocardiac control attributable to 1) reorganization of the viable intrinsic cardiac nervous system, 2) reinnervation by the extrinsic autonomic nervous system, or 3) both.

Muscle ultrastructure and biochemistry of lowland Tibetans.

Muscle ultrastructure and biochemistry in vastus lateralis muscle biopsies and the response to exercise of 8 lowland Tibetans (T) were compared with those of 8 Nepalese lowlanders (N). Blood hemoglobin was lower in T than in N (119 +/- 3 vs. 131 +/- 2 g/l; P < 0.05). Peak O2 consumption per kilogram of body mass was similar [37.9 +/- 2.2 (T) vs. 40.1 +/- 1.36 ml.min-1.kg body mass-1 (N)]. Maximum exercise blood lactate was the same [11.4 (T) +/- 0.5 vs. 11.3 +/- 0.6 mM (N)]. Muscle fiber type distribution was similar [type I, 58.6 +/- 3.4 (N) vs. 57.0 +/- 3.4% (T); type IIa, 24.1 +/- 3.5 vs. 27.1 +/- 1.6%; type IIb, 17.4 +/- 1.4 vs. 15.9 +/- 2.9%]. T had smaller fiber cross-sectional areas [3,413 +/- 677 (T) vs. 3,895 +/- 447 microns 2 (N); P < 0.05] but had similar number of capillaries per muscle fiber [1.35 +/- 0.23 (T) vs. 1.46 +/- 0.08 (N)] and muscle fiber area supplied per capillary [399 +/- 29 (T) vs. 382 +/- 65 mm2 (N)]. Total mitochondrial volume density was much lower in T (3.99 +/- 0.17%) than in N (5.51 +/- 0.19%) (P < 0.025). Mirroring mitochondrial volume density, citrate synthase and 3-hydroxyacyl-CoA dehydrogenase activities were lower in T than in N (P < 0.05). The activities of L-lactate dehydrogenase and hexokinase were the same in both groups. T had significantly less muscle fiber lipid droplets than did N, which correlated with the low activity of 3-hydroxyacyl-CoA dehydrogenase (r = 0.57, P = 0.02). In conclusion, lowland-born T have a low mitochondrial volume-to-specific peak O2 consumption ratio, which, based on previous measurements on altitude-born Sherpas (B. Kayser, H. Hoppeler, H. Claassen and P. Cerretelli. J. Appl. Physiol. 70: 1938-1942, 1991), appears to be an inborn feature.

Peak blood lactate and blood lactate vs. workload during acclimatization to 5,050 m and in deacclimatization.

Peak blood lactate ([Labl]peak) and blood lactate concentration ([Labl]) vs. workload (W) relationships during acclimatization to altitude and in the deacclimatization were evaluated in 10 Caucasian lowlanders at sea level (SL0); after approximately 1 wk (Alt1wk), 3 wk (Alt3wk), and 5 wk (Alt5wk) at 5,050 m; and weekly during the first 5 wk after return to sea level (SL1wk-SL5wk). Incremental bicycle ergometer exercises (30 W added every 4 min up to exhaustion) were performed. At Alt1wk and at Alt5wk, the experiments were repeated in hypobaric normoxia (Alt1wk-O2 and Alt5wk-O2). [Labl] was determined at rest and during the last approximately 30 s of each W. [Labl]peak was taken as the highest [Labl] during recovery. Acid-base status (pH and concentration of HCO-3 in arterialized capillary blood) was determined at rest. Mean [Labl]peak values were 11.5 (SL0), 8.0 (Alt1wk), 6.4 (Alt3wk), 6.3 (Alt5wk), 8.0 (SL1wk), 9.4 (SL2wk), 10.8 (SL3wk), 11.3 (SL4wk), and 11.6 (SL5wk) mM. At Alt1wk-O2 and Alt5wk-O2, peak W increased, compared with Alt1wk and Alt5wk, whereas no changes were observed for [Labl]peak. [Labl] vs. W was shifted to the left (i.e., higher [Labl] values were found for the same W) at Alt1wk compared with SL0 and partially shifted back to the right (i.e., lower [Labl] values were found for the same W) at Alt3wk and Alt5wk. At Alt1wk-O2 and Alt5wk-O2, [Labl] vs. W values were superimposed on that at SL0. At SL1wk-SL5wk, [Labl] vs. W values were shifted to the right compared with that at SL0. At Alt1wk, a condition of respiratory alkalosis was found, which was only partially compensated for during acclimatization. At SL1wk, the acid-base status was back to normal. We conclude that 1) the reduced [Labl]peak at altitude is still present for 2-3 wk after return from altitude; is not attributable to reduced peak W nor to hypoxia per se, nor to a reduced buffer capacity; alternatively, it could be related to some central determinants of fatigue. 2) The [Labl] vs. W leftward shift at altitude was due to hypoxia per se. 3) The factor(s) responsible for the [Labl] vs. W partial rightward shift during acclimatization could still be effective during the first weeks after return to sea level.

Maximal rate of blood lactate accumulation during exercise at altitude in humans.

The lower peak lactate accumulation in blood ([La(b)]p) at altitude may be associated with a reduced maximal glycolytic flux. Based on certain assumptions, the latter can be indirectly evaluated in vivo, during short supramaximal exercises, by measuring the maximal rate of lactate accumulation in blood (delta [La(b)]max). delta [La(b)]max was determined on six white subjects at sea level (SL1), after approximately 1 wk (Alt1) and 4 wk (Alt2) of a 35-day sojourn at 5,050 m, and 1 wk after return to sea level (SL2). The subjects performed exercises of increasing duration (5, 15, 25, 35, 45 s or until exhaustion) on a bicycle ergometer at loads = 200% of the individual Wmax. The latter was previously determined in each condition as the greatest work rate that could be sustained for 2-4 min during an incremental exercise. Net [La(b)] accumulation (delta [La(b)]) was measured after each exercise bout. delta [La(b)] resulted to be linearly related to exercise duration. The slopes of the individual delta [La(b)] vs. exercise duration lines were taken as delta [La(b)]max. Exhaustion times were approximately 30-45 s in all conditions. [La(b)]p (in mM) during recovery after the exhaustive load was higher at SL1 (10.22 +/- 1.09; means +/- SD) than at Alt1 (5.08 +/- 0.82), Alt2 (8.13 +/- 2.67), and SL2 (8.18 +/- 1.43). delta [La(b)]max was lower at Alt1 (0.09 +/- 0.02) and at Alt2 (0.17 +/- 0.05) than at SL1 (0.25 +/- 0.05) and SL2 (0.23 +/- 0.06). Both [La(b)]p and delta [La(b)]max increased during acclimatization.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of pulmonary CO2 flow in the control of the phase I ventilatory response to exercise in humans.

To gain an insight into the origin of the phase I ventilatory response to exercise (ph I) in humans, pulmonary ventilation (VE) and end-tidal partial pressures of oxygen and carbon dioxide (PETO2 and PETCO2, respectively) were measured breath-by-breath in six male subjects during constant-intensity exercise on the cycle ergometer at 50, 100 and 150 W, with eupnoeic normocapnia (N) or hyperpnoeic hypocapnia (H) established prior to the exercise test. Cardiac output (Qc) was also determined beat-by-beat by impedance cardiography on eight subjects during moderate exercise (50 W), and the CO2 flow to the lungs (Qc.Cv-CO2 where Cv-CO2 is concentration of CO2 in mixed veneous blood) was estimated with a time resolution of one breathing cycle. In N, the initial abrupt increase of VE during ph I (delta VE approximately 18 1.min-1 above rest) was followed by a transient fall. When PETCO2 started to increase (and PETO2 decreased) VE increased again (phase II ventilatory response, ph II). In H, during ph I delta VE was similar to that of N. By contrast, during ph II delta VE kept gradually decreasing and started to increase only when PETCO2 had returned to approximately 40 mmHg (5.3 kPa). Thus, as a result of the prevailing initial conditions (N or H) a temporal shift of the time-course of VE during ph II became apparent. No correlation was found between CO2 flow to the lungs and VE during ph I. These results are interpreted as suggesting that an increased CO2 flow to the lungs does not constitute an important factor for the initial hyperventilatory response to exercise. They are rather compatible with a neural origin of ph I, and would support the "neurohumoral" theory of ventilatory control during exercise.