Toenail onychomycosis: an important global disease burden.

Onychomycosis is a fungal infection of the nail plate or nail bed. It does not usually cure itself and it can trigger more infectious lesions in other parts of the body. The reported prevalence of onychomycosis is increasing in Western countries, presumably due to lifestyle changes and the ageing of the population. Approximately 10% of the general population, 20% of the population aged>60 years, up to 50% of people aged>70 years and up to one-third of diabetic individuals have onychomycosis. Care should be taken for the accurate diagnosis and timely treatment of toenail onychomycosis to prevent complications. Current treatment options have relatively limited therapeutic success, particularly long-term. Oral medications are associated with high recurrence rates and treatment failure, and are not suitable for many cases due to potential adverse effects. Topical medications are recommended only for mild to moderate cases. The cost of therapies may also be prohibitive in some cases. In the light of these issues, more research is warranted for the investigation and development of more effective and economical options for the treatment and prophylaxis of toenail onychomycosis. In patient populations such as diabetic individuals, where onychomycosis can provoke lower extremity complications, professional podiatry care of toenails and feet should be encouraged.

Phox2a gene, A6 neurons, and noradrenaline are essential for development of normal respiratory rhythm in mice.

Although respiration is vital to the survival of all mammals from the moment of birth, little is known about the genetic factors controlling the prenatal maturation of this physiological process. Here we investigated the role of the Phox2a gene that encodes for a homeodomain protein involved in the generation of noradrenergic A6 neurons in the maturation of the respiratory network. First, comparisons of the respiratory activity of fetuses delivered surgically from heterozygous Phox2a pregnant mice on gestational day 18 showed that the mutants had impaired in vivo ventilation, in vitro respiratory-like activity, and in vitro respiratory responses to central hypoxia and noradrenaline. Second, pharmacological studies on wild-type neonates showed that endogenous noradrenaline released from pontine A6 neurons potentiates rhythmic respiratory activity via alpha1 medullary adrenoceptors. Third, transynaptic tracing experiments in which rabies virus was injected into the diaphragm confirmed that A6 neurons were connected to the neonatal respiratory network. Fourth, blocking the alpha1 adrenoceptors in wild-type dams during late gestation with daily injections of the alpha1 adrenoceptor antagonist prazosin induced in vivo and in vitro neonatal respiratory deficits similar to those observed in Phox2a mutants. These results suggest that noradrenaline, A6 neurons, and the Phox2a gene, which is crucial for the generation of A6 neurons, are essential for development of normal respiratory rhythm in neonatal mice. Metabolic noradrenaline disorders occurring during gestation therefore may induce neonatal respiratory deficits, in agreement with the catecholamine anomalies reported in victims of sudden infant death syndrome.

Altered respiratory activity and respiratory regulations in adult monoamine oxidase A-deficient mice.

The abnormal metabolism of serotonin during the perinatal period alters respiratory network maturation at birth as revealed by comparing the monoamine oxidase A-deficient transgenic (Tg8) with the control (C3H) mice (Bou-Flores et al., 2000). To know whether these alterations occur only transiently or induce persistent respiratory dysfunction during adulthood, we studied the respiratory activity and regulations in adult C3H and Tg8 mice. First, plethysmographic and pneumotachographic analyses of breathing patterns revealed weaker tidal volumes and shorter inspiratory durations in Tg8 than in C3H mice. Second, electrophysiological studies showed that the firing activity of inspiratory medullary neurons and phrenic motoneurons is higher in Tg8 mice and that of the intercostal motoneurons in C3H mice. Third, histological studies indicated abnormally large cell bodies of Tg8 intercostal but not phrenic motoneurons. Finally, respiratory responses to hypoxia and lung inflation are weaker in Tg8 than in C3H mice. dl-p-chlorophenyl-alanine treatments applied to Tg8 mice depress the high serotonin level present during adulthood; the treated mice recover normal respiratory responses to both hypoxia and lung inflation, but their breathing parameters are not significantly affected. Therefore in Tg8 mice the high serotonin level occurring during the perinatal period alters respiratory network maturation and produces a permanent respiratory dysfunction, whereas the high serotonin level present in adults alters the respiratory regulatory processes. In conclusion, the metabolism of serotonin plays a crucial role in the maturation of the respiratory network and in both the respiratory activity and the respiratory regulations.

Changes in human respiratory sensation induced by acute high altitude hypoxia.

Respiratory sensation was studied in European low-landers at an altitude of 4382 m after a helicopter flight in order to investigate the acute and prolonged effects of high altitude hypoxia. At rest the ability to detect four inspiratory resistive loads can be used to create a sensitivity index P(A) without taking the response bias (B) into account, based on the Sensory Decision Theory. In 6 subjects respiratory sensitivity increased significantly under acute and prolonged hypoxia after 3-4 days of high altitude exposure. The respiratory sensitivity increased with the hyperventilation and mouth pressure increase induced by hypoxia. Hypoxia might also have feedback effects on the peripheral and central nervous integration of the respiratory sensation stimuli. One subject suffering from acute mountain sickness showed a severe decrease in his sensitivity index P(A) under hypoxic conditions, while the parameters of his cardiorespiratory function evolved in the same classical way as the other subjects who adapted well to altitude hypoxia. The increase in respiratory sensation may be the first necessary step in altitude acclimatization and might serve as a useful marker of this adaptation.

Changes in respiratory muscle activity in conscious cats during experimental dives at 101 ATA.

The rationale for the present study was to test the hypothesis that increased work of breathing during experimental deep diving may lead to respiratory muscle fatigue. For this purpose, electromyograms (EMGs) of respiratory and skeletal muscles, plus electrocardiogram and electroencephalogram (EEG) derivatives, were continuously recorded in conscious cats. In each muscle group, the ratio of power in a high (H) to that in a low (L) band of EMG frequencies was computed. Direct diaphragmatic stimulation in selected animals produced a mass action potential to obtain the muscle fiber conduction velocity (MFCV). The maximal pressure was 101 ATA (1,000 msw) with a maximal duration of 72 h. Four cats breathed an He-O2 mixture and five others a ternary mixture (10% N2 in He-O2). Inspired O2 partial pressure was 350 Torr. With the He-O2 mixture, all the animals died within 2-54 h during the study at maximal depth. EEG signs of high-pressure nervous syndrome (HPNS) were present in all cats, and low-frequency (11-14 Hz) hyperbaric tremor discontinuously contaminated all EMG tracings. The H/L ratio computed from diaphragmatic and intercostal muscle EMGs increased after 12 h at 101 ATA. With the He-N2-O2 mixture, the cats survived until the end of the sojourn at 101 ATA, during which no hyperbaric tremor was detected from EMG tracings, and EEG signs of HPNS were weak or absent. From 31 ATA, the H/L ratio decreased significantly in respiratory but not in skeletal muscles; this was associated with decreased MFCV in the diaphragm after several hours at maximal depth.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in airway resistance induced by nasal inhalation of cold dry, dry, or moist air in normal individuals.

Nasopulmonary bronchomotor reflexes elicited by mechanical or irritant stimulation of the nose have been described in animals and asthmatic patients. However, few studies were devoted to the consequences of nasal breathing of cold and dry air or of only dry or only moist air on the bronchomotor control in normal individuals. The present study reported changes in interruption resistance (Rint) measured during eupneic breathing of moderately cold (-4 or -10 degrees C) and dry [0.3% relative humidity (RH)] air or of room air at 23 degrees C that is either dry (0.3% RH) or moist (97% RH). Nasal inhalation of cold (-4 degrees C) dry air or of only dry air significantly increased baseline Rint value (17 and 21%, respectively) throughout the 15-min test periods. The response to cold was significantly accentuated when the air temperature was lowered to -10 degrees C (42%). After nasal anesthesia or inhalation of a cholinergic antagonist, cold air did not induce a change in Rint. Nasal inhalation of moist room air had no effect. No Rint changes were measured during oral breathing of the three test agents. It is concluded that the activation of cold receptors or osmoreceptors in the nasal mucosa induces protective bronchoconstrictor responses in normal individuals.

Relationship between Cr and breathing pattern in mechanically ventilated patients.

In mechanically ventilated patients the natural gas-conditioning process of the upper airways is bypassed by the use of an endotracheal tube or a tracheostomy. We hypothesized that under these conditions the breathing pattern may greatly influence the convective respiratory heat loss (Cr). Cr values were computed from minute ventilation (VE) and inspiratory and expiratory gas temperatures, which were measured in six patients under mechanical ventilation for the management of cranial trauma. In each patient the effects of 11-20 different breathing patterns were investigated. Relationships between Cr and VE and between combined tidal volume and respiratory frequency were obtained by simple and multiple linear regression methods, respectively. Comparison of the standard errors of estimate indicated that multiple linear regression gives the best fit. Thus, Cr was highly dependent on the breathing pattern and was not related only to VE. For the same VE value, Cr was higher when VE was achieved with high tidal volume and low respiratory frequency. These data are consistent with previous studies in which thermal exchanges through the upper airways were taxed by hyperventilation of frigid air.

Relationship among EMG and contractile responses of the diaphragm elicited by hypotension.

In a canine model, we investigated the effects of severe hypotension on the indexes of diaphragmatic failure. We measured 1) the transdiaphragmatic pressure obtained in response to 20- and 100-Hz stimulation of phrenic nerves (Pdi20 and Pdi100), 2) the power spectrum of diaphragmatic electromyogram (EMG), 3) the ratio of integrated diaphragmatic EMG to Pdi (Edi/Pdi), and 4) the rate of relaxation of Pdi100 and Pdi20. Arterial blood pressure (Pa) was reduced to 40-50 mmHg by a balloon inflated in the inferior vena cava and was maintained at this level until Pdi100 declined to 75% of the control value (100% shock time, ST). A recovery period of 60 min at normal Pa was allowed. During hypotension, Pdi100 and Pdi20 declined only at 100% ST [95.0 +/- 13.0 (SE) min]; however, only Pdi100 recovered within 15 min. The power spectrum shifted to low frequencies early and progressively during shock period. Edi/Pdi rose significantly at 80 and 100% ST and recovered within 15 min. The relaxation rate of Pdi20 and Pdi100 increased significantly at 100% ST only. We conclude that 1) diaphragmatic contractility is depressed during severe hypotension, 2) changes in the power spectrum occurred first in the shock state, followed by alterations in Edi/Pdi, and subsequently both changes in the frequency-pressure curve and relaxation rate occurred last.

Ascent rate, age, maximal oxygen uptake, adiposity, and circulating venous bubbles after diving.

Decompression sickness in diving is recognized as a multifactorial phenomenon, depending on several factors, such as decompression rate and individual susceptibility. The Doppler ultrasonic detection of circulating venous bubbles after diving is considered a useful index for the safety of decompression because of the relationship between bubbles and decompression sickness risk. The aim of this study was to assess the effects of ascent rate, age, maximal oxygen uptake (VO(2 max)), and percent body fat on the production of bubbles after diving. Fifty male recreational divers performed two dives at 35 m during 25 min and then ascended in one case at 9 m/min and in the other case at 17 m/min. They performed the same decompression stops in the two cases. Twenty-eight divers were Doppler monitored at 10-min intervals, until 60 min after surfacing, and the data were analyzed by Wilcoxon signed-rank test to compare the effect of ascent rate on the kinetics of bubbles. Twenty-two divers were monitored 60 min after surfacing. The effect on bubble production 60 min after surfacing of the four variables was studied in 47 divers. The data were analyzed by multinomial log-linear model. The analysis showed that the 17 m/min ascent produced more elevated grades of bubbles than the 9 m/min ascent (P < 0.05), except at the 40-min interval, and showed relationships between grades of bubbles and ascent rate and age and interaction terms between VO(2 max) and age, as well as VO(2 max) and percent body fat. Younger, slimmer, or aerobically fitter divers produced fewer bubbles compared with older, fatter, or poorly physically fit divers. These findings and the conclusions of previous studies performed on animals and humans led us to support that ascent rate, age, aerobic fitness, and adiposity are factors of susceptibility for bubble formation after diving.

Hypoxemia does not affect the strength of the inspiration-inhibiting Breuer-Hering reflex.

Several studies were focused on the consequences of reduced PaO2 (hypoxemia) on the Breuer-Hering inspiration-inhibiting vagal reflex. However, these data are often contradictory and do not allow us to decide whether hypoxemia interacts with the central integration of pulmonary vagal afferents and/or exerts peripheral influence on pulmonary stretch receptor (PSR) activity. The present study was performed in anesthetized rabbits breathing different gas mixtures containing O2, N2 and CO2. Intravenous injection of bicarbonates and CO2 addition in the inspired mixture maintained pHa and PaCO2 within their physiological ranges. The Breuer-Hering reflex, assessed from the changes in diaphragmatic EMG activity, was elicited either by inflating the lungs at different volumes above the functional residual capacity (PSR activation) or by direct electrical stimulation of vagal afferents (central stimulation). Hypoxemia never significantly modified the strength of the reflex or its threshold. Thus, acute hypoxemia present at high altitude does not seem to modify the key role played by PSR afferents in the ventilatory control.

Influence of respiratory afferents upon the proprioceptive reflex of skeletal muscles in healthy humans.

Relationships between respiratory afferents and the motor drive to skeletal muscles are well documented in animals, but human data are scarce. Tonic vibratory response (TVR) elicited by mechanical tendon vibrations were explored in an arm (extensor digitorum, ED) and a leg (vastus lateralis, VL) muscle, in healthy subjects. Tendon vibrations were delivered during unloaded breathing and after 10 breathing cycles while the subject breathed through an inspiratory or expiratory resistive load in order to activate respiratory afferents. Inspiratory loaded breathing significantly enhanced TVR in ED and VL muscles whereas the effects of expiratory loading depended on the vibrated muscle (increased TVR in ED; decreased TVR in VL). These results suggest that inspiratory muscle afferents activated during inspiratory loading facilitate the gamma motor drive to arm and leg muscles whereas the activation of pulmonary vagal afferents during expiratory loading can exert a facilitating or suppressive influence on the gamma motor drive, depending on the limb muscle group.

Increasing background inspiratory resistance changes somatosensory sensations in healthy man.

The central purpose of the study was to investigate if increasing background inspiratory resistance, a circumstance which activated afferents from the lungs and respiratory muscles, modified somatosensory and/or auditory sensations in healthy individuals. Estimation of mechanical stimulations applied on the middle finger (somatosensory sensation) and unilateral sound-pressure stimulations (auditory sensation) was based on the computation of Stevens' power function psi = k.phi n, where psi is the estimate and phi is either the somatosensory stimuli or sound-pressures. This was studied during eupnoeic unloaded ventilation then during a 10-min period of loaded breathing followed by a 10-min recovery period. Loaded breathing significantly lowered the estimate of somatosensory stimuli (decreased n coefficient). This effect persisted during the two first minutes of recovery period. By contrast, loaded breathing did not modify the perception of auditory stimulus. As somesthetic and respiratory afferents, but not auditory afferents, project on the same area in the sensory cortex we suggest the existence of central interactions which could explain observations of the difficulties to execute accurate tasks in patients suffering from obstructive lung disease independently from the alterations in their arterial blood gases.

Central inhibitory effect of adenosine deaminase on carotid blood flow increase at high pressure.

Carotid blood flow in rats was measured by implanted transit-time ultrasonic flowprobes throughout hyperbaric experiments conducted up to 70 bar (7 MPa) with a helium-oxygen hyperoxic (PO2 = 400 mbar) mixture. Before the hyperbaric experiment, an intracerebroventricular (ICV) injection of phosphate saline-buffered solution (PBS) or adenosine deaminase (ADA, 100 U.ml-1) in PBS was performed. Throughout the hyperbaric experiment carotid blood flow increased with ambiant pressure in PBS-treated rats. Conversely, the increase in carotid blood flow was attenuated by ADA treatment. These results suggest that the increase in carotid blood flow at high ambiant pressure could result from an increase of adenosine concentration in the rat brain.

The sensation of respiration in men experiencing high-altitude chronic hypoxia.

Respiratory sensation was studied in seven European lowlanders during a Himalayan expedition at over 6000 m. At rest, the ability to detect added inspiratory resistive loads can be used to create a sensitivity index P(A) taking response bias (B) into account based on Sensory Decision Theory. The data indicate that respiratory sensitivity may be involved in successful adaptation to hypoxia. Respiratory sensitivity improved during the first stages of exposure to altitude and returned to baseline after 17- and 27-day stays under chronic hypoxic conditions. The improvement in respiratory sensation could be a primary signal in the physiological and psychological adaptation to high altitude and change in sensation may reflect the degree of altitude adaptation.

Effects of compression rate on rats carotid blood flow.

The effects of compression rate on carotid blood flow were investigated in awake rats submitted to hyperbaric experiments conducted up to 70 bar (7 MPa, gauge pressure) with either slow compression (0.1 bar/min), i.e., inducing only mild High Pressure Neurological Syndrome (HPNS), or fast compression (2 bar/min), i.e., in the earlier time course of experiments leading to epileptic seizures. Implanted transit-time ultrasonic flowprobes were used, and data were analyzed by regression methods. Mean carotid blood flow increased with ambient pressure during either low or high compression rate, but the increase was significantly more important with the latter. These results evidenced that carotid blood flow increased with ambient pressure, and moreover that this enhancement depends on compression rate.

Long-term exposure of adults to outdoor air pollution is associated with increased airway obstruction and higher prevalence of bronchial hyperresponsiveness.

The authors studied the association between long-term exposure (i.e., > 10 y) to outdoor air pollution and the severity of obstructive pulmonary disease and prevalence of bronchial hyperreactivity to beta2 agonists in two groups of adult patients who were of similar ages and who had similar smoking habits. The subjects lived in downtown districts or in the outer suburbs of Marseilles, the neighborhood that contained air samplers. The regions were similar with respect to sulfur dioxide levels, but levels of nitric oxides and particulate matter (10 millimeters or less) were higher in the downtown area than the suburbs. The authors assessed airway obstruction, as determined by a decrease in forced expiratory volume in 1 s, mean forced expiratory flow measured between 25% and 75% of vital capacity, and an elevated value of central airway resistance. The authors tested the changes in these variables induced by inhalation of a beta2 agonist. Baseline lung function was altered more significantly in both male and female patients who lived in downtown Marseilles than in those who resided in the suburbs, and the differences persisted regardless of the season during which the study occurred. Prevalence of bronchial hyperreactivity and symptoms of asthma (but not of rhinitis) were higher in the downtown than suburban male subjects. The results of this study suggest that an association exists between actual environmental exposure to outdoor air pollution (i.e., nitrogen oxides and/or particulate matter of 10 millimeters or less) and respiratory effects in sensitive adults represented by patients with chronic obstructive pulmonary disease or asthma.

[Comparison between left and right humeral arterial pressure. Indirect measurement with an automatic apparatus]. / Comparaison des pressions artérielles humérales droites et gauches. Mesure indirecte avec un appareil automatique.

Is humeral blood pressure identical in the right arm and left arm? We attempted to answer this question by simultaneous measurement of pressure on each side by a semi-automatic indirect method. Results were analysed by the linear regressions method. This study showed that it is possible to estimate the pressure on one side on the basis of a measurement made on the opposite side. The accuracy of this estimation is +/- 10 mmHg regarding the blood pressure of a given individual and is +/- 4 mmHg in terms of the mean blood pressure of the population in general. Thus, provided there is no anatomical abnormality of the arterial system, it would seem to make no difference if blood pressure is measured on the left side or right side.

Ret deficiency in mice impairs the development of A5 and A6 neurons and the functional maturation of the respiratory rhythm.

Although a normal respiratory rhythm is vital at birth, little is known about the genetic factors controlling the prenatal maturation of the respiratory network in mammals. In Phox2a mutant mice, which do not express A6 neurons, we previously hypothesized that the release of endogenous norepinephrine by A6 neurons is required for a normal respiratory rhythm to occur at birth. Here we investigated the role of the Ret gene, which encodes a transmembrane tyrosine kinase receptor, in the maturation of norepinephrine and respiratory systems. As Ret-null mutants (Ret-/-) did not survive after birth, our experiments were performed in wild-type (wt) and Ret-/- fetuses exteriorized from pregnant heterozygous mice at gestational day 18. First, in wt fetuses, quantitative in situ hybridization revealed high levels of Ret transcripts in the pontine A5 and A6 areas. Second, in Ret-/- fetuses, high-pressure liquid chromatography showed significantly reduced norepinephrine contents in the pons but not the medulla. Third, tyrosine hydroxylase immunocytochemistry revealed a significantly reduced number of pontine A5 and A6 neurons but not medullary norepinephrine neurons in Ret-/- fetuses. Finally, electrophysiological and pharmacological experiments performed on brainstem 'en bloc' preparations demonstrated impaired resting respiratory activity and abnormal responses to central hypoxia and norepinephrine application in Ret-/- fetuses. To conclude, our results show that Ret gene contributes to the prenatal maturation of A6 and A5 neurons and respiratory system. They support the hypothesis that the normal maturation of the respiratory network requires afferent activity corresponding to the A6 excitatory and A5 inhibitory input balance.

Ventilatory failure in cats during prolonged exposure to very high pressure.

Ten adult, awake cats were exposed to high pressure (7.5, 9, or 10 MPa) of a heliox (He-O2) or trimix (He-N2-O2) gas mixture. Total duration of the experiment, i.e., duration of compression plus sojourn at maximal pressure, varied between 23 and 59 h. Throughout the experiment, minute ventilation (VE), heart rate, and rectal temperature were recorded. The total mass of gas (Mt) breathed by each animal was determined from the product of VE, gas density (p), and time (t). As previously shown, VE was increased in all animals breathing heliox mixtures, whereas this was never observed in trimix experiments. Ventilatory arrest occurred before cardiac failure in 3 animals breathing heliox mixtures, where the highest values of Mt were measured; the others survived. Rectal temperature, t, or p values did not account for the difference between those animals surviving and those who died. Thus, increased ventilation in high density gas mixtures was responsible for increased values of Mt. Present observations suggest that ventilatory failure associated to the highest values of Mt is related to respiratory muscle fatigue.

Pulmonary stretch receptor discharges and vagal regulation of respiration differ between two mouse strains.

1. Experiments were performed on adult pentobarbitone-anaesthetized mice of the OF1 and the C3H/HeJ (C3H) strains, to analyse the regulation of respiration by pulmonary stretch receptors (PSRs). 2. Although the mean respiratory period, inspiratory and expiratory durations, and tidal volume did not differ significantly between the two strains, the inspiratory onset was drastically inhibited in OF1 mice but only slightly inhibited in C3H mice in response to tracheal occlusion performed at the very end of inspiration. 3. Low current electrical stimulation of the vagus nerve induced inspiratory onset inhibition in both strains, suggesting that the weak inspiratory onset inhibition elicited by tracheal occlusion in C3H mice did not originate from a low sensitivity of the respiratory centres to PSRs. 4. During normal respiration, PSR firing rate increased with tidal volume, but reached significantly higher values in OF1 than C3H mice. During tracheal occlusion, PSR firing rate was significantly higher at the end of inspiration and during the first third of the occlusion period in OF1 than C3H mice. 5. The airway pressure resistance was significantly higher in OF1 than C3H mice. After abolishing the tracheo-bronchial muscle tone with atropine in OF1 mice, tracheal occlusions induced weak inspiratory onset inhibitions resembling the C3H mouse responses. 6. The possibility that differences in tracheo-bronchial tone between OF1 and C3H mice may lead to a greater PSR discharge and thus to a powerful inhibition on the OF1 medullary respiratory centres during tracheal occlusion is discussed.