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Biomedical subjects

C Gómez

Publications and source records attributed to C Gómez.

At least 19 recordsLinked to original sources

Differential effects of unilateral olfactory deprivation on noradrenergic and cholinergic systems in the main olfactory bulb of the rat.

The lack of environmental olfactory stimulation produced by sensory deprivation causes significant changes in the deprived olfactory bulb. Olfactory transmission in the main olfactory bulb (MOB) is strongly modulated by centrifugal systems. The present report examines the effects of unilateral deprivation on the noradrenergic and cholinergic centrifugal systems innervating the MOB. The morphology, distribution, and density of positive axons were studied in the MOBs of control and deprived rats, using dopamine-beta-hydroxylase (DBH)-immunohistochemistry and acetylcholinesterase (AChE) histochemistry in serial sections. Catecholamine content was compared among the different groups of MOBs (control, contralateral, and ipsilateral to the deprivation) using high-performance liquid chromatography analysis. Sensory deprivation revealed that the noradrenergic system developed adaptive plastic changes after olfactory deprivation, including important modifications in its fiber density and distribution, while no differences in cholinergic innervation were observed under the same conditions. The noradrenergic system underwent an important alteration in the glomerular layer, in which some glomeruli showed a dense noradrenergic innervation that was not detected in control animals. The DBH-positive glomeruli with the highest noradrenergic fiber density were compared with AChE-stained sections and it was observed that the strongly noradrenergic-innervated glomeruli were always atypical glomeruli (characterized by their strong degree of cholinergic innervation). In addition to the morphological findings, our biochemical data revealed that olfactory deprivation caused a decrease in the content of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the ipsilateral MOB in comparison to the contralateral and control MOBs, together with an increase in noradrenaline levels in both the ipsilateral and contralateral MOBs. Our results show that regulation of the noradrenergic centrifugal system in the MOB depends on environmental olfactory stimulation and that it is highly reactive to sensory deprivation. By contrast, the cholinergic system is fairly stable and does not exhibit clear changes after the loss of sensory inputs.

3,4-Dihydroxyphenylacetic Acid↗

Microvascular perfusion 1 week and 6 months after myocardial infarction by first-pass perfusion cardiovascular magnetic resonance imaging.

OBJECTIVE: To characterise the evolution of myocardial perfusion during the first 6 months after myocardial infarction by first-pass perfusion cardiovascular magnetic resonance imaging (CMR) and determine its significance. DESIGN: Prospective cohort design. SETTING: Single-centre study in a teaching hospital in Spain. PATIENTS: 40 patients with a first ST-elevation myocardial infarction, single-vessel disease and thrombolysis in myocardial infarction (TIMI) grade 3 flow (stent in 33 patients) underwent rest and low-dose dobutamine CMR 7 (SD 1) and 184 (SD 11) days after infarction. Microvascular perfusion was assessed at rest by visual assessment and quantitative analysis of first-pass perfusion CMR. Of the 640 segments, 290 segments subtended by the infarct-related artery (IRA) were focused on. RESULTS: Both 1 week and 6 months after infarction, segments with normal perfusion showed more wall thickening, contractile reserve and wall thickness, and less transmural necrosis, p <0.05 in all cases. Of 76 hypoperfused segments at the first week, 47 (62%) normalised perfusion at the sixth month. However, 42 segments (14% of the whole group) showed chronic abnormal perfusion; these segments showed worse CMR indices in the late phase (p<0.05 in all cases). CONCLUSIONS: In patients with an open IRA, more than half of the segments with abnormal perfusion at the first week are normally perfused after six months. First-pass perfusion CMR shows that in a small percentage of segments, abnormal perfusion may become a chronic phenomenon-these areas have a more severe deterioration of systolic function, wall thickness, contractile reserve and the transmural extent of necrosis.

Cohort Studies↗

Efficacy and potential for resistance selection of antipseudomonal treatments in a mouse model of lung infection by hypermutable Pseudomonas aeruginosa.

Hypermutable Pseudomonas aeruginosa strains are found with high frequency in the lungs of patients with chronic infections and are associated with high antibiotic resistance rates. The in vivo consequences of hypermutation for treatment in a mouse model of lung infection using strain PAO1 and its hypermutable derivative PAOdeltamutS are investigated. Groups of 30 mice were treated for 3 days with humanized regimens of ciprofloxacin (CIP), tobramycin (TOB), CIP plus TOB, or placebo, and mortality, total lung bacterial load, and 4x- and 16x-MIC mutants were recorded. The rates of mutation and the initial in vivo frequencies of mutants (at the onset of treatment) were also estimated and the in vitro- and in vivo-selected mutants characterized. Since both strains had identical MICs, the same pharmacokinetic/pharmacodynamic (PK/PD) parameters were obtained: area under the 24-h concentration-time curve (fAUC)/MIC = 385 for CIP and maximum concentration of drug in serum (fC(max))/MIC = 19 for TOB. Despite adequate PK/PD parameters, persistence of high bacterial numbers and amplification (50,000-fold) of resistant mutants (MexCD-OprJ hyperexpression) were documented with CIP treatment for PAOdeltamutS, in contrast to complete resistance suppression for PAO1 (P < 0.01), showing that conventional PK/PD parameters may not be applicable to infections by hypermutable strains. On the other hand, the efficacy of TOB monotherapy in terms of mortality reduction and bacterial load was very low regardless of the strain but not due to resistance development, since mutants were not selected for PAO1 and were only modestly amplified for PAOdeltamutS. Finally, the CIP-plus-TOB combination was synergistic, further reducing mortality and bacterial load and completely preventing resistance even for PAOdeltamutS (P < 0.01 compared to monotherapy), showing that it is possible to suppress resistance selection in infections by hypermutable P. aeruginosa using appropriate combined regimens.

Animals↗

Ochratoxin A-producing fungi from grapes intended for liqueur wine production.

The ochratoxigenic mycobiota of grapes intended for liqueur wines from four Spanish vineyards were studied. The specific wine-making technology of these wines requires overripening of the grapes on the vine or extended post-harvest exposure of the grapes in the sun. In every vineyard, samples were taken at three different developmental stages: veraison, harvesting time and after over-ripening. With the maturation of the berries there was a clear increase of Aspergillus spp. In the last sampling time studied, they were isolated from the 90.3% of the plated berries. Black aspergilli (mainly A. niger aggregate and A. carbonarius) were predominant among the different Aspergillus spp. isolated and constituted 98.5% of the total Aspergillus strains isolated. At harvesting time and after over-ripening, the percentage of colonized berries with A. carbonarius exceeded that of Aspergillus niger aggregate. Due to their low frequency of isolation, Penicillium spp. and Aspergillus spp. outside black aspergilli are not an important source of ochratoxin A in grapes for liqueur wine production. On the contrary, 98.5% of the A. carbonarius isolates screened were able to produce ochratoxin A. Although the possible participation of different ochratoxin A-producing species may occur, our results confirm that A. carbonarius is the most important source of ochratoxin A in liqueur wines, increasing its occurrence along the ripening of grapes.

Aspergillus↗

Determinants of incidence of osteoporotic fractures in the female Spanish population older than 50.

It is well known that the adoption of preventive measures for osteoporosis may contribute to minimizing its impact as a result of bone fractures. However, there are well-recognized risk factors involved in the onset of osteoporosis that are not possible to modify. Better knowledge of these non-modifiable factors could aid prevention in subjects at high risk of fractures. The aim of this study was to evaluate the likely association between gynecological, reproductive and family history of hip fracture with the incidence of vertebral and nonvertebral osteoporotic fractures in women older than 50. We studied 255 women aged 50 and over, randomly selected from a Spanish population that had participated in a study of prevalence of vertebral fractures (EVOS study). This cohort was prospectively followed for 8 years by means of four postal questionnaires, in order to find out the incidence of nonvertebral fractures. Concerning the incidence of vertebral fractures, participants were invited to repeat the lumbar spine X-rays 4 years after the initial study. A total of 31 women had incident osteoporotic fractures. The analysis of gynecological variables showed that an increase in the age at menarche was a risk factor for all incident osteoporotic fractures [OR=1.57 (1.04-2.37)]. The presence of amenorrhea at any age during the fertile period was associated with higher incidence of all osteoporotic fractures [OR=6.30 (1.61-24.70)]. Among all the reproductive variables analyzed (pregnancy, number of live births and breast-feeding) only pregnancy was an important protective factor in preventing incident Colles fracture [OR=0.15 (0.03-0.62)]. A family history of hip fracture was associated with a higher incidence of all osteoporotic fractures [OR=3.59 (1.01-12.79)]. In summary, a late age at menarche, the presence of amenorrhea and having close relatives with hip fracture were all risk factors which, independently of bone mineral density (BMD) and age, were associated with higher incidence of all osteoporotic fractures. Pregnancy was an important protective factor for the incidence of Colles fractures.

Aged↗

Performance of a new nebulizer system for simultaneous determination of Sb, Sn (hydride generation), V, and Zn by ICP-OES.

A new nebulizer system is described that extends the analytical capability of the inductively coupled plasma technique to include the simultaneous determination of two elements Sb and Sn (hydride-forming), with two conventional elements, V and Zn. The main advantage of this system is its simultaneous determination of elements that form volatile hydrides and elements that do not, without any instrumental changes. Optimization of reaction and instrumental conditions was performed to characterize the new system. The performance of the new nebulizer system was evaluated by studying the effect of some transition metals (Ni, Cu, Co, and Fe, 1-1000 mg L(-1)) on the Sb, Sn, V, and Zn emission signals (1 mg L(-1)). Interferences from transition metal ions were found to be insignificant for determination of the four elements in presence of L: -cysteine. Long-term and short-term stability was also evaluated. The precision, expressed as RSD for 15 replicate measurements was 0.7% for Sb, 1.7% for Sn, 2.5% for V, and 2.3% for Zn at 200 microg L(-1) of each analyte. The detection limits obtained were 0.52, 1.3, 3.2, and 4.7 microg L(-1) for Sb, Sn, V, and Zn, respectively. Spike and recovery experiments were performed on the NIST 1643c trace metals in water standard reference material and results were in agreement with the certified values.

Journal Article↗

Heterogeneous targeting of centrifugal inputs to the glomerular layer of the main olfactory bulb.

The centrifugal systems innervating the olfactory bulb are important elements in the functional regulation of the olfactory pathway. In this study, the selective innervation of specific glomeruli by serotonergic, noradrenergic and cholinergic centrifugal axons was analyzed. Thus, the morphology, distribution and density of positive axons were studied in the glomerular layer of the main olfactory bulb of the rat, using serotonin-, serotonin transporter- and dopamine-beta-hydroxylase-immunohistochemistry and acetylcholinesterase histochemistry in serial sections. Serotonin-, serotonin transporter-immunostaining and acetylcholinesterase-staining revealed a higher heterogeneity in the glomerular layer of the main olfactory bulb than previously reported. In this sense, four types of glomeruli could be identified according to their serotonergic innervation. The main distinctive feature of these four types of glomeruli was their serotonergic fibre density, although they also differed in their size, morphology and relative position throughout the rostro-caudal main olfactory bulb. In this sense, some specific regions of the glomerular layer were occupied by glomeruli with a particular morphology and a characteristic serotonergic innervation pattern that was consistent from animal to animal. Regarding the cholinergic system, we offer a new subclassification of glomeruli based on the distribution of cholinergic fibres in the glomerular structure. Finally, the serotonergic and cholinergic innervation patterns were compared in the glomerular layer. Sexual differences concerning the density of serotonergic fibres were observed in the atypical glomeruli (characterized by their strong cholinergic innervation). The present report provides new data on the heterogeneity of the centrifugal innervation of the glomerular layer that constitutes the morphological substrate supporting the existence of differential modulatory levels among the entire glomerular population.

Acetylcholine↗

Polymer-filled nanoporous silica aerogels as hosts for highly stable solid-state dye lasers.

New hybrid solid-state dye laser materials based on highly porous silica aerogels have been synthesized. The open porous network of the aerogel was saturated with laser dyes dissolved in appropriate organic monomers, and polymerization took place inside the silica structure. The resulting polymer-filled nanoporous aerogel (PFNPA) was cast in a cylindrical shape, forming monoliths that were used as gain media in solid-state dye lasers. When the PFNPA incorporated pyrromethene dyes, highly photostable laser emission with good lasing efficiency was obtained. Under the demanding conditions of tightly focused transversal pumping with 532 nm, 5 mJ pulses at 10 Hz repetition rate, the commercial dye Pyrromethene 567 exhibited laser action with only a 10% drop in the laser output after 10(6) pump pulses in the same position of the sample.

Journal Article↗

T-kininogen can either induce or inhibit proliferation in Balb/c 3T3 fibroblasts, depending on the route of administration.

T-kininogen (T-KG) is a precursor of T-kinin, the most abundant kinin in rat serum, and also acts as a strong and specific cysteine proteinase inhibitor. Its expression is strongly induced during aging in rats, and expression of T-KG in Balb/c 3T3 fibroblasts results in inhibition of cell proliferation. However, T-KG is a serum protein produced primarily in the liver, and thus, most cells are only exposed to the protein from the outside. To test the effect of T-KG on fibroblasts exposed to exogenous T-KG, we purified the protein from the serum of K-kininogen-deficient Katholiek rats. In contrast to the results obtained by transfection, exposure of Balb/c 3T3 fibroblasts to exogenously added T-KG leads to a dose-dependent increase in [3H]-thymidine incorporation. This response does not require kinin receptors, but it is clearly mediated by activation of the ERK pathway. As a control, we repeated the transfection experiments, using a different promoter. The results are consistent with our published data showing that, under these circumstances, T-KG inhibits cell proliferation. We conclude that T-KG exerts opposite effects on fibroblast proliferation, depending exclusively on the way that it is administered to the cells (transfection versus exogenous addition).

Aging↗

[Impact of conservative oncoplastic techniques in a surgery program for women with breast cancer].

OBJECTIVES: To evaluate the impact of conservative oncoplastic techniques in a surgery program for women with breast cancer. PATIENTS AND METHOD: The study group was composed of women who underwent a conservative oncoplastic technique and the control group consisted of women who underwent conservative (tumorectomy/quadrantectomy) and radical (mastectomy) techniques. Women with tumors smaller than 3 cm, axillary clinical stages N0-N1a-b and multifocal processes (infiltrating and/or in situ) were eligible for inclusion. Women with T3-4 tumors and reduced breast volume, and those in whom postoperative radiotherapy and disease-free margins during intraoperative study were not feasible were excluded. RESULTS: One hundred sixty women underwent surgery during the study period. Fifty oncoplastic techniques (29 to avoid mastectomy and 21 to improve the result of a conservative technique), 57 conservative techniques and 53 mastectomies were performed. The techniques used for breast reconstruction were superior mammoplasty with transversal scar (23 patients), mammoplasty with superior pedicle (10 patients), mammoplasty with inferior pedicle (10 patients), J-shapped mammoplasty (four patients) and oblique mammoplasty (three patients). The mean operating time in the group undergoing oncoplastic techniques (131 minutes) was higher than that in the group undergoing conservative (56 minutes) and radical (93 minutes) techniques. The incidence of postoperative complications was higher with radical techniques (35%), mainly due to axillary seromas after lymphadenectomy, than with conservative (25%) and oncoplastic (24%) techniques. CONCLUSIONS: Oncoplastic techniques are an effective and efficient alternative to conventional surgical techniques in women with breast cancer.

Algorithms↗

Prophylaxis of early bacterial infections after autologous peripheral blood stem cell transplantation (PBSCT): a matched-pair study comparing oral fluoroquinolones and intravenous piperacillin-tazobactam.

The safety and efficacy of early bacterial prophylaxis with piperacillin-tazobactam were prospectively evaluated in 51 autologous peripheral blood stem cell transplantation (PBSCT) recipients. The results were compared with those obtained in 51 control patients receiving oral fluoroquinolones in a retrospective matched-pair control study. Overall, 76% of the study group and 98% of the control group developed at least one febrile episode during neutropenia (P=0.002). Time from neutropenia to the first febrile episode (FFE) was significantly longer in the study group than in the control group (P=0.04). Once a febrile episode appeared, the duration of fever was significantly longer in cases than in controls (median of 5 and 2 days respectively, P<0.001), and led to a more frequent use of empirical amphotericin B (AmB), not statistically significant (P=0.13). However, the total time of antibiotic administration was significantly greater in the control than in the study group (P=0.05). The duration of AmB treatment shows a trend toward a longer duration in the control than in study group (P=0.2). Overall, 86% of the Gram-positive bacteremia and 85% of the Gram-negative bacteria were susceptible to the tested antibiotics. Our study suggests that a subgroup of patients could benefit from prophylaxis with piperacillin-tazobactam without increasing toxicity or bacterial resistance.

Adolescent↗

Impact of different strategies of second-line stem cell harvest on the outcome of autologous transplantation in poor peripheral blood stem cell mobilizers.

The optimal approach to obtain an adequate graft for transplantation in patients with poor peripheral blood stem cell (PBSC) mobilization remains unclear. We retrospectively assessed the impact of different strategies of second-line stem cell harvest on the transplantation outcome of patients who failed PBSC mobilization in our institution. Such patients were distributed into three groups: those who proceeded to steady-state bone marrow (BM) collection (group A, n = 34); those who underwent second PBSC mobilization (group B, n = 41); those in whom no further harvesting was carried out (group C, n = 30). PBSC harvest yielded significantly more CD34+ cells than BM collection. Autologous transplantation was performed in 30, 23 and 11 patients from groups A, B and C, respectively. Engraftment data and transplantation outcome did not differ significantly between groups A and C. By contrast, group B patients had a faster neutrophil recovery, required less platelet transfusions and experienced less transplant-related morbidity, as reflected by lower antibiotics needs and shorter hospital stays. In conclusion, remobilization of PBSC constitutes an effective approach to ensure a rapid hematopoietic engraftment and a safe transplantation procedure for poor mobilizers, whereas unprimed BM harvest does not provide any clinical benefit in this setting.

Adult↗

Prevalence of osteoporosis in men and determinants of changes in bone mass in a non-selected Spanish population.

Osteoporotic studies conducted exclusively in men have been limited by the discrepancies in defining densitometric osteoporosis and, also, because osteoporosis has traditionally been associated only with women. The aims of this study were to describe the prevalence of low bone mineral density (BMD) and osteoporotic fractures as well as the rate of bone loss. The analysis of some risk factors for accelerated bone loss was also evaluated. Men aged 50 years and over, randomly selected from the Oviedo municipal register (n = 308), completed a questionnaire regarding risk factors related to osteoporosis; they underwent two lateral radiographs of the dorsal and lumbar spine and a dual X-ray absorptiometry (DXA) study at the lumbar spine and hip. In the 4th year of the follow-up period, participants were invited to undergo repeats of the same tests that had been carried out in the initial study. The prevalence of densitometric osteoporosis in men older than 50 years, standardized by age, was 8.1% with regard to at least one of the four studied bone areas, with a slight increase with age. The prevalence of osteoporotic fracture, standardized by age, was 24.4%, with a marked increase with age. Osteoporotic prevalent fracture was independently associated only with the rate of change in lumbar spine BMD. From all the osteoporotic risk factors analyzed, only low milk consumption and regular smoking were independently associated with loss of bone mass. In summary, prevalent osteoporotic fracture was independently associated with the rate of change in the lumbar spine BMD but not in the other segments studied. Avoiding smoking and ensuring an adequate milk intake might prevent the loss of bone mass in men.

Absorptiometry, Photon↗

Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life.

OBJECTIVE: To analyze the prevalence and demography of chronic daily headache (CDH) with analgesic overuse. METHODS: A population of 9,984 inhabitants aged 14 or older living in Santoña, Spain, was studied. The authors personally interviewed 4,855 subjects, using a quota sampling approach. Those with headache for > or = 10 days/month and some analgesic use were asked to fill in a diary over the course of 1 month. Then, subjects were classified into CDH with or without analgesic overuse subtypes. Quality of life (Short Form-36 Health Survey [SF-36]) was also assessed in this second interview. RESULTS: Headache for > or = 10 days/month with analgesic consumption was reported by 332 subjects. Seven had secondary headache. Seventy-four (standardized prevalence 1.41%, 95% CI 1.1 to 1.8) fulfilled criteria for CDH with analgesic overuse. Prevalence in women (2.6%, 2.0 to 3.3) was much higher than in men (0.19%, 0.006 to 0.52). Mean age was 56 years (range 19 to 82 years). As recalled by the subjects, the mean age at onset of CDH was 38 years (range 9 to 82 years), whereas the mean age at onset of CDH with frequent analgesic consumption was 45 years (range 19 to 80 years) and that of primary headache was 22 years (range 5 to 60 years). CDH subjects showed a significant decrease in each SF-36 health-related score as compared with healthy control subjects. Transformed migraine was diagnosed in 49 (prevalence 0.9%), chronic tension-type headache in 20 (0.4%), and new daily persistent headache in 5 (0.1%). Thirty-five percent of patients overused simple analgesics, 22% ergotics, 12.5% opioids, and 2.7% triptans; the remaining 27.8% were overusing different combinations. CONCLUSION: CDH with analgesic overuse is a common disorder in the general population, mainly in women in their fifties, in whom 5% meet its diagnostic criteria.

Adolescent↗

[Age influence in otoacoustic emissions for hearing loss screening in infants].

OBJECTIVE: To determine the most favorable age for detection of otoacoustic emissions in newborns and for repeated testing. METHODS: Observational, retrospective, descriptive study in 2,567 newborns. RESULTS: The incidence of any degree of hearing loss was 7 per thousand newborns. It was proportionately higher in the group that did not have otologic risk factors The distribution of otoacoustic emissions by age groups followed a significant linear trend in the first month of life. The time lapse to obtain a positive result on the second otoacoustic emission test was 6 days from the first one. CONCLUSIONS: Otoacoustic emission screening should be performed in all newborns as late as possible after birth (from the first 48 hours after birth), but before hospital discharge for the test to be effective and efficient. A repeat test, if required, must be performed at least six days after failing the first one.

Age Factors↗

Cytarabine release from comatrices of albumin microspheres in a poly(lactide-co-glycolide) film: in vitro and in vivo studies.

Cytarabine (ara-C) was included in albumin microspheres and these microspheres were immersed in a poly(lactide-co-glycolide) (PLGA) film to constitute a comatrix system to develop a prolonged form of release. Cytarabine-loaded albumin microspheres were synthesized by emulsion, and 25 or 50 mg of drug were included in the disperse phase. Thus, microspheres with 46+/-4 microg drug/mg microspheres and 50+/-5 microg drug/mg microspheres were obtained, which means a percentage of incorporation efficiency of 42+/-4% and 25+/-2%, respectively. These cytarabine-loaded microspheres were used to prepare PLGA-comatrices. Kinetic release studies indicated that total cytarabine release only takes place in the presence of protease, probably due to the fact that glutaraldehyde establishes covalent links with the amine side group of the drug and cross-links it with the protein matrix. A slower kinetic release of the drug was obtained from PLGA-comatrices, although only 80% of the included cytarabine was released on day 7. The comatrices were subcutaneously implanted in the back of rats and in both cases the ara-C administered dose was 36 mg of ara-C per kg of body weight. The drug was detected in plasma 10 days. The mean residence time (MRT) of the drug administered by these comatrices was 87-91 times larger when compared to the value obtained when the drug was administered in solution by intraperitoneal injection. The histological studies show that a degradative process of the comatrices takes place. The comatrices do not damage surrounding tissue; a normal regeneration of the implanted zone was observed.

Animals↗

Effects of obesity upon genioglossus structure and function in obstructive sleep apnoea.

Obesity is a common feature of the obstructive sleep apnoea syndrome. It can influence the structure and function of skeletal muscles. However, its effects upon the upper airway muscles have not been explored directly. This study assessed the structure and function of the genioglossus in patients with obstructive sleep apnoea syndrome and in healthy subjects (with and without obesity, defined by a body mass index > 30 kg x m(-2)). Further, to investigate the effects of continuous positive airway pressure (CPAP) treatment, patients with obstructive sleep apnoea syndrome after at least 1 yr under CPAP were also studied. The study found that obese and nonobese patients showed different in vitro geniglossus endurance properties. In obese patients, geniglossus endurance was indistinguishable from normal while, nonobese patients, at diagnosis, showed increased genioglossus fatigability; this was not observed in patients treated with CPAP. By contrast, patients with obstructive sleep apnoea syndrome showed at diagnosis a higher percentage of type II fibres than controls and patients under CPAP treatment independently of obesity. This difference is mainly due to a predominance of subtype IIb fibre. This difference was not observed in the group of patients treated with CPAP. Genioglossus twitch force was normal in all patients. These results suggest that different pathogenic mechanisms may underlie the development of obstructive sleep apnoea syndrome in obese and nonobese patients. This observation may have potential clinical implications.

Adult↗