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Biomedical subjects

S E Martin

Publications and source records attributed to S E Martin.

At least 55 records · Page 3Linked to original sources
PubMed1997

Studies in a large family with late-onset Alzheimer disease (LOAD).

A large 10-generation family with late-onset Alzheimer disease (LOAD) inherited as an autosomal dominant trait was evaluated historically, clinically, and genetically. The family origin was traced to a founder couple of French ancestry with approximately 3,000 descendants. Although the transmission of a genetic predisposition to LOAD is demonstrated through male individuals, a predominance of affected women is observed. Currently, 14 individuals, 12 of whom are women, are classified as affected with Alzheimer disease (AD). Among the affected, the age of onset ranged from 55 to 78 years. Genotyping of the apolipoprotein E (APOE) locus demonstrated that homozygotes for the E4 allele (APOE4) developed signs of AD in their late 60s, whereas affected heterozygotes presented with the disease in their 70s. A significantly higher APOE4 frequency was observed in affected family members than in those unaffected (0.79 vs. 0.25, chi 2 = 9.919, p = 0.0016, df = 1). Survival for more than 15 years after diagnosed onset was observed in a number of those affected and can be attributed to an improved environment, including excellent care and management during the disabling phase of illness. Alternatively, it may be an example of the genetic heterogeneity in AD. Complete documentation of large families such as the one presented will facilitate the discovery of the multiple genetic factors involved in the pathogenesis of AD.

Aged↗
PubMed1997

Microarousals in patients with sleep apnoea/hypopnoea syndrome.

Upper airway obstructions during sleep cause recurrent brief awakenings or microarousals. Standard criteria exist for sleep and respiratory event scoring, however, there are different definitions currently used to score microarousals. We therefore compared three definitions of microarousal (ranging from 1.5-3 s in duration) and one of awakening (>15 s). We examined their occurrence at the termination of apnoeas and hypopnoeas and their correlation with daytime sleepiness in patients with sleep apnoea/hypopnoea syndrome (SAHS). Sixty-three patients (aged 49, SD 10) had overnight polysomnography, multiple sleep latency tests (MSLT) and Epworth Sleepiness Scales (ESS). There were significantly more microarousals by any definition than there were awakenings (P<0.001) and there were more 1.5 s than 3 s microarousals (P<0.001). Significantly more apnoeas and hypopnoeas were terminated by 1.5 s microarousals (83% and 81%) than by 3 s microarousals (75%) (all P<0.001). Apnoea/ hypopnoea index (AHI) correlated significantly with objective daytime sleepiness (rho=-0.30, P<0.01). There were weakly significant relationships between all three microarousal definitions (-0.24<rho<-0.22, 0.03<P<0.04) and objective daytime sleepiness. None of the arousal definitions correlated with Epworth Sleepiness Scales scores. These results suggest that although 1.5 s microarousals are found at the end of more respiratory events, relationships between 3 and 1.5 s definitions, and daytime sleepiness are similar. This indicates that any of the three microarousal definitions can be used for visual assessment of sleep fragmentation.

Arousal↗
PubMed1997

Effect of CPAP therapy on daytime function in patients with mild sleep apnoea/hypopnoea syndrome.

BACKGROUND: Continuous positive airway pressure (CPAP) is an effective treatment in patients with moderate and severe sleep apnoea/hypopnoea syndrome (SAHS), but the minimum illness severity at which patients obtain benefit from CPAP is unclear. A study was therefore undertaken to investigate whether CPAP improves symptoms and daytime function in patients with mild SAHS. METHODS: Sixteen consecutively recruited patients with mild SAHS (5.0-14.9 apnoeas + hypopnoeas per hour slept and two or more symptoms of SAHS) participated in a prospective placebo controlled randomised crossover trial to assess the effects of CPAP on symptoms and daytime function. Patients spent four weeks on placebo and four weeks on CPAP, undergoing assessments of sleepiness, symptoms, cognitive performance, and well being on the last day of each treatment. Data from the placebo and CPAP assessments were compared. RESULTS: The mean (SE) objective effective use of CPAP was 2.8 (0.7) hours per night. Significant improvements in symptom score (-1.7 (0.5), p < 0.01), mental flexibility (-14 (5) seconds, p = 0.02), and depression rating (-1.6 (0.8), p = 0.03) on CPAP were observed. However, no significant differences in subjective or objective sleepiness were found. Ten of the 16 patients preferred CPAP and opted to continue with this treatment, although this proportion was non-significant (p > 0.4). The eight patients with best CPAP use showed an additional CPAP related improvement in quality of life (-4.4 (1.8), p = 0.03). Those who complied better with CPAP therapy also had a higher average microarousal frequency (p < 0.01) and apnoea+hypopnoea index (p = 0.02) than the poorer compliers. CONCLUSIONS: The results of this study provide evidence for improvements in symptoms and daytime function for patients with mild SAHS treated with CPAP.

Activities of Daily Living↗
PubMed1997

The effect of nonvisible sleep fragmentation on daytime function.

Patients with sleep apnea/hypopnea syndrome (SAHS) suffer from impaired daytime function that correlates with hypoxemia and visible electroencephalographic (EEG) arousals. However, not all breathing irregularities during sleep terminate with visible EEG arousal. We hypothesized that sleep disturbance without visible EEG change may impair daytime function. Twelve normal subjects spent two pairs of 2 nights each in the laboratory. The first night of each pair was for acclimatization. On the second night, subjects either slept undisturbed or had sleep fragmented every minute to cause a transient increase in arterial blood pressure or increase in heart rate without visible EEG arousal. We tested daytime function after each study night. We presented 253 +/- 23 tones (mean +/- SD), 79 +/- 7% of which did not cause visible EEG arousals. Fragmentation did not alter total sleep time (undisturbed: 419 +/- 27 min; fragmented: 414 +/- 32 min; p = 0.5) or arousal frequency (undisturbed: 22 +/- 4/h; fragmented: 25 +/- 6/h; p = 0.4). Fragmentation reduced slow-wave sleep (undisturbed: 24 +/- 5%; fragmented: 20 +/- 4%; p < 0.01), mean sleep onset latency on the multiple sleep latency test (MSLT) (undisturbed: 8.0 +/- 3.1; fragmented: 6.2 +/- 2.1 min; p = 0.01) and the maintenance of wakefulness test (MWT) (undisturbed: 29.0 +/- 10.0 min; fragmented 25.7 +/- 9.7 min; p = 0.04). Fragmentation decreased hedonic tone at 7 A.M. (27 +/- 4, 25 +/- 6; p = 0.03). Nonvisible (autonomic) sleep fragmentation makes normal subjects sleepier and impairs their mood.

Adult↗
PubMed1997

The effect of age, sex, obesity and posture on upper airway size.

Most patients with sleep apnoea/hypopnoea syndrome (SAHS) are middle-aged men. As there are conflicting data on the effects of age and gender on upper airway calibre, we tested the hypothesis that increasing age and the male sex predispose to upper airway narrowing in normal subjects. We measured upper airway calibre using acoustic reflection in 60 men and 54 women (median 35, range 16-74 yrs) both seated and supine. All upper airway dimensions, except oropharyngeal junction (OPJ), decreased with increasing age in both men and women (r > -0.24, p < or = 0.05) while supine (r2 > 0.06). Men had greater changes in airway area at OPJ on lying down (mean (SEM) 0.5 (0.1), 0.2 (0.1) cm2; p < 0.02). Men had greater body mass indices (mean (SD) 26 (4), 24 (4) kg.m-2; p = 0.04), and larger neck circumferences (mean (SD) 38 (3), 33 (2) cm; p < 0.0001) than women. For any body mass index, neck circumference was larger in men than women (p < 0.001). This study shows that upper airway size decreases with increasing age in both men and women, and that men have greater upper airway collapsibility on lying down at oropharyngeal junction than women.

Aging↗
PubMed1996

Ambulatory blood pressure on and off continuous positive airway pressure therapy for the sleep apnea/hypopnea syndrome: effects in "non-dippers".

Ambulatory blood pressure (BP) monitoring was performed in 13 patients with the sleep apnea/ hypopnea syndrome (SAHS) during a randomized, placebo controlled crossover trial of the effects of continuous positive airway pressure (CPAP) therapy. BP was monitored at half-hourly intervals for a 24-hour period both on CPAP and on an oral placebo, each given for a minimum of 3 weeks. Objective effective CPAP use averaged 4.3 hours per night. Weight and anti-hypertensive medications remained stable over the study period. Systolic, diastolic and mean arterial BP for 24-hour, daytime and nighttime periods were not significantly different on placebo compared to CPAP. Those patients with no significant overnight fall in BP on placebo ("non-dippers") showed a significant improvement in daytime mean arterial BP on CPAP (98 +/- 4 mm Hg) compared to placebo (102 +/- 4 mm Hg; p = 0.01). These findings, in a well-controlled trial, suggest that BP is not reduced by CPAP in a heterogeneous group of SAHS patients, but it may be selectively improved in those patients most at risk for cardiovascular morbidity and mortality.

Adult↗
PubMed1996

The effect of sleep fragmentation on daytime function.

Patients with the sleep apnea/hypopnea syndrome suffer from impaired daytime function. This has been attributed to both sleep fragmentation and hypoxemia. To help understand which is casual, we studied the effects of sleep fragmentation alone on daytime function. Sixteen normal subjects were studied on two pairs of two nights. The first night of each pair was for acclimatization, and on the second the subject either slept undisturbed or had sleep fragmented with sound pulses every 2 min. Sound volume and duration was titrated to cause a return to theta or alpha rhythm on the EEG for at least 3 s. Study nights were followed by daytime testing of psychometric function and mood and by a multiple sleep latency test (MSLT) and a maintenance of wakefulness test (MWT). Total sleep time did not differ between study nights (400 +/- 20 SD min undisturbed, 396 +/- 24 min fragmented; p = 0.6). Fragmentation decreased sleep latency on both the MSLT (11 +/- 3, 7 +/- 2 min; p = 0.001) and the MWT (34 +/- 8, 24 +/- 10 min; p<0.001). Energetic arousal (22 +/- 4, 19 +/- 4; p = 0.005) and hedonic tone (29 +/- 4, 27 +/- 4; p = 0.05) decreased after fragmentation. Fragmentation impaired daytime function adjudged by the Trailmaking B (p = 0.05) and PASAT 4-s tests (p<0.03). One night of sleep fragmentation makes normal subjects sleepier during the day, impairs their subjective assessment of mood, and decreases mental flexibility and sustained attention.

Arousal↗
PubMed1996

Arousals and the sleep apnea/hypopnea syndrome.

As daytime deficits in sleep apnea/hypopnea syndrome (SAHS) correlate poorly with earlier definitions of arousals, we investigated the relationship between microarousals and sleepiness in 63 patients with SAHS. There was a poor correlation between mean sleep latency and microarousal frequency. To determine whether arousals not detected by current definitions could account for some of the residual variance in normal subjects we used sound to induce "arousals" that were detected by rises in blood pressure but produced no visible EEG change. Such autonomic arousals produced an increase in sleepiness. We conclude that arousals not scored currently on polysomnography may contribute to the sleepiness of patients with SAHS.

Arousal↗
PubMed1995

The genetic defect in two well-studied cases of Bernard-Soulier syndrome: a point mutation in the fifth leucine-rich repeat of platelet glycoprotein Ib alpha.

Bernard-Soulier syndrome (B-Ss) is a rare congenital bleeding disorder caused by abnormal giant platelets, thrombocytopenia, and defective glycoprotein (GP) Ib-V-IX, the adhesion receptor for von Willebrand factor (vWF). This report describes the molecular defect in two related individuals with well-established B-Ss whose platelets exhibit decreased GPIb-IX and normal GPV on their surfaces. The GPIb-V-IX genes of the two patients were analyzed by Southern blotting, hetero-duplex analysis, and polymerase chain reaction (PCR) amplification/sequencing. A point mutation was found in codon 129 of the GPIb alpha gene that results in the substitution of proline for leucine in the first position of the fifth leucine-rich glycoprotein repeat of the mature gene product. The mutation (CTC: leucine, wild-type to CCC: proline, mutant) eliminates a Sac I restriction site, facilitating analysis of the mutation in the propositi (both homozygotes), unaffected family members (8 heterozygotes and 8 wild-type), and 58 normal controls (116 wild-type alleles). The status of the genomes was confirmed by the sequencing of platelet cDNA. The mutation does not affect transcription of the Ib-IX genes, as estimated by PCR and Northern blot analysis, but it does inhibit surface expression of the receptor as assessed by transient transfection of mutant and wild-type GPIb alpha genes into mouse Ib beta-IX L cells. Many of the cells (43%) transfected with the normal gene express surface GPIb alpha, whereas untransfected cells and those transfected with the mutant gene lack surface GPIb alpha entirely. Patient platelets were tested both for vWF binding in the presence of ristocetin and for surface GPIb-IX expression. In these instances, despite their inability to agglutinate with ristocetin and vWF, patient platelets exhibit about 40% of normal vWF binding and 40% of normal Ib-IX surface antigens. The results suggest that the described mutation (GPIb alpha: Leu129 -> Pro) affects the conformation of the GPIb-V-IX receptor, alters its availability on platelet surfaces, and causes the observed Bernard-Soulier phenotype.

Alleles↗
PubMed1995

Interaction of the effects of domperidone and sub-anaesthetic concentrations of isoflurane on the immediate and sustained hypoxic ventilatory response in humans.

Twenty normal male subjects with brisk hypoxic ventilatory responses were recruited and ventilatory responses to sustained isocapnic hypoxia (SaO2 80.4 (SD 1.3)% for 20 min) were studied on separate days under four conditions: hypoxia alone, with or without domperidone, and 0.1 MAC of end-tidal isoflurane, with or without domperidone. Ventilatory variables were subjected to analysis of variance with estimation of the effects of isoflurane and domperidone, and their interaction. Isoflurane reduced the initial increase in ventilation significantly by 3.12 (95% confidence limits 1.69, 4.55) litre min-1 (P < 0.05) and domperidone increased the initial increase in ventilation by 1.78 (0.35, 3.21) litre min-1 (P < 0.05). Neither isoflurane nor domperidone affected the subsequent ventilatory decline. No interaction was found between these agents. These results confirm that 0.1 MAC of isoflurane suppressed the initial hypoxic ventilatory response but not the subsequent ventilatory decline when hypoxia was sustained. Domperidone offset the suppressive effect of isoflurane on the hypoxic ventilatory response but no interaction was detected.

Adult↗
PubMed1995

Does sleep enhance the effect of subanesthetic isoflurane on hypoxic ventilation?

After surgery, patients may receive little audiovisual stimulation and may sleep. Lack of audiovisual stimulation enhances the suppression of the hypoxic ventilatory response (HVR) by 0.1 minimum alveolar anesthetic concentration (MAC) isoflurane. Sleep also reduces the HVR and may thus increase the risk of hypoxia in patients at this time. We therefore measured the ventilatory response in volunteers to a sustained step hypoxic stimulus (mean arterial oxygen saturation [SaO2] 80% [SEM 0.3] for 20 min) in the presence of 0.1 MAC isoflurane, with subjects in the awake and asleep states. The behavioral states were studied in random order in nine male subjects. The combination of isoflurane and sleep significantly reduced (P < 0.05) normoxic ventilation (6.71 [0.39] vs 8.24 [0.29] L/min) and increased end-tidal PCO2 (PETCO2) (43.1 [0.5] vs 40.4 [0.8] mm Hg) compared with the awake state. However, ventilation was similar in the asleep and awake states during early (15.10 [1.35] vs 15.50 [1.61] L/min) and late (10.45 [0.97] vs 11.03 [0.99] L/min) hypoxia in the presence of isoflurane. Thus sleep did not reduce ventilation during hypoxia in the presence of isoflurane sedation. The increase in PETCO2 during sleep may have offset suppression of the HVR.

Adult↗
PubMed1995

The effect of posture on airway caliber with the sleep-apnea/hypopnea syndrome.

Snoring and sleep apnea are more common in the supine than seated position. We therefore studied the effect of posture on upper-airway caliber in normal subjects, snorers, and subjects with the sleep-apnea/hypopnea syndrome (SAHS). We measured upper-airway cross-sectional area by acoustic reflection in 110 SAHS patients (apnea/hypopnea index [AHI] > 15), 70 snorers without SAHS (AHI < 15), and 40 male controls matched for body-mass index (BMI) to the 40 SAHS patients. SAHS patients in the seated position had smaller upper-airway areas at the orophyngeal junction (OPJ) than either the snorers (p < 0.01) or the normal subjects (p < 0.02), but there were no differences between groups in airway cross-sectional areas in the supine or lateral recumbent positions. SAHS patients had significantly smaller decreases in OPJ area from the seated to either the supine (p < 0.001) or lateral recumbent (p < 0.001) positions than did the snorers. SAHS patients also had smaller (p < 0.05) decreases in OPJ area upon lying down than did the BMI-matched normal subjects. These data are compatible with SAHS patients defending their upper airway more upon lying down than do snorers or normal subjects.

Acoustics↗
PubMed1994

Improved outcome for high-risk acute myeloid leukemia patients using autologous bone marrow transplantation and monoclonal antibody-purged bone marrow.

We have conducted a 9-year multicenter trial of autologous bone marrow transplantation (ABMT) for acute myeloid leukemia (AML). Remission BM was purged in vitro using monoclonal antibodies (MoAbs; PM-81, AML-2-23) and complement targeting myeloid differentiation antigens (CD15, CD14). In 1988, the preparative regimen changed from 60 mg/kg/d cyclophosphamide x 2 and fractionated total body irradiation (TBI) total dose, 1,200 cGy (Cy/fTBI), to 4 mg/kg/d busulfan x 4 and 60 mg/kg/d Cy x 2 (Bu/Cy2). Recent analysis (October 1, 1993) shows that the Bu/Cy2 regimen along with the same MoAb purging method yields an improved outcome. Seven first complete-remission (CR) (CR1), 45 second- or third-CR (CR2/3), and 11 first-relapse (R1) patients were treated with chemotherapy and TBI or chemotherapy alone followed by ABMT with MoAb-purged BM. Median age at ABMT for those patients in CR 2/3 and R1 patients was 36 years. Twenty-nine CR 2/3 and R1 patients were conditioned with Cy/fTBI, and 27 CR2/3 and R1 patients were conditioned with Bu/CY. Using the Kaplan-Meier method, the CY/fTBI, CR2/3, and R1 patients have a 3-year disease-free survival (DFS) of 21%. On the other hand, the Bu/Cy2, CR2/3, and R1 patients have a 3-year DFS of 48%. Nineteen CR2/3 and R1 patients relapsed post-ABMT. On analysis by conditioning regimen, those treated with Cy/fTBI have a 3-year relapse rate (RR) of 58%, whereas the patients conditioned with Bu/Cy2 have a 39% 3-year RR. Long-term DFS can be achieved in about 50% of patients with advanced remissions and relapsed AML using Bu/Cy2 with MoAb-purged BM.

Adolescent↗
PubMed1994

Effect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome.

Continuous positive airway pressure (CPAP) is the treatment of choice for the sleep apnoea/hypopnoea syndrome (SAHS); it is usually given with the aim of improving daytime cognitive function, mood, and sleepiness. However, its efficacy has not been validated by controlled trials. We have carried out a randomised, placebo-controlled, crossover study of objective daytime sleepiness, symptoms, cognitive function, and mood in a consecutive series of 32 SAHS patients with a median apnoea plus hypopnoea frequency of 28 (range 7-129) per hour slept. Patients were treated with 4 weeks each of CPAP and an oral placebo, which they were told might improve upper airway muscle function during sleep. Assessments on the last day of each treatment included a multiple sleep latency test and tests of symptom scores, mood profiles, and cognitive performance. The patients had significantly less daytime sleepiness on CPAP than during the placebo period (mean sleep latency 7.2 [SE 0.7] vs 6.1 [0.7] min, p = 0.03). There were also improvements with CPAP in symptom ratings (2.1 [0.2] vs 4.3 [0.3], p < 0.001), mood (p < 0.05 for several measures), and cognitive performance, which showed improved vigilance (obstacles hit in Steer Clear "driving" test 76 [5] vs 81 [6], p < 0.01), mental flexibility (trail-making B time 66 [5] vs 75 [5] s, p < 0.05), and attention (p < 0.05). Objectively monitored CPAP use averaged only 3.4 (0.4) hours per night, but this study provides evidence of improved cognitive performance even at this low level of CPAP compliance.

Affect↗
PubMed1994

Studies on the platelet surface-associated von Willebrand factor.

The contribution of platelets to the prevention and control of bleeding depends not only on the plasma and vessel wall von Willebrand (vW) factor, but also on the vW factor originating from platelets. Although platelet vW factor is mainly stored in the alpha-granules, small amounts of vW factor have been detected on the platelet surface under conditions without direct stimulation. This communication focuses on the small amount of vW factor associated with the surface of platelets. EDTA-washed platelets in a calcium-free medium containing prostaglandin E1 (PGE1) were exposed to anti-vW factor F(ab')2 fragments. The platelet-associated anti-vW factor antibodies were separated from the free fragments by gel chromatography. Normal platelets were compared to platelets from patients with Bernard Soulier syndrome, Glanzmann's thrombasthenia, and Hermansky-Pudlak syndrome. These experiments showed that, in the absence of extracellular calcium, vW factor can be detected on the surface of washed platelets independent of glycoproteins Ib and IIb-IIIa, and despite markedly reduced intracellular calcium content. This particular platelet surface expression of vW factor is probably the result of disturbing the platelet during the in vitro manipulation. von Willebrand factor is an extremely important element in the multiple molecular interactions required to stop and anchor the platelet in areas of high flow rates. Mechanical perturbation of platelets leading to surface expression of the vW factor helps increase its availability for such critical interactions.

Albinism, Oculocutaneous↗
PubMed1994

Compliance with CPAP therapy in patients with the sleep apnoea/hypopnoea syndrome.

BACKGROUND: Continuous positive airway pressure (CPAP) therapy is the treatment of choice for the sleep apnoea/hypopnoea syndrome. Compliance with this relatively obtrusive therapy has not been well studied. METHODS: Usage of CPAP was investigated in 54 patients with sleep apnoea/hypopnoea syndrome (median 36 (range 7-129) apnoeas + hypopnoeas/hour slept) over the first 1-3 months after starting CPAP therapy. In all cases CPAP usage was monitored by hidden time clocks that indicated for how long the machines were switched on--that is, the CPAP run time. In 32 patients the time at which the CPAP mask pressure was at the therapeutic level of CPAP pressure set for that patient--that is, the mask time--was also monitored. In all patients objective daytime sleepiness was assessed by multiple sleep latency before and after CPAP therapy. RESULTS: The mean (SE) nightly CPAP run time was 4.7 (0.4) hours. There was no correlation between run time and severity of the sleep apnoea/hypopnoea syndrome as assessed by apnoea + hypopnoea frequency or multiple sleep latency, and no correlation between CPAP usage and improvement in multiple sleep latency. Thirty two patients in whom mask time was recorded had therapeutic CPAP pressures for 89% (3%) of their CPAP run times. Patients who experienced side effects from CPAP used their CPAP machines significantly less than those who did not. CONCLUSIONS: Patients with sleep apnoea/hypopnoea syndrome used CPAP for less than five hours/night on average with no correlation between severity of sleep apnoea/hypopnoea syndrome and CPAP usage. Patients who complained of side effects used their CPAP therapy less. It is recommended that, as a minimum, CPAP run time should be regularly recorded in all patients receiving CPAP therapy.

Female↗