PubMed Health⌕ Search

Biomedical subjects

Allan I Pack

Publications and source records attributed to Allan I Pack.

At least 19 recordsLinked to original sources
PubMed2026

Cross-species variant-to-function analyses implicate MEIS1 in conferring sleep abnormalities and impaired cerebellar development.

Genome-wide association studies (GWAS) have identified numerous loci for insomnia, yet functional validation of effector genes remains limited because most risk variants lie in noncoding regions, and the true causal gene is not known. Here, we use prior human cell-based variant-to-gene mapping to nominate six insomnia effector genes and test them in zebrafish, a tractable diurnal vertebrate model well suited for sleep phenotyping. Our CRISPR-based behavioral screening identifies the MEIS1 ortholog, meis1b, as a regulator of sleep maintenance, with crispants displaying impaired nighttime-specific sleep maintenance and increased sleep latency. Comparative chromatin analyses reveal conserved regulatory architecture spanning the human insomnia-associated locus and selectively implicate meis1b, whereas the duplicated ohnolog meis1a was dispensable. Developmental profiling further shows that meis1b is expressed in cerebellar granule progenitors, paralleling human MEIS1 expression, and that its disruption impairs cerebellar development. Together, these findings establish zebrafish as an efficient vertebrate platform for functional interrogation of GWAS candidates and support an evolutionarily conserved cerebellar role for MEIS1 in sleep maintenance.

Animals↗
PubMed2025

Polygenic scores for obstructive sleep apnoea reveal pathways contributing to cardiovascular disease.

BACKGROUND: Obstructive sleep apnoea (OSA) is a common chronic condition, with obesity its strongest risk factor. Polygenic scores (PGSs) summarise the genetic liability to phenotype and can provide insights into relationships between phenotypes. Recently, large datasets that include genetic data and OSA status became available, providing an opportunity to utilise PGS approaches to study the genetic relationship between OSA and other phenotypes, while differentiating OSA-specific from obesity-specific genetic factors. METHODS: Using race/ethnic diverse samples from over 1.2 million individuals from the Million Veteran Program, FinnGen, TOPMed, All of Us (AoU), Geisinger's MyCode, MGB Biobank, and the Human Phenotype Project, we developed and assessed PGSs for OSA, both without (BMIunadjOSA-PGS) and with adjustment for the genetic contributions of BMI (BMIadjOSA-PGS). FINDINGS: Adjusted odds ratios (ORs) for OSA per 1 standard deviation of the PGSs ranged from 1.38 to 2.75. The associations of BMIadjOSA- and BMIunadjOSA-PGSs with CVD outcomes in AoU shared both common and distinct patterns. Only BMIunadjOSA-PGS was associated with type 2 diabetes, heart failure, and coronary artery disease, while both BMIadjOSA- and BMIunadjOSA-PGSs were associated with hypertension and stroke. Sex stratified analyses revealed that BMIadjOSA-PGS association with hypertension was driven by females (OR = 1.1, p-value = 0.002, OR = 1.01 p-value = 0.2 in males). OSA PGSs were also associated with body fat measures with some sex-specific associations. INTERPRETATION: Distinct components of OSA genetic risk are related and independent of obesity. Sex-specific associations with body fat distribution measures may explain differing OSA risks and associations with cardiometabolic morbidities between sexes. FUNDING: R01AG080598.

Humans↗
PubMed2006

Novel method for high-throughput phenotyping of sleep in mice.

Assessment of sleep in mice currently requires initial implantation of chronic electrodes for assessment of electroencephalogram (EEG) and electromyogram (EMG) followed by time to recover from surgery. Hence, it is not ideal for high-throughput screening. To address this deficiency, a method of assessment of sleep and wakefulness in mice has been developed based on assessment of activity/inactivity either by digital video analysis or by breaking infrared beams in the mouse cage. It is based on the algorithm that any episode of continuous inactivity of > or =40 s is predicted to be sleep. The method gives excellent agreement in C57BL/6J male mice with simultaneous assessment of sleep by EEG/EMG recording. The average agreement over 8,640 10-s epochs in 24 h is 92% (n = 7 mice) with agreement in individual mice being 88-94%. Average EEG/EMG determined sleep per 2-h interval across the day was 59.4 min. The estimated mean difference (bias) per 2-h interval between inactivity-defined sleep and EEG/EMG-defined sleep was only 1.0 min (95% confidence interval for mean bias -0.06 to +2.6 min). The standard deviation of differences (precision) was 7.5 min per 2-h interval with 95% limits of agreement ranging from -13.7 to +15.7 min. Although bias significantly varied by time of day (P = 0.0007), the magnitude of time-of-day differences was not large (average bias during lights on and lights off was +5.0 and -3.0 min per 2-h interval, respectively). This method has applications in chemical mutagenesis and for studies of molecular changes in brain with sleep/wakefulness.

Algorithms↗
PubMed2006

Consequences of comorbid insomnia symptoms and sleep-related breathing disorder in elderly subjects.

BACKGROUND: The prevalence of sleep-related breathing disorder (SRBD) and insomnia symptoms increases considerably with advancing age, but little is known about their cooccurrence and their effects on daytime functioning when present together. METHODS: Older adults with (cases, n = 99) and without (controls, n = 100) symptoms of insomnia underwent 2 nights of in-laboratory polysomnography, daytime nap, and neurobehavioral testing and completed study questionnaires. Predictors of SRBD were identified (apnea-hypopnea index [indicating number of events per hour], > or =15). Participants were divided into 4 groups--with and without insomnia and with and without SRBD--and the groups were compared on measures of daytime functioning. RESULTS: Cases had a lower rate of SRBD (29.3%) than controls (38.0%). Body mass index (calculated as weight in kilograms divided by height in meters squared) of 30 or higher, neck circumference greater than 15.5 inches, and a history of "loud snoring" or "stops breathing, chokes, or struggles for breath" were independently predictive of SRBD in participants with insomnia symptoms. Having both insomnia symptoms and SRBD was associated with significantly lower daytime functioning and longer psychomotor reaction times compared with having neither condition. CONCLUSION: Because insomnia comorbid with SRBD is associated with the greatest functional impairment, and SRBD is commonly found in the elderly population, health care providers should also consider SRBD in elderly patients with insomnia symptoms.

Aged↗
PubMed2006

Multiple mechanisms limit the duration of wakefulness in Drosophila brain.

The functions of sleep and what controls it remain unanswered biological questions. According to the two-process model, a circadian process and a homeostatic process interact to regulate sleep. While progress has been made in understanding the molecular and cellular functions of the circadian process, the mechanisms of the homeostatic process remain undiscovered. We use the recently established sleep model system organism Drosophila melanogaster to examine dynamic changes in gene expression during sleep and during prolonged wakefulness in the brain. Our experimental design controls for circadian processes by killing animals at three matched time points from the beginning of the consolidated rest period [Zeitgeber time (ZT) 14)] under two conditions, sleep deprived and spontaneously sleeping. Using ANOVA at a false discovery rate of 5%, we have identified 252 genes that were differentially expressed between sleep-deprived and control groups in the Drosophila brain. Using linear trends analysis, we have separated the significant differentially expressed genes into nine temporal expression patterns relative to a common anchor point (ZT 14). The most common expression pattern is a decrease during extended wakefulness but no change during spontaneous sleep (n = 114). Genes in this category were involved in protein production (n = 47), calcium homeostasis, and membrane excitability (n = 5). Multiple mechanisms, therefore, act to limit wakefulness. In addition, by studying the effects of the mechanical stimulus used in our deprivation studies during the period when the animals are predominantly active, we provide evidence for a previously unappreciated role for the Drosophila immune system in the brain response to stress.

Animals↗
PubMed2006

Impaired performance in commercial drivers: role of sleep apnea and short sleep duration.

Sleepiness plays an important role in major crashes of commercial vehicles. Because determinants are likely to include inadequate sleep and sleep apnea, we evaluated the role of short sleep durations over 1 wk at home and sleep apnea in subjective sleepiness (Epworth Sleepiness Scale), objective sleepiness (reduced sleep latency as determined by the Multiple Sleep Latency Test), and neurobehavioral functioning (lapses in performance, tracking error in Divided Attention Driving Task) in commercial drivers. Studies were conducted in 247 of 551 drivers at higher risk for apnea and in 159 of 778 drivers at lower risk. A multivariate linear association between the sets of outcomes and risk factors was confirmed (p < 0.0001). Increases in subjective sleepiness were associated with shorter sleep durations but not with increases in severity of apnea. Increases in objective sleepiness and performance lapses, as well as poorer lane tracking, were associated with shorter sleep durations. Associations with sleep apnea severity were not as robust and not strictly monotonic. A significant linear association with sleep apnea was demonstrated only for reduced sleep latency. The effects of severe apnea (apnea-hypopnea index, at least 30 episodes/h), which occurred in 4.7%, and of sleep duration less than 5 h/night, which occurred in 13.5%, were similar in terms of their impact on objective sleepiness. Thus, addressing impairment in commercial drivers requires addressing both insufficient sleep and sleep apnea, the former being more common.

Automobile Driving↗
PubMed2006

A novel gain-of-function mutant of the cyclic GMP-dependent protein kinase egl-4 affects multiple physiological processes in Caenorhabditis elegans.

cGMP-dependent protein kinases are key intracellular transducers of cell signaling. We identified a novel dominant mutation in the C. elegans egl-4 cGMP-dependent protein kinase (PKG) and show that this mutation causes increased normal gene activity although it is associated with a reduced EGL-4 protein level. Prior phenotypic analyses of this gain-of-function mutant demonstrated a reduced longevity and a reduced feeding behavior when the animals were left unperturbed. We characterize several additional phenotypes caused by increased gene activity of egl-4. These phenotypes include a small body size, reduced locomotion in the presence of food, a pale intestine, increased intestinal fat storage, and a decreased propensity to form dauer larvae. The multiple phenotypes of egl-4 dominant mutants are consistent with an instructive signaling role of PKG to control many aspects of animal physiology. This is among the first reported gain-of-function mutations in this enzyme of central physiological importance. In a genetic screen we have identified extragenic suppressors of this gain-of-function mutant. Thus, this mutant promises to be a useful tool for identifying downstream targets of PKG.

Alleles↗
PubMed2006

Risk factors for excessive sleepiness in older adults.

OBJECTIVE: To determine risk factors for excessive daytime sleepiness in older adults. METHODS: This is a cross-sectional study assessing multiple risk factors for excessive daytime sleepiness in older subjects (mean age, 78 years; range 65-98 years) with (n=149) and without (n=144) complaints of frequent excessive daytime sleepiness. Assessment of risk factors included full in-laboratory sleep studies. RESULTS: Excessive sleepiness among the elderly is multifactorial. Multivariable modeling identified the following as simultaneously significant risk factors for excessive sleepiness: severe sleep-disordered breathing (apnea-hypopnea index, >30 episodes/hr), self-report of poor sleep quality, increased percentage of time in rapid eye movement sleep, pain at night at least three times per week, wheezing or whistling from chest at night, and medications with sleepiness as a side effect. Male sex also was associated with increased risk, whereas alcohol use (more than seven beverages per week) reduced the risk for sleepiness. Multiple risk factors were more commonly present in those with complaints of sleepiness. The presence of periodic limb movements, which are common in older adults, was not associated with sleepiness. INTERPRETATION: There is a distinct differential diagnosis of excessive daytime sleepiness in older adults. Many of the risk factors that we identified are treatable.

Aged↗
PubMed2006

Age-related changes in adenosine metabolic enzymes in sleep/wake regulatory areas of the brain.

The impact of age on the enzymatic activities of adenosine metabolic enzymes, i.e., adenosine deaminase, adenosine kinase, cytosolic- and ecto-5'-nucleotidase have been assessed in the brain sleep/wake regulatory areas of young, intermediate and old rats (2, 12 and 24 months, respectively). There were significant spatial differences in the distribution of enzymes of adenosine metabolism in the brain. Age did not impact on the enzymatic activity of adenosine deaminase. Adenosine kinase activity increased significantly in the cerebral cortex of old animals. However, there were no differences in the activity of adenosine kinase between young and intermediate aged rats. The largest age-related changes were in the activity of cytosolic- and ecto-5'-nucleotidase and there was a significant age-related increase in the activity of these enzymes in the sleep/wake regulatory areas. In addition, the activity of cytosolic- and ecto-5'-nucleotidase increased in the cerebral cortex of old and intermediate age rats when compared to young animals. An increase in the enzymatic activities in the cerebral cortex of adenosine kinase and 5'-nucleotideases was accompanied by an increase in the level of their mRNA. An increase in the activity of 5'-nucleotideases with age likely leads to an increase in adenosine levels in the brain.

5'-Nucleotidase↗
PubMed2006

Genetic basis for sleep regulation and sleep disorders.

Sleep disorders arise by an interaction between the environment and the genetic makeup of the individual but the relative contribution of nature and nurture varies with diseases. At one extreme are the disorders with simple Mendelian patterns of inheritance such as familial advanced sleep phase syndrome, and at the other extreme are diseases such as insomnia, which can be associated with a multitude of medical and psychiatric conditions. In this article, we review data on the relative contribution of genetic and environmental factors in the pathogenesis of various sleep disorders. The understanding of many of these disorders has been advanced by the study of sleep and circadian rhythms in model laboratory organisms. We summarize this model system research and how it relates to human sleep disorders. The current challenge in this field is the identification of susceptibility genetic loci for complex diseases such as obstructive sleep apnea. We anticipate such identification will increase our ability to assess risk for disease before symptom onset and by doing so will shift the focus from treatment to prevention of disease.

Circadian Rhythm↗
PubMed2006

Sleepiness and relationships in obstructive sleep apnea.

This is a qualitative analysis of data from a multisite study of 156 participants with Obstructive Sleep Apnea (OSA). Participants completed a battery of tests, including the Functional Outcomes of Sleep Questionnaire (FOSQ) that contains an item assessing the impact of OSA on relationships. Approximately one third of participants wrote comments; they were predominately male, mean age 44.7, with severe OSA. Interpersonal themes expressed included work and marital problems and social life restriction. Intrapersonal themes included embarrassment and poor mood. This report adds specific details to previous reports of impaired relationships in OSA, and stresses the importance of assessing this critical area.

Conflict, Psychological↗
PubMed2005

Advances in sleep-disordered breathing.

Since the original clarification of the obstructive nature of obstructive sleep apnea (OSA) in 1965, much has been learned about the disorder. It is a condition with a high prevalence with obesity as a major risk factor. It aggregates in families, a relationship that is not simply explained by obesity. Premenopausal women are relatively protected from the disorder because OSA is uncommon in this group. Its prevalence in women rises after menopause. Although OSA is a risk factor for excessive sleepiness, there is developing evidence that it is also a risk factor for hypertension, acute cardiovascular events, and insulin resistance. The first line of therapy is nasal continuous positive airway pressure. Data as to the efficacy of continuous positive airway pressure in severe OSA have come from randomized, placebo-controlled clinical trials with the endpoints being sleepiness, quality of life, and 24-h ambulatory blood pressure. Data are currently less convincing for treatment outcomes in mild to moderate OSA, and new clinical trials to assess outcomes in this group are underway. Thus, even though this field only began toward the end of the first century of the American Thoracic Society, substantial progress has been made, and OSA has increasingly emerged as a major public health concern.

Cardiovascular Diseases↗
PubMed2005

Family aggregation of upper airway soft tissue structures in normal subjects and patients with sleep apnea.

RATIONALE: Sleep apnea is believed to be a genetic disorder. Thus, we hypothesized that anatomic risk factors for sleep apnea would demonstrate family aggregation. OBJECTIVES: We used volumetric magnetic resonance imaging in a sib pair "quad" design to study the family aggregation of the size of upper airway soft tissue structures that are associated with increased risk for obstructive sleep apnea. METHODS: We examined 55 sleep apnea probands (apnea-hypopnea index [AHI]: 43.2 +/- 26.3 events/h), 55 proband siblings (AHI: 11.8 +/- 16.6 events/h), 55 control subjects (AHI: 2.1 +/- 1.7 events/h), and 55 control siblings (AHI: 4.2 +/- 4.0 events/h). The study design used exact matching on ethnicity and sex, frequency matching on age, and statistical control for visceral neck fat and craniofacial dimensions. MEASUREMENTS AND MAIN RESULTS: The data support our a priori hypothesis that the volume of the important upper airway soft tissue structures is heritable. The volume of the lateral pharyngeal walls (h(2) = 36.8%; p = 0.001), tongue (h(2) = 36.5%; p = 0.0001), and total soft tissue (h(2) = 37.5%; p = 0.0001) demonstrated significant levels of heritability after adjusting for sex, ethnicity, age, visceral neck fat, and craniofacial dimensions. In addition, our data indicate that heritability of the upper airway soft tissue structures is found in normal subjects and patients with apnea. Thus, it is not simply a consequence of the prevalence of apnea. CONCLUSIONS: This is the first time family aggregation of size of the upper airway soft tissue structures has been demonstrated.

Adult↗
PubMed2005

Changes in upper airway size during tidal breathing in children with obstructive sleep apnea syndrome.

UNLABELLED: We performed respiratory-gated magnetic resonance imaging to evaluate airway dynamics during tidal breathing in 10 children with obstructive sleep apnea syndrome (OSAS; age, 4.3 +/- 2.3 years) and 10 matched control subjects (age, 5.0 +/- 2.0 years). We hypothesized that respiratory cycle fluctuations in upper airway cross-sectional area would be larger in children with OSAS. METHODS: Studies were performed under sedation. Respiratory gating was performed automatically at 10, 30, 50, 70, and 90% of inspiratory and expiratory volume. Airway cross-sectional area was measured at four ascending oropharyngeal levels at each increment of the respiratory cycle. RESULTS: We noted the following in subjects with OSAS compared with control subjects: (1) a smaller upper airway cross-sectional area, particularly during inspiration; (2) airway narrowing occurred during inspiration without evidence of complete airway collapse; (3) airway dilatation occurred during expiration, particularly early in the phase; and (4) magnitude of cross-sectional areas fluctuations during tidal breathing noted in OSAS at levels 1 through 4 were 317, 422, 785, and 922%, compared with 19, 15 17, and 24% in control subjects (p < 0.001, p < 0.005, p < 0.001, and p < 0.001, respectively). CONCLUSIONS: Fluctuations in airway area during tidal breathing are significantly greater in subjects with OSAS compared with control subjects. Resistive pressure loading is a probable explanation, although increased airway compliance may be a contributing factor.

Anatomy, Cross-Sectional↗
PubMed2005

Differences in activity of cytochrome C oxidase in brain between sleep and wakefulness.

STUDY OBJECTIVES: Increased mRNA level of subunit 1 cytochrome c oxidase (COXI) during wakefulness and after short-term sleep deprivation has been described in brain. We hypothesized that this might contribute to increased activity of cytochrome oxidase (COX) enzyme during wakefulness, as part of the mechanisms to provide sufficient amounts of adenosine triphosphate to meet increased neuronal energy demands. DESIGN: COX activity was measured in isolated mitochondria from different brain regions in groups of rats with 3 hours of spontaneous sleep, 3 hours of spontaneous wake, and 3 hours of sleep deprivation. The group with 3 hours of spontaneous wake was added to delineate the circadian component of changes in the enzyme activity. Northern blot analysis was performed to examine the mRNA levels of 2 subunits of the enzyme COXI and COXIV, encoded by mitochondrial and nuclear DNA, respectively. SETTING: Laboratory of Biochemistry, Department of Animal Biology, and Center for Sleep and Respiratory Neurobiology, University of Pennsylvania. PARTICIPANTS: 2-month-old male Fischer rats (N = 21) implanted for polygraphic recording. MEASUREMENTS AND RESULTS: For COX activity, there was a main effect by analysis of variance of experimental group (P < .0001) with significant increases in COX activity in wake and sleep-deprived groups as compared to the sleep group. A main effect of brain region was also significant (P < .001). There was no difference between brain regions in the degree of increase in enzyme activity in wakefulness. Both COXI and COXIV mRNA were increased with wakefulness as compared to sleep. CONCLUSIONS: There is an increase in COX activity after both 3 hours of spontaneous wake and 3 hours of sleep deprivation as compared with 3 hours of spontaneous sleep in diverse brain regions, which could be, in part, explained by the increased levels of bigenomic transcripts of the enzyme. This likely contributes to increased adenosine triphosphate production during wakefulness. ABBREVIATIONS: ADP, adenosine diphosphate; ATP, adenosine triphosphate; COXI, cytochrome c oxidase subunit 1 mRNA; COX, cytochrome c oxidase (protein); CREB, cyclic AMP response element binding protein; DNA, deoxyribonucleic acid; EDTA, ethylenediaminetetraacetic acid; EEG, electroencephalography; EMG, electromyography; GABP, GA binding protein; HEPES, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; mRNA, messenger ribonucleic acid; NADH, nicotinamid adenine dinucleotide, reduced; NDII, NADH dehydrogenase subunit 2 mRNA; NRF, nuclear respiratory factor.

Animals↗