Predictors of moderate to severe obstructive sleep apnea: identification of sex differences.

PURPOSE: Home sleep apnea tests are recommended only for patients at high risk of moderate to severe obstructive sleep apnea (OSA, apnea-hypopnea index [AHI] ≥ 15/h). We evaluated 14 factors known to be associated with OSA and identified sex differences in predictors of moderate to severe OSA. METHODS: Retrospective analysis was done on 545 subjects who completed sleep questionnaires and underwent diagnostic polysomnogram at a tertiary sleep center. Univariate and multivariate analysis was conducted separately in males and females to determine which variables were independent predictors of moderate to severe OSA. RESULTS: Overall, physical traits were stronger predictors in both males and females. For each sex, only 3 variables were found to be independently predictive of moderate to severe OSA. In order of predictive strength, this included body mass index (BMI) ≥ 38 kg/m2 (aOR 5.80, p < 0.001), neck circumference (NC) ≥ 17 in. (aOR 2.52, p = 0.002), and Epworth sleepiness scale (ESS) ≥ 13 (aOR 2.22, p = 0.015) for males and age ≥ 50 years (aOR 4.19, p < 0.001), NC ≥ 14.5 in. (aOR 3.13, p = 0.003), and report of morning headaches (aOR 2.00, p = 0.039) for females. Applying the Bonferroni correction, BMI and NC remained significant for males, and age and NC remained significant for females. CONCLUSIONS: In a subject population referred for sleep evaluation at a tertiary care center only a few variables are independently predictive of moderate to severe OSA, and these variables differed between males and females. Only BMI, NC, and a high ESS were independently predictive of moderate to severe OSA in males, whereas age, NC, and morning headaches were independently predictive in females.

Regulation of Ca²âº/calmodulin-dependent protein kinase II signaling within hippocampal glutamatergic postsynapses during flurazepam withdrawal.

Cessation of one-week oral administration of the benzodiazepine flurazepam (FZP) to rats results in withdrawal anxiety after 1 day of withdrawal. FZP withdrawal is correlated with synaptic incorporation of homomeric GluA1-containing α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) in the proximal stratum radiatum of CA1 neurons. After 2 days of withdrawal, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylates GluA1 subunits at Ser(831), increasing channel conductance. Secondary to AMPAR potentiation, GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), known binding partners of CaMKII, are selectively removed from the postsynaptic density (PSD). While activation of synaptic CaMKII is known to involve translocation to the PSD, CaMKII bound to NMDARs may be removed from the PSD. To distinguish these possibilities, the current studies used postembedding immunogold electron microscopy to investigate alterations in CaMKII signaling at CA1 stratum radiatum synapses after 2 days of FZP withdrawal. These studies revealed decreased total, but not autophosphorylated (Thr(286)) CaMKIIα expression in CA1 PSDs. The removal of CaMKII-GluN2B complexes from the PSD during drug withdrawal may serve as a homeostatic mechanism to limit AMPAR-mediated CA1 neuron hyperexcitability and benzodiazepine withdrawal anxiety.

Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors.

Benzodiazepines (BDZs) depress neuronal excitability via positive allosteric modulation of inhibitory GABA(A) receptors (GABA(A)R). BDZs and other positive GABA(A)R modulators, including barbiturates, ethanol, and neurosteroids, can also inhibit L-type voltage-gated calcium channels (L-VGCCs), which could contribute to reduced neuronal excitability. Because neuronal L-VGCC function is up-regulated after long-term GABA(A)R modulator exposure, an interaction with L-VGCCs may also play a role in physical dependence. The current studies assessed the effects of BDZs (diazepam, flurazepam, and desalkylflurazepam), allopregnanolone, pentobarbital, and ethanol on whole-cell Ba(2+) currents through recombinant neuronal Ca(v)1.2 and Ca(v)1.3 L-VGCCs expressed with ß(3) and α(2)δ-1 in HEK293T cells. Allopregnanolone was the most potent inhibitor (IC(50), ∼10 µM), followed by BDZs (IC(50), ∼50 µM), pentobarbital (IC(50), 0.3-1 mM), and ethanol (IC(50), ∼300 mM). Ca(v)1.3 channels were less sensitive to pentobarbital inhibition than Ca(v)1.2 channels, similar to dihydropyridine (DHP) L-VGCC antagonists. All GABA(A)R modulators induced a negative shift in the steady-state inactivation curve of Ca(v)1.3 channels, but only BDZs and pentobarbital induced a negative shift in Ca(v)1.2 channel inactivation. Mutation of the high-affinity DHP binding site (T1039Y and Q1043M) in Ca(v)1.2 channels reduced pentobarbital potency. Despite the structural similarity between benzothiazepines and BDZs, mutation of an amino acid important for diltiazem potency (I1150A) did not affect diazepam potency. Although L-VGCC inhibition by BDZs occurred at concentrations that are possibly too high to be clinically relevant and is not likely to play a role in the up-regulation of L-VGCCs during long-term treatment, pentobarbital and ethanol inhibited L-VGCCs at clinically relevant concentrations.

Chronic benzodiazepine administration potentiates high voltage-activated calcium currents in hippocampal CA1 neurons.

Signs of physical dependence as a consequence of long-term drug use and a moderate abuse liability limit benzodiazepine clinical usefulness. Growing evidence suggests a role for voltage-gated calcium channel (VGCC) regulation in mediating a range of chronic drug effects from drug withdrawal phenomena to dependence on a variety of drugs of abuse. High voltage-activated (HVA) calcium currents were measured in whole-cell recordings from acutely isolated hippocampal CA1 neurons after a 1-week flurazepam (FZP) treatment that results in withdrawal-anxiety. An approximately 1.8-fold increase in Ca(2+) current density was detected immediately after and up to 2 days but not 3 or 4 days after drug withdrawal. Current density was unchanged after acute desalkyl-FZP treatment. A significant negative shift of the half-maximal potential of activation of HVA currents was also observed but steady-state inactivation remained unchanged. FZP and diazepam showed use- and concentration-dependent inhibition of Ca(2+) currents in hippocampal cultured cells following depolarizing trains (FZP, IC(50) = 1.8 microM; diazepam, IC(50) = 36 microM), pointing to an additional mechanism by which benzodiazepines modulate HVA Ca(2+) channels. Systemic preinjection of nimodipine (10 mg/kg), an L-type (L)-VGCC antagonist, prevented the benzodiazepine-induced increase in alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid receptor (AMPAR)-mediated miniature excitatory postsynaptic current in CA1 neurons 2 days after FZP withdrawal, suggesting that AMPAR potentiation, previously linked to withdrawal-anxiety may require enhanced L-VGCC-mediated Ca(2+) influx. Taken together with prior work, these findings suggest that enhanced Ca(2+) entry through HVA Ca(2+) channels may contribute to hippocampal AMPAR plasticity and serve as a potential mechanism underlying benzodiazepine physical dependence.