Cyclooxygenase-2 polymorphisms and risk of systemic lupus erythematosus in Koreans

Cyclooxygenase-2 (COX-2) is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. Upregulation of COX-2 in human lupus T cells resists anergy and apotosis. We investigated the COX-2 gene for functional variants that may influence susceptibility, clinical outcomes and severity of systemic lupus erythematosus (SLE) in a Korean population. The study included 345 patients with SLE and 400 unrelated healthy controls. Genotyping for the −765G → C polymorphism of COX-2 was performed by PCR–RFLP analysis. No difference in the distribution of the genotype frequencies between patients and controls was found. COX-2 genotypes were not associated with clinical features except hematologic abnormalities and anti-RNP antibody. We did not detect any association between COX-2 genotype and disease severity in SLE patients. These results suggest that the −765G → C polymorphism of COX-2 does not play a significant role in the development of SLE in a Korean population. A possible protective effect of the low activity C allele against the production of anti-RNP antibodies merits further investigation.     

The semi-seated position slightly reduces the effort to breathe during difficult weaning

Purpose

The influence of posture on breathing effort in patients with difficult weaning is unknown. We hypothesized that posture could modulate the breathing effort in difficult-to-wean patients.

Methods

A prospective, crossover, physiologic study was performed in 24 intubated patients breathing with pressure support who had already failed a spontaneous breathing trial or an extubation episode. Their median duration of mechanical ventilation before measurements was 25?days. Breathing pattern, occlusion pressure (P _0.1), intrinsic PEEP (PEEP_i), and inspiratory muscle effort evaluated by the pressure?Ctime product of the respiratory muscles and the work of breathing were measured during three postures: the seated position in bed (90°LD), simulating the position in a chair, the semi-seated (45°), and the supine (0°) positions consecutively applied in a random order. A comfort score was obtained in 17 cooperative patients. The influence of position on chest wall compliance was measured in another group of 11 sedated patients.

Results

The 45° position was associated with the lowest levels of effort (p????0.01) and occlusion pressure (p?<?0.05), and tended to be more often comfortable. Respiratory effort was the lowest at 45° in 18/24 patients. PEEP_i and PEEP_i-related work were slightly higher in the supine position (p????0.01), whereas respiratory effort, heart rate, and P _0.1 values were increased in the seated position (p?<?0.05).

Conclusion

A 45° position helps to unload the respiratory muscles, moderately reduces PEEP_i, and is often considered as comfortable. The semi-seated position may help the weaning process in ventilator-dependent patients.     

Obstructive Sleep Apnea Using Watch‐PAT 200 Is Independently Associated With an Increase in Morning Blood Pressure Surge in Never‐Treated Hypertensive Patients

This study aimed to examine the association between obstructive sleep apnea (OSA) and morning blood pressure surge in never‐treated patients with essential hypertension. This prospective study included a total of 58 patients (mean age, 51.7 years; 55.2% men) with never‐treated essential hypertension. The patients were divided into non‐OSA (n=23, 49.3±12.7 years) and OSA (n=35, 53.2±9.8 years) groups. The OSA group was defined as having an apnea‐hypopnea index level >5 as measured by the Watch‐PAT 200. The authors collected 24‐hour ambulatory BP, plasma aldosterone concentration, and plasma renin activity data from all of the patients. The measured sleep‐trough morning systolic blood pressure (SBP) increases were higher in the OSA group than in the non‐OSA group (28.7±11.8 mm Hg vs 19.6±12.8 mm Hg, P=.008). The sleep‐trough morning SBP increase was inversely correlated with the lowest oxygen saturation (r=−0.272, P=.039). OSA known to be associated with increased daytime and nocturnal sympathetic activity was associated with significantly higher sleep‐trough morning SBP levels in this study.

Obstructive sleep apnea (OSA) is a common disorder characterized by episodes of upper airway obstruction during sleep. The prevalence of OSA (apnea±hypopnea index [AHI] ≥5) in adults 30 to 69 years is estimated at 17%, increasing to 23% to 35% in relatively unselected hypertensive populations.¹, ² OSA is associated with endothelial dysfunction, metabolic syndrome, atherosclerosis, and cardiovascular disorders.³, ⁴, ⁵, ⁶, ⁷ Morning blood pressure (BP) surge (MS) is a normal physiological phenomenon; however, extreme MS is a risk factor for stroke and cardiovascular mortality.⁸, ⁹, ¹⁰ Sympathetic activity is suspected to play a role as an underlying mechanism in OSA and MS.⁷, ¹¹, ¹², ¹³ Few studies have evaluated the association between OSA and MS.¹⁴, ¹⁵ Peripheral arterial tone (PAT) is based on the pulsatile plethysmographic signal that is measured on a finger, which could serve as a single noninvasive substitute for sympathetic activity.¹⁶ This study aimed to examine the association of sleep parameters with WATCH^‐PAT 200 (WP200; (Itamar Medical Ltd, Caesarea, Israel) based on measurements of PAT variations and MS in never‐treated patients with essential hypertension.¹⁶, ¹⁷, ¹⁸, ¹⁹     

Elevated pulmonary artery systolic storage volume associated with improved ventilation-to-perfusion ratios in acute respiratory failure.

The possibility that an elevated pulmonary artery systolic storage volume (PASSV) correlates with improved overall ratios of ventilation-to-perfusion and hence benefits gas exchange in acute respiratory failure was examined. We examined this by assessing the correlation between PASSV and both the physiologic dead space to tidal volume ratio (VD/VT) and intrapulmonary shunt fraction (Qsp/Qt). The VD/VT and Qsp/Qt were used as an index of distribution of ventilation-to-perfusion as well as efficiency of pulmonary gas exchange. Twenty-eight patients suffering from acute respiratory failure were included. All required mechanical ventilation. PASSV was calculated from the pulmonary artery (PA) compliance and mean PA systolic distending pressure. Pulmonary arteriolar pressures were computed by Fourier analysis. PA compliance was derived from the PA time constant and the PA resistance. Storage volume fraction of stroke volume index (PASSV/SVI) was used to compare individual variations. There were inverse linear relationships between PASSV/SVI and VD/VT (r = 0.693, p less than 0.0001), and between PASSV/SVI and Qsp/Qt (r = 0.427, p = 0.012). Also, a direct correlation was found between VD/VT and PA time constant (r = 0.503, p = 0.002). The patients were divided into two groups based on PASSV/SVI to evaluate the effect of other hemodynamic data on PASSV. Comparison of the two groups revealed that VD/VT and Qsp/Qt were lower (p less than 0.0001, and p = 0.018, respectively), PA time constant was higher (p less than 0.001), and right ventricular stroke-work index was higher (p = 0.005) in the group with a high PASSV/SVI. There were no differences in other hemodynamic data between the two groups. These data suggest that an elevated PASSV may indeed benefit gas exchange in acute respiratory failure.     

Patterns of cardiorespiratory coordination in young women with recurrent major depressive disorder treated with escitalopram or venlafaxine

Evidence from previous studies suggests autonomic dysregulation in patients with major depressive disorder (MDD). Antidepressant treatment may also affect central autonomic function. We investigated whether the type of antidepressant might be associated with the pattern of cardiorespiratory coordination in non-depressed women with recurrent MDD. Resting electrocardiograms and respiratory signals were simultaneously recorded from 38 euthymic women with recurrent MDD who were treated with either escitalopram (n=19) or venlafaxine (n=19) monotherapy and from 38 healthy women. Linear measures of heart rate variability were extracted to assess cardiac autonomic control. Sample entropy (SampEn) was computed to assess the complexity of heart rate and respiratory signals, and cross-SampEn was calculated to measure the nonlinear interaction of both signals. Significant decreases in the cardiovagal tone and cardiorespiratory coupling of women with recurrent MDD receiving venlafaxine, and tendencies toward lower cardiovagal tone and cardiorespiratory coupling in women with recurrent MDD receiving escitalopram were observed when compared with healthy controls. Effect sizes for these differences were large between women receiving venlafaxine and healthy controls. We found a positive association between cardiorespiratory decoupling and venlafaxine dose. Norepinephrine-enhancement, within a therapeutic dose range, seems to be closely associated with decreased vagal tone and reduced nonlinear coupling between heart rate and respiration in euthymic women with recurrent MDD. However, the effects of serotonin enhancement on cardiovagal tone should be considered. Our results suggest that the pharmacodynamic properties of antidepressants may affect autonomic regulation of women with recurrent MDD even in euthymic state.     

Cochlear Implantation in Auditory Neuropathy

Objective: Auditory neuropathy is a recently described clinical entity characterized by sensorineural hearing loss in which the auditory evoked potential (ABR) is absent but otoacoustic emissions are present. This suggests a central locus for the associated hearing loss. In this study the results observed in a child with auditory neuropathy who received a cochlear implant are presented and compared with those of a matched group of children who were recipients of implants. Methods: A single-subject, repeated-measures design, evaluating closed-set and open-set word recognition abilities was used to assess the subject and a control group of matched children with implants who had also experienced a progressive sensorineural hearing loss. Results: The subject demonstrated improvements in vowel recognition (82% correct) by 1 year after implantation, which were only slightly lower than the control group. Consonant recognition and open-set word recognition scores were significantly lower. Conclusion: Caution should be exercised when considering cochlear implantation in children with auditory neuropathy. As with conventional hearing aids, less than optimal results may be seen.     

Asymmetric protonation of glutamate residues drives a preferred transport pathway in EmrE

EmrE is an Escherichia coli multidrug efflux pump and member of the small multidrug resistance (SMR) family that transports drugs as a homodimer by harnessing energy from the proton motive force. SMR family transporters contain a conserved glutamate residue in transmembrane 1 (Glu14 in EmrE) that is required for binding protons and drugs. Yet the mechanism underlying proton-coupled transport by the two glutamate residues in the dimer remains unresolved. Here, we used NMR spectroscopy to determine acid dissociation constants (pK_a) for wild-type EmrE and heterodimers containing one or two Glu14 residues in the dimer. For wild-type EmrE, we measured chemical shifts of the carboxyl side chain of Glu14 using solid-state NMR in lipid bilayers and obtained unambiguous evidence on the existence of asymmetric protonation states. Subsequent measurements of pK_a values for heterodimers with a single Glu14 residue showed no significant differences from heterodimers with two Glu14 residues, supporting a model where the two Glu14 residues have independent pK_a values and are not electrostatically coupled. These insights support a transport pathway with well-defined protonation states in each monomer of the dimer, including a preferred cytoplasmic-facing state where Glu14 is deprotonated in monomer A and protonated in monomer B under pH conditions in the cytoplasm of E. coli. Our findings also lead to a model, hop-free exchange, which proposes how exchangers with conformation-dependent pK_a values reduce proton leakage. This model is relevant to the SMR family and transporters comprised of inverted repeat domains.

Antibiotic resistance arises from multiple molecular mechanisms, including the enzymatic breakdown of drugs, mutations of target proteins, reduced drug influx, and the activation of efflux pumps (1). The efflux mechanism by membrane protein transporters is one of the broadest resistance mechanisms that requires active transport to reduce the internal drug concentration. Four out of five drug efflux families are secondary active transporters and share the following features: i) broad binding specificity to toxic compounds including antibiotics, antiseptics, and cationic dyes, ii) undergo conformational exchange to catalyze the substrate transport across the membrane, and iii) contain essential anionic residues needed for binding protons and/or substrates.Escherichia coli EmrE from the SMR family has served as a model of drug transport since it contains the minimal required complexity (110 residues) and shares each of the features found in other drug transporters. Namely, it forms an antiparallel homodimer that is required for drug efflux (2–6), it undergoes conformational exchange needed for drug transport (7, 8), and it contains a conserved anionic residue at Glu14 in each monomer of the dimer that is essential for antiport of protons (3, 5, 6, 9–11). While these studies provided insight into features of EmrE needed for drug efflux, key questions remain about the ion-coupled transport mechanism. Specifically, it is unclear whether the two Glu14 residues can exhibit differential protonation states in a lipid bilayer environment and whether deprotonation at one monomer influences the acid dissociation constant (pK_a) of the other monomer in the dimer (i.e., electrostatic coupling).Here, we used NMR spectroscopy and pH titrations to quantify chemical shift perturbations of Glu14 and surrounding residues in a monomer specific manner within the EmrE dimer. These measurements allowed us to derive monomer specific changes for accurately assessing the Glu14 protonation states within EmrE and determine that the two Glu14 residues in the dimer have independent pK_a values. Using our findings, we propose a transport model for EmrE with Glu14 protonation states specified for each monomer and discuss the implications of this model for minimizing proton leakage while achieving efficient proton-coupled drug efflux.     

Sédation inhalée en réanimation: que reste-t-il de l’AnaConDa™ ?

Sedation contributes to patient’s comfort and plays an essential role in the intensive care unit (ICU). Several clinical studies have reported the occasional use of volatile halogenated agents in the ICU; however, long-term use is possible in routine for the provision of a dedicated evaporator filter (AnaConDa? [ACD]). Because of their low cost and pharmacological characteristics with a rapid therapeutic effect, a high therapeutic index, a possible use regardless of age and underlying medical conditions, and a good knowledge of their adverse effects, halogenated agents could be considered like possible ideal anesthetic agents in the ICU. The objective of this technical note is to clarify the potential indications of ACD device and describe its operative principles and potential drawbacks.