To determine how the obstructive sleep apnea (OSA) patient's pathophysiological traits predict the success of the treatment aimed at stabilization or increase in respiratory motor outputs, we studied 26 newly diagnosed OSA patients [apnea-hypopnea index (AHI) 42 ± 5 events/h with 92% of apneas obstructive] who were treated with O2 supplementation, an isocapnic rebreathing system in which CO2 was added only during hyperpnea to prevent transient hypocapnia, and a continuous rebreathing system. We also measured each patient's controller gain below eupnea [change in minute volume/change in end-tidal Pco2 (ΔVe/ΔPetCO2)], CO2 reserve (eupnea-apnea threshold PetCO2), and plant gain (ΔPetCO2/ΔVe), as well as passive upper airway closing pressure (Pcrit). With isocapnic rebreathing, 14/26 reduced their AHI to 31 ± 6% of control (P < 0.01) (responder); 12/26 did not show significant change (nonresponder). The responders vs. nonresponders had a greater controller gain (6.5 ± 1.7 vs. 2.1 ± 0.2 l·min(-1)·mmHg(-1), P < 0.01) and a smaller CO2 reserve (1.9 ± 0.3 vs. 4.3 ± 0.4 mmHg, P < 0.01) with no differences in Pcrit (-0.1 ± 1.2 vs. 0.2 ± 0.9 cmH2O, P > 0.05). Hypercapnic rebreathing (+4.2 ± 1 mmHg PetCO2) reduced AHI to 15 ± 4% of control (P < 0.001) in 17/21 subjects with a wide range of CO2 reserve. Hyperoxia (SaO2 ∼95-98%) reduced AHI to 36 ± 11% of control in 7/19 OSA patients tested. We concluded that stabilizing central respiratory motor output via prevention of transient hypocapnia prevents most OSA in selected patients with a high chemosensitivity and a collapsible upper airway, whereas increasing respiratory motor output via moderate hypercapnia eliminates OSA in most patients with a wider range of chemosensitivity and CO2 reserve. Reducing chemosensitivity via hyperoxia had a limited and unpredictable effect on OSA.

Background: To determine the clinical activity and safety of Chinese herbal medicine (CHM) combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in patients with advanced pulmonary adenocarcinoma (ADC) and the ability of CHM combined with EGFR-TKI to activate EGFR mutations. Methods: Three hundred and fifty-four patients were randomly assigned to EGFR-TKI (erlotinib 150 mg/d, gefitinib 250 mg/d, or icotinib 125 mg tid/d) plus CHM (TKI+CHM, N = 185) or EGFR-TKI plus placebo (TKI+placebo, N = 169). Progression-free survival (PFS) was the primary end point; the secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life [Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS)], and safety. Results: The median PFS was significantly longer for the TKI+CHM group (13.50 months; 95% CI, 11.20–16.46 months) than with the EGFR-TKI group (10.94 months; 95% CI, 8.97–12.45 months; hazard ratio, 0.68; 95% CI, 0.51–0.90; P = 0.0064). The subgroup analyses favored TKI+CHM as a first-line treatment (15.97 vs. 10.97 months, P = 0.0447) rather than as a second-line treatment (11.43 vs. 9.23 months, P = 0.0530). Patients with exon 19 deletion had a significantly longer PFS than with 21 L858R. The addition of CHM to TKI significantly improved the ORR (64.32% vs. 52.66%, P = 0.026) and QoL. Drug-related grade 1–2 adverse events were less common with TKI+CHM. Conclusions: TKI+CHM improved PFS when compared with TKI alone in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Clinical Trial Registration: , identifier NCT01745302.

Unstable periodic breathing with intermittent ventilatory overshoots and undershoots commonly occurs in chronic heart failure, in hypoxia, with chronic opioid use and in certain types of obstructive sleep apnea. Sleep promotes breathing instability because it unmasks a highly sensitive dependence of the respiratory control system on chemoreceptor input, because transient cortical arousals promote ventilatory overshoots and also because upper airway dilator muscle tonicity is reduced and airway collapsibility enhanced. We will present data in support of the premise that carotid chemoreceptors are essential in the pathogenesis of apnea and periodicity; however it is the hyperadditive influence of peripheral chemoreceptor sensory input on central chemosensitivity that accounts for apnea and periodic breathing. This chemoreceptor interdependence also provides a significant portion of the normal drive to breathe in normoxia (i.e. eupnea) and in acute hypoxia. Finally, we discuss the effects of preventing transient hypocapnia (via selective increases in FICO(2)) on centrally mediated types of periodic breathing and even some varieties of cyclical obstructive sleep apnea.

Exopolysaccharides (EPS) produced by some lactic acid bacteria are often used by the dairy industry to improve the rheological and physical properties of yogurt, but the relationship between their structure and functional effect is still unclear. The EPS from different species, or different strains from the same species, may differ in terms of molar mass, repeating unit structure, and EPS yield during fermentation of milk. This study aimed to characterize the detailed properties of EPS produced from 7 strains of Streptococcus thermophilus, which is one of the key cultures used for yogurt manufacture. Milk was fermented with strains DGCC 7698, DGCC 7710, DGCC 7785, ST-10255y, St-143, STCth-9204, and ST4239. These strains were selected because they have been used in previous studies on yogurt texture, but a complete description of their EPS structural properties has not yet been reported. All strains were fermented under a similar acidification rate by adjusting the level of supplementation with peptone or the inoculation level, which allowed for a comparison of EPS yields under similar growth conditions (reconstituted skim milk at 40°C). The EPS from each strain was isolated and the weight-average molar mass and z-average root mean square radius determined using size-exclusion chromatography multiangle laser light scattering. The monosaccharide composition of EPS was determined using gas chromatography-mass spectrometry, and repeating unit structure was determined using nuclear magnetic resonance spectroscopy. The weight-average molar mass values of EPS ranged from 0.14 to 1.61 × 10 g/mol. All 7 EPS samples were uncharged. The strains ST-10255y and ST4239 had EPS with the same repeating unit structure. The monosaccharide compositions of the various EPS were mainly composed of glucose and galactose, with low levels of rhamnose in the EPS isolated from DGCC 7698, and N-acetylgalactosamine in the EPS from DGCC 7785, ST-10255y, and ST4239. The yields of EPS (measured when fermented milks reached pH 4.6) ranged from 8.0 to 76.4 mg of glucose equivalents/kg. In addition to (free) EPS, some strains were also able to produce capsular polysaccharide (associated with the bacterial cells) when observed with negative staining technique. The results of our study will help the dairy industry to better understand the mechanism by which different strains of Streptococcus thermophilus affect yogurt texture.

No abstract

The adverse effects of high environmental temperature exposure on animal reproductive functions have been concerned for many decades. However, the molecular basis of heat stress (HS)-induced decrease of sperm motility has not been entirely elucidated. We hypothesized that the deteriorate effects of HS may be mediated by damage of mitochondrial function and ATP synthesis. To test this hypothesis, we use mature boar sperm as model to explore the impacts of HS on mitochondrial function and sperm motility. A 6 h exposure to 42°C (HS) induced significant decrease in sperm progressive motility. Concurrently, HS induced mitochondrial dysfunction that is indicated by decreased of membrane potential, respiratory chain complex I and IV activities and adenosine triphosphate (ATP) contents. Exogenous ATP abolished this effect suggesting that reduced of ATP synthesis is the committed step in HS-induced reduction of sperm motility. At the molecular level, the mitochondrial protein contents were significantly decreased in HS sperm. Notably, the cytochrome c oxidase subunit 4, which was synthesized in cytoplasm and translocated into mitochondria, was significantly lower in mitochondria of HS sperm. Glycogen synthase kinase-3α (GSK3α), a negative regulator of sperm motility that is inactivated by Ser21 phosphorylation, was dephosphorylated after HS. The GSK3α inhibitor CHIR99021 was able to abolish the effects of HS on sperm and their mitochondria. Taken together, our results demonstrate that HS affects sperm motility through downregulation of mitochondrial activity and ATP synthesis yield, which involves dephosphorylation of GSK3α and interference of mitochondrial remodeling.

No abstract

Melatonin, the major pineal secretory product, has a significant impact on the female reproductive system. Recently, the beneficial effects of melatonin on mammalian oocyte maturation and embryonic development have drawn increased attention. However, the exact underlying mechanisms remain to be fully elucidated. This study demonstrates that supplementing melatonin to in vitro maturation (IVM) medium enhances IVM rate, lipid droplets (LDs) accumulation as well as triglyceride content in porcine oocytes. Decrease of mitochondrial membrane potential, mitochondrial respiratory chain complex IV activity as well as mitochondrial reactive oxygen species (mROS) content indicated that melatonin induced a decrease of mitochondrial activity. The copy number of mitochondrial DNA (mtDNA) which encodes essential subunits of oxidative phosphorylation (OXPHOS), was not affected by melatonin.However, the expression of mtDNA-encoded genes was significantly down-regulated after melatonin treatment. The DNA methyltransferase DNMT1, which regulates methylation and expression of mtDNA, was increased and translocated into the mitochondria in melatonintreated oocytes. The inhibitory effect of melatonin on the expression of mtDNA was significantly prevented by simultaneous addition of DNMT1 inhibitor, which suggests that melatonin regulates the transcription of mtDNA through up-regulation of DNMT1 and mtDNA methylation.Increase of triglyceride contents after inhibition of OXPHOS indicated that mitochondrial quiescence is crucial for LDs accumulation in oocytes. Taken together, our results suggest that melatonin-induced reduction in mROS production and increase in IVM, and LDs accumulation in porcine oocytes is mediated by mitochondrial quiescence. K E Y W O R D SDNA methyltransferase 1, in vitro maturation, melatonin, mitochondrial quiescence, oocyte