Growth of Synechococcus 6311 in the presence of 0.5 molar NaCI is accompanied by significant changes in membrane lipid composition. Upon transfer of the cells from a 'low salt' (0.015 molar NaCI) to 'high salt' (0.5 molar NaCI) growth medium at different stages of growth, a rapid decrease in palmitoleic acid (C16:1A9) content was accompanied by a concomitant increase in the amount of the two C18:1 acids (C18:1A9, C18:IAI1), with the higher increase in oleic acid C18:1A9 content. These changes began to occur within the first hour after the sudden elevation of NaCI and progressed for about 72 hours. The percentage of palmitic acid (C16:0) and stearic acid (C18:0) remained almost unchanged in the same conditions. High salt-dependent changes within ratios of polar lipid classes also occurred within the first 72 hours of growth. The amount of monogalactosyl diacylglycerol (bilayer-destabilizing lipid) decreased and that of the digalactosyl diacylglycerol (bilayer-stabilizing lipid) increased. Consequently, in the three day old cells, the ratio of monogalactosyl diacylglycerol to digalactosyl diacylglycerol in the membranes of high saltgrown cells was about half of that in the membranes of low saltgrown cells. The total content of anionic lipids (phosphatidylglycerol and sulfoquinovosyl diacylglycerol) was always higher in the isolated membranes and the whole cells from high salt-grown cultures compared to that in the cells and membranes from low salt-grown cultures. All the observed rearrangements in the lipid environment occurred in both thylakoid and cytoplasmic membranes. Similar lipid composition changes, however, to a much lesser extent, were also observed in the aging, low salt-grown cultures. The observed changes in membrane fatty acids and lipids composition correlate with the alterations in electron and ion transport activities, and it is concluded that the rearrangement of the membrane lipid environment is an essential part of the process by which cells control membrane function and stability. up to 0.6 M NaCl. Transfer from low salt (0.015 M NaCi) to high salt (0.5 M NaCI) medium initiates multiple changes in the composition of the cytoplasmic membrane and in activities of membrane-bound enzymes. These changes include alterations in the distribution of integral membrane proteins as seen by freeze-fracture electron microscopy ( 13), increased sodium/proton exchange activity (3) and an increase in the content and activity of Cyt c oxidase (8,19).It has been well recognized that membrane lipid composition modulates the physiological properties of membranes such as barrier function, transport, and signaling. As most protein-lipid interactions are achieved through direct contact ofthe given fatty acid, lipid, or lipid domains with the protein, changes in lipid environment will affect protein function. While changes in the lipid head group composition may alter electrostatic interactions between charged domains on the protein surface and the lipid head group, alterations in the hydrocarbon region will af...
Background: Therapeutic approaches to spinal cord stimulation (SCS) continue to evolve and improve patient outcomes in patients receiving SCS therapy secondary to failed back surgery syndrome. Objectives: The aim of this study was to evaluate pain relief and other patient outcomes of SCS using selected high-dose programming parameters. Study Design: This was a prospective cohort study. Setting: This study took place at 11 centers in North America. Methods: Forty-four SCS-naive patients underwent trialing, starting with 1,000 Hz frequency, 90 µs pulse width followed by 300 Hz frequency, 800 µs pulse width, if pain relief was inadequate. Patients with 50% or greater pain relief were eligible for permanent implantation. Patient’s pain rating, global impression of change, health-related quality of life, functional disability, satisfaction/ recommendation, stimulation perception, device programming, and adverse events were assessed at 3 months postimplant. Results: There were significant improvements from baseline in mean Numeric Rating Scale (NRS11) pain scores for overall pain (7.5 to 3.8; P < 0.01), back pain (7.2 to 3.4; P < 0.01), leg pain (7.2 to 3.1; P < 0.01), Oswestry Disability Index (ODI) score (51.5 to 32.1; P < 0.01), and European Quality of Life–Five Dimensions, version 5L score (EQ-5D-5L) (0.58 to 0.74; P < 0.01). Twentyeight of 32 patients (88%) had significant, favorable improvement in Patient Global Impression of Change (PGIC). Eighty-four percent of patients were “satisfied,” and 78.1% would “definitely” recommend SCS. Eighteen patients (56%) used 1,000 Hz frequency and 90 µs pulse width exclusively; these patients experienced mean NRS-11 overall pain score improvement of 4.7 points. Device-, therapy-, or procedure-related adverse events were experienced in 19 patients (40%, 19 of 48), and all events resolved without reoperation and were similar to those observed with traditional SCS systems. Limitations: There was no active or sham comparator group, and therefore the reported effects may not be solely attributable to therapy effects and may be related to other, nonspecific effects of SCS. Conclusions: Improvements in pain relief, PGIC, EQ-5D-5L, ODI, and patient satisfaction were all clinically relevant and statistically significant. Future studies are needed to understand how these high-dose parameters perform versus a standard comparator. Key words: Spinal cord stimulation, high-frequency electrical stimulation, failed back surgery syndrome, neurostimulation, prospective, nonrandomized study
Background Few studies have evaluated patterns of systemic opioid use among patients initiating spinal cord stimulation therapy for chronic pain. This study evaluated systemic opioid discontinuation and/or dose reduction, and total healthcare cost following start of spinal cord stimulation therapy. Methods Using a commercial insurance claims database (2008-2017), we analyzed opioid utilization patterns in patients initiating spinal cord stimulation therapy, over a 1-year baseline and 2 year follow-up. The primary endpoint was defined as either discontinuation (= 365-day gap between prescription fills or total days' supply in follow-up = 30 days) OR = 50% reduction in average daily morphine milligram equivalent dose. “Costs” were defined as total payer plus patient out-of-pocket payments. Results 5,878 patients met selection criteria. 152 (2.6%) showed no opioid prescription data at any point in the study period. Among patients with one or more prescriptions, 42.0% met the primary endpoint (22.0% discontinued and 20.0% reduced their dose by 50% or more). Mean total adjusted costs were significantly reduced in years 1 and 2 of follow-up relative to baseline (excluding device insertion costs). The average time to breakeven when accounting for device trial and permanent insertion cost was 3.1 years among those that met the composite endpoint and 4.2 years among those who did not. Conclusions This analysis shows that among patients who continue spinal cord stimulation therapy for at least two years, a significant proportion were able to reduce and/or discontinue systemic opioid use, with costs following start of therapy significantly reduced relative to baseline.
Objectives Primary objectives were to evaluate the safety and systemic pharmacokinetics (PK) of DARE-HRT1, an intravaginal ring (IVR), which releases 17β2-Estradiol (E2) with progesterone (P4) for 28 days in healthy postmenopausal women. Methods This was a randomized, open-label, 2-arm, parallel group study in 21 healthy postmenopausal women with an intact uterus. Women were randomized (1:1) to either DARE-HRT1 IVR1 (E2 80 μg/d with P4 4 mg/d) or DARE-HRT1 IVR2 (E2 160 μg/d with P4 8 mg/d). They used the IVR for three 28-day cycles, inserting a new IVR monthly. Safety was measured by treatment emergent adverse events and changes in systemic laboratories and the endometrial bilayer width. Baseline adjusted plasma PK of E2, P4, and estrone (E1) was described. Results Both DARE-HRT1 IVR were safe. All treatment emergent adverse events were mild or moderate and were distributed similarly among IVR1 versus IVR2 users. Month 3 median maximum plasma (C max) P4 concentrations were 2.81 and 3.51 ng/mL and C max E2 was 42.95 and 77.27 pg/mL for IVR1 and IVR2 groups, respectively. Month 3 median steady state (C ss) plasma P4 concentrations were 1.19 and 1.89 ng/mL, and C ss E2 was 20.73 and 38.16 pg/mL for IVR1 and IVR2 users, respectively. Conclusions Both DARE-HRT1 IVRs were safe and released E2 in systemic concentrations, which were in the low, normal premenopausal range. Systemic P4 concentrations predict endometrial protection. Data from this study support further development of DARE-HRT1 for the treatment of menopausal symptoms.
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