Treatments for Age-related Vocal Atrophy: A Systematic Review.

OBJECTIVE: Age-related vocal atrophy (ARVA) can dramatically affect voice, communication, and quality of life. The objectives of this systematic review were to (1) determine whether treatments for ARVA were superior to controls (2) compare the relative efficacy of procedural and behavioral treatments (3) review the various types of outcome measures, and (4) evaluate the quality of studies. REVIEW METHODS: The literature was searched using strategies designed by a medical librarian (2/18/21, updated 3/9/22). Studies investigating treatments for bilateral vocal atrophy were included. Studies involving unilateral atrophy, presbyphonia (without endoscopic findings), or an absent comparator group were excluded. The Preferred Reporting Items for Systematic Reviews and Meta-analyses checklist was used to guide this study. RESULTS: After applying the inclusion/exclusion criteria, 8 articles remained, including 4 randomized trials and 4 cohort studies, and a narrative synthesis was performed. Surgical and behavioral treatments for ARVA appeared to be superior to control groups, based on specific outcome measures. However, the superiority of these treatments over controls was not uniformly observed across multiple outcome measures. When comparing different treatments, superiority could not be established based on the quality and completeness of the studies included in the systematic review. Outcome measures also varied between individual studies. Finally, the risk of bias was analyzed and scored. Consistent point deductions among reviewed studies were noted. CONCLUSIONS: When comparing treatments for ARVA. Surgery and voice therapy were both superior to control groups based on specific outcome measures from different domains. Superiority of one treatment could not be established. LEVEL OF EVIDENCE: N/A Laryngoscope, 133:2846-2855, 2023.

Dynamics of lidocaine in topical anesthesia for office-based laryngeal procedures: A pilot study.

OBJECTIVES: To study topical lidocaine for office-based laryngeal procedures recording onset, duration, and subjective experience of topical anesthesia. STUDY DESIGN: Nine healthy volunteers were anesthetized with 4 % lidocaine endoscopically. Laryngeal sensitivity prior to and during anesthesia was recorded until normal sensation returned measured by air-puff sensory testing. Subjective experience of the process was recorded. METHODS: Questionnaires regarding subjective experience were completed prior to, during, and after anesthesia. Laryngeal sensitivity via air-pulse trigger of the laryngeal adductor reflex (LAR) prior to and after 3 mL shower of 4 % lidocaine was recorded at 30 second intervals until the larynx was insensate with no LAR at 10 mmHg. Time to anesthesia was recorded and post-endoscopy questionnaire was given. Upon subjective change in sensation, sensitivity via air-pulse trigger of the LAR was recorded until baseline sensation returned. A post-anesthesia questionnaire recorded the subjective experience. RESULTS: Average time to full anesthesia was 110 s (±31.2). Subjective return of sensation was noted at 10 min (±2.5), however time to return to normal LAR was 22 min (±5.8). Based on three standard deviations, 99.7 % of the population will be anesthetized at 3.4 min, report subjective change at 18.2 min and regain full sensation at 40 min. CONCLUSIONS: Office-based laryngeal procedures should be performed at least 2 min following topical 4 % lidocaine with a window for manipulation of at least 16 min. Oral intake should be delayed for over 45 min to ensure complete return of sensation. The laryngeal shower of lidocaine is subjectively tolerated. LEVEL OF EVIDENCE: 2C Outcomes Research.

Safety and Predictors of 30-Day Adverse Events of Laryngeal Framework Surgery: An Analysis of ACS-NSQIP data.

OBJECTIVES/HYPOTHESIS: To characterize and identify predictors of 30-day adverse events in patients undergoing laryngeal framework surgery (LFS). STUDY DESIGN: This study is a retrospective analysis of the National Surgical Quality Improvement dataset. METHODS: LFS cases were identified from the American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) database from 2008 to 2018. Demographic variables, patient comorbidities, and perioperative outcomes (any adverse event, 30-day readmission, 30-day reoperation, and unplanned intubation) were extracted. Patient-specific and surgery-specific factors associated with perioperative adverse events were examined using descriptive statistics and univariate logistic regression (LR). RESULTS: Of 283 patients who underwent LFS, 225 underwent laryngoplasty medialization, 56 underwent laryngoplasty medialization with arytenoidectomy or arytenoidopexy via an external approach, and 2 underwent local myocutaneous or fasciocutaneous advancement flap along with laryngoplasty. Medical comorbidities were present in 33.6% of patients and 57.9% were American Society of Anesthesiologists (ASA) Class III/IV (57.9%). LFS was performed as same-day surgery in 30.7% of cases. Fourteen patients (4.9%) suffered an adverse condition within 30 days following surgery. In univariate LR, ASA Class III or IV (odds ratio [OR] 4.6, 95% confidence interval [CI] 1.2-30.1) was the only predictor associated with any adverse event. Arytenoid adduction (AA) was associated with increased risk of reoperation within 30 days of the initial surgery (OR 6.4, 95% CI 1.0-49). CONCLUSIONS: LFS is a generally safe procedure with infrequent perioperative adverse events. In the ACS-NSQIP database, ASA classification of III or IV was associated with a higher risk for any 30-day adverse event and AA was associated with a higher risk for 30-day reoperation. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1414-1420, 2022.

Assessing the Clinical Utility of the Early Postoperative Pharyngogram in Hypopharyngeal Surgery for Dysphagia.

OBJECTIVES/HYPOTHESIS: To evaluate the clinical utility of postoperative contrast x-ray pharyngograms (XRP) for detecting pharyngoesophageal leaks following hypopharyngeal dysphagia surgery. STUDY DESIGN: Retrospective cohort study. METHODS: Medical records were reviewed of patients undergoing endoscopic (E-) or open (O-) Zenker's diverticulectomy (-ZD) with cricopharyngeal myotomy (-CPM) and CPM alone from 2008 to 2020 at one academic institution. Exclusion criteria were patients who were fed enterally or underwent repair of epiphrenic diverticula or O-CPM during laryngectomy. XRP clinical indication, impact on clinical care, and factors associated with use patterns were examined using descriptive statistics and logistic regression (LR). RESULTS: Of 152 subjects, 52% underwent O-ZD, 30% O-CPM, 15% E-ZD, and 3% E-CPM. An XRP was ordered for 65% of subjects, mostly routinely (94%). Among the four clinically apparent leaks observed in this cohort, early postoperative XRP confirmed one. It did not identify any clinically silent leaks. In univariate LR, undergoing XRP was associated with increasing day of diet advancement (odds ratio [OR] 4.7, 95% confidence interval [CI] 2.5-10.5) and hospital stay duration (OR 3.2, 95% CI 2.1-5.2), as well as surgeon specialty of otolaryngology compared to general surgery (OR 12.8, 95% CI 4.8-40.8) and procedure sub-type (O-CPM: OR 0.03, 95% CI 0.002-0.16). In multivariate LR, the following variables were significantly associated with XRP use: hospital stay (OR 1.7; 95% CI 1.1-3.0), otolaryngology (OR 105; 95% CI 15.4-2193), O-CPM (OR 0.03; 95% CI 0.002-0.16), and E-CPM (OR 0.04, 95% CI 0.002-0.60). CONCLUSIONS: Prospective, multi-institutional studies are needed to confirm the low clinical utility we observed of early, postoperative XRP following hypopharyngeal surgery for dysphagia. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:272-277, 2022.

Recurrent Respiratory Papillomatosis Office versus Operating Room: Systematic Review and Meta-Analysis.

OBJECTIVES: Recurrent respiratory papillomatosis can be treated in the office or operating room (OR). The choice of treatment is based on several factors, including patient and surgeon preference. However, there is little data to guide the decision-making. This study examines the available literature comparing operative treatment in-office versus OR. METHODS: A systematic review was performed following Preferred Reporting Items for Systematic Reviews guidelines. Of 2,864 articles identified, 78 were reviewed full-length and 18 were included. Outcomes of interest were recurrence and complication rates, number of procedures, time interval between procedures, and cost. RESULTS: Only one study compared outcomes of operative in-office to OR treatments. The weighted average complication rate for OR procedures was 0.02 (95% confidence interval [CI] 0.00-0.32), n = 8, and for office procedures, 0.17 (95% CI 0.08-0.33), n = 6. The weighted average time interval between OR procedures was 10.59 months (5.83, 15.35) and for office procedures 5.40 months (3.26-7.54), n = 1. The weighted average cost of OR procedures was $10,105.22 ($5,622.51-14,587.83), n = 2 versus $2,081.00 ($1,987.64-$2,174.36), n = 1 for office procedures. CONCLUSION: Only one study compares office to OR treatment. The overall data indicate no differences aside from cost and imply that office procedures may be more cost-effective than OR procedures. However, the heterogeneous data limits any strong comparison of outcomes between office and OR-based treatment of laryngeal papillomas. More studies to compare the two treatment settings are warranted.

Prospective Randomized Trial Comparing Opioids versus Nonsteroidal Antiinflammatory Drugs for Postoperative Analgesia in Outpatient Rhinoplasty.

BACKGROUND: The misuse and abuse of opioids, including overprescription, has led to the current opioid epidemic and national crisis. There is a national effort to eliminate the unnecessary prescription of opioids for analgesia. METHODS: Seventy patients were randomized to receive postoperative analgesia with either 5 mg hydrocodone with 325 mg acetaminophen (opioid control group) or 400 mg of ibuprofen [nonsteroidal antiinflammatory drug (NSAID) experimental group]. Pain levels were assessed on postoperative days 1, 2, and 7. Outcome measures included numeric pain rating scores and assessments of frequency and amount of analgesic used. RESULTS: There was no significant difference in gender (p = 0.81) or age (p = 0.61) between groups. On postoperative day 0, the NSAID group (mean ± SD, 2.54 ± 1.57) was found to be noninferior to the opioid group (mean ± SD, 3.14 ± 1.75; p = 0.003). On postoperative day 1, the NSAID group showed a lower mean pain score (mean ± SD, 1.84 ± 1.29) than the opioid group (mean ± SD, 2.46 ± 1.90; p = 0.01). However, on postoperative day 7, the difference in pain scores between the NSAID (mean ± SD, 3.29 ± 2.14) and opioid (mean ± SD, 3.14 ± 2.12; p = 0.17) groups lost statistical significance. There was no significant difference in mean day of medication cessation between the NSAID (mean ± SD, 4.73 ± 1.57) and opioid (mean ± SD, 4.28 ± 2.23; p = 0.26) groups. Seventy-six percent of patients who were prescribed opioids took fewer than eight tablets. Five patients escalated from NSAIDs to opioids. There were no adverse effects related to NSAID use. CONCLUSIONS: NSAIDs are an acceptable and safe alternative to opioids for postoperative analgesia in rhinoplasty and potentially lead to better overall pain control in some patients. Significantly reducing or eliminating opioid prescriptions may be considered in light of the current opioid epidemic. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Management of Iatrogenic Cervical Esophageal Perforations: A Narrative Review.

Importance: Esophageal perforations are difficult to diagnose and have a high mortality rate. Cervical esophageal perforations (CEPs) are the second most common anatomic type of esophageal perforations and are most often due to iatrogenic injury. They are often managed more conservatively than thoracic perforations. The current literature on CEPs is mostly observational, with a paucity of prospective controlled studies. In addition, there is scarce literature focusing specifically on iatrogenic CEPs (iCEPs) as an entity of their own. Observations: The existing studies on esophageal perforations address treatment by anatomic location and by cause, but few focus specifically on iCEPs. The cricopharynx is the most common site for injury in diagnostic endoscopy. The standard treatment is generally conservative management with drainage unless the perforation is greater than 2 cm, the diagnosis is delayed, or the patient shows signs of sepsis, which would prompt surgical intervention, most commonly in the form of primary repair via open or endoscopic approach. An open approach has been the mainstay of therapy; however, use of endoscopic clips, stents, and suturing is increasingly on the rise. Guideline recommendations on the optimal therapeutic approach for iCEPs are lacking. The most consistent recommendation in the literature is immediate and individualized treatment. Conclusions and Relevance: The management of iCEPs is controversial. There is a need for additional prospective studies comparing treatment options for iCEPs to establish a gold standard treatment and to assess for the expanding role of endoscopic interventions.

Decreased Tongue Volume Post Radiation.

OBJECTIVES: To evaluate volume changes within the tongue post chemoradiation therapy (CRT). STUDY DESIGN: Retrospective review. SETTING: Academic Medical Center. SUBJECTS AND METHODS: Subjects included 19 patients that received CRT as the primary treatment for tonsillar or hypopharynx squamous cell carcinoma. Tongue volumes were calculated by three raters from thin slice computed tomography images collected before treatment and up to 29 months post-CRT. Body mass index (BMI) was also collected at each time point. RESULTS: Inter-rater reliability was high with an ICC of 0.849 (95% CI = 0.773, 0.905). Linear mixed effects modeling showed a mean decrease of 0.45 cm3 (standard error of the mean [SEM] = 0.11) in tongue volume per month post-CRT (P < .001). However, the addition of BMI to the model was significant (χ2 (4) = 25.0, P < .001), indicating that BMI was a strong predictor of tongue volume, with a mean decrease of 1.75 cm3 (SEM = 0.49) in tongue volume per unit decrease in BMI (P < .001) and reducing the post-CRT effect on tongue volume decrease per month to 0.23 cm3 (P = .02). BMI significantly (P < .001) decreased by 0.11 units (SEM = 0.02) per month post radiation. CONCLUSION: Tongue dysfunction and decreased tongue strength are significant contributors to the dysphagia that patients experience after receiving CRT. In this study, both tongue volume and BMI decreased post-CRT; therefore, BMI could potentially be used as a predictor of tongue volume post-CRT.

Long-Acting Cabotegravir Protects Macaques Against Repeated Penile Simian-Human Immunodeficiency Virus Exposures.

We used a novel penile simian-human immunodeficiency virus (SHIV) transmission model to investigate whether long-acting cabotegravir (CAB LA) prevents penile SHIV acquisition in macaques. Twenty-two macaques were exposed to SHIV via the foreskin and urethra once weekly for 12 weeks. Of these, 6 received human-equivalent doses of CAB LA, 6 received oral emtricitabine/tenofovir disoproxil fumarate, and 10 were untreated. The efficacy of CAB LA was high (94.4%; 95% confidence interval, 58.2%-99.3%) and similar to that seen with oral emtricitabine/tenofovir disoproxil fumarate (94.0%; 55.1%-99.2%). The high efficacy of CAB LA in the penile transmission model supports extending the clinical advancement of CAB LA preexposure prophylaxis to heterosexual men.

Improving On-time Discharge in Otolaryngology Admissions.

OBJECTIVE: We conducted a quality improvement project to increase the rate of discharges before noon (DBN) in the otolaryngology department at a tertiary care center. METHODS: Based on a Plan-Do-Study-Act framework, monthly discharge data and observed-to-expected (O:E) length of stay were collected and shared with the department members monthly. A target of 43% DBN was predetermined by the center (Plan). The following interventions were implemented (Do): discharge planning starting at the time of admission, focus on early attending-to-resident team communication, placement of discharge order prior to rounding, and weekly reminders to the entire department. RESULTS: Discharges were monitored for 3 years. For the year prior to this study, a minority of patients were discharged before noon (12 months: 75 of 190, 36%). During the first 6 months of monitoring (Study), no significant improvement was identified (34 of 95, 36%). After interventions, performance significantly improved (31 months: 250 of 548, 68%). The performance was consistently above the predetermined target of 43%. During the study time, O:E length of stay remained below the predetermined target (O:E ratio, 0.90; hospital target, 0.93). DISCUSSION: Comprehensive discharge planning beginning at the time of admission, weekly reminders, and improved communication (Act) can help to prioritize DBN and increase the percentage of discharges before noon. IMPLICATIONS FOR PRACTICE: By utilizing a quality improvement framework, significant improvements in timely discharge can be achieved and sustained with changes in workflow and departmental culture. These changes can be achieved without increases in resources or prolonging the length of stay.

Impact of Q-Griffithsin anti-HIV microbicide gel in non-human primates: In situ analyses of epithelial and immune cell markers in rectal mucosa.

Natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. We here assessed the effect of rectal application of an anti-HIV lectin-based microbicide Q-Griffithsin (Q-GRFT) in rectal tissue samples from rhesus macaques. E-cadherin+ cells, CD4+ cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. Variations in cell numbers between baseline, placebo and Q-GRFT treated samples were analyzed using random intercept linear mixed effect models. The frequencies of rectal E-cadherin+ cells remained stable despite multiple tissue samplings and Q-GRFT gel (0.1%, 0.3% and 1%, respectively) treatment. Whereas single dose application of Q-GRFT did not affect the frequencies of rectal CD4+ cells, multi-dose Q-GRFT caused a small, but significant increase of the frequencies of intra-epithelial CD4+ cells (placebo: median 4%; 1% Q-GRFT: median 7%) and of the CD4+ lamina propria cells (placebo: median 30%; 0.1-1% Q-GRFT: median 36-39%). The resting time between sampling points were further associated with minor changes in the total and CD4+ rectal mucosal cell levels. The results add to general knowledge of in vivo evaluation of anti-HIV microbicide application concerning cellular effects in rectal mucosa.

Laryngeal distribution of adult-onset recurrent respiratory papillomatosis: A longitudinal study.

OBJECTIVES/HYPOTHESIS: To describe recurrence patterns in patients with recurrent respiratory papillomatosis (RRP) following surgical intervention. STUDY DESIGN: Single-center, retrospective, longitudinal case series. METHODS: Initial and follow-up laryngoscopic examinations of seven previously untreated adult-onset RRP patients were reviewed. Patients were followed longitudinally for periods ranging from 3 months to 7 years. Lesion locations were recorded using a twenty-one region laryngeal schematic, and maps were generated to illustrate the distribution of disease before and after cold-knife or potassium-titanyl-phosphate laser intervention. Univariate and multivariate analyses were employed to examine variables affecting recurrence patterns. RESULTS: Across all patients, a statistically significant correlation between initial distribution and primary recurrence was observed. Seventy-five percent of new lesions were adjacent to regions with preexisting disease; 83% of new glottic lesions were adjacent to preexisting glottic lesions, and 66% of supraglottic lesions were adjacent to preexisting supraglottic regions. No statistically significant differences in recurrence rate were observed across sites. CONCLUSIONS: In previously untreated patients with adult-onset recurrent respiratory papillomatosis, lesions tended to recur either in the same regions or regions adjacent to those affected at the time of initial surgery. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1993-1997, 2019.

Novel fatty acyl apoE mimetic peptides have increased potency to reduce plasma cholesterol in mice and macaques.

Ac-hE18A-NH2 is a dual-domain apoE mimetic peptide that possesses the putative receptor binding domain from apoE (LRKLRKRLLR, denoted hE; residues 141-150) covalently attached to lipid-associating peptide 18A. Like apoE, Ac-hE18A-NH2 reduces plasma cholesterol in animal models and exhibits anti-inflammatory properties independent of its cholesterol-reducing effect. Ac-hE18A-NH2 has already undergone phase I clinical trials as a lipid-lowering agent. To explore the therapeutic potential more, we designed and synthesized new analogues by linking ɑ-aminohexanoic acid, octanoic acid, or myristic acid to LRRLRRRLLR-18A-NH2 ([R]hE18A-NH2) and examined the cholesterol-lowering potency in animals. The modified peptides effectively reduced plasma cholesterol in apoE-null mice fed standard chow or a Western diet; the myristyl analogue was the most effective. A single administration of the myristyl analogue reduced plasma total and LDL cholesterol in a dose-dependent manner in hypercholesterolemic cynomolgus macaques for up to 1 week despite the continuation of a cholesterol-supplemented diet. The myristyl peptide (7.4 mg/kg) reduced total and LDL cholesterol at 24 h by 64% and 74%, respectively; plasma HDL levels were modestly reduced and returned to baseline by day 7. These new analogues should exhibit enhanced potency at lower doses than Ac-hE18A-NH2, which may make them attractive therapeutic candidates for clinical trials.

ApoA-I Mimetic Peptide 4F Reduces Age-Related Lipid Deposition in Murine Bruch's Membrane and Causes Its Structural Remodeling.

PURPOSE: Accumulation of lipoprotein-derived lipids including esterified and unesterified cholesterol in Bruch's membrane of human eyes is a major age-related change involved in initiating and sustaining soft drusen in age-related macular degeneration (AMD). The apolipoprotein (apo) A-I mimetic peptide 4F is a small anti-inflammatory and anti-atherogenic agent, and potent modifier of plasma membranes. We evaluated the effect of intravitreally-injected 4F on murine Bruch's membrane. METHODS: We tested single intravitreal injections of 4F doses (0.6 µg, 1.2 µg, 2.4 µg, and placebo scrambled peptide) in ApoEnull mice ≥10 months of age. After 30 days, mice were euthanized. Eyes were processed for either direct immunofluorescence detection of esterified cholesterol (EC) in Bruch's membrane whole mounts via a perfringolysin O-based marker linked to green fluorescent protein or by transmission electron microscopic visualization of Bruch's membrane integrity. Fluorescein isothiocyanate-conjugated 4F was traced after injection. RESULTS: All injected eyes showed a dose-dependent reduction of Bruch's membrane EC with a concomitant ultrastructural improvement compared to placebo treated eyes. At a 2.4 µg dose of 4F, EC was reduced on average by ~60% and Bruch's membrane returned to a regular pentalaminar structure and thickness. Tracer studies confirmed that injected 4F reached intraocular targets. CONCLUSION: We demonstrated a highly effective pharmacological reduction of EC and restoration of Bruch's membrane ultrastructure. The apoA-I mimetic peptide 4F is a novel way to treat a critical AMD disease process and thus represents a new candidate for treating the underlying cause of AMD.

Analysis of putative mucosal SHIV susceptibility factors during repeated DMPA treatments in pigtail macaques.

BACKGROUND: Depot-medroxyprogesterone acetate (DMPA) has been associated in some studies with increased HIV susceptibility in women. We used a pigtail macaque model to document the effects of repeated DMPA treatments and their potential contribution to increased SHIV susceptibility. METHODS: Nine pigtails were administered 2.5, 1.5, or 0.5 mg/kg DMPA in study weeks one and four. Menstrual cycling, vaginal epithelial thickness, and other SHIV susceptibility factors were monitored for a mean of 24 study weeks. RESULTS: All DMPA treatments suppressed menstrual cycling and increased vaginal pH. The vaginal epithelium thinned naturally during baseline menstrual cycles (from mean of 351 to 161 µm in late-luteal phase). Following DMPA, the non-nucleated layer was temporarily absent. Two weeks post-second DMPA injection, mean epithelial thickness was 53, 45, and 167 µm for the descending doses, respectively. CONCLUSIONS: All animals showed temporal vaginal epithelial thinning with loss of the non-nucleated layer, and vaginal pH changes post-DMPA injections.

Pharmacokinetic and safety analyses of tenofovir and tenofovir-emtricitabine vaginal tablets in pigtailed macaques.

Vaginal rapidly disintegrating tablets (RDTs) containing tenofovir (TFV) or TFV and emtricitabine (FTC) were evaluated for safety and pharmacokinetics in pigtailed macaques. Two separate animal groups (n = 4) received TFV (10 mg) or TFV-FTC (10 mg each) RDTs, administered near the cervix. A third group (n = 4) received 1 ml TFV gel. Blood plasma, vaginal tissue biopsy specimens, and vaginal fluids were collected before and after product application at 0, 0.5, 1, 4, and 24 h. A disintegration time of <30 min following vaginal application of the RDTs was noted, with negligible effects on local inflammatory cytokines, vaginal pH, and microflora. TFV pharmacokinetics were generally similar for both RDTs and gel, with peak median concentrations in vaginal tissues and vaginal secretions being on the order of 10(4) to 10(5) ng/g (147 to 571 µM) and 10(6) ng/g (12 to 34 mM), respectively, at 1 to 4 h postdose. At 24 h, however, TFV vaginal tissue levels were more sustained after RDT dosing, with median TFV concentrations being approximately 1 log higher than those with gel dosing. FTC pharmacokinetics after combination RDT dosing were similar to those of TFV, with peak median vaginal tissue and fluid levels being on the order of 10(4) ng/g (374 µM) and 10(6) ng/g (32 mM), respectively, at 1 h postdose with levels in fluid remaining high at 24 h. RDTs are a promising alternative vaginal dosage form, delivering TFV and/or FTC at levels that would be considered inhibitory to simian-human immunodeficiency virus in the macaque vaginal microenvironment over a 24-h period.

Comparison of anti-endotoxin activity of apoE and apoA mimetic derivatives of a model amphipathic peptide 18A.

Endotoxemia is a major cause of chronic inflammation, and is an important pathogenic factor in the development of metabolic syndrome and atherosclerosis. Human apolipoprotein E (apoE) and apoA-I are protein components of high-density lipoprotein, which have strong anti-endotoxin activity. Here, we compared anti-endotoxin activity of Ac-hE18A-NH2 and 4F peptides, modified from model amphipathic helical 18A peptide, to mimic, respectively, apoE and apoA-I properties. Ac-hE18A-NH2, stronger than 4F, inhibited endotoxin activity and disaggregated Escherichia coli 055:B5 (wild smooth serotype). Ac-hE18A-NH2 and 4F inhibited endotoxin activity of E. coli 026:B6 (rough-like serotype) to a similar degree. This suggests that Ac-hE18A-NH2 as a dual-domain molecule might interact with both the lipid A and headgroup of smooth LPS, whereas 4F binds lipid A. In C57BL/6 mice, Ac-hE18A-NH2 was superior to 4F in inhibiting the inflammatory responses mediated by E. coli 055:B5, but not E. coli 026:B6. However, in THP-1 cells, isolated human primary leukocytes, and whole human blood, Ac-hE18A-NH2 reduced responses more strongly than 4F to both E. coli serotypes either when peptides were pre-incubated or co-incubated with LPS, indicating that Ac-hE18A-NH2 also has strong anti-inflammatory effects independent of endotoxin-neutralizing properties. In conclusion, Ac-hE18A-NH2 is more effective than 4F in inhibiting LPS-mediated inflammation, which opens prospective clinical applications for Ac-hE18A-NH2.

Evaluation of pigtail macaques as a model for the effects of copper intrauterine devices on HIV infection.

BACKGROUND: Long-acting, hormonal contraception may increase HIV risk. Copper intrauterine devices (IUDs) could serve as non-hormonal alternatives. We pilot a pigtail macaque model for evaluating HIV susceptibility factors during copper IUD use. METHODS: Frameless and flexible GyneFix(®) copper IUDs were surgically implanted into three SHIVSF 162p3 -positive macaques via hysterotomy and monitored for up to 4 months. Four macaques served as non-IUD controls. RESULTS: All animals retained the devices without complications. No consistent change in vaginal viral RNA or inflammatory cytokines was seen. Two animals had altered menstrual cycles and experienced marked thinning of vaginal epithelium after IUD insertion. Histological examination of uterine tissue at necropsy revealed endometrial ulceration and lymphocytic inflammation with glandular loss at sites of direct IUD contact. CONCLUSIONS: Although the need for insertion surgery could limit its usefulness, this model will allow studies on copper IUDs and SHIV shedding, disease progression, and HIV susceptibility factors.

Quercetin prevents left ventricular hypertrophy in the Apo E knockout mouse.

Hypercholesterolemia is a risk factor for the development of hypertrophic cardiomyopathy. Nevertheless, there are few studies aimed at determining the effects of dietary compounds on early or mild cardiac hypertrophy associated with dyslipidemia. Here we describe left ventricular (LV) hypertrophy in 12 week-old Apo E(-/-) hypercholesterolemic mice. The LV end diastolic posterior wall thickness and overall LV mass were significantly increased in Apo E(-/-) mice compared with wild type (WT) controls. Fractional shortening, LV end diastolic diameter, and hemodynamic parameters were unchanged from WT mice. Oral low dose quercetin (QCN; 0.1 µmol QCN/kg body weight for 6 weeks) significantly reduced total cholesterol and very low density lipoprotein in the plasma of Apo E(-/-) mice. QCN treatment also significantly decreased LV posterior wall thickness and LV mass in Apo E(-/-) mice. Myocardial geometry and function were unaffected in WT mice by QCN treatment. These data suggest that dietary polyphenolic compounds such as QCN may be effective modulators of plasma cholesterol and could prevent maladaptive myocardial remodeling.