Sham-treated Subjects Research Articles

A Pivotal Study on the Safety and Effectiveness of a Targeted Alkali Thermolysis Patch for Treatment of Primary Axillary Hyperhidrosis or Excessive Axillary Sweating.

One-third of US adults are bothered by excessive sweating, approximately 5% are diagnosed with hyperhidrosis. A topical patch using targeted alkali thermolysis (TAT) was developed for treatment of this condition. This study was intended to assess the efficacy and safety of the TAT-Patch for axillary sweat reduction. A randomized, multicenter, double-blind, sham-controlled, pivotal trial enrolled 120 subjects to a bilateral axillary treatment with a TAT patch (63 subjects) or sham patch (57 subjects). The primary end point was achieved; 64% of TAT-treated versus 44% of sham-treated subjects (p = .0332) improved from Hyperhidrosis Disease Severity Scale (HDSS) 3/4 to HDDS 1/2 at 4 weeks. Targeted alkali thermolysis treatment also showed a statistically significant improvement over sham treatment for all secondary end points, including gravimetric sweat production and subject-reported quality-of-life (QoL) assessments. The duration of effect is approximately 3 months, determined by the time to return to baseline HDSS. Mild-to-moderate treatment-site adverse events (AEs) were reported in 22% of TAT patch subjects. No serious or severe AEs were reported. HDSS, GSP, and QoL findings confirm clinically meaningful sweat reduction and a significant improvement in quality of life following a single TAT patch treatment. This device has potential to offer a new, noninvasive treatment option that is well tolerated with minimal downtime.

Indole-3-propionic acid alleviates ischemic brain injury in a mouse middle cerebral artery occlusion model

Increasing evidence highlights the importance of gut microbiota and its metabolites as an environmental factor affecting ischemic stroke. However, the role of microbial indole metabolites in ischemic stroke remains largely unknown. Here, we evaluated the effects and the underlying mechanism of indole-3-propionic acid (IPA) in a mouse model of acute middle cerebral artery occlusion (MCAO) and the mechanisms underlying these effects. We collected blood samples and evaluated serum indole derivatives levels using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS) in 8–10-week-old male C57 mice undergoing MCAO or sham. Intragastric IPA administration (400 μg/20 g/d) was performed in mice with MCAO, and its effects and mechanisms were assessed. We found that the serum IPA levels were significantly lower in mice with MCAO than in sham-treated subjects. 16S rRNA gene sequencing revealed that IPA treatment ameliorated the MCAO-induced alterations of the gut microbiome structure, specifically reshaping the microbial community composition in mice with MCAO to resemble that in the mice from the control group, with an increase in the abundance of probiotics and a decrease in the abundance of harmful bacteria. IPA repaired the integrity of the intestinal barrier and regulated the activities of regulatory T cells (Tregs) and Th17 cells in the gut-associated lymphoid tissue. Intragastric IPA administration effectively alleviated neuroinflammation, neurological impairment and brain infarction. Of note, Tregs in the IPA treatment group inhibited A1 reactive astrogliosis in vitro. The beneficial effects of IPA are thus mediated by the gut microbiota, which could enable the development of prebiotics for microbiome-based treatments for ischemic stroke.

Endocrine regulation of egg rejection in an avian brood parasite host.

Parasite-host coevolution can lead to novel behavioural adaptations in hosts to resist parasitism. In avian obligate brood parasite and host systems, many host species have evolved diverse cognitive and behavioural traits to recognize and reject parasitic eggs. Our understanding of the evolution and ecology of these defences hinges on identifying the mechanisms that regulate them. We hypothesized that corticosterone, a hormone linked to stress response, vigilance and the suppression of parental behaviour, stimulates the rejection of foreign eggs by brood parasite hosts. We experimentally reduced circulating glucocorticoid levels with mitotane injections in American robins Turdus migratorius and found that the mitotane-treated birds rejected foreign eggs at a lower frequency compared to the sham-treated subjects. This is the first study to causally identify a potential mechanism of a widespread defence behaviour, and it is consistent with egg rejection being mediated by stress physiology.

A DOUBLE-MASKED, RANDOMIZED, SHAM-CONTROLLED, SINGLE-CENTER STUDY WITH PHOTOBIOMODULATION FOR THE TREATMENT OF DRY AGE-RELATED MACULAR DEGENERATION.

The LIGHTSITE I study investigated the efficacy and safety of photobiomodulation (PBM) treatment in subjects with dry age-related macular degeneration. Thirty subjects (46 eyes) were treated with the Valeda Light Delivery System, wherein subjects underwent two series of treatments (3× per week for 3-4 weeks) over 1 year. Outcome measures included best-corrected visual acuity, contrast sensitivity, microperimetry, central drusen volume and drusen thickness, and quality of life assessments. Photobiomodulation-treated subjects showed a best-corrected visual acuity mean letter score gain of 4 letters immediately after each treatment series at Month 1 (M1) and Month 7 (M7). Approximately 50% of PBM-treated subjects showed improvement of ≥5 letters versus 13.6% in sham-treated subjects at M1. High responding subjects (≥5-letter improvement) in the PBM-treated group showed a gain of 8 letters after initial treatment (P < 0.01) and exhibited earlier stages of age-related macular degeneration disease. Statistically significant improvements in contrast sensitivity, central drusen volume, central drusen thickness, and quality of life were observed (P < 0.05). No device-related adverse events were reported. Photobiomodulation treatment statistically improved clinical and anatomical outcomes with more robust benefits observed in subjects with earlier stages of dry age-related macular degeneration. Repeated PBM treatments are necessary to maintain benefits. These pilot findings support previous reports and suggest the utility of PBM as a safe and effective therapy in subjects with dry age-related macular degeneration.

Effect of Single-Session, Cryogen-Cooled Monopolar Radiofrequency Therapy on Sexual Function in Women with Vaginal Laxity: The VIVEVE I Trial.

Objective: This subanalysis of the VIVEVE I trial aimed to evaluate the impact of cryogen-cooled monopolar radiofrequency (CMRF) therapy, for the treatment of vaginal laxity, on the domains of sexual function included in the Female Sexual Function Index (FSFI).Materials and Methods: The VIVEVE I clinical trial was prospective, randomized, single-blind, and Sham-controlled. Nine clinical study centers in Canada, Italy, Spain, and Japan were included. This subanalysis included premenopausal women with self-reported vaginal laxity who had ≥1 term vaginal delivery and a baseline FSFI total score ≤26.5, indicating sexual dysfunction. Enrolled subjects were randomized (2:1) to receive CMRF therapy [Active (90 J/cm2) vs. Sham (≤1 J/cm2)] delivered to the vaginal tissue. Independent analyses were conducted for each FSFI domain to evaluate both the mean change, as well as the clinically important change for Active- versus Sham-treated subjects at 6 months post-intervention.Results: Subjects randomized to Active treatment (n = 73) had greater improvement than Sham subjects (n = 35) on all FSFI domains of sexual function at 6 months postintervention. The analysis of covariance change from baseline analyses showed statistically significant improvements, in favor of Active treatment, for sexual arousal (p = 0.004), lubrication (p = 0.04), and orgasm (p = 0.007). In addition, Active treatment was associated with clinically important and statistically significant improvements in sexual desire [Odds ratio (OR) = 3.01 (1.11–8.17)], arousal [OR = 2.73 (1.06–7.04)], and orgasm [OR = 2.58 (1.08–6.18)].Conclusions: This subanalysis showed CMRF therapy is associated with statistically significant and clinically important improvements in sexual function in women with vaginal laxity. These findings provide the first randomized, placebo-controlled energy-based device evidence for functional improvements associated with a nonsurgical modality for a highly prevalent and undertreated condition.

Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study.

BackgroundClinical observations and results from recent studies support the use of non-invasive vagus nerve stimulation (nVNS) for treating cluster headache (CH) attacks. This study compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH).MethodsAfter completing a 1-week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment.ResultsThe Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14%) and sham (12%) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48%) was superior to sham (6%; p < 0.01). No significant differences between nVNS (5%) and sham (13%) were seen in the cCH subgroup.ConclusionsCombing both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy in eCH but not in cCH. These results confirm and extend previous findings regarding the efficacy, safety, and tolerability of nVNS for the acute treatment of eCH.

Low-Level Laser Therapy for Reducing the Hip, Waist, and Upper Abdomen Circumference of Individuals with Obesity.

To assess the effectiveness of low-level laser therapy (LLLT) for reducing hip, thigh, and abdomen circumference of individuals with body-mass index (BMI) between 30 and 40 kg/m2. Previous studies demonstrated the effectiveness of LLLT for reducing body circumference in the hips, thighs, and abdomen of nonobese individuals with a BMI <30 kg/m2. In this randomized, double-blind sham-controlled study, obese, but otherwise healthy, individuals were randomized to undergo 30-min LLLT (n = 28) or sham treatments (n = 25) three times weekly for 4 weeks. Body measurements were obtained after 2 and 4 weeks of treatment and 2 weeks post-treatment ( ClinicalTrials.gov Identifier: NCT01821352). After 4 weeks, 20 LLLT-treated subjects (71.43%) achieved ≥7.2 cm decrease in combined measurements versus three sham-treated subjects (12%; p < 0.00005). The mean (standard deviation) decrease in combined measurement for LLLT-treated subjects was 10.52 (7.59) cm (p < 0.0001 vs. baseline) versus 1.80 (3.20) cm for sham-treated subjects. Among subjects with a combined ≥7.2 cm decrease, the mean total decrease 2 weeks post-treatment was 15.21 cm. There were no adverse events. Based on these results, the device was cleared by the U.S. Food and Drug Administration as a noninvasive esthetic treatment for reduction of circumference of hips, waist, and upper abdomen when applied to individuals with a BMI between 30 and 40 kg/m2.

Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study.

ObjectiveTo evaluate non‐invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment.BackgroundMany patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments.MethodsOne hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double‐blind phase; completers could enter a 3‐month nVNS open‐label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15‐60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified.ResultsThe intent‐to‐treat population comprised 133 subjects: 60 nVNS‐treated (eCH, n = 38; cCH, n = 22) and 73 sham‐treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS‐treated subjects and 15.1% of sham‐treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double‐blind phase and 18/128 subjects in the open‐label phase. No serious ADEs occurred.ConclusionsIn one of the largest randomized sham‐controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well‐tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.

A Double-Blind, Sham-Controlled Study Demonstrating the Effectiveness of Low-Level Laser Therapy Using a 532-nm Green Diode for Contouring the Waist, Hips, and Thighs

Introduction: A low-level laser therapy (LLLT) device emitting 635 nm of red light is an effective, noninvasive method of reducing the circumference of the waist, hips, thighs, and upper arms. This randomized, double-blind, sham-controlled study assessed the effectiveness of an LLLT device emitting 532 nm of green light for body contouring using the same treatment protocol as the red 635-nm LLLT device. Materials and Methods: Enrolled subjects were 18–65 years of age with a body mass index (BMI) &lt;30 kg/m2. The LLLT device consists of 5 independent diodes, each emitting 17 mW of green laser light with a frequency of 532 nm (Erchonia ML Scanner, Erchonia Corporation, McKinney, Tex). Subjects were randomized to receive active (n = 35) or sham LLLT treatments (n = 32) over a 2-week period. Three treatments were administered each week, 2–3 days apart. Efficacy assessments included waist, hip, and thigh circumference measurements; body weight; and BMI following 3 LLLT treatments (week 1), 6 LLLT treatments (week 2), and 2 weeks following the final procedure. A treatment satisfaction survey was completed at week 2. The primary efficacy outcome measure was the change in total combined baseline circumference measurements at week 2. The criterion for individual treatment success was ≤3.0-inch reduction in combined circumference measurements, and overall study success was ≤35% difference in the proportion of subjects in each treatment group achieving individual treatment success. Secondary efficacy outcomes included the change in total combined baseline circumference measurements at each subject evaluation as well as satisfaction survey results. Results: At week 2, the LLLT-treated subjects demonstrated a mean (SD) decrease in total combined circumference measurements of 3.9 (3.0) inches (P &lt;.0001) compared with 1.1 (2.3) inches for sham-treated subjects. Among LLLT-treated subjects, 24 (68.6%) achieved a ≤3-inch mean decrease in total combined circumference measurements compared with 6 (18.8%) in the sham group (P &lt; .0001). The effects of LLLT treatment were independent of baseline body weight, BMI, and total baseline circumference measurement. Compared to baseline measures, the LLLT-treated subjects demonstrated significant decreases in circumference measures for each individual treatment area at the week 1, week 2, and 2 weeks posttreatment evaluations. Among subjects responding to the satisfaction survey, an overall satisfaction response was obtained from 65% of LLLT subjects versus 19% of sham-treated subjects. Conclusions: The use of LLLT device equipped with 532-nm green diodes is a safe and effective means for noninvasive body contouring of the waist, hips, and thighs.

Efficacy and Safety of a Low-level Laser Device in the Treatment of Male and Female Pattern Hair Loss: A Multicenter, Randomized, Sham Device-controlled, Double-blind Study

SignificanceMale and female pattern hair loss are common, chronic dermatologic disorders with limited therapeutic options. In recent years, a number of commercial devices using low-level laser therapy have been promoted, but there have been little peer-reviewed data on their efficacy.ObjectiveTo determine whether treatment with a low-level laser device, the US FDA-cleared HairMax Lasercomb®, increases terminal hair density in both men and women with pattern hair loss.MethodsRandomized, sham device-controlled, double-blind clinical trials were conducted at multiple institutional and private practices. A total of 146 male and 188 female subjects with pattern hair loss were screened. A total of 128 male and 141 female subjects were randomized to receive either a lasercomb (one of three models) or a sham device in concealed sealed packets, and were treated on the whole scalp three times a week for 26 weeks. Terminal hair density of the target area was evaluated at baseline and at 16- and 26-week follow-ups, and analyzed to determine whether the hypothesis formulated prior to data collection, that lasercomb treatment would increase terminal hair density, was correct. The site investigators and the subjects remained blinded to the type of device they dispensed/received throughout the study. The evaluator of masked digital photographs was blinded to which trial arm the subject belonged.ResultsSeventy-eight, 63, 49, and 79 subjects were randomized in four trials of 9-beam lasercomb treatment in female subjects, 12-beam lasercomb treatment in female subjects, 7-beam lasercomb treatment in male subjects, and 9- and 12-beam lasercomb treatment in male subjects, compared with the sham device, respectively. Nineteen female and 25 male subjects were lost to follow-up. Among the remaining 122 female and 103 male subjects in the efficacy analysis, the mean terminal hair count at 26 weeks increased from baseline by 20.2, 20.6, 18.4, 20.9, and 25.7 per cm2 in 9-beam lasercomb-treated female subjects, 12-beam lasercomb-treated female subjects, 7-beam lasercomb-treated male subjects, and 9- and 12-beam lasercomb-treated male subjects, respectively, compared with 2.8 (p < 0.0001), 3.0 (p < 0.0001), 1.6 (p = 0.0017), 9.4 (p = 0.0249), and 9.4 (p = 0.0028) in sham-treated subjects (95 % confidence interval). The increase in terminal hair density was independent of the age and sex of the subject and the lasercomb model. Additionally, a higher percentage of lasercomb-treated subjects reported overall improvement of hair loss condition and thickness and fullness of hair in self-assessment, compared with sham-treated subjects. No serious adverse events were reported in any subject receiving the lasercomb in any of the four trials.Conclusions and relevanceWe observed a statistically significant difference in the increase in terminal hair density between lasercomb- and sham-treated subjects. No serious adverse events were reported. Our results suggest that low-level laser treatment may be an effective option to treat pattern hair loss in both men and women. Additional studies should be considered to determine the long-term effects of low-level laser treatment on hair growth and maintenance, and to optimize laser modality.

Noninvasive Brain Stimulation for Treatment of Right- and Left-Handed Poststroke Aphasics

Background: Accumulating evidence from single case studies, small case series and randomized controlled trials seems to suggest that inhibitory noninvasive brain stimulation (NIBS) over the contralesional inferior frontal gyrus (IFG) of right-handers in conjunction with speech and language therapy (SLT) improves recovery from poststroke aphasia. Application of inhibitory NIBS to improve recovery in left-handed patients has not yet been reported. Methods: A total of 29 right-handed subacute poststroke aphasics were randomized to receive either 10 sessions of SLT following 20 min of inhibitory repetitive transcranial magnetic stimulation (rTMS) over the contralesional IFG or 10 sessions of SLT following sham stimulation; 2 left-handers were treated according to the same protocol with real rTMS. Language activation patterns were assessed with positron emission tomography prior to and after the treatment; 95% confidence intervals for changes in language performance scores and the activated brain volumes in both hemispheres were derived from TMS- and sham-treated right-handed patients and compared to the same parameters in left-handers. Results: Right-handed patients treated with rTMS showed better recovery of language function in global aphasia test scores (t test, p < 0.002) as well as in picture-naming performance (ANOVA, p = 0.03) than sham-treated right-handers. In treated right-handers, a shift of activation to the ipsilesional hemisphere was observed, while sham-treated patients consolidated network activity in the contralesional hemisphere (repeated-measures ANOVA, p = 0.009). Both left-handed patients also improved, with 1 patient within the confidence limits of TMS-treated right-handers (23 points, 15.9-28.9) and the other patient within the limits of sham-treated subjects (8 points, 2.8-14.5). Both patients exhibited only a very small interhemispheric shift, much less than expected in TMS-treated right-handers, and more or less consolidated initially active networks in both hemispheres. Conclusion: Inhibitory rTMS over the nondominant IFG appears to be a safe and effective treatment for right-handed poststroke aphasics. In the 2 cases of left-handed aphasics no deterioration of language performance was observed with this protocol. However, therapeutic efficiency is less obvious and seems to be more related to the dominance pattern prior to the stroke than to the TMS intervention.

A double‐blind, placebo‐controlled randomized trial evaluating the ability of low‐level laser therapy to improve the appearance of cellulite

Cellulite is present in 90% of post-adolescent women. Several technologies have been developed for treating cellulite; however, they all involve some degree of massage or mechanical manipulation. The purpose of this study was to assess the effectiveness of a low-level laser light device employing green 532 nm diodes as a stand-alone procedure without massage or mechanical manipulation for improving the appearance of cellulite in the thighs and buttocks. This double-blind study randomized subjects to undergo treatment with the LLLT device (N = 34) or sham treatment (N = 34). During a 2-week treatment phase, each subject received three weekly treatment sessions 2-3 days apart. During each session, the front and back of the hips, thighs, and waist were exposed for 15 minutes (30 minutes total). Nineteen subjects in the LLLT group achieved a decrease of one or more stages on the Nurnberger-Muller grading scale (55.88%) versus three subjects (8.82%) in the sham-treated group (P < 0.0001). Two LLLT-treated subjects achieved 2-stage improvements on the Nurnberger-Muller Scale at the 2-week study endpoint and four did at the 6-week follow-up evaluation versus none of the sham-treated subjects at either time point. Subjects treated with LLLT achieved a significant decrease in combined baseline thigh circumference at the 2-week study endpoint and 6-week follow-up evaluation (for each, p < 0.0001 vs. baseline) versus no change for sham-treated subjects. LLLT-treated subjects also showed significant decreases in mean baseline body weight (P < 0.0005), BMI (P < 0.001), and percent BSA affected by cellulite (P < 0.0005) versus no change for any parameter among sham-treated subjects. Most LLLT-treated subjects (62.1%) were Very Satisfied or Somewhat Satisfied with the improvement in cellulite they received versus 25.8% of sham-treated subjects. There were no reports of adverse events. Low-level laser therapy using green 532 nm diodes is safe and effective for improving the appearance of cellulite in the thighs and buttocks. In contrast with other technologies, LLLT is effective as a stand-alone procedure without requiring massage or mechanical manipulation. Future studies will assess the long-term benefits of LLLT for the treatment of cellulite.

Changes in Vision- and Health-Related Quality of Life in Patients with Diabetic Macular Edema Treated with Pegaptanib Sodium or Sham

To compare vision function and self-reported quality of life (QoL) in patients with diabetic macular edema (DME) treated with intravitreous pegaptanib 0.3 mg or sham injection. This randomized (1:1), controlled, multicenter trial included subjects with DME (center point thickness on OCT, ≥ 250 μm) and visual acuity (VA) ≤ 65 letters and ≥ 35 letters. In year 1, pegaptanib or sham was administered every 6 weeks with focal/grid photocoagulation at investigator discretion after week 18. Subjects received injections as often as every 6 weeks per pre-specified criteria in year 2. Primary efficacy endpoint: proportion gaining ≥10 letters of VA from baseline to week 54. Change in QoL from baseline to weeks 54 and 102 was assessed with the 25-item National Eye Institute-Visual Function Questionnaire (NEI-VFQ 25) and the EQ-5D. One hundred thirty-three pegaptanib- and 127 sham-treated subjects were in the year 1 intent-to-treat population. From baseline to week 54, ≥ 10 letter gains seen in 49 (36.8%) pegaptanib- and 25 (19.7%) sham-treated subjects (odds ratio [95% CI]: 2.38 [1.32-4.30]; P = 0.0047). At 2 years, the VA trend favored pegaptanib. The NEI-VFQ 25 domains of Near Vision, Distance Vision, and Social Functioning (week 54) and Distance Vision, Social Functioning, Mental Health, and Composite Score (week 102) demonstrated clinically meaningful (>5-point between-group difference) and statistically significant (P < 0.05) benefits favoring pegaptanib. No significant difference in the mean change in generic EQ-5D-weighted utility scores was seen. The VA improvement from pegaptanib treatment versus sham is reflected by improved vision-related QoL as reported by the DME patient (ClinicalTrials.gov number, NCT00605280).

A Phase 2/3, Multicenter, Randomized, Double-Masked, 2-Year Trial of Pegaptanib Sodium for the Treatment of Diabetic Macular Edema

To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia. Randomized (1:1), sham-controlled, multicenter, parallel-group trial. Subjects with DME. Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria. The primary efficacy endpoint was the proportion gaining ≥ 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout. In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of ≥ 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P<0.05) to sham at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102. At week 102, pegaptanib-treated subjects gained, on average, 6.1 letters versus 1.3 letters for sham (P<0.01). Fewer pegaptanib- than sham-treated subjects received focal/grid laser treatment (week 54, 31/133 [23.3%] vs 53/127 [41.7%], respectively, P = 0.002; week 102, 27/107 [25.2%] vs 45/100 [45.0%], respectively, P = 0.003). The pegaptanib treatment group showed significantly better results on the National Eye Institute-Visual Functioning Questionnaire than sham for subscales important in this population. Pegaptanib was well tolerated; the frequencies of discontinuations, adverse events, treatment-related adverse events, and serious adverse events were comparable in the pegaptanib and sham groups. Patients with DME derive clinical benefit from treatment with the selective vascular endothelial growth factor antagonist pegaptanib 0.3 mg. These findings indicate that intravitreal pegaptanib is effective in the treatment of DME and, taken together with prior study data, support a positive safety profile in this population. Proprietary or commercial disclosure may be found after the references.

Pegaptanib Sodium for Macular Edema Secondary to Central Retinal Vein Occlusion

To assess the safety and efficacy of intravitreous pegaptanib sodium for the treatment of macular edema following central retinal vein occlusion (CRVO). This dose-ranging, double-masked, multicenter, phase 2 trial included subjects with CRVO for 6 months' or less duration randomly assigned (1:1:1) to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks (0.3 mg and 1 mg, n=33; sham, n=32). Visual acuity at week 30. In the primary analysis at week 30, 12 of 33 (36%) subjects treated with 0.3 mg of pegaptanib sodium and 13 of 33 (39%) treated with 1 mg gained 15 or more letters from baseline vs 9 of 32 (28%) sham-treated subjects (P= .48 for 0.3 mg and P= .35 for 1 mg of pegaptanib sodium vs sham). In secondary analyses, subjects treated with pegaptanib sodium were less likely to lose 15 or more letters (9% and 6%; 0.3-mg and 1-mg pegaptanib sodium groups, respectively) compared with sham-treated eyes (31%; P= .03 for 0.3 mg and P= .01 for 1 mg of pegaptanib sodium vs sham) and showed greater improvement in mean visual acuity (+7.1 and +9.9, respectively, vs -3.2 letters with sham; P= .09 for 0.3 mg and P= .02 for 1 mg of pegaptanib sodium vs sham). By week 1, the mean central retinal thickness decreased in the 0.3-mg and 1-mg pegaptanib sodium groups by 269 microm and 210 microm, respectively, vs 5 microm with sham (P< .001). Based on this 30-week study, intravitreous pegaptanib sodium appears to provide visual and anatomical benefits in the treatment of macular edema following CRVO. Benefits accrued with intravitreous pegaptanib sodium treatment of macular edema following CRVO suggest a role for vascular endothelial growth factor in the pathogenesis of this condition. clinicaltrials.gov Identifier: NCT00088283.

Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial

Aims:To evaluate the safety of up to 3 years of pegaptanib sodium therapy in the treatment of neovascular age-related macular degeneration (NV-AMD).Methods:Two concurrent, prospective, multicentre, double-masked studies randomised subjects with...

Gastro-oesophageal Reflux in Obese Subjects: Influence of Overweight, Weight Loss and Chronic Gastric Balloon Distension

Background: Gastro-oesophageal reflux is an obesity-related health risk assumed to improve after weight loss. Prolonged intragastric balloon distension might oppose this. The purpose of the study was to investigate the prevalence of gastro-oesophageal reflux in untreated obese subjects and to study the consequences of weight loss with or without intragastric balloon treatment. Methods: Patients participating in a randomized double-blind, sham-controlled trial received balloon or sham treatment for the first 13 weeks. Thereafter, all subjects received a balloon for the remaining year. Twenty-four-hour pH recordings were made at the start, after 13 weeks of balloon or sham treatment, after 26 and 52 weeks of balloon treatment and 13 weeks after balloon removal. Results: Group-wise, pH data of 42 untreated patients (BMI 43.4 kg/m 2 ) were highly abnormal. On an individual level, 22 subjects (52%) had some evidence of reflux, 17 patients (40%) showed pathological total reflux times and 8 (19%) had combined total, upright and supine reflux with grade B reflux oesophagitis in only one patient. Albeit poorly, oesophageal acid exposure was related to body weight and visceral fat distribution. A reduction in acid reflux was observed in sham-treated weight-losing subjects, whereas in balloon-treated subjects supine reflux and duration of the longest reflux increased. In the second 13-week period, the initially improved pH values worsened by balloon placement in sham-treated subjects. Values in balloon-balloon-treated subjects stabilized. After 52 weeks, acid reflux levelled off at pretreatment values and further improved after balloon removal. At these times, decreased visceral fat masses correlated significantly with diminished oesophageal exposure to acid. Conclusions: Obesity predisposed to gastro-oesophageal reflux. Body weight loss and, strikingly, visceral fat loss resulted in improved reflux parameters. Adverse effects on acid reflux by gastric balloon distension wore off over time.

Effects of lesions of the central nucleus of the amygdala on anxiety-like behaviors in the rat

The effects of lesions of the central nucleus of the amygdala on anxiety-like behaviors in the rat were determined using two animal models, the conditioned suppression of drinking (CSD) and defensive burying paradigms. For CSD conflict testing, water-restricted rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. CSD test sessions were 10 min in duration and were conducted 4 days per week. After at least 3 weeks of conflict testing, both punished (30–40 shocks per session) and unpunished (10–12 ml water per session) responding had stabilized. Subjects then received bilateral electrolytic lesions of the central nucleus of the amygdala or sham lesions. After a 1-week recovery period, CSD conflict testing was reinstated and continued for 20 weeks. Amygdaloid-lesioned subjects accepted significantly more shocks than did sham controls. In addition, acute challenges with the benzodiazepine chlordiazepoxide (2.5–10 mg/kg, IP, 30-min pretreatment), the barbiturate phenobarbital (20 mg/kg, IP, 10-min pretreatment), and carbamazepine (10 mg/kg, IP, 10-min pretreatment) produced an increase in punished responding in both amygdaloid-lesioned and sham-treated subjects. Analysis of covariance (ANCOVA)-based adjusted means for the change in shocks received were not significantly different between the two groups. Following completion of the CSD studies, subjects were tested in the defensive burying paradigm. Although there was no significant difference between lesioned and sham-treated subjects on the percent of animals that exhibited burying, subjects with lesions of the central nucleus of the amygdala exhibited a significantly greater latency to initiate defensive burying. Lesioned subjects also exhibited a shorter duration of defensive burying than sham-treated subjects; however, this difference was not statistically significant. These data suggest that although the central nucleus of the amygdala contributes to baseline anxiety-like behaviors the anxiolytic-like effects of chlordiazepoxide, phenobarbital, and carbamazepine do not appear to be dependent upon the integrity of this amygdaloid nucleus.

Frontal cortex lesions block the opioid and nonopioid hypoalgesia elicited by brief shocks but not the nonopioid hypoalgesia elicited by long shocks.

Previous research (Grau, 1987a, 1987b) suggests that forebrain systems play an essential role in the hypoalgesia observed after brief shock but not long shock. Additional research has shown that pentobarbital anesthesia and decerebration block the hypoalgesia observed after 3 brief (0.75-s) shocks but not the hypoalgesia observed after 3 long (25-s) shocks. This is a study of whether a specific forebrain lesion, a frontal cortex lesion, would have a similar impact on hypoalgesia induced by brief (0.75 s) and long (25-s) shocks. Frontal cortex lesions, like decerebration and pentobarbital anesthesia, eliminated the hypoalgesia observed after brief but not long shocks. Because other research suggests that the stress of surgery may influence whether the hypoalgesia elicited by shock is opioid or nonopioid, the 2nd experiment was to examine whether the sham operation per se alters the form of the hypoalgesia observed after brief shock. It does not; in the sham-treated subjects, brief shock induced the usual transient nonopioid hypoalgesia followed by prolonged opioid hypoalgesia. These data suggest that frontal cortex lesions block nonopioid and opioid hypoalgesia observed after brief shock.