Visible Blue Light Therapy: Molecular Mechanisms and Therapeutic Opportunities.

BACKGROUND: Visible light is absorbed by photoacceptors in pigmented and non-pigmented mammalian cells, activating signaling cascades and downstream mechanisms that lead to the modulation of cellular processes. Most studies have investigated the molecular mechanisms and therapeutic applications of UV and the red to near infrared regions of the visible spectrum. Considerably less effort has been dedicated to the blue, UV-free part of the spectrum. OBJECTIVE: In this review, we discuss the current advances in the understanding of the molecular photoacceptors, signaling mechanisms, and corresponding therapeutic opportunities of blue light photoreception in non-visual mammalian cells in the context of inflammatory skin conditions. METHODS: The literature was scanned for peer-reviewed articles focusing on the molecular mechanisms, cellular effects, and therapeutic applications of blue light. RESULTS: At a molecular level, blue light is absorbed by flavins, porphyrins, nitrosated proteins, and opsins; inducing the generation of ROS, nitric oxide release, and the activation of G protein coupled signaling. Limited and contrasting results have been reported on the cellular effects of blue light induced signaling. Some investigations describe a regulation of proliferation and differentiation or a modulation of inflammatory parameters; others show growth inhibition and apoptosis. Regardless of the elusive underlying mechanism, clinical studies show that blue light is beneficial in the treatment of inflammatory skin conditions. CONCLUSION: To strengthen the use of blue light for therapeutic purposes, further in depth studies are clearly needed with regard to its underlying molecular and cellular mechanisms, and their translation into clinical applications.

Low-dose 5-fluorouracil trabeculectomy as initial surgery in uncomplicated glaucoma: long-term followup.

OBJECTIVE: To compare the effectiveness of trabeculectomy with adjunctive, low-dose, subconjunctival 5-fluorouracil (5-FU) to trabeculectomy alone in patients with uncomplicated glaucoma undergoing their first incisional surgical procedure. DESIGN: Retrospective, nonrandomized comparative trial. PARTICIPANTS: Consecutive series of 52 patients and 74 control subjects. INTERVENTION: Trabeculectomy was performed in all patients. Study patients received adjunctive, subconjunctival injections of 5-FU up to 14 days from the date of surgery. MAIN OUTCOME MEASURES: Intraocular pressure, number of postoperative antiglaucoma medications, interventions, and complications were evaluated. RESULTS: Mean followup for all patients was 58.1 +/- 44.1 months (range, 1.1-159.9 months). Mean followup for successful eyes was 55.9 +/- 47.1 months (range, 7.6-159.9 months). The cumulative 5-year success (intraocular pressure [IOP] < or = 21 mmHg) was 77.8% in the 5-FU group and 62.2% in the control group (P = 0.02, Wilcoxon test. Complete success (IOP < or = 21 mmHg without medications) at 5 years was lower in both the 5-FU group (72.3%) and the control group (51.3%). Postoperative mean IOP at 5 years for all successful patients was lower in eyes receiving 5-FU (10.7 +/- 3.6 mmHg vs. 16.0 +/- 6.1 mmHg [P = 0.02, t-test]). For those patients considered to be complete successes, there was no difference in IOP between the two groups of patients at any evaluated time interval. Patients in the 5-FU group were using 0.7 +/- 1.1 medications at final followup compared with 1.8 +/- 1.4 medications in the control group (P = < 0.0001, t test). Bleb-related ocular infection occurred in 6.3% of patients and was more common in patients receiving 5-FU than controls (6 of 52 vs 2 of 74, respectively; P = 0.05, Fischer's exact test). CONCLUSIONS: Adjunctive, low-dose 5-FU at the time of initial surgery in uncomplicated glaucoma improves long-term IOP control and reduces the need for postoperative, antiglaucoma therapy. Eyes receiving 5-FU are at greater risk of developing late bleb-related ocular infection.

Late-onset bleb leaks after glaucoma filtering surgery.

OBJECTIVE: To determine the incidence of focal, late-onset, conjunctival bleb leaks after glaucoma filtering surgery. DESIGN: Prospective, cross-sectional analysis. SETTING: Tertiary care outpatient referral center. PATIENTS: Consecutive patients who underwent glaucoma filtering surgery prior to June 1996 presenting for evaluation from September 2,1996, through November 15,1996. Five hundred twenty-five eyes of 525 consecutive patients were enrolled in the study. INTERVENTION: Bleb height (elevated or flat), area (diffuse or localized), and wall thickness (thin, thick, or encapsulated) were classified. Each bleb was tested for focal leakage using a moistened fluorescein strip, cobalt blue illumination, and slit-lamp biomicroscopy. Diffuse transconjunctival aqueous flow did not qualify as a focal leak. MAIN OUTCOME MEASURE: Seidel-positive aqueous leakage. RESULTS: Bleb leakage occurred in 14 eyes following trabeculectomy (mitomycin C treatment, 10 eyes; 5-fluorouracil treatment, 3 eyes; no antifibrosis agent, 1 eye) and in 1 eye following combined cataract and glaucoma surgery with adjunctive mitomycin C therapy. Bleb leakage occurred more frequently in eyes that received mitomycin C (10 [3.7%] of 273 eyes) than 5-fluorouracil (3 [1.4%] of 213 eyes) or no antifibrosis agent (1 [2.6%] of 39 eyes), using Kaplan-Meier estimates (P=.008, log-rank test). Conjunctival blebs were significantly thinner after trabeculectomy with mitomycin C than with 5-fluorouracil (P=.001). Bleb wall thickness was greater following combined cataract and glaucoma surgery than following trabeculectomy alone (P=.008). Age (P=.84), sex (P=.68), race (P=.77), duration of mitomycin C exposure (P=.62), number of antiglaucoma medications (P=.16), and total 5-fluorouracil dose (P=.85) were not associated with late-onset leaks. CONCLUSIONS: The risk of late-onset focal bleb leakage increases following trabeculectomy with mitomycin C therapy. Late leakage after combined cataract and glaucoma surgery is infrequent.

Phase II trial of 5-fluorouracil, leucovorin, interferon-alpha-2a, and cisplatin as neoadjuvant chemotherapy for locally advanced esophageal carcinoma.

BACKGROUND: Most patients with esophageal carcinoma present with locally advanced disease and a poor prognosis. Surgery or radiation provides palliation for locally advanced esophageal carcinoma. The role of neoadjuvant therapy remains to be defined. We administered neoadjuvant chemotherapy consisting of 5-fluorouracil (5-FU), leucovorin, interferon-alpha, and cisplatin to 11 patients with locally advanced disease. METHODS: Eleven patients with squamous cell or adenocarcinoma of the esophagus were treated peroperatively with two to three cycles of combination chemotherapy. Nine patients underwent resection with curative intent. RESULTS: Six patients received three cycles of chemotherapy, and five received two. Dose reduction was necessary for two patients. One patient achieved a pathologic complete response, histologically confirmed. Of the eleven patients, two did not undergo surgery because of progressive disease during chemotherapy. Seven of the 9 patients relapsed after surgery and 2 have been disease free for 27 months. CONCLUSIONS: The combination 5-FU leucovorin, interferon-alpha-2a, and cisplatin administered in a neoadjuvant setting resulted in a median survival of 11.8 months with a median time to relapse of 7 months.

Trabeculectomy at the inferior limbus.

OBJECTIVE: To evaluate intraocular pressure (IOP) control and surgical complications following trabeculectomy with 5-fluorouracil (5-FU) or mitomycin at the inferior limbus. METHODS: The charts of all patients undergoing trabeculectomy at the inferior limbus from July 1984 to March 1993 were reviewed. Surgical success was defined as IOP greater than 4 mm Hg and less than 22 mm Hg and at least a 20% reduction from preoperative IOP. PATIENTS: All 101 eyes of 101 patients had undergone prior intraocular surgery at the superior limbus. Mean patient age was 57.5 +/- 2.0 (+/-SE) years; mean follow-up was 23.4+/-2.3 months; mean preoperative IOP was 32.8+/-0.9 mm Hg; and mean number of preoperative antiglaucoma medications was 2.8+/-0.1. RESULTS: Ninety-four eyes (93.1%) received postoperative 5-FU (mean total dose, 36.3+/-1.7 mg) and seven eyes (6.9%) received intraoperative mitomycin (0.5 mg/mL). Cumulative success for all eyes at 2 and 5 years was 56% and 38%, respectively. Intraocular pressure control without medications was achieved in 39% and 15% of eyes at 2 and 5 years, respectively. Complications included 5-FU epitheliopathy (34.0% of eyes receiving 5-FU), early wound leak (26.7%), choroidal effusion (25.7%), late bleb leak (12.9%), and late bleb-related endophthalmitis (11.9%). CONCLUSION: Although trabeculectomy at the inferior limbus offers the opportunity for surgical success in eyes at high risk of failure, this procedure carries an increased risk for late complications and should be reserved for cases in which the therapeutic options are extremely limited.

[Methanol formation in vitro and in vivo (methanol formation after pectin administration)]. / Zur Methanolbildung in vitro und in vivo (Methanolbildung nach Pektingaben).

1. In the course of 34 days the detectable methanol concentration in freshly squeezed grapefruit and organ juices as well as in grapefruit and orange juice mixes increased to a maximum level of approximately 600 mg/kg. This increase could already be detected at the beginning of the examination i.e. as early as 1 or 2 days after squeezing the fruit juices. At the beginning of the experiments the methanol concentrations were between 10 and 270 mg/kg. 2. After the consumption of pectin (40 g on one day and 2 x 40 g on two days) blood or serum-methanol values respectively were observed which were clearly above the level of chronic alcohol abuse (10 mg/kg). After the ingestion of ethanol (0.5 g/kg bodyweight) the serum-methanol concentration increased even further.

Sub-Tenon's anesthesia for trabeculectomy.

Sub-Tenon's anesthesia for anterior segment surgery avoids the risks associated with retrobulbar and peribulbar injections. Localized injections over the appropriate rectus muscles ensure patient comfort as well as optimal exposure of the surgical field in eyes undergoing trabeculectomy. We have used this technique without significant complications in approximately 400 procedures.

Acute selective withdrawal of testosterone negative feedback increases luteinizing hormone secretion without altering hypothalamic catecholaminergic neuronal activity.

Orchidectomy results in increased LH and FSH levels by removal of negative feedback at the hypothalamus and pituitary gland. However, the precise central nervous system mechanisms involved in elevation of gonadotropins after castration are unclear. We tested the hypothesis that catecholamine neuronal activity mediates the rise in serum LH that occurs after withdrawal of testosterone (T) negative feedback. The effects of acute and selective T withdrawal on brain catecholamine and LHRH activity and serum LH levels were determined in adult male rats. At the time of orchidectomy, rats were given sc implants of both T-containing and empty Silastic capsules. After recovery from surgery, the T-containing capsule was atraumatically removed from half of the animals (T-withdrawn), while the empty capsule was removed from the remaining rats (T-replaced). Rats were killed before and 6, 12, and 24 h after capsule removal. Serum T and LH levels were determined by RIA. Catecholamine content in microdissected nuclei of the LHRH neuronal system [medial preoptic nucleus, suprachiasmatic nucleus, retrochiasmatic area, arcuate nucleus (ARC), and median eminence (ME)] was measured by HPLC with electrochemical detection. Norepinephrine turnover rate was also determined in these areas by measuring the rate of decline of NE levels after blockade of synthesis with diethyldithiocarbamate. Additionally, LHRH content was measured by RIA within the ARC and ME. In T-replaced rats, the T capsules maintained serum T and LH levels within the normal range for intact male rats. In T-withdrawn rats, T levels fell into castrate range by 6 h after removal of the T capsule [0.12 +/- 0.04 ng/ml (mean +/- SEM); P less than 0.01 vs. T-replaced], and LH levels increased significantly from 0.23 +/- 0.04 ng/ml before capsule removal to 1.31 +/- 0.14 and 2.80 +/- 0.20 ng/ml 12 and 24 after T withdrawal, respectively (both P less than 0.01 vs. T-replaced). Despite a marked increase in serum LH levels, no significant changes in catecholamine content or NE turnover rate were observed in any of the hypothalamic nuclei of the LHRH neuronal system at any time after T withdrawal. ARC and ME LHRH levels also did not change significantly at any point after T withdrawal. These results suggest that activation of hypothalamic catecholamine neuronal activity is not required for the rise in serum LH levels after acute withdrawal of T negative feedback.