Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study.

STUDY OBJECTIVES: We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months. METHODS: Clinical data obtained from the medical records of 61 patients treated at the Horikoshi Psychosomatic Clinic between December 2020 and February 2022 were analyzed, including the Athens Insomnia Scale, Epworth Sleepiness Scale, and Perceived Deficits Questionnaire-5. The primary outcome was the mean change in Athens Insomnia Scale score after 3 months. Secondary outcomes were the mean changes in the Epworth Sleepiness Scale and Perceived Deficits Questionnaire-5 scores over 3 months. We also compared pre- and post-diazepam equivalents. RESULTS: The mean Athens Insomnia Scale score decreased over 3 months after switching to lemborexant (1 mo: -2.98 ± 5.19, P < .001; 2 mo: -3.20 ± 5.64, P < .001; 3 mo: -3.38 ± 5.61, P < .001). Mean Epworth Sleepiness Scale score did not change from baseline to 1 month (-0.49 ± 3.41, P = 0.27), 2 months (0.082 ± 4.62, P = .89), or 3 months (-0.64 ± 4.80, P = .30). Mean Perceived Deficits Questionnaire-5 score did improve from baseline to 1 month (-1.17 ± 2.47, P = .004), 2 months (-1.05 ± 2.97, P = .029), and 3 months (-1.24 ± 3.06, P = .013). There was also a reduction in the total diazepam equivalent (baseline vs 3 mo: 14.0 ± 20.2 vs 11.3 ± 20.6, P < .001). CONCLUSIONS: Our study showed that, by switching to lemborexant from other hypnotics, the risks associated with benzodiazepines and Z-drugs may be reduced. CITATION: Horikoshi S, Miura I, Suzuki Y, et al. Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. J Clin Sleep Med. 2023;19(10):1753-1758.

Improvement of cellulosic biomass-degrading enzyme production by reducing extracellular protease production in Aspergillus aculeatus.

We investigated the effects of deleting major extracellular protease-encoding genes on cellulolytic and xylanolytic enzyme production in Aspergillus aculeatus. We first investigated the effect of prtT deletion, a positive transcription factor for extracellular protease-encoding genes in Aspergillus, on extracellular protease production in A. aculeatus. Genetic analysis indicated that among the major extracellular proteases, pepIIa and pepIIb are controlled by PrtT, but pepI is not. Thus, we generated a mutant with deletion of the two genes prtT and pepI (ΔprtTΔpepI) and one with deletion of the three genes pepI, pepIIa, and pepIIb (ΔpepIΔIIaΔIIb). Extracellular protease activities decreased in both ΔprtTΔpepI and ΔpepIΔIIaΔIIb to 3% of that in the control strain (MR12). Comparative time-course analyses indicated that endoglucanase activity in ΔprtTΔpepI increased to double that in MR12. Xylanase activities increased in both ΔprtTΔpepI and ΔpepIΔIIaΔIIb to fourfold higher than that in MR12 at maximum. ß-Glucosidase activities were increased in ΔprtTΔpepI and ΔpepIΔIIaΔIIb 1.3- and 1.4-fold higher than that in MR12 at maximum, respectively. Residual activities of endoglucanase, xylanase, and ß-glucosidase after 7 days of incubation at 37°C in the culture supernatant were 63%, 36%, and 48% of the original in MR12. Residual endoglucanase activities were more than 80% of the original in ΔprtT, ΔprtTΔpepI, and ΔpepIΔIIaΔIIb. Residual xylanase activities were not improved in all test strains. ß-Glucosidase remained almost 97% of the original in ΔprtTΔpepI. These findings indicated that the reduction of extracellular proteases effectively improved cellulolytic and xylanolytic enzyme production and stability in A. aculeatus.

Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions.

Metformin is a metabolic disruptor, and its efficacy and effects on metabolic profiles under different oxygen and nutrient conditions remain unclear. Therefore, the present study examined the effects of metformin on cell growth, the metabolic activities and consumption of glucose, glutamine, and pyruvate, and the intracellular ratio of nicotinamide adenine dinucleotide (NAD+) and reduced nicotinamide adenine dinucleotide (NADH) under normoxic (21% O2) and hypoxic (1% O2) conditions. The efficacy of metformin with nutrient removal from culture media was also investigated. The results obtained show that the efficacy of metformin was closely associated with cell types and environmental factors. Acute exposure to metformin had no effect on lactate production from glucose, glutamine, or pyruvate, whereas long-term exposure to metformin increased the consumption of glucose and pyruvate and the production of lactate in the culture media of HeLa and HaCaT cells as well as the metabolic activity of glucose. The NAD+/NADH ratio decreased during growth with metformin regardless of its efficacy. Furthermore, the inhibitory effects of metformin were enhanced in all cell lines following the removal of glucose or pyruvate from culture media. Collectively, the present results reveal that metformin efficacy may be regulated by oxygen conditions and nutrient availability, and indicate the potential of the metabolic switch induced by metformin as combinational therapy.

Hypoxically cultured cells of oral squamous cell carcinoma increased their glucose metabolic activity under normoxic conditions.

OBJECTIVE: The oxygen concentration within cancer tissue is known to be low, but is expected to increase rapidly when oxygen is supplied by angiogenesis and hematogenous metastasis, suggesting that rapid increases in oxygen levels might influence cancer cell physiology. Therefore, we investigated the effects of oxygen concentration fluctuations on the glucose metabolism of cancer cells. METHODS: The glucose metabolism of oral squamous cell carcinoma (HSC-2 and HSC-3) and normal epithelial (HaCaT) cells cultured under normoxic (21% oxygen) or hypoxic (1% oxygen) conditions was measured using a pH-stat system under normoxic or hypoxic conditions. The acidic end-products and reactive oxygen species (ROS) generated by glucose metabolism were also measured. RESULTS: Under normoxic conditions, the metabolic activity of hypoxically cultured cancer cells was significantly increased, and the production of acids other than lactate was upregulated, while the normal cells did not respond to rapid increases in oxygen levels. ROS production was higher in normoxic conditions in all cells, especially the hypoxically cultured HSC-3 cells. CONCLUSIONS: Rapid increases in oxygen levels might enhance the glucose metabolism of hypoxically cultured cancer cells by mainly activating the TCA cycle and electron transport system, which might activate cancer cells through the ATP and ROS generation.

Correlation between glucuronidation and covalent adducts formation with proteins of nonsteroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause idiosyncratic liver injury. Mechanisms involved in NSAID-induced liver injury are complex. Previous studies have suggested that acyl glucuronide of NSAIDs (NSAIDs-Glu) plays an important role in the development of liver injury via covalently binds to proteins and the resultant adduct induces immunological toxicity. As only some NSAIDs-Glu are commercially available, the evaluation of covalent protein adduct formation using ready-made NSAIDs-Glu is difficult and inconvenient. Moreover, glucuronidation potency varies with the NSAID, including stereoisomers. Therefore, in this study, we simultaneously examined the glucuronidation and covalent adduct formation using enantiomers of parent NSAIDs (ibuprofen, naproxen, pranoprofen, ketoprofen, and flurbiprofen) in rat liver microsomes. Glucuronides and covalent adducts were quantified by HPLC. The amount of covalent adduct increased with NSAIDs-Glu formation in the rat liver microsomes in a time-dependent manner. A significant positive correlation was observed between the AUC of NSAIDs-Glu and that of covalent adduct, except ketoprofen. Although ketoprofen exhibited the highest glucuronidation rate among the NSAIDs investigated, the amount of covalent adduct was similar to that for pranoprofen, which had the lowest glucuronidation rate. Thus, it may be difficult for ketoprofen glucuronide to covalently bind with proteins in the rat liver microsomes. Our results suggested that the amount of glucuronide formed is a key factor in predicting covalent bond formation with protein in NSAIDs, in addition to degradability and bindability with proteins of NSAIDs-Glu. Further studies are required to confirm the relationship between the tendency of glucuronidation and the formation of covalent adducts of NSAIDs.

Partitioned airs at microscale and nanoscale: thermal diffusivity in ultrahigh porosity solids of nanocellulose.

High porosity solids, such as plastic foams and aerogels, are thermally insulating. Their insulation performance strongly depends on their pore structure, which dictates the heat transfer process in the material. Understanding such a relationship is essential to realizing highly efficient thermal insulators. Herein, we compare the heat transfer properties of foams and aerogels that have very high porosities (97.3-99.7%) and an identical composition (nanocellulose). The foams feature rather closed, microscale pores formed with a thin film-like solid phase, whereas the aerogels feature nanoscale open pores formed with a nanofibrous network-like solid skeleton. Unlike the aerogel samples, the thermal diffusivity of the foam decreases considerably with a slight increase in the solid fraction. The results indicate that for suppressing the thermal diffusion of air within high porosity solids, creating microscale spaces with distinct partitions is more effective than directly blocking the free path of air molecules at the nanoscale.

Avaliação fitoquímica e potencial cicatrizante do extrato etanólico dos frutos de Jucá (Libidibia ferrea) em ratos Wistar / Phytochemical evaluation and wound healing potential of the fruit extract ethanolic of Jucá (Libidibia ferrea) in Wistar rats

Libidibia ferrea é uma planta muito utilizada popularmente para fins terapêuticos, inclusive para acelerar processos de cicatrização de feridas cutâneas. O presente trabalho pesquisou a composição química e avaliou o potencial cicatrizante do extrato etanólico dos frutos de L. ferrea (Mart. ex Tul.) em ratos. Foram utilizados 24 ratos Wistar divididos em quatro grupos. De todos os animais, foi retirado um fragmento de pele do dorso e cada grupo recebeu um tratamento diferente: solução de NaCl 0,9%, digliconato de clorexidina 1%, extrato etanólico dos frutos de Libidibia ferrea 12,5% e 50%. O processo de cicatrização foi avaliado macro e microscopicamente. Para a cicatrização de pele em ratos o extrato etanólico dos frutos de L. ferrea a 12,5% é significativamente mais eficiente do que a 50%. Saponinas, ácidos orgânicos, açúcares redutores, fenóis e taninos, sesquiterpenolactonas e outras lactonas, e antraquinonas foram encontrados no extrato.

Libidibia ferrea is a plant popularly used for therapeutic purposes, including processes to accelerate wound healing. The present investigation analyzed the chemical composition and the healing potential of ethanolic extract of the fruits of L. ferrea (Mart. ex Tul.) in rats. This study used 24 Wistar rats divided into four groups. In all animals a piece of skin on the back was removed and each group received a different treatment: NaCl 0.9%, Chlorhexidine digluconate 1%, ethanol extract of the fruits of Libidibia ferrea 12.5% and 50%. The healing process was evaluated macroscopically and microscopically. The ethanolic extract of the fruits of L. ferrea 12.5% was significantly more efficient than the 50% healing in rat skin.

Three cases of rhegmatogenous retinal detachment associated with regressed retinoblastoma after conservative tumor therapy.

PURPOSE: To report three cases of rhegmatogenous retinal detachment associated with regressed retinoblastoma after conservative therapy. METHODS: Three eyes of three patients with rhegmatogenous retinal detachment, in which retinal breaks were present at the edge of the tumor scar, were treated with vitrectomy and scleral buckling. RESULTS: In two eyes, in which cryopexy and silicone oil injection were performed, a preretinal membrane was formed that was comprised primarily of glial cells. Additional vitrectomy and membrane peeling reattached the retina. In one eye, in which photocoagulation and gas injection were performed, an initial vitrectomy and scleral buckling reattached the retina without postoperative membrane formation. CONCLUSION: Vitrectomy and scleral buckling contributed to closure of the irregularly shaped retinal tear at the edge of the tumor scar. Photocoagulation and gas injection instead of cryopexy and silicone oil injection may avoid postoperative glial proliferation from the tumor scar.

Aerogels with 3D ordered nanofiber skeletons of liquid-crystalline nanocellulose derivatives as tough and transparent insulators.

Aerogels of high porosity and with a large internal surface area exhibit outstanding performances as thermal, acoustic, or electrical insulators. However, most aerogels are mechanically brittle and optically opaque, and the structural and physical properties of aerogels strongly depend on their densities. The unfavorable characteristics of aerogels are intrinsic to their skeletal structures consisting of randomly interconnected spherical nanoparticles. A structurally new type of aerogel with a three-dimensionally ordered nanofiber skeleton of liquid-crystalline nanocellulose (LC-NCell) is now reported. This LC-NCell material is composed of mechanically strong, surface-carboxylated cellulose nanofibers dispersed in a nematic LC order. The LC-NCell aerogels are transparent and combine mechanical toughness and good insulation properties. These properties of the LC-NCell aerogels could also be readily controlled.

The Cryptochrome/Photolyase Family in aquatic organisms.

The Cryptochrome/Photolyase Family (CPF) represents an ancient group of widely distributed UV-A/blue-light sensitive proteins sharing common structures and chromophores. During the course of evolution, different CPFs acquired distinct functions in DNA repair, light perception and circadian clock regulation. Previous phylogenetic analyses of the CPF have allowed reconstruction of the evolution and distribution of the different CPF super-classes in the tree of life. However, so far only limited information is available from the CPF orthologs in aquatic organisms that evolved in environments harboring great diversity of life forms and showing peculiar light distribution and rhythms. To gain new insights into the evolutionary and functional relationships within the CPF family, we performed a detailed study of CPF members from marine (diatoms, sea urchin and annelid) and freshwater organisms (teleost) that populate diverse habitats and exhibit different life strategies. In particular, we first extended the CPF family phylogeny by including genes from aquatic organisms representative of several branches of the tree of life. Our analysis identifies four major super-classes of CPF proteins and importantly singles out the presence of a plant-like CRY in diatoms and in metazoans. Moreover, we show a dynamic evolution of Cpf genes in eukaryotes with various events of gene duplication coupled to functional diversification and gene loss, which have shaped the complex array of Cpf genes in extant aquatic organisms. Second, we uncover clear rhythmic diurnal expression patterns and light-dependent regulation for the majority of the analyzed Cpf genes in our reference species. Our analyses reconstruct the molecular evolution of the CPF family in eukaryotes and provide a solid foundation for a systematic characterization of novel light activated proteins in aquatic environments.

Survey of microphthalmia in Japan.

PURPOSE: To report the current status of patients with microphthalmia based on a cross-sectional survey of patient hospital visits. METHODS: A questionnaire was sent to the departments of ophthalmology in 1,151 major Japanese hospitals to survey the following: the number of patients with microphthalmia who visited the outpatient clinics between January 2008 and December 2009; gender; age; family history; associated ocular anomalies; complications and systemic diseases; surgical treatment; vision and management. A retrospective quantitative registry of 1,254 microphthalmic eyes (851 patients) from 454 hospitals (39.4%) was compiled. RESULTS: Of the patients for whom data were available, 50% ranged in age from 0 to 9 years. The major ocular findings were nanophthalmos, coloboma, and vitreoretinal malformations. Ocular complications frequently developed, including cataracts, glaucoma, and retinal detachment. Surgery was performed in 21.4% of all cases, and systemic diseases were present in 31% of all cases. The vision associated with microphthalmia exceeded 0.1 in about 30% of the eyes. Glasses and low vision aids were used by 21.6% of patients. CONCLUSIONS: Patients with microphthalmia often have ocular and systemic anomalies. Early assessment and preservation of vision and long-term complication management are needed.

Clinical features of congenital retinal folds.

PURPOSE: To investigate the clinical features and prognosis of congenital retinal folds without systemic associations. DESIGN: Retrospective observational case series. METHODS: The characteristics, clinical course, ocular complications, and best-corrected visual acuity (BCVA) of eyes with congenital retinal folds were studied during the follow-up periods. The affected and fellow eyes were examined by slit-lamp biomicroscopy, binocular indirect ophthalmoscopy, and fundus fluorescein angiography. The parents and siblings of each patient also underwent ophthalmoscopic examinations. The BCVA was measured using a Landolt ring VA chart. RESULTS: One hundred forty-seven eyes of 121 patients with congenital retinal folds were examined. Fifty-five patients (45.5%) were female. The fold was unilateral in 95 patients (78.5%), and 69 of those patients (72.6%) had retinal abnormalities in the fellow eye. The meridional distribution of folds was temporal in 136 eyes (92.5%). The family history was positive in 32 patients (26.4%). Secondary fundus complications, including fibrovascular proliferation and tractional, rhegmatogenous, and exudative retinal detachments, developed in 44 eyes (29.9%). The BCVAs could be measured in 119 eyes and ranged from 20/100 to 20/20 in 5 eyes (4.2%), 2/100 to 20/200 in 45 eyes (37.8%), and 2/200 or worse in 69 eyes (58.0%). The follow-up periods ranged from 4 to 243 months (mean, 79.7 ± 58.9 months). CONCLUSIONS: These clinical features suggested that most congenital retinal folds may result from insufficient retinal vascular development, as in familial exudative vitreoretinopathy, rather than persistent fetal vasculature. Adequate management of active retinopathy and late-onset complications, especially retinal detachment, is required.

Ultradian rhythm in the intestine of Caenorhabditis elegans is controlled by the C-terminal region of the FLR-1 ion channel and the hydrophobic domain of the FLR-4 protein kinase.

Defecation behavior in Caenorhabditis elegans is driven by an endogenous ultradian clock in the intestine. Its periods are positively regulated by FLR-1, an ion channel of the epithelial sodium channel/degenerin superfamily, and FLR-4, a protein kinase with a hydrophobic domain at the carboxyl terminus. FLR-1 has many putative phosphorylation sites in the C-terminal intracellular region. This structure implies that the periods may be regulated by the phosphorylation of FLR-1 by FLR-4, but it remains to be clarified. Here, we show that a truncated FLR-1 lacking the C-terminal intracellular region resulted in longer periods, suggesting that this region is involved in the negative regulation of defecation cycle periods. Contrary to our expectation, FLR-4 was still necessary for the function of the truncated FLR-1. Furthermore, FLR-4 containing a kinase-dead mutation or lacking the whole kinase domain was sufficient for normal defecation cycle periods. FLR-4 was necessary for the stable expression of FLR-1::GFP, and its hydrophobic domain was sufficient also for this function. FLR-1 and FLR-4 are often colocalized in the plasma membrane. These data showed an unexpected role of FLR-4: its hydrophobic domain stabilizes the FLR-1 ion channel, a key regulator of defecation cycle periods in the intestine.

Risk factors for recurrent fibrovascular proliferation in aggressive posterior retinopathy of prematurity after early vitreous surgery.

PURPOSE: To analyze risk factors for postoperative recurrence of fibrovascular tissue in eyes with aggressive posterior retinopathy of prematurity (AP ROP) treated with early vitreous surgery. DESIGN: Retrospective, consecutive, observational case series. METHODS: Thirty-one patients (50 eyes) with AP ROP who underwent early vitreous surgery between March 2005 and April 2008 participated. Eyes with stage 4A or 4B disease in which fibrovascular tissue was not attached to the vitreous base were included; those in which fibrovascular tissue was attached extensively to vitreous base or those without dense photocoagulation to the nonvascularized retina were excluded. Eligible eyes were divided into 2 groups based on postoperative recurrence or no recurrence of fibrovascular tissue. Data on gender, gestational age, birth weight, Apgar score, intubation duration, severe systemic complications, preoperative ROP stage, zone, fibrovascular tissue and vitreous base adhesion, clock hours of fibrovascular tissue, postmenstrual age at the initial application of dense photocoagulation, dense photocoagulation to both vascularized and nonvascularized retina, postmenstrual age at vitrectomy, and intraoperative hemorrhage were collected and analyzed. RESULTS: Fifty eyes of 31 patients underwent early vitrectomy. Seven (14%) eyes were excluded and 43 eyes (86%) were included. Eight (18%) of 43 eyes had a recurrence of fibrovascular tissue. Both univariate and multivariate analysis indicated application of dense photocoagulation to both the vascularized and nonvascularized retina was a significant factor in the decreased recurrence of fibrovascular tissue (P = .002 and P = .008, respectively). CONCLUSIONS: Application of preoperative dense photocoagulation to vascularized and nonvascularized retina may be important for lowering the recurrence of fibrovascular tissue in eyes with AP ROP.

Effect of early vitreous surgery for aggressive posterior retinopathy of prematurity detected by fundus fluorescein angiography.

OBJECTIVE: To assess the effect of early vitrectomy for aggressive posterior retinopathy of prematurity (APROP) using fundus fluorescein angiography. DESIGN: Retrospective, observational case series. PARTICIPANTS: Eleven eyes of 7 patients with APROP that underwent early vitreous surgery. METHODS: All eyes underwent vitrectomy with lensectomy that removed the vitreous gel around the fibrovascular proliferative tissue, but not the proliferative tissue when fibrovascular proliferation and retinal detachment occurred despite retinal photocoagulation. Fundus fluorescein angiography was performed before and after the early vitreous surgery. MAIN OUTCOME MEASURES: Dye leakage from the fibrovascular tissue, dilation and tortuosity of the retinal vasculature, and shunt vessels were evaluated by fundus fluorescein angiography. The status of the retinal reattachment was assessed postoperatively. RESULTS: Nine eyes had severe dye leakage from the fibrovascular tissue and 2 eyes had moderate leakage seen by preoperative fluorescein angiography. Severe dilation and tortuosity of the retinal vessels were detected in 10 eyes and shunt vessels in 7 eyes. Six to 12 days after successful surgery, the retina reattached and dilation and tortuosity of the retinal vessels decreased substantially. Dye leakage diminished markedly in all eyes, resolved completely in 7 eyes, and was still apparent slightly in 4. At the final examination, fibrovascular proliferation and retinal detachment did not progress in any eyes; however, 2 eyes had a dragged or folded retina. Follow-up ranged from 6 to 19 months (mean, 9.2). CONCLUSIONS: Early vitrectomy that removes vitreous gel from around the proliferative tissue promptly reduces vascular activity and may limit progression of retinal detachment in APROP.

Ocular manifestations and prognosis of shaken baby syndrome in two Japanese children's hospitals.

PURPOSE: To distinguish the profiles of patients and ophthalmologic features and to describe the prognosis of shaken baby syndrome (SBS) in Japan. METHODS: Charts of child abuse cases involving retinal hemorrhage at Kanagawa Children's Medical Center and the National Center for Child Health and Development between January 1997 and December 2007 were retrospectively reviewed. The mean follow-up period was 22.2 months (range, 0-115 months). RESULTS: Twenty-one boys and 11 girls were identified. The mean age at the initial visit was 7.0 months (range, 4 days to 17 months). Four boys died during hospitalization. Seventeen eyes of ten patients (31%) had vitreous hemorrhage; 16 eyes of eight patients (25%) had a more favorable ocular prognosis with no apparent complications. Eight infants (25%) had been born prematurely. The mean maternal age was 29.9 years, and mothers were the primary perpetrator in 19 cases (59%). CONCLUSIONS: The clinical features of SBS in Japan are comparable to those in the Western literature. However, we have also found some idiosyncratic features in Japanese SBS cases; the mother is more frequently the perpetrator and abusive parents are older than in the United States, possibly reflecting current trends in Japan toward later marriage.

Evaluation of scleral buckling for stage 4A retinopathy of prematurity by fluorescein angiography.

PURPOSE: To determine the early efficacy of scleral buckling for active neovascularization by fundus fluorescein angiography (FA) in eyes with stage 4A retinopathy of prematurity. DESIGN: A retrospective, nonrandomized, observational case series. METHODS: Patients who underwent scleral buckling for stage 4A ROP at the National Center for Child Health and Development, Tokyo, Japan, from October 2007 through November 2008 were included. Preoperative and postoperative FA and fundus photographs obtained with a wide-field digital pediatric imaging system were reviewed. Three patients (5 eyes; gestational ages at birth, 23 to 25 weeks; birth weights, 574 to 811 g) with zone II stage 4A ROP who underwent postoperative FA, 2 weeks or less after scleral buckling (range, 7 to 12 days; postmenstrual ages at postoperative FA, 41 to 45 weeks) were evaluated. Patients who underwent postoperative FA 2 weeks or more after scleral buckling were excluded. RESULTS: Despite fluorescein leakage from fibrovascular tissue in all eyes before surgery, markedly decreased leakage occurred only between 7 to 12 days after surgery. The retinas were reattached completely in all eyes after surgery. CONCLUSIONS: Scleral buckling may prevent progression of retinal detachment in stage 4A ROP by reducing the tractional force and stabilizing the neovascular activity of the fibrovascular tissue.

Vascular abnormalities in aggressive posterior retinopathy of prematurity detected by fluorescein angiography.

PURPOSE: To evaluate fluorescein angiography (FA) in eyes with aggressive posterior retinopathy of prematurity (AP-ROP). DESIGN: Retrospective, nonrandomized case series. PARTICIPANTS: Three patients (6 eyes) with AP-ROP. METHODS: Three patients (6 eyes) diagnosed with AP-ROP during ROP screening between July 2007 and July 2008 were included in this study. Fundus photographs and FA were obtained before and after laser and surgical treatment using a wide-field digital pediatric imaging system. MAIN OUTCOME MEASURES: Fluorescein angiography and fundus photographs. RESULTS: At the initial stage of AP-ROP, FA showed vascular abnormalities, including capillary nonperfusion throughout the vascularized retina, shunting in the vascularized retina, a circumferential demarcation line, and limited vessel development, which was difficult to identify only by ophthalmoscopy. After treatment, FA showed poorly developed retinal vessels, including 4 small major vessels without an arcade pattern, small macular vessels, an inhomogeneous capillary bed, and absence of a capillary-free zone in the fovea. CONCLUSIONS: Capillary bed loss throughout the vascularized posterior retina is characteristic of AP-ROP and may exacerbate retinopathy.

Generation and suppression of 3-/4-functionalized benzynes using zinc ate base (TMP-Zn-ate): new approaches to multisubstituted benzenes.

We present full details of our new methods for preparing functionalized benzynes with lithium di-alkyl(2,2,6,6-tetramethylpiperidino)zincate (R2Zn(TMP)Li) through deprotonative zincation as a key reaction. In this system, by choosing appropriate ligands for the zincate, either regioselective zincation of functionalized haloaromatics or the generation of substituted benzynes can be controlled in good yields with excellent chemoselectivity, using the same substrate. Zincation with (t)Bu2Zn(TMP)Li followed by electrophilic trapping or zincation with Me2Zn(TMP)Li followed by nucleophilic or diene trapping is shown to be a powerful tool for the chemoselective preparation of 1,2,3-/1,2,4-trisubstituted benzene derivatives. These methods offer far greater generality than previous methods for the synthesis of multifunctionalized benzenes. Computational/theoretical studies of the reaction mechanism of this unique benzyne formation indicated that preferential coordination of the dialkylzinc moiety of zincate to halogen is the reason for the reduced activation energy of the elimination, that is, for the formation of the benzyne. The role of the ligands on Zn in accelerating/decelerating the elimination is also discussed.