Synthesis of Imidazol[1,5-a]indole-1,3-diones from Imidazolidene-2,4-diones

Copper and tributyltin hydride catalysed cyclization, through the N-aryl bond formation, of imidazolidine-2,4-diones (11–16,18) yielded imidazo[1,5-a]indole-1,3-diones (5–10) in high yields (72–100%). The ease of cyclization was found to be consistent with the normal halogen reactivity and the type of substituents. The highly substituted imidazole-2,4-dione 15 gave brominated 19 and tin incorporated heterocycles 20 when treated with copper bromide and tributyltin hydride, respectively.KEYWORDS: Indoles, imidazolidine-2,4-diones, arylaldehyhydes, copper bronze, tributyl tin hydride

Synthesis of Indoles: Tetrahydropyrazino[1,2-a]indole-1,4-dione and Pyrazino[1,2-a]indole-6,13-diones from Piperazine-2,5-diones

The readily available piperazine-2,5-dione has been used to prepare both 1:1 (1–3), with stereotopic methylene protons; and 2:1 (4–6) arylmethylenepiperazine-2,5-diones in above average yields. The halo-derivatives, 1, 4 and 5 were cyclized to pyrazino[1,2-a]indoles, 7–9, using copper bronze. Indole compounds 7 and 9 were further treated, separately, with lithium aluminium hydride, sodium borohydride, lithium hydroxide monohydrate and butyl lithium to yield 2-substituted indoles 10–13.Keywords: Indoles, piperazine-2,5-diones, arylaldehydes, 1:1 adducts, 2:1 adducts

How serpins transport hormones and regulate their release

The adaptation of the serpin framework and its mechanism to perform diverse functions is epitomised in the hormone carriers of the blood. Thyroxine and the corticosteroids are transported bound in a 1:1 ratio on almost identical sites in the two homologous binding-globulins, TBG and CBG. Recent structural findings show an equilibrated, rather than on-and-off, release of the hormones from the carriers, reflecting small reversible movements of the hinge region of the reactive loop that modify the conformational flexibility of the underlying hormone-binding site. Consequently, contrary to previous concepts, the binding affinities of TBG and CBG are not fixed but can be allosterically modified to allow differential hormone delivery. Notably, the two carriers function like protein thermocouples with a surge in hormone release as body temperatures rise in fevers, and conversely a large diminution in free hormone levels at hibernation temperatures. By comparison angiotensinogen, the source of the angiotensin peptides that control blood pressure, does not appear to utilise the serpin mechanism. It has instead evolved a 63 residue terminal extension containing the buried angiotensin cleavage site, which on interaction moves into the active cleft of the renin. The conformational shift involved is critically linked by a labile disulphide bridge. The observation of changes in the redox status of this S-S bridge, in the hypertensive complication of pregnancy, pre-eclampsia, has opened an unexpected level of regulation at what is the initial stage in the control of blood pressure.This research was supported by the Wellcome Trust (Principal Research Fellowship to RJR, grant 082961/Z/07/Z) and by the British Heart Foundation grant 12/41/29679. The research was facilitated by a Wellcome Trust Strategic Award (100140) to the Cambridge Institute for Medical Research

Subretinal pigment epithelial deposition of Drusen components including hydroxyapatite in a primary cell culture model

Purpose: Extracellular deposits containing hydroxyapatite, lipids, proteins, and trace metals that form between the basal lamina of the RPE and the inner collagenous layer of Bruch's membrane are hallmarks of early AMD. We examined whether cultured RPE cells could produce extracellular deposits containing all of these molecular components. Methods: Retinal pigment epithelium cells isolated from freshly enucleated porcine eyes were cultured on Transwell membranes for up to 6 months. Deposit composition and structure were characterized using light, fluorescence, and electron microscopy; synchrotron x-ray diffraction and x-ray fluorescence; secondary ion mass spectroscopy; and immunohistochemistry. Results: Apparently functional primary RPE cells, when cultured on 10-μm-thick inserts with 0.4-μm-diameter pores, can produce sub-RPE deposits that contain hydroxyapatite, lipids, proteins, and trace elements, without outer segment supplementation, by 12 weeks. Conclusions: The data suggest that sub-RPE deposit formation is initiated, and probably regulated, by the RPE, as well as the loss of permeability of the Bruch's membrane and choriocapillaris complex associated with age and early AMD. This cell culture model of early AMD lesions provides a novel system for testing new therapeutic interventions against sub-RPE deposit formation, an event occurring well in advance of the onset of vision loss

Classification Criteria for Intermediate Uveitis, Non–Pars Planitis Type

Purpose: To determine classification criteria for intermediate uveitis, non-pars planitis type (IU- NPP, also known as undifferentiated intermediate uveitis) / Design: Machine learning of cases with IU-NPP and 4 other intermediate uveitides. / Methods: Cases of intermediate uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used on the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated on the validation set. / Results: Five hundred eighty-nine of cases of intermediate uveitides, including 114 cases of IU-NPP, were evaluated by machine learning. The overall accuracy for intermediate uveitides was 99.8% in the training set and 99.3% in the validation set (95% confidence interval 96.1, 99.9). Key criteria for IU-NPP included unilateral or bilateral intermediate uveitis with neither 1) snowballs in the vitreous nor 2) snowbanks on the pars plana. Other key exclusions included: 1) multiple sclerosis, 2) sarcoidosis, and 3) syphilis. The misclassification rates for pars planitis were 0 % in the training set and 0% in the validation set, respectively. / Conclusions: The criteria for IU-NPP had a low misclassification rate and appeared to perform well enough for use in clinical and translational research

Classification Criteria for Multiple Sclerosis-Associated Intermediate Uveitis

PURPOSE: The purpose of this study was to determine classification criteria for multiple sclerosis-associated intermediate uveitis. DESIGN: Machine learning of cases with multiple sclerosis-associated intermediate uveitis and 4 other intermediate uveitides. METHODS: Cases of intermediate uveitides were collected in an informatics-designed preliminary database, and a final database was constructed of cases achieving supermajority agreement on the diagnosis, using formal consensus techniques. Cases were split into a training set and a validation set. Machine learning using multinomial logistic regression was used in the training set to determine a parsimonious set of criteria that minimized the misclassification rate among the intermediate uveitides. The resulting criteria were evaluated in the validation set. RESULTS: A total of 589 cases of intermediate uveitides, including 112 cases of multiple sclerosis-associated intermediate uveitis, were evaluated by machine learning. The overall accuracy for intermediate uveitides was 99.8% in the training set and 99.3% in the validation set (95% confidence interval: 96.1-99.9). Key criteria for multiple sclerosis-associated intermediate uveitis included unilateral or bilateral intermediate uveitis and multiple sclerosis diagnosed by the McDonald criteria. Key exclusions included syphilis and sarcoidosis. The misclassification rates for multiple sclerosis-associated intermediate uveitis were 0 % in the training set and 0% in the validation set. CONCLUSIONS: The criteria for multiple sclerosis-associated intermediate uveitis had a low misclassification rate and appeared to perform sufficiently well enough for use in clinical and translational research

Surgical physiology of inguinal hernia repair - a study of 200 cases

BACKGROUND: Current inguinal hernia operations are generally based on anatomical considerations. Failures of such operations are due to lack of consideration of physiological aspects. Many patients with inguinal hernia are cured as a result of current techniques of operation, though factors that are said to prevent hernia formation are not restored. Therefore, the surgical physiology of inguinal canal needs to be reconsidered. METHODS: A retrospective study is describer of 200 patients operated on for inguinal hernia under local anaesthesia by the author's technique of inguinal hernia repair. RESULTS: The posterior wall of the inguinal canal was weak and without dynamic movement in all patients. Strong aponeurotic extensions were absent in the posterior wall. The muscle arch movement was lost or diminished in all patients. The movement of the muscle arch improved after it was sutured to the upper border of a strip of the external oblique aponeurosis (EOA). The newly formed posterior wall was kept physiologically dynamic by the additional muscle strength provided by external oblique muscle to the weakened muscles of the muscle arch. CONCLUSIONS: A physiologically dynamic and strong posterior inguinal wall, and the shielding and compression action of the muscles and aponeuroses around the inguinal canal are important factors that prevent hernia formation or hernia recurrence after repair. In addition, the squeezing and plugging action of the cremasteric muscle and binding effect of the strong cremasteric fascia, also play an important role in the prevention of hernia

Dessins d'enfants in N=2 generalised quiver theories

We study Grothendieck’s dessins d’enfants in the context of the N=2 supersymmetric gauge theories in (3 + 1) dimensions with product SU (2) gauge groups which have recently been considered by Gaiotto et al.. We identify the precise context in which dessins arise in these theories: they are the so-called ribbon graphs of such theories at certain isolated points in the moduli space. With this point in mind, we highlight connections to other work on trivalent dessins, gauge theories, and the modular group

Rituximab in refractory Vogt–Koyanagi–Harada disease

IntroductionVogt–Koyanagi–Harada (VKH) prognosis depends on early recognition and treatment; chronic disease may be developed when either delayed or inadequate treatment is performed, whereas other cases despite correct treatment are refractory to different drugs and also become chronic. We report a case of refractory VKH controlled with rituximab treatment.Case reportA 41-year-old female with painful visual loss and headache was examined. (VA 0.4 in RE and hand movements (HM) in LE). Retinal examination demonstrated multiple serous retinal detachments in both eyes. High-dose oral steroids were started, followed by progressive tapering of prednisone. New acute anterior and posterior relapses were achieved, and other immunommodulators were progressively added—new high-dose steroid treatment, adalimumab, cyclosporine, and methotrexate—but patient had new anterior and posterior recurrences associated with tinnitus and headache. Thus, an infusion of 1 g of rituximab was administered after 15 months follow-up; the VA was 0.2 in RE and counting fingers in LE. Three additional doses of 1 g each were administered 1, 6, and 16 months later. We have achieved a final VA after 34 months follow-up of 0.2 in RE and HM in LE, with definitive control of inflammation, without acute relapses since rituximab was administered.ConclusionAfter searching PubMed/Medline, this is the first report of VKH disease treated with rituximab. Additional studies are warranted to confirm the efficacy of this new approach for inflammatory control in refractory cases of VKH disease