Traceless Templated Amide-Forming Ligations.

Template assistance allows organic reactions to occur under highly dilute conditions-where intermolecular reactions often fail to proceed-by bringing reactants into close spatial proximity. This strategy has been elegantly applied to numerous systems, but always with the retention of at least one of the templating groups in the product. In this report, we describe a traceless, templated amide-forming ligation that proceeds at low micromolar concentration under aqueous conditions in the presence of biomolecules. We utilized the unique features of an acylboronate-hydroxylamine ligation, in which covalent bonds are broken in each of the reactants as the new amide bond is formed. By using streptavidin as a template and acylboronates and O-acylhydroxylamines bearing desthiobiotins that are cleaved upon amide formation, we demonstrate that traceless, templated ligation occurs rapidly even at submicromolar concentrations. The requirement for a close spatial orientation of the functional groups-achieved upon binding to streptavidin-is critical for the observed enhancement in the rate and quantity of product formed.

Chemoselective Acylation of Primary Amines and Amides with Potassium Acyltrifluoroborates under Acidic Conditions.

Current methods for constructing amide bonds join amines and carboxylic acids by dehydrative couplings-processes that usually require organic solvents, expensive and often dangerous coupling reagents, and masking other functional groups. Here we describe an amide formation using primary amines and potassium acyltrifluoroborates promoted by simple chlorinating agents that proceeds rapidly in water. The reaction is fast at acidic pH and tolerates alcohols, carboxylic acids, and even secondary amines in the substrates. It is applicable to the functionalization of primary amides, sulfonamides, and other N-functional groups that typically resist classical acylations and can be applied to late-stage functionalizations.

Boronic Acid-Catalyzed, Highly Enantioselective Aza-Michael Additions of Hydroxamic Acid to Quinone Imine Ketals.

Boronic acid is one of the most versatile organic molecules in chemistry. Its uses include organic reactions, molecular recognition, assembly, and even medicine. While boronic acid catalysis, which utilizes an inherent catalytic property, has become an important research objective, it still lags far behind other boronic acid chemistries. Here, we report our discovery of a new boronic acid catalysis that enables the aza-Michael addition of hydroxamic acid to quinone imine ketals. By using 3-borono-BINOL as a chiral boronic acid catalyst, this reaction could be implemented in a highly enantioselective manner, paving the way to densely functionalized cyclohexanes.

In situ assembled boronate ester assisted chiral carboxylic acid catalyzed asymmetric trans-aziridinations.

We developed herein a new chiral Brønsted acid catalyst which is composed of two independent organic molecules, a chiral diol, and 2-boronobenzoic acid. In situ formation of a boronate ester was utilized as a key process to generate an active catalyst. This boronate ester assisted chiral carboxylic acid catalyst was successfully applied to the trans-aziridination of N-Boc and N-benzyl imines with N-phenyldiazoacetamide. This is the first catalyst to achieve high enantioselectivities using N-benzyl imines.

Risk Factors and Visual Sequel of Non-Arteritic Ischemic Optic Neuropathy in Saudi Arabia.

Objective: To provide the demographic data, risk factors, and visual prognosis of patients from a Saudi population diagnosed with non-arteritic anterior ischemic optic neuropathy (NAION). Materials and Methods: A retrospective observational case series of 120 patients (146 eyes) with NAION from the King Khaled Eye Specialist Hospital or King Abdulaziz University Hospital from 1998 to 2015. Patients with other retinal pathology or glaucoma were excluded from the study. Additionally, a subgroup analysis was performed to compare the long-term assessment between diabetic and non-diabetic patients and its effects on NAION. Results: The mean duration of follow-up was 1.7 ± 2.4 years. The mean age of the study population was 55.0 ± 10.1 years. NAION was present in the fellow eye of 26 patients, and the median time for involvement was less than 1 year from the presentation. There was no significant difference in the best-corrected visual acuity between diabetics and non-diabetics at presentation or last visit (P = 0.868, P = 0.599, respectively). Conclusions: The majority of patients with NAION also had coexisting diabetes mellitus. Diabetes mellitus had no significant effect on NAION during the presentation, follow-up, and last visit.

Diagnosis and classification of optic neuritis.

There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.

Horner syndrome associated with ipsilateral facial and extremity anhydrosis.

We report a patient with Horner syndrome together with anhidrosis affecting the ipsilateral face and extremities confirmed with starch-iodine and sympathetic skin response testing. No anatomic lesion was apparent. This is the first reported case in which Horner syndrome has been associated with such extensive hemibody sympathetic dysfunction in the absence of other neurologic findings. We propose a developmental disorder of neural crest migration as the cause.

Covalently functionalized amide cross-linked hydrogels from primary amines and polyethylene glycol acyltrifluoroborates (PEG-KATs).

A new method for the rapid preparation of chemically cross-linked hydrogels based on a multi-arm polyethylene glycol (PEG) bearing potassium acyl trifluoroborate (KAT) functional groups with multi-dentate amines is described. These scaffolds - prepared in aqueous buffer - give strong, transparent hydrogels. At pH 3, the gel formation is complete within seconds, and the reaction rate can be tuned by modulating the pH. Rheology measurements show that the hydrogel properties can be tuned as a function of both the weight percent of solids in the gel and the denticity of amine cross-linker, allowing for predictable formation of gels with desired traits. This process relies on a rapid amide-forming reaction of KATs and in situ generated N-chloroamines. Numerous commercially available amines, including di-, tri- and tetra-functional amines as well as peptides and carbohydrates serve as effective cross-linkers. Monodentate amines included in the gelation mixture are covalently linked into the gel matrix by amide-bonds, allowing gels containing immobilized molecules including dyes, sensors, or biotin amine, to be prepared in a single step from simple starting materials. The ability to induce gelation only upon addition of equimolar amounts of an inexpensive inducer (N-chlorosuccinimide) allows premixed components to be stored as an aqueous solution for weeks and converted to gels on demand.

Changes in mechanical, chemical, and thermal sensitivity of the cornea after topical application of nonsteroidal anti-inflammatory drugs.

PURPOSE: In addition to their well-known anti-inflammatory actions, some of the nonsteroidal anti-inflammatory drugs (NSAIDs) appear to have an analgesic effect. In human subjects, the changes in threshold and intensity of sensations evoked by mechanical, chemical, and thermal stimulation of the cornea induced by topical administration of two commercial NSAIDs, diclofenac sodium (Voltaren; Novartis, Basel, Switzerland) and flurbiprofen (Ocuflur; Allergan, Irvine, CA), were studied. METHODS: Corneal sensitivity was measured in 10 young, healthy subjects with a gas esthesiometer. Chemical (10%-70% CO2 in air), mechanical (0-264 mL/min), and thermal (corneal temperature changes between -4.5 degrees C and +3 degrees C around the normal value) stimuli were applied to the center of the cornea. The intensity and perceived magnitude of the psychophysical attributes of the evoked sensation were scored at the end of the pulse in a 10-cm, continuous visual analog scale (VAS). The threshold was expressed as the stimulus intensity that evoked a VAS score >0.5. Sensitivity was measured in both eyes of each subject on two separate days, one without treatment and the other 30 minutes after topical application of 0.03% flurbiprofen (seven subjects) or 0.1% diclofenac sodium (six subjects). RESULTS: Diclofenac attenuated significantly all the sensation parameters evoked by high-intensity mechanical, chemical, and thermal stimuli. Flurbiprofen produced a slight reduction of the sensations evoked by mechanical and chemical stimulation that became significant only for the irritation caused by chemical stimuli of maximum intensity (70% CO2). None of the drugs modified significantly the detection threshold of the different stimuli. CONCLUSIONS: Flurbiprofen had a very limited effect on sensations evoked by corneal stimulation, whereas diclofenac reduced the intensity of sensations evoked by stimuli of different modality, suggesting a mild local anesthetic effect of this drug on all types of corneal sensory fibers. Such anesthetic action could explain the analgesic effect that has been reported after topical application of diclofenac in inflamed human eyes.

Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies.

Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover "hidden mutations" such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5' exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5'-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading.

Unilateral optic neuritis, scleritis and exudative retinal detachment due to recurrent orbital pseudotumor.

Idiopathic orbital inflammation, also known as orbital pseudotumor, describes a spectrum of idiopathic, non-neoplastic, non-infectious, space-occupying orbital lesions without identifiable local or systemic cause. The condition occurs mainly in young adults who may present with acute pain, proptosis, chemosis and limitations of extraocular movements. Decreased vision due to optic nerve infiltration and macular edema as a result of scleritis is less common sequel of orbital pseudotumor. Herein, we present a case of unilateral orbital pseudotumor in a young male who presented with chief complaints of painful decreased vision which was attributed to optic neuritis and macular edema as a result of scleritis. Imaging studies were helpful in the establishment of the correct diagnosis and patient's complaints improved with administration of systemic corticosteroids.

Femoroacetabular impingement and low energy posterior hip dislocation: a case report.

We report a case of a 28-year-old male who sustained an indirect injury of his left hip while playing soccer, which resulted in a posterior fracture-dislocation. Radiological examination showed signs of combined femoroacetabular impingement (FAI). We discuss the role of FAI as a risk factor for hip dislocation in low energy sport injuries.

Asistencia al parto eutócico: recomendaciones para la práctica clínica / Attending the normal labour: recommendations for clinical practice

En este artículo se revisan diferentes prácticas obstétricas habituales en la atención al parto en España y se efectúan recomendaciones para la práctica clínica

This article reviews the routine obstetric procedures employed during delivery in Spain and offers recommendations for clinical practice