The acceptance of the clinical photographic posture assessment tool (CPPAT).

BACKGROUND: There is a lack of evidence-based quantitative clinical methods to adequately assess posture. Our team developed a clinical photographic posture assessment tool (CPPAT) and implemented this tool in clinical practice to standardize posture assessment. The objectives were to determine the level of acceptance of the CPPAT and to document predictors as well as facilitators of and barriers to the acceptance of this tool by clinicians doing posture re-education. METHODS: This is a prospective study focussing on technology acceptance. Thirty-two clinician participants (physical therapists and sport therapists) received a 3-5 h training workshop explaining how to use the CPPAT. Over a three-month trial, they recorded time-on-task for a complete posture evaluation (photo - and photo-processing). Subsequently, participants rated their acceptance of the tool and commented on facilitators and barriers of the clinical method. RESULTS: Twenty-three clinician participants completed the trial. They took 22 (mean) ± 10 min (SD) for photo acquisition and 36 min ± 19 min for photo-processing. Acceptance of the CPPAT was high. Perceived ease of use was an indirect predictor of intention to use, mediated by perceived usefulness. Analysis time was an indirect predictor, mediated by perceived usefulness, and a marginally significant direct predictor. Principal facilitators were objective measurements, visualization, utility, and ease of use. Barriers were time to do a complete analysis of posture, quality of human-computer interaction, non-automation of posture index calculation and photo transfer, and lack of versatility. CONCLUSION: The CPPAT is perceived as useful and easy to use by clinicians and may facilitate the quantitative analysis of posture. Adapting the user-interface and functionality to quantify posture may facilitate a wider adoption of the tool.

Squaramides as novel class I and IIB histone deacetylase inhibitors for topical treatment of cutaneous t-cell lymphoma.

A series of squaramide-based hydroxamic acids were designed, synthesized and evaluated against human HDAC enzyme. Squaramides were found to be potent in the Hut78 cell line, but initially suffered from low solubility. Leads with improved solubility and metabolic profiles were shown to be class I, IIB and IV selective.

Test-retest reliability of posture measurements in adolescents with idiopathic scoliosis.

BACKGROUND CONTEXT: Posture changes are a major consequence of idiopathic scoliosis (IS). Posture changes can lead to psychosocial and physical impairments in adolescents with IS. Therefore, it is important to assess posture, but the test-retest reliability of posture measurements still remains unknown in this population. PURPOSE: The primary objective of the present study was to determine the test-retest reliability of 25 head and trunk posture indices using the Clinical Photographic Postural Assessment Tool (CPPAT) in adolescents with IS. The secondary objective was to determine the standard error of measurement and the minimal detectable change. STUDY DESIGN/SETTING: This is a prospective test-retest reliability study carried out at two tertiary university hospital centers. PATIENTS SAMPLE: Forty-one adolescents with IS, aged 10-16 years old with curves 10°-45° and treated by medical intervention, were recruited. METHODS: Two posture assessments were done using the CPPAT 5-10 days apart following a standardized procedure. Photographs were analyzed with the CPPAT software by digitizing reference landmarks placed on the participant by a physiotherapist evaluator. Generalizability theory was used to obtain a coefficient of dependability, standard error of measurement, and the minimal detectable change at 90% confidence interval. RESULTS: Fourteen of 25 posture indices had a good reliability (ϕ≥0.78), 10 had moderate reliability (ϕ=0.55-0.74), and 1 had poor reliability (ϕ=0.45). The most reliable posture indices were waist angle asymmetry (ϕ=0.93), right waist angle (ϕ=0.91), and frontal trunk list (ϕ=0.92). Right sagittal trunk list was the least reliable posture index (ϕ=0.45). The MDC90 values ranged from 2.6 to 10.3° for angular measurements and from 8.4 to 35.1 mm for linear measurements. CONCLUSIONS: The present study demonstrates that most posture indices, especially the trunk posture indices, are reproducible in time among adolescents with IS and provides reference values. Clinicians and researchers can use these reference values to assess change in posture over time attributable to treatment effectiveness.

Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.

The use of an interleukin ß antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1ß into active IL-1ß, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved.

Intrinsic Property Forecast Index (iPFI) as a Rule of Thumb for Medicinal Chemists to Remove a Phototoxicity Liability.

Phototoxicity occurs when UV irradiation causes otherwise benign compounds to become irritant, sensitizers, or even genotoxic. This toxicity is particularly a concern after topical application and in dermatological programs where skin irritation can be incompatible with the desired therapeutic outcome. This brief article establishes that the intrinsic property forecast index (iPFI) can be used to evaluate the probability of a compound being phototoxic and gives medicinal chemists a practical tool to handle this liability.

Discovery and Characterization of CD12681, a Potent RORγ Inverse Agonist, Preclinical Candidate for the Topical Treatment of Psoriasis.

With possible implications in multiple autoimmune diseases, the retinoic acid receptor-related orphan receptor RORγ has become a sought-after target in the pharmaceutical industry. Herein are described the efforts to identify a potent RORγ inverse agonist compatible with topical application for the treatment of skin diseases. These efforts culminated in the discovery of N-(2,4-dimethylphenyl)-N-isobutyl-2-oxo-1-[(tetrahydro-2H-pyran-4-yl)methyl]-2,3-dihydro-1H-benzo[d]imidazole-5-sulfonamide (CD12681), a potent inverse agonist with in vivo activity in an IL-23-induced mouse skin inflammation model.

New Caspase-1 inhibitor by scaffold hopping into bio-inspired 3D-fragment space.

Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors.

Applying the pro-drug approach to afford highly bioavailable antagonists of P2Y(14).

Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.

The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14.

A weak, UDP-competitive antagonist of the pyrimidinergic receptor P2RY(14) with a naphthoic acid core was identified through high-throughput screening. Optimization provided compounds with improved potency but poor pharmacokinetics. Acylglucuronidation was determined to be the major route of metabolism. Increasing the electron-withdrawing nature of the substituents markedly reduced glucuronidation and improved the pharmacokinetic profile. Additional optimization led to the identification of compound 38 which is an 8 nM UDP-competitive antagonist of P2Y(14) with a good pharmacokinetic profile.

Pharmacological and genetic evidence that cathepsin B is not the physiological activator of rodent prorenin.

Renin is the first enzyme in the renin-angiotensin-aldosterone system which is the principal regulator of blood pressure and hydroelectrolyte balance. Previous studies suggest that cathepsin B is the activator of the prorenin zymogen. Here, we show no difference in plasma renin activity, or mean arterial blood pressure between wild-type and cathepsin B knockout mice. To account for potential gene compensation, a potent, selective, reversible cathepsin B inhibitor was developed to determine the role of cathepsin B on prorenin processing in rats. Pharmacological inhibition of cathepsin B in spontaneously hypertensive and double transgenic rats did not result in a reduction in renal mature renin protein levels or plasma renin activity. We conclude that cathepsin B does not play a significant role in this process in rodents.

Occurrence of an ascending aorta aneurysm 25 years after cure of a tetralogy of Fallot.

The patient, who had undergone a complete cure of a tetralogy of Fallot 25 years previously, was discovered to have an ascending aorta aneurysm on echography. Bentall's procedure was carried-out, using a modified indirect coronary artery transplantation based on the Cabrol technique. As reported in the literature complications are mainly right sided and less frequently occur on the left side in this disease. Including the hypothesis of the overload volume which may provoke aortic root dilation, there is also an intrinsic pathology of the media which could often be related to embryogenesis abnormalities, i.e., abnormal migration of cardiac neural crest cells which may explain this condition.

Diastereoselective zinco-cyclopropanation of chiral allylic alcohols with gem-dizinc carbenoids.

The highly diastereoselective zinco-cyclopropanation of chiral allylic alcohols using gem-dizinc carbenoids is described. The reaction produces three contiguous stereogenic centers, and the resulting chiral cyclopropylzinc derivatives can be trapped with electrophiles with retention of configuration. Simple functional group manipulations lead to the efficient synthesis of orthogonally protected 1,2,3-substituted cyclopropane derivatives.

New synthetic route for the enantioselective total synthesis of salinosporamide A and biologically active analogues.

[reaction: see text] A total synthesis of the salinosporamide analogue 3 is described that starts with the novel cyclization 4 --> 5.

Simple enantiospecific syntheses of the C(2)-diastereomers of omuralide and 3-methylomuralide.

[reaction: see text] Syntheses of two novel omuralide derivatives are described.

An efficient, stereocontrolled synthesis of a potent omuralide-salinosporin hybrid for selective proteasome inhibition.

A short and highly stereocontrolled synthesis of the potent proteasome inhibitor 3 from the (S)-threonine-derived oxazoline 4 has been developed. The synthetic sequence is summarized in Scheme 1. Aldol coupling of the zinc enolate of 4 with isobutyraldehyde and subsequent silylation provided the TBS ether 5 diastereoselectively (10:1). Reductive cleavage of the oxazoline ring of 5 followed by Swern oxidation of the resulting amino alcohol afforded amino ketone 6, converted further by N-acylation to the acrylamide 7, whose structure was confirmed by X-ray crystallographic analysis. Acrylamide 7 was cyclized to 8 by a novel application of the Kulinkovich Ti(II)-cyclopentene complex. Silylation of 8 to 9 and radical cyclization at low temperature produced the bicyclic lactam 10 with complete control of all stereocenters. Hydroxy desilylation and N-deprotection of 10 gave the dihydroxy ester 11, which was converted to 3 by a novel three-step sequence: (1) demethylation with [Me2AlTeMe]2, (2) combined beta-lactonization and chlorination, and (3) desilylation to effect cleavage of the TBS ether.

Asymmetric synthesis in a Norrish type II cleavage reaction induced by crystal chirality.

Moderate to high enantiomeric excesses for the cis and trans olefinic products of a Norrish type II cleavage reaction have been obtained for the first time through the use of the solid-state ionic chiral auxiliary approach.

First evidence for the formation of a geminal dizinc carbenoid: a highly stereoselective synthesis of 1,2,3-substituted cyclopropanes.

Significant amounts of novel gem-dizinc carbenoids (RZnCHIZnR) are formed when diethylzinc is mixed with iodoform in CH2Cl2 at 0 degrees C. This reagent was shown to be effective in the cyclopropanation of butenediol derivatives to generate a cyclopropylzinc intermediate that could be trapped with a variety of electrophiles. 1,2,3-Substituted cyclopropane derivatives are formed with excellent diastereoselectivities by using this simple procedure.