Defining subgroups of patients with a stiff and painful shoulder: an analytical model using cluster analysis.

PURPOSE: The primary purpose of this research was to develop a classification system for patients with stiff and painful shoulders using hierarchical cluster analysis. METHODS: Medical charts of 52 patients treated for stiff and painful shoulders were reviewed for descriptive and clinical data after completion of their rehabilitation. A clinician-reported outcome was derived from ratings of three members of the American Society of Shoulder and Elbow Therapists. Data were subjected to cluster analysis using the hierarchical method. Analysis of difference tests was performed to determine if differences between clusters could be found with either initial examination or outcome data. RESULTS: Two clusters emerged from the clustering process: a healthy, strong, and mobile group of 32 patients, and an unhealthy, weak, and immobile groups consisting of 20 patients. Significant differences in initial examination measures between clusters were found for the presence of co-morbidities, range of motion for shoulder flexion, abduction, external rotation, and internal rotation, and strength of the shoulder external rotators and in the empty can position. Significant differences between clusters were found for shoulder flexion, abduction, and external rotation range of motion, and clinician-reported outcome at the time of patient discharge. CONCLUSION: Patients with stiff and painful shoulders in this study were classified into two distinct subgroups using hierarchical cluster analysis based on demographic attributes and initial examination findings. The findings from this study also suggest that patients who may be at risk for a poorer outcome can be identified based on initial examination measures. By identifying these patients early in rehabilitation who have a poorer prognosis, improved patient education, alternative interventions or diagnostic tests may be utilized on their behalf.Implications for rehabilitationPatients with stiff and painful shoulders were classified into two subgroups using hierarchical cluster analysis based on demographic attributes and initial examination findings.Significant differences in mean clinician-reported outcome was also noted between clusters, with the patients who were healthier, stronger, and more mobile having a significantly better outcome than those patients who were more unhealthy, weak, and immobile.The findings from this study suggest that patients can be identified on initial examination who may be at risk for a poorer outcome.By identifying these patients early in rehabilitation who have a poorer prognosis, improved patient education, alternative interventions, or diagnostic tests may be utilized on their behalf sooner in the course of care.

Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.

We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein-protein interaction surfaces for fragment binding. We screened the FOL library against leukotriene A4 hydrolase (LTA4H) by X-ray crystallography. A diverse set of fragments including derivatives of resveratrol, nicotinamide, and indole were identified as efficient ligands for LTA4H. These fragments were elaborated in a small number of synthetic cycles into potent inhibitors of LTA4H representing multiple novel chemotypes for modulating leukotriene biosynthesis. Analysis of the fragment-bound structures also showed that the fragments comprehensively recapitulated key chemical features and binding modes of several reported LTA4H inhibitors.

Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene ( SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound 11a possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound 11a up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, compound 11a induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.