International physical therapists consensus on clinical descriptors for diagnosing rotator cuff related shoulder pain: A Delphi study.

BACKGROUND: There is a lack of standardized criteria for diagnosing rotator cuff related shoulder pain (RCRSP). OBJECTIVE: To identify the most relevant clinical descriptors for diagnosing RCRSP. METHODS: A Delphi study was conducted through use of an international physical therapists expert panel. A 3-round Delphi survey involving an international panel of physical therapists experts with extensive clinical, teaching, and research experience was conducted. A search query was performed in Web of Science, along with a manual search, to find the experts. The first round was composed of items obtained from a previous pilot Delphi study along with new items proposed by the experts. Participants were asked to rate items across six clinical domains using a five-point Likert scale. An Aiken's Validity Index ≥ 0.7 was considered indicative of group consensus. RESULTS: Fifteen experts participated in the Delphi survey. After the three rounds, consensus was reached on 18 clinical descriptors: 10 items were included in the "subjective examination" domain, 1 item was included in the "patient-reported outcome measures" domain, 3 items in the "diagnostic examination" domain, 2 items in the "physical examination" domain", and 2 items in the "functional tests" domain. No items reached consensus within the "special tests" domain. The reproduction of symptoms in relation to the application of load, the performance of overhead activities, and the need of active and resisted movement assessment were some of the results with greatest consensus. CONCLUSION: In this Delphi study, a total of 18 clinical descriptors across six clinical domains were agreed upon for diagnosing RCRSP.

Erratum: Petrofsky, J., et al. Greater Postural Sway and Tremor during Balance Tasks in Patients with Plantar Fasciitis Compared to Age-Matched Controls. Healthcare 2020, 8, 219.

Some details of the author affiliations should be corrected in the article [...].

Greater Postural Sway and Tremor during Balance Tasks in Patients with Plantar Fasciitis Compared to Age-Matched Controls.

Plantar fasciitis (PF) is a common condition found in men and women and can reoccur throughout life. PF is commonly diagnosed by prolonged foot pain lasting more than 3 months and a plantar fascia over 0.4 mm thick, as measured using ultrasound imaging. This study examined the ability to balance and the occurrence of muscle tremor during different balance tasks in patients with PF compared to their control counterparts. Fifty subjects (25 patients with PF and 25 control subjects) participated in this study. Subjective pain (measured with a visual analog scale (VAS)), pressure pain threshold (PPT), and postural sway and tremor during eight different balance tasks were measured. Postural sway was measured by a balance platform, while tremor was measured as the mechanical movement of the platform in the 8 Hz frequency range. Thickness of plantar fascia, subjective pain, and PPT were significantly greater in the PF group compared to the controls (p < 0.001). Postural sway and 8 Hz tremor were significantly greater in the PF group compared to the control group for all eight balance tasks (p < 0.01). These results indicate that the lack of plantar fascia elasticity is probably the cause of the reduced balance and increased muscle tremor.

Evidence of dynamic visual acuity impairment in asymptomatic mixed martial arts fighters.

AIM: The purpose of this study was to determine the amount of visual acuity loss with head movement in actively training mixed martial arts (MMA) fighters. METHODS: Vestibulo-ocular reflex function of 22 asymptomatic, male MMA fighters (age = 29.2 ± 5.1) was assessed by taking the difference between static visual acuity and the dynamic visual acuity test, in both yaw and pitch planes. RESULTS: The mean static visual acuity testing logMAR was -0.173 (standard deviation [SD] = 0.114). Mean dynamic visual acuity test values decreased with head movement to 0.196 logMAR (SD = 0.103) in yaw; p < 0.001, and to 0.283 logMAR (SD = 0.133) in pitch; p < 0.001. CONCLUSION: MMA fighters had a decay, beyond normal ranges, in visual acuity during head movement. These decreases may suggest vestibulo-ocular reflex impairment and were unrelated to self-reported concussion history. These results should be cautiously interpreted since there was not a control group.

Long-term results of radial extracorporeal shock wave treatment for chronic plantar fasciopathy: A prospective, randomized, placebo-controlled trial with two years follow-up.

Numerous randomized controlled trials (RCTs) demonstrated efficacy and safety of extracorporeal shock wave therapy (ESWT) for chronic plantar fasciopathy (cPF). However, only two such RCTs investigated a follow-up period of more than 1 year, both applying focused ESWT. Corresponding data for radial ESWT (rESWT) have not yet been reported. We therefore tested the hypothesis that rESWT is effective and safe for the management of cPF with long-term follow-up of 2 years. To this end n = 50 patients with cPF were randomly allocated to either two sessions of rESWT (one session per week; 2,000 shock waves with energy flux density of 0.16 mJ/mm2 per session) (n = 25) or to placebo treatment (n = 25). Evaluation was by change in Visual Analog Scale (VAS) score and Roles and Maudsley (RM) score. Mean pretreatment VAS scores for the rESWT and placebo groups were 8.5 and 8.9, respectively. 1, 3, 6, 12, and 24 months after treatment, the mean VAS scores for the rESWT and placebo groups were 0.6, 1.1, 0.5, 2.3, and 1.4 and 7.6, 7.7, 7.4, 6.9, and 5.6 (p < 0.001), respectively. Differences in mean RM scores were statistically significant between groups at 1, 3, 6, 12, and 24 months post treatment, but not at baseline. There were no significant complications. These data indicate that rESWT is effective and safe for the management of cPF with long-term follow-up of 2 years. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1532-1538, 2017.

New concepts in restoring shoulder elevation in a stiff and painful shoulder patient.

The treatment and evaluation of a stiff and painful shoulder, characteristic of adhesive capsulitis and "frozen" shoulders, is a dilemma for orthopedic rehabilitation specialists. A stiff and painful shoulder is all-inclusive of Adhesive capsulitis and Frozen Shoulder diagnoses. Adhesive capsulitis and frozen shoulder will be referred to as a stiff and painful shoulder, throughout this paper. Shoulder motion occurs in multiple planes of movement. Loss of shoulder mobility can result in significant functional impairment. The traditional treatment approach to restore shoulder mobility emphasizes mobilization of the shoulder overhead. Forced elevation in a stiff and painful shoulder can be painful and potentially destructive to the glenohumeral joint. This manuscript will introduce a new biomechanical approach to evaluate and treat patients with stiff and painful shoulders.

Gluteus medius strengthening and the use of the Donatelli Drop Leg Test in the athlete.

OBJECTIVES: To evaluate and strengthen the posterior segment of the gluteus medius. DESIGN: A technical description of a novel examination and rehabilitation protocol. SETTING: The gluteus medius, primarily a hip abductor, serves several important functions in the athlete. Weakness of the gluteus medius has been linked to injuries in the shoulder and iliotibial band, as well as ankle instability. Though previously treated as a homogenous muscle, recent studies of the gluteus medius show three segments with distinct function and activation - the anterior, middle, and posterior. Current rehabilitation protocol focuses primarily on the anterior and middle segments, neglecting the posterior. CONCLUSION: We propose a three-stage protocol for strengthening and rehabilitation of the injured athlete and the Drop Leg Test, which can be used to identify weakness in the posterior segment of the gluteus medius.

Subscapularis syndrome: a case report.

UNLABELLED: Dysfunction of the subscapularis muscle is introduced in this case report as a potential factor for consideration in the etiology and/or consequential sequelae of subacromial impingement syndrome. Although dysfunction of the supraspinatus and infraspinatus are implicated as being most commonly involved with subacromial impingement pathology, the subscapularis is often overlooked and therefore undertreated. Identifying the subscapularis' potential involvement in patients with subacromial impingement pathology may offer insight into shoulder impingement dysfunction and injury treatment options available to specifically address subscapularis dysfunction. In this manuscript, a case report is presented to highlight the signs and symptoms of subscapularis pathology concordant with subacromial impingement syndrome and provide a clinical rationale for treatment. The purpose of this case report is not to suggest a new approach to shoulder rehabilitation, but rather to prompt the consideration of subscapularis dysfunction when evaluating and treating patients with subacromial impingement pathology. LEVEL OF EVIDENCE: 5.

Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors.

Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.

Sport-specific biomechanics of spinal injuries in the athlete (throwing athletes, rotational sports, and contact-collision sports).

Athletes consistently recruit or transfer high levels of repetitive force through the spine. Proper force transmission from the legs to the hips and pelvis and through the trunk is vital. Hip and pelvis joint restrictions and muscle strength deficits coupled with poor endurance of the trunk muscle will lead to spinal instability, which is habitually described in symptomatic athletes. A rehabilitation program that targets the unstable base first, and then progresses to strengthening of the pelvis and hips and targets control of movement in a sport-specific approach, should result in pain reduction, skill enhancement, and a safe return to play.

Optimization of a potent class of arylamide colony-stimulating factor-1 receptor inhibitors leading to anti-inflammatory clinical candidate 4-cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino)acetyl]-4-piperidinyl]phenyl]-1H-imidazole-2-carboxamide (JNJ-28312141).

A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC(50) = 0.69 nM, cell assay IC(50) = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.

Reducing ion channel activity in a series of 4-heterocyclic arylamide FMS inhibitors.

During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resultant compounds retained excellent potency and exhibited diminished ion channel activity.

Chronic plantar fasciitis treated with two sessions of radial extracorporeal shock wave therapy.

BACKGROUND: Radial extracorporeal shock wave therapy (RSWT) has been previously demonstrated as an efficient treatment option for chronic plantar fasciitis (PF) when administered in three sessions. The present study tested the hypothesis that chronic PF can also be treated successfully with RSWT when only two treatment sessions are performed. MATERIALS AND METHODS: A total of 50 patients with unilateral, chronic PF were randomly assigned to either RSWT (n = 25) or placebo treatment (n = 25). RSWT was applied in two sessions 1 week apart (2,000 impulses with energy flux density = 0.16 mJ/mm(2) per session). Placebo treatment was performed with a clasp on the heel. Endpoints were changes in the Visual Analog Scale (VAS) score and the modified Roles & Maudsley (RM) score from baseline to 4 weeks, 12 weeks and 24 weeks followup. RESULTS: Mean VAS scores were reduced after RSWT from 8.5 +/- 0.3 (mean +/- SEM) at baseline to 0.6 +/- 1.5 at 4 weeks, 1.1 +/- 0.3 at 12 weeks and 0.5 +/- 0.1 at 24 weeks from baseline. Similar changes were found for mean RM scores from baseline after RSWT but were not observed after placebo treatment. Statistical analysis demonstrated that RSWT resulted in significantly reduced mean VAS scores and mean RM scores at all followup intervals compared to placebo treatment (each with p < 0.001). No serious adverse events of RSWT were observed. CONCLUSION: RSWT was successful in the treatment of chronic PF even when only two sessions with 2,000 impulses each were performed 1 week apart.

JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia.

There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80(+) tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.

Pyrido[2,3-d]pyrimidin-5-ones: a novel class of antiinflammatory macrophage colony-stimulating factor-1 receptor inhibitors.

A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.

Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor.

A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.

Synthesis and evaluation of novel 3,4,6-substituted 2-quinolones as FMS kinase inhibitors.

A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.

Potent 2'-aminoanilide inhibitors of cFMS as potential anti-inflammatory agents.

A series of 2'-aminoanilides have been identified which exhibit potent and selective inhibitory activity against the cFMS tyrosine kinase. Initial SAR studies within this series are described which examine aroyl and amino group substitutions, as well as the introduction of hydrophilic substituents on the benzene core. Compound 47 inhibits the isolated enzyme (IC(50)=0.027 microM) and blocks CSF-1-induced proliferation of bone marrow-derived macrophages (IC(50)=0.11 microM) and as such, serves as a lead candidate for further optimization studies.

Electromyographic analysis of core trunk, hip, and thigh muscles during 9 rehabilitation exercises.

STUDY DESIGN: Prospective, single-group, repeated-measures design. OBJECTIVE: To identify exercises that could be used for strength development and the exercises that would be more appropriate for endurance or stabilization training. BACKGROUND: The exercises analyzed are often used in rehabilitation programs for the spine, hip, and knee. They are active exercises using body weight for resistance; thus a clinician is unable to determine the amount of resistance being applied to a muscle group. Electromyographic (EMG) analysis can provide a measure of muscle activation so that the clinician can have a better idea about the effect the exercise may have on the muscle for strength, endurance, or stabilization. METHODS AND MEASURES: Surface EMG analysis was carried out in 19 males and 11 females while performing the following 9 exercises: active hip abduction, bridge, unilateral-bridge, side-bridge, prone-bridge on the elbows and toes, quadruped arm/lower extremity lift, lateral step-up, standing lunge, and using the Dynamic Edge. The rectus abdominis, external oblique abdominis, longissimus thoracis, lumbar multifidus, gluteus maximus, gluteus medius, vastus medialis obliquus, and hamstring muscles were studied. RESULTS: In healthy subjects, the lateral step-up and the lunge exercises produced EMG levels greater than 45% maximum voluntary isometric contraction (MVIC) in the vastus medialis obliquus, which suggests that they may be beneficial for strengthening that muscle. The side-bridge exercise could be used for strengthening the gluteus medius and the external oblique abdominis muscles, and the quadruped arm/lower extremity lift exercise may help strengthen the gluteus maximus muscle. All the other exercises produced EMG levels less than 45% MVIC, so they may be more beneficial for training endurance or stabilization in healthy subjects. CONCLUSION: Our results suggest these exercises could be used for a core rehabilitation or performance enhancement program. Depending on the individual needs of a patient or athlete, some of the exercises may be more beneficial than others for achieving strength.

Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo.

The activity and stability of the p53 tumor suppressor are regulated by the human homologue of the mouse double minute 2 (Hdm2) oncoprotein. It has been hypothesized that small molecules disrupting the Hdm2:p53 complex would allow for the activation of p53 and result in growth suppression. We have identified small-molecule inhibitors of the Hdm2:p53 interaction using our proprietary ThermoFluor microcalorimetry technology. Medicinal chemistry and structure-based drug design led to the development of an optimized series of benzodiazepinediones, including TDP521252 and TDP665759. Activities were dependent on the expression of wild-type (wt) p53 and Hdm2 as determined by lack of potency in mutant or null p53-expressing cell lines or cells engineered to no longer express Hdm2 and wt p53. TDP521252 and TDP665759 inhibited the proliferation of wt p53-expressing cell lines with average IC(50)s of 14 and 0.7 micromol/L, respectively. These results correlated with the direct cellular dissociation of Hdm2 from wt p53 observed within 15 minutes in JAR choriocarcinoma cells. Additional activities of these inhibitors in vitro include stabilization of p53 protein levels, up-regulation of p53 target genes in a DNA damage-independent manner, and induction of apoptosis in HepG2 cells. Administration of TDP665759 to mice led to an increase in p21(waf1/cip1) levels in liver samples. Finally, TDP665759 synergizes with doxorubicin both in culture and in an A375 xenograft model to decrease tumor growth. Taken together, these data support the potential utility of small-molecule inhibitors of the Hdm2:p53 interaction for the treatment of wt p53-expressing tumors.