Important clinical descriptors to include in the examination and assessment of patients with femoroacetabular impingement syndrome: an international and multi-disciplinary Delphi survey.

PURPOSE: Determine which examination findings are key clinical descriptors of femoroacetabular impingement syndrome (FAIS) through use of an international, multi-disciplinary expert panel. METHODS: A three-round Delphi survey utilizing an international, multi-disciplinary expert panel operationally defined from international publications and presentations was utilized. RESULTS: All six domains (subjective examination, patient-reported outcome measures, physical examination, special tests, physical performance measures, and diagnostic imaging) had at least one descriptor with 75% consensus agreement for diagnosis and assessment of FAIS. Diagnostic imaging was the domain with the highest level of agreement. Domains such as patient-reported outcome measures (PRO's) and physical examination were identified as non-diagnostic measures (rather as assessments of disease impact). CONCLUSION: Although it also had the greatest level of variability in description of examination domains, diagnostic imaging continues to be the preeminent diagnostic measure for FAIS. No single domain should be utilized as the sole diagnostic or assessment parameter for FAIS. While not all investigated domains provide diagnostic capability for FAIS, those that do not are able to serve purpose as a measure of disease impact (e.g., impairments and activity limitations). The clinical relevance of this Delphi survey is the understanding that a comprehensive assessment measuring both diagnostic capability and disease impact most accurately reflects the patient with FAIS. LEVEL OF EVIDENCE: V.

Physical examination tests for screening and diagnosis of cervicogenic headache: A systematic review.

It has been suggested that differential diagnosis of headaches should consist of a robust subjective examination and a detailed physical examination of the cervical spine. Cervicogenic headache (CGH) is a form of headache that involves referred pain from the neck. To our knowledge, no studies have summarized the reliability and diagnostic accuracy of physical examination tests for CGH. The aim of this study was to summarize the reliability and diagnostic accuracy of physical examination tests used to diagnose CGH. A systematic review following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was performed in four electronic databases (MEDLINE, Web of Science, Embase and Scopus). Full text reports concerning physical tests for the diagnosis of CGH which reported the clinometric properties for assessment of CGH, were included and screened for methodological quality. Quality Appraisal for Reliability Studies (QAREL) and Quality Assessment of Studies of Diagnostic Accuracy (QUADAS-2) scores were completed to assess article quality. Eight articles were retrieved for quality assessment and data extraction. Studies investigating diagnostic reliability of physical examination tests for CGH scored poorer on methodological quality (higher risk of bias) than those of diagnostic accuracy. There is sufficient evidence showing high levels of reliability and diagnostic accuracy of the selected physical examination tests for the diagnosis of CGH. The cervical flexion-rotation test (CFRT) exhibited both the highest reliability and the strongest diagnostic accuracy for the diagnosis of CGH.

Risk stratification of patients with low back pain seen in physical therapy practice.

DESIGN: A secondary analysis of a retrospective cohort was conducted using data obtained from a commercial outcomes database. OBJECTIVE: To identify predictive characteristics related to patients with lumbar impairments who have a high risk of a bad prognosis (lowest functional recovery compared to visit utilization) as well as those who are at low risk of a bad prognosis (highest functional recovery compared to visit utilization). BACKGROUND: Lumbar impairments are highly prevalent and routinely cause people to seek medical care, including physiotherapy. Most prognostic studies focus solely on good outcomes but do not factor in the intensity of care needed to achieve the outcome. Understanding care intensity needed per outcome achieved could help assign appropriate care quantities. METHODS: Data from 6379 patients with lumbar impairments were analyzed to determine predictive characteristics that identify patients who either have a low or high risk of a bad prognosis to physiotherapy care. Multinomial regression was used to identify significant patient characteristics predictive of treatment response. RESULTS: Statistically significant predictors for high risk categorization included older age, longer duration of symptoms, surgical history, current use of medications, lower levels of disability at baseline, and insurance categorization. Statistically significant predictors of low risk categorization included younger age, male gender, shorter duration of symptoms, no surgical history, higher levels of disability at baseline, and insurance status. CONCLUSION: Selected variables were associated with both poor and good recovery. Further research on prognosis, efficacy of physiotherapy care, and cost appear warranted for patients with lumbar impairments.

Diagnostic accuracy of clinical tests for the diagnosis of hip femoroacetabular impingement/labral tear: a systematic review with meta-analysis.

BACKGROUND: Surgery for hip femoroacetabular impingement/acetabular labral tear (FAI/ALT) is exponentially increasing despite lacking investigation of the accuracy of various diagnostic measures. Useful clinical utility of these measures is necessary to support diagnostic imaging and subsequent surgical decision-making. OBJECTIVE: Summarise/evaluate the current diagnostic accuracy of various clinical tests germane to hip FAI/ALT pathology. METHODS: A computer-assisted literature search of MEDLINE, CINAHL and EMBASE databases using keywords related to diagnostic accuracy of the hip joint, as well as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for the search and reporting phases of the study. Quality assessment of bias and applicability was conducted using the Quality of Diagnostic Accuracy Studies-2 (QUADAS-2). Random effects models were used to summarise sensitivities (SN), specificities (SP), diagnostic odds ratio (DOR) and respective confidence intervals (CI). RESULTS: The employed search strategy revealed 21 potential articles, with one demonstrating high quality. Nine articles qualified for meta-analysis. The meta-analysis demonstrated that flexion-adduction-internal rotation (pooled SN ranging from 0.94 (95% CI 0.90 to 0.97) to 0.99 (95% CI 0.98 to 1.00); DOR 5.71 (95% CI 0.84 to 38.86) to 7.82 (95% CI 1.06 to 57.84)) and flexion-internal rotation (pooled SN 0.96 (95% CI 0.81 to 0.99); DOR 8.36 (95% CI 0.41 to 171.3) tests possess only screening accuracy. CONCLUSIONS: Few hip physical examination tests for diagnosing FAI/ALT have been investigated in enough studies of substantial quality to direct clinical decision-making. Further high-quality studies across a wider spectrum of hip pathology patients are recommended to discern the confirmed clinical utility of these tests. TRIALS REGISTRATION NUMBER: PROSPERO Registration # CRD42014010144.

Noncanonical expression of caudal during early embryogenesis in the pea aphid Acyrthosiphon pisum: maternal cad-driven posterior development is not conserved.

Previously we identified anterior localization of hunchback (Aphb) mRNA in oocytes and early embryos of the parthenogenetic and viviparous pea aphid Acyrthosiphon pisum, suggesting that the breaking of anterior asymmetry in the oocytes leads to the formation of the anterior axis in embryos. In order to study posterior development in the asexual pea aphid, we cloned and analysed the developmental expression of caudal (Apcad), a posterior gene highly conserved in many animal phyla. We found that transcripts of Apcad were not detected in germaria, oocytes and embryos prior to the formation of the blastoderm in the asexual (viviparous) pea aphid. This unusual expression pattern differs from that of the existing insect models, including long- and short-germ insects, where maternal cad mRNA is passed to the early embryos and forms a posterior-anterior gradient. The first detectable Apcad expression occurred in the newly formed primordial germ cells and their adjacent blastodermal cells during late blastulation. From gastrulation onward, and as in other insects, Apcad mRNA is restricted to the posteriormost region of the germ band. Similarly, in the sexual (oviparous) oocytes we were able to identify anterior localization of Aphb mRNA but posterior localization of Apcad was not detected. This suggests that cad-driven posterior development is not conserved during early embryogenesis in asexual and sexual pea aphids.

Anterior development in the parthenogenetic and viviparous form of the pea aphid, Acyrthosiphon pisum: hunchback and orthodenticle expression.

In the dipteran Drosophila, the genes bicoid and hunchback work synergistically to pattern the anterior blastoderm during embryogenesis. bicoid, however, appears to be an innovation of the higher Diptera. Hence, in some non-dipteran insects, anterior specification instead relies on a synergistic interaction between maternally transcribed hunchback and orthodenticle. Here we describe how orthologues of hunchback and orthodenticle are expressed during oogenesis and embryogenesis in the parthenogenetic and viviparous form of the pea aphid, Acyrthosiphon pisum. A. pisum hunchback (Aphb) mRNA is localized to the anterior pole in developing oocytes and early embryos prior to blastoderm formation - a pattern strongly reminiscent of bicoid localization in Drosophila. A. pisum orthodenticle (Apotd), on the other hand, is not expressed prior to gastrulation, suggesting that it is the asymmetric localization of Aphb, rather than synergy between Aphb and Apotd, that regulates anterior specification in asexual pea aphids.

Hox genes and the phylogeny of the arthropods.

The arthropods are the most speciose, and among the most morphologically diverse, of the animal phyla. Their evolution has been the subject of intense research for well over a century, yet the relationships among the four extant arthropod subphyla - chelicerates, crustaceans, hexapods, and myriapods - are still not fully resolved. Morphological taxonomies have often placed hexapods and myriapods together (the Atelocerata) [1, 2], but recent molecular studies have generally supported a hexapod/crustacean clade [2-9]. A cluster of regulatory genes, the Hox genes, control segment identity in arthropods, and comparisons of the sequences and functions of Hox genes can reveal evolutionary relationships [10]. We used Hox gene sequences from a range of arthropod taxa, including new data from a basal hexapod and a myriapod, to estimate a phylogeny of the arthropods. Our data support the hypothesis that insects and crustaceans form a single clade within the arthropods to the exclusion of myriapods. They also suggest that myriapods are more closely allied to the chelicerates than to this insect/crustacean clade.

Effect of a 17alpha-(3-hydroxypropyl)-17beta-acetyl substituent pattern on the glucocorticoid and progestin receptor binding of 11beta-arylestra-4,9-dien-3-ones.

[structure: see text]. Replacing the 17alpha-acetoxy substituent in an antiprogestational 17beta-acetyl-11beta-arylestra-4,9-dien-3-one by 3-hydroxypropyl significantly diminished glucocorticoid receptor binding with little effect on progestin receptor binding.

28-day toxicology test: indenopyridine RTI 4587-056 in male Sprague-Dawley rats.

The potential toxicity of RTI 4587-056, a hexahydroindenopyridine analog of SANDOZ 20-438, was examined in adult male Sprague-Dawley rats. Testicular, intestinal, and erythropoietic histology was assessed after 28 days of gavage treatment at 0, 10, and 100 mg/kg/day. During the first 10 days, dose-related clinical signs included mild to moderate lethargy shortly after dosing, lower consumption of feed and water, and body weight loss or decreased weight gain. Tolerance developed, such that lethargy disappeared and weight gains were equivalent to the control group during the second through fourth weeks. The compound did not affect intestinal epithelium or bone marrow. RTI 4587-056 was a highly effective antispermatogenic agent at both doses causing epididymal hypospermia and testicular atrophy. Based upon the Spermatogenic Index ratings, still lower doses would be effective male contraceptive agents. RTI 4587-056 has potential as a male contraceptive without overt side effects. Further testing is required.

Hox genes in brachiopods and priapulids and protostome evolution.

Understanding the early evolution of animal body plans requires knowledge both of metazoan phylogeny and of the genetic and developmental changes involved in the emergence of particular forms. Recent 18S ribosomal RNA phylogenies suggest a three-branched tree for the Bilateria comprising the deuterostomes and two great protostome clades, the lophotrochozoans and ecdysozoans. Here, we show that the complement of Hox genes in critical protostome phyla reflects these phylogenetic relationships and reveals the early evolution of developmental regulatory potential in bilaterians. We have identified Hox genes that are shared by subsets of protostome phyla. These include a diverged pair of posterior (Abdominal-B-like) genes in both a brachiopod and a polychaete annelid, which supports the lophotrochozoan assemblage, and a distinct posterior Hox gene shared by a priapulid, a nematode and the arthropods, which supports the ecdysozoan clade. The ancestors of each of these two major protostome lineages had a minimum of eight to ten Hox genes. The major period of Hox gene expansion and diversification thus occurred before the radiation of each of the three great bilaterian clades.

A mitochondrial control region and cytochrome b phylogeny of sika deer (Cervus nippon) and report of tandem repeats in the control region.

Sika deer (Cervus nippon Temminck) are endemic to mainland and insular Asia. Numerous subspecies have been named, but they are not quantitatively well defined. Portions of the mitochondrial cytochrome b gene (450 bp) and control region (512 bp) were sequenced from 28 individuals belonging to five sika subspecies and two Cervus elaphus subspecies. Phylogenetic trees constructed using these sequences clearly demonstrated that sika are monophyletic with respect to C. elaphus. A survey of variation in the control region showed that approximately half the variation occurred in a 100-base segment between positions 150 and 250 in the left domain of the control region. Within this region there were three tandemly repeated copies of a 39-base motif. In addition, two of the samples (C. n. aplodontus and C. n. hortulorum) contained, respectively, two and four additional copies of the repeated motif.

The novel progesterone receptor antagonists RTI 3021-012 and RTI 3021-022 exhibit complex glucocorticoid receptor antagonist activities: implications for the development of dissociated antiprogestins.

We have identified two novel compounds (RTI 3021-012 and RTI 3021-022) that demonstrate similar affinities for human progesterone receptor (PR) and display equivalent antiprogestenic activity. As with most antiprogestins, such as RU486, RTI 3021-012, and RTI 3021-022 also bind to the glucocorticoid receptor (GR) with high affinity. Unexpectedly, when compared with RU486, the RTI antagonists manifest significantly less GR antagonist activity. This finding indicates that, with respect to antiglucocorticoid function, receptor binding affinity is not a good predictor of biological activity. We have determined that the lack of a clear correlation between the GR binding affinity of the RTI compounds and their antagonist activity reflects the unique manner in which they modulate GR signaling. Previously, we proposed a two step "active inhibition" model to explain steroid receptor antagonism: 1) competitive inhibition of agonist binding; and 2) competition of the antagonist bound receptor with that activated by agonists for DNA response elements within target gene promoters. Accordingly, we observed that RU486, RTI 3021-012, and RTI 3021-022, when assayed for PR antagonist activity, accomplished both of these steps. Thus, all three compounds are "active antagonists" of PR function. When assayed on GR, however, RU486 alone functioned as an active antagonist. RTI 3021-012 and RTI 3021-022, on the other hand, functioned solely as "competitive antagonists" since they were capable of high affinity GR binding, but the resulting ligand receptor complex was unable to bind DNA. These results have important pharmaceutical implications supporting the use of mechanism based approaches to identify nuclear receptor modulators. Of equal importance, RTI 3021-012 and RTI 3021-022 are two new antiprogestins that may have clinical utility and are likely to be useful as research reagents with which to separate the effects of antiprogestins and antiglucocorticoids in physiological systems.

Characterization of infectious aerosols in health care facilities: an aid to effective engineering controls and preventive strategies.

Assessment of strategies for engineering controls for the prevention of airborne infectious disease transmission to patients and to health care and related workers requires consideration of the factors relevant to aerosol characterization. These factors include aerosol generation, particle size and concentrations, organism viability, infectivity and virulence, airflow and climate, and environmental sampling and analysis. The major focus on attention to engineering controls comes from recent increases in tuberculosis, particularly the multidrug-resistant varieties in the general hospital population, the severely immunocompromised, and those in at-risk and confined environments such as prisons, long-term care facilities, and shelters for the homeless. Many workers are in close contact with persons who have active, undiagnosed, or insufficiently treated tuberculosis. Additionally, patients and health care workers may be exposed to a variety of pathogenic human viruses, opportunistic fungi, and bacteria. This report therefore focuses on the nature of infectious aerosol transmission in an attempt to determine which factors can be systematically addressed to result in proven, applied engineering approaches to the control of infectious aerosols in hospital and health care facility environments. The infectious aerosols of consideration are those that are generated as particles of respirable size by both human and environmental sources and that have the capability of remaining viable and airborne for extended periods in the indoor environment. This definition precludes skin and mucous membrane exposures occurring from splashes (rather than true aerosols) of blood or body fluids containing infectious disease agents. There are no epidemiologic or laboratory studies documenting the transmission of bloodborne virus by way of aerosols.

Molecular instability in the COII-tRNA(Lys) intergenic region of the human mitochondrial genome: multiple origins of the 9-bp deletion and heteroplasmy for expanded repeats.

We have identified two individuals from Glasgow in Scotland who have a deletion of one of two copies of the intergenic 9-bp sequence motif CCCCCTCTA, located between the cytochrome oxidase II (COII) and lysine tRNA (tRNA(Lys)) genes of the human mitochondrial genome. Although this polymorphism is common in Africa and Asia, it has not been reported in Northern Europe. Analysis of the mitochondrial DNA control region sequences of these two individuals suggests that they belong to a lineage that originated independently of the previously characterized African and Asian 9-bp deleted lineages. Among the Scottish population we have also identified a maternal lineage of three generations exhibiting heteroplasmy for two, three and four copies of the CCCCCTCTA motif. Polymerase chain reaction amplification across the COII-tRNA(Lys) intergenic region of these individuals gives different ratios of the three product lengths that are dependent on the concentration of the DNA-binding dye crystal violet. To investigate whether changes in repeat number were generated de novo, we constructed clones containing known numbers of the CCCCCTCTA motif. In the presence of high concentrations of crystal violet we obtained two, three and four copies of this motif when the amplification template contained only four copies. Various DNA-binding drugs are known to stabilize bulged structures in DNA and contribute to the process of slipped-strand mispairing during DNA replication. These results suggest that the COII-tRNA(Lys) intergenic region is unstable owing to slipped-strand mispairing. Although sequences containing four copies of the CCCCCTCTA motif are less stable in vitro, we observed an increase in the proportion of mitochondrial genomes with four repeats between-a mother and a daughter in the heteroplasmic lineage. From this we conclude that drift in the germ-line lineage is a main factor in the maintenance or loss of heteroplasmy.

16 alpha-substituted analogs of the antiprogestin RU486 induce a unique conformation in the human progesterone receptor resulting in mixed agonist activity.

Previously, we have shown that agonists and antagonists interact with distinct, though overlapping regions within the human progesterone receptor (hPR) resulting in the formation of structurally different complexes. Thus, a link was established between the structure of a ligand-receptor complex and biological activity. In this study, we have utilized a series of in vitro assays with which to study hPR pharmacology and have identified a third class of hPR ligands that induce a receptor conformation which is distinct from that induced by agonists or antagonists. Importantly, when assayed on PR-responsive target genes these compounds were shown to exhibit partial agonist activity; an activity that was influenced by cell context. Thus, as has been shown previously for estrogen receptor, the overall structure of the ligand-receptor complex is influenced by the nature of the ligand. It appears, therefore, that the observed differences in the activity of some PR and estrogen receptor ligands reflect the ability of the cellular transcription machinery to discriminate between the structurally different complexes that result following ligand interaction. These data support the increasingly favored hypothesis that different ligands can interact with different regions within the hormone binding domains of steroid hormone receptors resulting in different biologies.

Structure-activity studies of 2,3,4,4a,5,9b-hexahydroindeno[1,2-c]pyridines as antispermatogenic agents for male contraception.

Analogs of (4aRS,5SR,9bRS)-2-ethyl-2,3,4,4a,5,9b-hexahydro-7-meth yl-5-p- tolyl-1H-indeno[1,2-c]pyridine (Sandoz 20-438, 10a; R1 = ethyl, R2 = R3 = methyl, R4 = H) have been synthesized and tested in mice for their ability to reduce testes weight and disrupt spermatogenesis. The activity was strongly dependent on stereoisomerism and chirality, consistent with a mechanism of action involving interaction with a specific macromolecule. It was affected by changes in the nitrogen substituent and most strikingly by changes in the p-substituent of the 5-aryl ring. A hydrogen, fluorine, hydroxy, or methoxy substituent led to loss of activity, whereas methyl (Sandoz 20-438, 10a), carboxylate (RTI-4587-054, 10k; R1 = ethyl, R2 = methyl, R3 = COOH, R4 = H), ester (RTI-4587-056, 12b; R1 = ethyl, R2 = methyl, R3 = COOMe, R4 = H), formyl (RTI-4587-030, 12i; R1 = ethyl, R2 = methyl, R3 = CHO, R4 = H), or hydroxymethyl (RTI-4587-055, 12g; R1 = ethyl, R2 = methyl, R3 = CH2OH, R4 = H) groups resulted in antispermatogenic compounds. Methyl ester 12b was an effective antifertility agent, without apparent effects on mating, when given orally to male mice at 7-15 mg/kg daily for 35 days. Further evaluation of these compounds as male contraceptive agents and probes for study of spermatogenesis appears warranted.

Comparison in humans of the potency and pharmacokinetics of intravenously injected cocaethylene and cocaine.

Cocaethylene (the ethyl ester of benzoylecgonine) is a product of the interaction between ethanol and cocaine. The results of preclinical studies and of a pilot clinical study have shown cocaethylene to produce pharmacologic effects similar to those of cocaine. However, no information is available concerning the potency and pharmacokinetics of cocaethylene in comparison to those of cocaine in humans. We report the results of a single-blind, crossover study in which six male, healthy, paid volunteers, who were moderate users of cocaine, were intravenously injected with the water soluble fumarate salt of cocaethylene (0.25 mg/kg cocaethylene base) or an equivalent dose of the water soluble hydrochloride salt of cocaine (0.25 mg/kg cocaine base). Each dose was dissolved in normal saline and injected over a 1-min interval. Test sessions were separated by a 1-week interval. The variables measured were: cocaine and cocaethylene plasma concentrations, subjective and cardiovascular effects. The results indicate, that in comparison to cocaine, cocaethylene had a significant smaller elimination rate constant (0.42 versus 0.67 l/h), had a longer elimination half-life (1.68 versus 1.07 h), and induced ratings of "high" and changes in heart rate that were of lower magnitude (65%, and 43%, respectively). During the period of time that pharmacologic effects were present the plasma concentrations of cocaine and cocaethylene were statistically indistinguishable. This finding supports the conclusion that in humans cocaethylene is less potent than cocaine.