Developing a standardized curriculum for teaching chiropractic technique.

OBJECTIVE: This is a report of the results of 4 facilitated workshops aimed at developing a standardized chiropractic technique curriculum. METHODS: Workshops were held at research conferences during 2014, 2016, 2018, and 2019. Participants were tasked with developing recommendations for diagnostic and therapeutic procedures appropriate for chiropractic technique programs. RESULTS: For diagnostic procedures, there was general agreement among participants that chiropractic programs should include diagnostic imaging, postural assessment, gait analysis, palpation (static, motion, and joint play/springing), global range of motion, and evidence-based orthopedic/neurological tests. No consensus could be reached with respect to chiropractic x-ray line marking (spinography) nor heat sensing instruments, and there was only partial consensus on leg length assessment. For therapeutic procedures, all participants agreed that the following should be included: high-velocity, low amplitude spinal and extremity manipulation, adjustments assisted by hand-held instruments, drop tables, flexion-distraction tables, and pelvic blocks. There was unanimous support for teaching mobilization of the spine and peripheral joints, as well as for manual and instrument-assisted soft tissue therapies. There were some overarching issues: participants strongly preferred assessment methods known to be reliable and valid and therapeutic procedures known to be safe and effective. Where evidence was lacking, they insisted that diagnostic and therapeutic methods at minimum have face validity and biological plausibility. However, they cautioned against applying aspects of evidence-based care too rigidly. CONCLUSIONS: Despite differing views on chiropractic terminology, philosophy, and scope of practice, participants' opinions were similar regarding diagnostic and therapeutic procedures that ought to be included in chiropractic technique programs.

The Association of Manual Muscle Tests and Treatment Outcomes With Headache and Cranial Dysfunctions: A Retrospective Case Series Report.

BACKGROUND: This study examine whether there is an interrelationship between cranio-sacral dysfunctions and the muscle inhibitions found in the muscles attaching to the skull in patients with headaches. PRIMARY STUDY OBJECTIVE: To present a retrospective case series report assessing the prevalence of positive manual muscle tests (MMTs) in the assessment and management of adults with headache and cervico-cranial dysfunctions and to present patient outcomes pre- and posttreatment. METHODS/DESIGN: Fifty-two patient files with headache (HA) (48 females, 4 males) were retrospectively examined. These patients had either primary (tension-type, migraine, or cervicogenic) or secondary HAs (that result from other medical conditions), according to the International Classification of Headache Disorders. A standardized MMT assessment of the major cervical muscles attaching to the skull was performed on every patient pre- and posttreatment, and a pre- and posttreatment numeric pain scale of neck and associated head pain was recorded. SETTING: The setting was an in-office clinical chiropractic trial. PRIMARY OUTCOME MEASURES: MMT and numeric pain scale of neck and associated head pain evaluation pre- and posttreatment. RESULTS: Muscle dysfunctions (inhibition) were found to be associated with HA in these patients as follows: sternocleidomastoid, 42 patients; deep neck flexors, 33 patients; anterior scalenes, 24 patients; and upper trapezius, 24 patients. Three patients with HA had no muscle inhibition. Cranial and upper cervical articular dysfunctions were found in 49 and 52 patients, respectively. In this group of 52 patients with HA, 49 patients had cranial dysfunctions that when treated with applied kinesiology improved all or a portion of the muscle inhibitions, whereas the initial numeric pain scale of neck and associated head pain simultaneously fell from an average of 6.75 to an average of 0.49. Odds ratios were calculated to be >1, meaning there was a positive correlation between positive MMT of these muscles (as well as upper cervical and cranial dysfunctions) and HAs in this cohort. CONCLUSION: A symptomatic group of patients with HA and cranial dysfunctions demonstrated MMT findings in the form of muscle inhibition. Cranial treatments to improve muscle strength were found to correlate with improvements in HA for these patients. This evidence may suggest that the MMT is a potentially useful test for evaluating pericranial muscular impairments in patients with cranial dysfunctions and HA.

Mapping Gene Expression in Excitatory Neurons during Hippocampal Late-Phase Long-Term Potentiation.

The persistence of long-lasting changes in synaptic connectivity that underlie long-term memory require new RNA and protein synthesis. To elucidate the temporal pattern of gene expression that gives rise to long-lasting neuronal plasticity, we analyzed differentially-expressed (DE) RNAs in mouse hippocampal slices following induction of late phase long-term potentiation (L-LTP) specifically within pyramidal excitatory neurons using Translating Ribosome Affinity Purification RNA sequencing (TRAP-seq). We detected time-dependent changes in up- and down-regulated ribosome-associated mRNAs over 2 h following L-LTP induction, with minimal overlap of DE transcripts between time points. TRAP-seq revealed greater numbers of DE transcripts and magnitudes of LTP-induced changes than RNA-seq of all cell types in the hippocampus. Neuron-enriched transcripts had greater changes at the ribosome-loading level than the total RNA level, while RNA-seq identified many non-neuronal DE mRNAs. Our results highlight the importance of considering both time course and cell-type specificity in activity-dependent gene expression during memory formation.

Differential regulation of type III secretion and virulence genes in Bordetella pertussis and Bordetella bronchiseptica by a secreted anti-σ factor.

The BvgAS phosphorelay regulates ∼10% of the annotated genomes of Bordetella pertussis and Bordetella bronchiseptica and controls their infectious cycles. The hierarchical organization of the regulatory network allows the integration of contextual signals to control all or specific subsets of BvgAS-regulated genes. Here, we characterize a regulatory node involving a type III secretion system (T3SS)-exported protein, BtrA, and demonstrate its role in determining fundamental differences in T3SS phenotypes among Bordetella species. We show that BtrA binds and antagonizes BtrS, a BvgAS-regulated extracytoplasmic function (ECF) sigma factor, to couple the secretory activity of the T3SS apparatus to gene expression. In B. bronchiseptica, a remarkable spectrum of expression states can be resolved by manipulating btrA, encompassing over 80 BtrA-activated loci that include genes encoding toxins, adhesins, and other cell surface proteins, and over 200 BtrA-repressed genes that encode T3SS apparatus components, secretion substrates, the BteA effector, and numerous additional factors. In B. pertussis, BtrA retains activity as a BtrS antagonist and exerts tight negative control over T3SS genes. Most importantly, deletion of btrA in B. pertussis revealed T3SS-mediated, BteA-dependent cytotoxicity, which had previously eluded detection. This effect was observed in laboratory strains and in clinical isolates from a recent California pertussis epidemic. We propose that the BtrA-BtrS regulatory node determines subspecies-specific differences in T3SS expression among Bordetella species and that B. pertussis is capable of expressing a full range of T3SS-dependent phenotypes in the presence of appropriate contextual cues.

Assessment of Consistency Between the Arm-Fossa Test and Gillet Test: A Pilot Study.

OBJECTIVE: The purpose of this pilot study was to test methods needed to conduct a study with adequate power to investigate consistency between the arm-fossa test (AFT) and the Gillet test. METHODS: A convenience sample of chiropractic college students enrolled in a weekend Sacro-Occipital Technique seminar participated. Each was tested with AFT and sacroiliac orthopedic tests, including the Gillet test. Statistical testing included calculation of κ for consistency of the AFT and Gillet test and their diagnostic efficiency. RESULTS: This study recruited 14 participants. Important issues arose in gathering and recording data, the standardization of examiner methods, and the flow of participants to examination stations. κ for AFT and Gillet test consistency = 0.55, corresponding to "moderate." CONCLUSION: This pilot suggests that the future study should include a mix of symptomatic and asymptomatic participants; record trichotomous data, where appropriate; use washout periods between diagnostic tests; and refine the selection of orthopedic tests deployed besides the AFT. The preliminary data are consistent with but do not establish due to the very small sample size and experimental design issues, that a positive AFT may be consistent with a negative Gillet test.

Crystallographic structure of a small molecule SIRT1 activator-enzyme complex.

SIRT1, the founding member of the mammalian family of seven NAD(+)-dependent sirtuins, is composed of 747 amino acids forming a catalytic domain and extended N- and C-terminal regions. We report the design and characterization of an engineered human SIRT1 construct (mini-hSIRT1) containing the minimal structural elements required for lysine deacetylation and catalytic activation by small molecule sirtuin-activating compounds (STACs). Using this construct, we solved the crystal structure of a mini-hSIRT1-STAC complex, which revealed the STAC-binding site within the N-terminal domain of hSIRT1. Together with hydrogen-deuterium exchange mass spectrometry (HDX-MS) and site-directed mutagenesis using full-length hSIRT1, these data establish a specific STAC-binding site and identify key intermolecular interactions with hSIRT1. The determination of the interface governing the binding of STACs with human SIRT1 facilitates greater understanding of STAC activation of this enzyme, which holds significant promise as a therapeutic target for multiple human diseases.

R + C Factors and Sacro Occipital Technique Orthopedic Blocking: a pilot study using pre and post VAS assessment.

INTRODUCTION: The concept of a systematic or predictive relationship between distant vertebral levels distinct from accumulative functional compensatory mechanisms, such as in scoliosis, has been perpetuated within chiropractic technique systems based on clinical observation and experience. This study seeks to investigate this relationship between the cervical and lumbar vertebrae. METHODS: Patients (experimental group n=26 and control group n=12) were selected from the patient base of one office, and were limited to patients that had sensitivity at specific cervical reflex points. Using a pre and post outcome measurement and sacro occipital technique R + C protocols, the related lumbar vertebra was adjusted in the direction indicated by the cervical vertebral sensitivity. RESULTS: Statistical analysis revealed there was a statistically significant difference between pre- and post-VAS measurements and found that the notable difference in mean change in VAS scores were statistically significantly different between the experimental and control groups (p < .001). CONCLUSION: The findings of this study suggest that further research into cervical and lumbar vertebra interrelationships, and the efficacy of orthopedic block treatment, may be warranted. Further studies are needed to confirm whether a causal relationship exists between lumbar manipulation and decreased cervical spine sensitivity.

INTRODUCTION: Le concept d'une relation systématique ou prédictive entre les niveaux distants vertébraux distincte des mécanismes compensatoires fonctionnels cumulatifs, comme en cas de scoliose, a été perpétué dans les systèmes de techniques chiropratiques fondés sur des observations cliniques et sur l'expérience. Cette étude cherche à examiner la relation entre les vertèbres cervicales et lombaires. MÉTHODOLOGIE: Les patients (groupe expérimental n=26 et groupe de contrôle n=12) ont été choisis parmi la clientèle d'un bureau, et se limitaient à ceux qui avaient une sensibilité à certains points de réflexe cervical. À l'aide d'une mesure avant et après et des protocoles de technique sacro occipitale R + C, la vertèbre lombaire liée était ajustée dans la direction indiquée par la sensibilité vertébrale cervicale. RÉSULTATS: Les analyses statistiques ont révélé une différence statistique importante entre les mesures avant et après VAS et ont indiqué que la différence de changement moyen des scores VAS étaient statistiquement très différente entre le groupe expérimental et le groupe de contrôle (p < 0,001). CONCLUSION: Les trouvailles de cette étude laissent entendre que des recherches supplémentaires sur les relations entre les vertèbres lombaires et cervicales, ainsi que l'efficacité du traitement de bloc orthopédique, peuvent être justifiées. D'autres études sont nécessaires pour confirmer s'il existe une relation de cause à effet entre la manipulation lombaire et la baisse de sensibilité de la colonne cervicale.

Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.

The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.

Evidence for a common mechanism of SIRT1 regulation by allosteric activators.

A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.

Discovery and evaluation of pyrazolo[1,5-a]pyrimidines as neuropeptide Y1 receptor antagonists.

A novel series of pyrazolo[1,5-a]pyrimidine derivatives was synthesized and evaluated as NPY Y1R antagonists. High binding affinity and selectivity were achieved with C3 trisubstituted aryl groups and C7 substituted 2-(tetrahydro-2H-pyran-4-ylamino)ethylamine moieties. Efforts to find close analogs with low plasma clearance in the rat and minimal p-glycoprotein efflux in the mouse were unsuccessful. Compound 2f (CP-671906) inhibited NPY-induced increases in blood pressure and food intake after iv and icv administration, respectively, in Sprague-Dawley (SD) rat models. Oral administration of compound 2f resulted in a modest, but statistically significant, reduction in food intake in a Wistar rat model of feeding behavior. Small inhibitions of food intake were also observed in an overnight fasting/refeeding model in SD rats. These data suggest a potential role for Y1R in the regulation of food intake in rodents.

Pyrido[2,3-b]pyrazines, discovery of TRPV1 antagonists with reduced potential for the formation of reactive metabolites.

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund's adjuvant (CFA)-induced chronic inflammatory pain after oral administration.

Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists.

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.

Multinational survey of chiropractic patients: reasons for seeking care.

INTRODUCTION: This study explores the extent to which consumers seek wellness care when choosing chiropractors whose practice methods are known to include periodic evaluative and interventional methods to maintain wellness and prevent illness. METHODS: Using an international convenience sample of Sacro-Occipital Technique (SOT) practitioners, 1316 consecutive patients attending 27 different chiropractic clinics in the USA, Europe and Australia completed a one-page survey on intake to assess reason for seeking care. A forced choice response was obtained characterizing the patient's reason for seeking chiropractic care. RESULTS: More than 40% of chiropractic patient visits were initiated for the purposes of health enhancement and/or disease prevention. CONCLUSION: Although prudence dictates great caution when generalizing from this study, if confirmed by subsequent research among other similar cohorts, the present results may lend support to continued arguments of consumer demand for a more comprehensive paradigm of chiropractic care, beyond routine musculoskeletal complaints, that conceptualizes the systemic, nonspecific effects of the chiropractic encounter in much broader terms.

Aminoquinazolines as TRPV1 antagonists: modulation of drug-like properties through the exploration of 2-position substitution.

A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.

The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept.

The clinical use of TRPV1 (transient receptor potential vanilloid subfamily, member 1; also known as VR1) antagonists is based on the concept that endogenous agonists acting on TRPV1 might provide a major contribution to certain pain conditions. Indeed, a number of small-molecule TRPV1 antagonists are already undergoing Phase I/II clinical trials for the indications of chronic inflammatory pain and migraine. Moreover, animal models suggest a therapeutic value for TRPV1 antagonists in the treatment of other types of pain, including pain from cancer. We argue that TRPV1 antagonists alone or in conjunction with other analgesics will improve the quality of life of people with migraine, chronic intractable pain secondary to cancer, AIDS or diabetes. Moreover, emerging data indicate that TRPV1 antagonists could also be useful in treating disorders other than pain, such as urinary urge incontinence, chronic cough and irritable bowel syndrome. The lack of effective drugs for treating many of these conditions highlights the need for further investigation into the therapeutic potential of TRPV1 antagonists.

From arylureas to biarylamides to aminoquinazolines: discovery of a novel, potent TRPV1 antagonist.

Bioisosteric replacement of piperazine with an aryl ring in lead VR1 antagonist 1 led to the biarylamide series. The development of B-ring SAR led to the conformationally constrained analog 70. The resulting aminoquinazoline 70 represents a novel VR1 antagonist with improved in vitro potency and oral bioavailability vs the analogous compounds from the lead series.

Symptomatic Arnold-Chiari malformation and cranial nerve dysfunction: a case study of applied kinesiology cranial evaluation and treatment.

OBJECTIVE: To present an overview of possible effects of Arnold-Chiari malformation (ACM) and to offer chiropractic approaches and theories for treatment of a patient with severe visual dysfunction complicated by ACM. CLINICAL FEATURES: A young woman had complex optic nerve neuritis exacerbated by an ACM type I of the brain. INTERVENTION AND OUTCOME: Applied kinesiology chiropractic treatment was used for treatment of loss of vision and nystagmus. After treatment, the patient's ability to see, read, and perform smooth eye tracking showed improvement. CONCLUSION: Further studies into applied kinesiology and cranial treatments for visual dysfunctions associated with ACM may be helpful to evaluate whether this single case study can be representative of a group of patients who might benefit from this care.