Evaluation in vitro of synthetic curcumins as agents promoting monocytic gene expression related to ß-amyloid clearance.

Accumulation of amyloid-beta (Aß) is one of the hallmarks of Alzheimer's disease (AD), and efficient clearance of Aß by cells of the innate immune system may be an important mechanism for controlling or preventing disease onset. It was reported that peripheral blood mononuclear cells (PBMCs) of most AD patients are defective in the phagocytosis of soluble Aß. Natural curcumins were shown to restore Aß phagocytosis by AD PBMCs and to up-regulate the expression of key genes including MGAT3 and those encoding Toll-like receptors (TLRs). Bisdemethoxycurcumin (BDC), a minor component of natural curcumin, was shown to have the greatest potency for stimulating AD PBMCs. Because natural curcumins have inherent limitations with regard to physicochemical properties, synthetic curcumin analogues were developed that showed improved solubility, stability, and bioavailability. An in vitro system using human monocytic cell lines (U-937, THP-1) was used to evaluate analogues for the potency of innate immune cell stimulation. These cell lines showed responses to curcuminoids and to 1α,25-dihydroxyvitamin D3 (VD3) resembling those seen in human PBMCs. From more than 45 curcuminoids analyzed, the most potent compounds possessing enhanced pharmaceutical properties were identified. The most promising candidates included prodrug versions containing water solubility-enhancing amino acids and stability-increasing modifications near the central diketone. In vivo studies showed compound (5) substantially increased bioavailability by combining several promising structural modifications. Studies examining ex vivo phagocytosis of Aß and bead particles in mouse microglia showed that BDC and several water-soluble analogues were quite effective compared to curcumin or an unnatural analogue. In vitro studies using monocytic cell lines reported herein complement those using human PBMCs and represent a routinely accessible and uniform cellular resource allowing direct comparisons between compounds.

Curcumins promote monocytic gene expression related to ß-amyloid and superoxide dismutase clearance.

Neurodegenerative diseases are associated with accumulation of modified proteins or peptides including amyloid-ß (Aß) in Alzheimer's disease (AD), and misfolded superoxide dismutase-1 (SOD-1) in amyotrophic lateral sclerosis (ALS). Clearance of Aß or SOD-1 by the innate immune system may be important for controlling or preventing disease onset. Curcumins restore Aß phagocytosis by peripheral blood mononuclear cells (PBMCs) from AD patients and Aß clearance with upregulation of key genes including MGAT3, vitamin D receptor (VDR) and Toll-like receptors (TLRs). Certain curcumins inhibit inflammatory processes of PBMCs from ALS patients. We developed an in vitro system using human monocytes from patients and monocytic cell lines (i.e. U-937, THP-1) for evaluating curcuminoid potency of innate immune cell stimulation. Bisdemethoxycurcumin and certain analogs potentiated MGAT3,VDR and TLR gene expression 3- to 300-fold in U-937 cells. The effect of curcumins on inflammation in monocytes from patients with ALS was examined. Recursive medicinal chemistry was applied to identify compounds that stimulate the innate immune system for use in the clearance of Aß in AD and the reversal of neuroinflammation and defective SOD-1 accumulation in ALS.

Parenteral indomethacin (the INDOTEST) in cluster headache.

The interval between indomethacin administration and clinical response may be extremely relevant in the assessment of chronic paroxysmal hemicrania (CPH) and other unilateral headache disorders like cluster headache (CH), with which CPH can be confounded. Indomethacin is inactive in CH; however, in some anecdotal reports in recent years, doubt has been cast on the ineffectiveness of indomethacin in CH. In this study, we have re-assessed the effect of indomethacin treatment in a group of 18 patients with episodic CH (three females and 15 males). From the day 8 of the active period, indomethacin 100 mg i.m. was administered every 12 h, for 2 consecutive days, in an open fashion. The mean daily attack frequency before the test (1.6 +/- 0.6) was not statistically different from that on day 1 (2.1 +/- 0.9) and day 2 (1.9 +/- 0.8) after indomethacin administration. The mean interval between indomethacin injection and the following attack (day 1 and day 2) was 4.6 + 1.1 h. We did not observe any refractory period in any patient after indomethacin. Since the 'expected' attack occurred when there theoretically could have been a protective effect after indomethacin administration, it can be reasonably assumed that there is no such protective effect. The use of a test dose of 100 mg i.m. indomethacin (INDOTEST) appears to provide a clear-cut answer in this situation. It may be a useful tool for a proper clinical assessment of unilateral headache with relatively short-lasting attacks when problems of classification arise. A correct diagnosis of CPH or CH is important, since a CPH diagnosis may imply a lifelong treatment with a potentially noxious drug.

3D kinematic analysis and clinical evaluation of neck movements in patients with whiplash injury.

In recent decades whiplash injuries, being a major reason for compensation claims, have become increasingly important in forensic medicine. In view of this, a reliable diagnostic method of assessing cervical range of motion (ROM) is needed. The aim of the present study was to evaluate neck function with a 3D kinematic method compared with clinical evaluation in whiplash injury. Seventy consecutive patients (M/F = 18/52) with a history of whiplash injury (WH) and 46 healthy volunteers (M/F = 24/22), mean age, respectively 33 +/- 9 and 28 +/- 6 years (mean+/-SD) entered the study. Patients suffered from neck pain and/or unilateral headache. A computerized kinematic analysis of the ROM (Elite system) using passive markers and two infrared TV cameras was used. Clinical evaluation of active ROM was also performed both in patients and in 61 controls (M/F = 23/38; mean age 47 +/- 18 years). Thirty out of 70 patients were tested at the time of their first consultation (T0) and 6 months later (T6), and 12 were also followed up after a year (T12). All neck movements, except extension, were significantly reduced in WH subjects compared with controls, in particular lateral bending. Comparing ROM at T0, T6 and T12, no significant differences were found. A global index of motion (GIM), obtained by calculating the sum of ROM in absolute value for all the movements acquired, was significantly reduced in WH compared with control subjects. The interobserver reliability of the clinical evaluation was globally acceptable. On the basis of the clinical evaluation, a significantly reduced ROM was found in all movements in WH subjects compared with an age-matched population. Computing the number of impaired cervical movements (ICMs), a significantly higher number was observed in WH patients than in controls, showing a decreasing trend at T6 and T12, with a significant improvement at T6 vs. T0. The computerized study of neck ROM may constitute a useful tool in the evaluation of WH at baseline and follow-up.

Cervicogenic headache: evaluation of the original diagnostic criteria.

A variety of headaches are frequently associated with the occurrence of neck pain. The purpose of this paper was to describe the adherence to diagnostic criteria of a series of patients enrolled on the basis of two clinical criteria: (1) unilateral headache without side-shift, and (2) pain starting in the neck and spreading to the fronto-ocular area. One hundred and thirty-two patients (36 male and 96 female) entered the study. Sixty-two patients were assigned to Group A (patients fulfilling criteria 1 and 2), 40 to Group B (criterion 2 only) and 12 to Group C (criterion 1, only). Eighteen subjects were excluded because X-rays of the neck were not available. Patients were evaluated regardless of whether or not they fell into one or more of the following diagnostic categories: cervicogenic headache (CEH), migraine without aura (M) and headache associated with disorders of the neck (HN) (IHS definitions). Fulfillment of the diagnostic criteria for CEH was found to be particularly frequent in Group A. A higher frequency of CEH diagnosis was found when two criteria were used (Group A) than in Group B (P = 0.001); in the former group a higher mean number of diagnostic criteria for CEH were also present (P = 0.001). Group A patients more frequently presented pain episodes of varying duration or fluctuating, continuous pain and moderate, non-excruciating, non-throbbing pain than Group B patients (P = 0.04 and P = 0.08, respectively). In Group C patients, the frequency of these two criteria was relatively low (17%) especially of the first mentioned variable. The presence of at least five of the seven 'pooled' CEH criteria (present in > or = 50% of the patients) might be deemed a reliable cut-off point, allowing the headache to be diagnosed as 'probable' CEH. If patients fulfilling M or HN criteria in addition to the CEH criteria are added to the 'pure' CEH group a total of 74% of Group A patients may have a CEH picture. The temporal pattern of pain and the quality of pain in Group A showed good sensitivity and specificity (> or = 75) when compared with Group B; therefore, the chances of diagnosing a definite CEH are significantly more frequent in patients presenting with unilateral pain that also begins as a neck pain. Head/neck trauma and radiological abnormalities in the cervical spine were not significantly associated with CEH, M or HN diagnoses. An improvement of the current diagnostic IHS criteria might make it possible to avoid the existing, partial overlap of CEH with HN and M. Extensive use should be made of the GON, and other, blockades in the routine work-up of CEH, both in the differential diagnosis and in the mixed forms (CEH + M, and CEH + HN), in order to improve the efficiency of the current diagnostic system.

Unilateral headaches and their relationship with cervicogenic headache.

The concept of headache originating/starting in the neck is revised and considered in the light of previous descriptions of syndromes and entities and with reference to the current diagnostic systems for the classification of headache and other head pain. Cervicogenic headache (CEH), a clinical picture recently described by Sjaastad and coworkers and listed in the International Association for the Study of Pain (IASP) Classification, is analyzed, also taking into consideration its diagnostic criteria in terms of sensitivity and specificity. The problem of a differential diagnosis with migraine, tension headache and other well defined forms of unilateral headaches is discussed with reference to a case series of 114 patients who were selected based on their adherence to two fundamental criteria: (i) side-locked unilaterality of pain; and (ii) pain starting in the neck and spreading to the fronto-orbital area. Based on the results, these simple criteria can contribute to a preliminary identification of possible CEH cases that may then undergo a sequence of clinical and instrumental procedures in order to confirm the diagnosis and, possibly, to localize the level(s) of dysfunction in the cervical spine which may be the target for therapeutic investigations, whether invasive or non-invasive.

Whiplash injuries: clinical picture and diagnostic work-up.

The term "whiplash" commonly refers to symptoms and signs associated with a mechanical event such as a sudden acceleration and deceleration of the neck (due, in the majority of cases, to a road accident), instead of to the mechanism itself. The recent Quebec Classification of Whiplash Associated Disorders (WAD) contributed to define nosographically all the clinical manifestations usually grouped under the terms acute/post-traumatic and late "syndrome". In the late phase of WAD, neck pain and neck muscle contraction have been reported in all cases, together with headache in over 50%. "Headache stemming from the neck", despite numerous attempts to classify this entity (i.e. cervicogenic headache) according to the IASP classification (headache associated with neck disorders), is still a subject of debate. An adequate multiparametric procedure is required to study WAD, which takes into account: the patient's principal details; an exact reconstruction of the event; description and analysis of the signs and symptoms, with various complications and correlated dysfunctions; an objective neurological and neck-shoulder examination; and a battery of complementary instrumental tests which are described in this study. These investigations include evaluation of muscle tension (manual palpation, algometry, EMG recording), kinematic analysis of the cervical spine, neuropsychological and psychological evaluation, and evaluation of disability. In order to assess cervical spine mobility in WAD patients, a 3D kinematic analysis by means of the ELITE system and clinical evaluation were performed in our setting. Seventy patients with whiplash injury and 46 healthy volunteers were enrolled in the study. Patients were tested at the time of first consultation and again 6 months and 12 months later. Clinical evaluation of the range of motion was performed both in patients and in 41 healthy volunteers. Furthermore, patients diagnosed according to the WAD Classification as grade 2 (n = 68) or grade 3 (16) underwent a Quality of life (QoL) evaluation, measured using the short form (36-item) Health Survey (SF36) and the migraine-specific questionnaire (MSQ). According to our data, whiplash patients showed an impairment of cervical spine mobility, as well as a poor QoL, compared to a control group population, even though we observed a trend towards improvement over time in cervical ROM.

Current methods for cervical spine movement evaluation: a review.

Cervical spine mobility is difficult to investigate accurately because of its anatomic structure and the compensatory movements. Different methods have been conceived in order to obtain a reliable measurement of cervical range of movement (ROM). We reviewed different instruments described in the literature: x-rays, CT and MRI, goniometer, inclinometer, cybex and related devices, and opto-electronic scanners. Cybex and 3D kinematic analysis by means of opto-electronic scanners (Elite system) seemed to be the most reliable and reproducible methods. Cybex equipment is relatively inexpensive and easy to use in a clinical setting, while the Elite system is expensive and requires special training of the personnel. However, the choice of method depends primarily on whether the physician's goal is a clinical screening or a thorough investigation of neck function (e.g., post-traumatic cervical spine disorders). For the first purpose, certain types of goniometers (gravity goniometer, ad modum Myrin), as well as the cybex, show good reproducibility and reliability in evaluating maximal cervical ROM (flexion-extension, rotation, lateral bending), while x-rays and, above all, 3D kinematic analysis (using opto-electronic scanners) are more suitable for diagnostic and follow-up evaluation of neck disorders.

A 3D kinematic method for evaluating voluntary movements of the cervical spine in humans.

The purpose of this study was to assess the reliability of a 3D kinematic method of evaluating movements of the cervical spine. Range of motion (ROM) of the cervical spine was evaluated in 8 control subjects during flexion-extension, rotation and lateral bending movements. The test was repeated on two separate occasions. The ROM test-retest difference ranged from 1.42 degrees for right axial rotation to 9.11 degrees for left axial rotation. The test showed good reliability, with an intraclass correlation coefficient which was higher than 0.74 in extension movement and excellent in flexion, axial rotation and lateral bending. In conclusion, the method proposed for the 3D kinematic analysis of neck movement proved to be useful and non-invasive and to show good-excellent reproducibility. Furthermore the method is easily applicable in clinical practice to evaluate neck function in cervical spine disorders.