Spine Healing Therapy

Dorn Spinal Therapy

Dorn Spinal Therapy has been in uses in the past 40 years. The credit of this method goes to Dieter Dorn, who has made a significant impact in the medical field. DORN- Method has been used on various patients where results could get witnessed instants. Due to the impact, this method has brought in the country. It has been declared the standard practice in treating Pelvical Disorders, Spinal, and Back pain. Dieter Dorn first used this method on his family, which was a sign of confidence in a method, which later gained much attention from different people in the country and also globally. Every day Dorn was able to offer treatment to 15- 20 patients in a day. His services were purely free which attracted attention both in the local and also global. The primary treatment that DORN-Method which could be treated using this method include spine healing therapy, misalignments of the spine, resolving pelvis and joints, and also solving out significant problems which could get attributed to vertebrae. Read more here...

Dorn Spinal Therapy Summary

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The Spine in the Lateral Projection

The effect on BMD measured in the AP or PA projection from aortic calcification, facet sclerosis, osteophytes, and other degenerative changes in the spine can be nullified by quantifying the bone density of the spine in the lateral projection as shown in Fig. 2-15B. In addition, the highly cortical posterior elements and a portion of the cortical shell of the vertebral body can be eliminated from the measurement, resulting in a more trabecular measure of bone density in the spine. The measurement is not a 100 trabecular measure as portions of the cortical vertebral body shell will still be included in the measurement. In addition to the elimination of artifact or confounding degenerative changes, the lateral spine BMD measurement is desirable in those circumstances in which a trabecular measure of bone density is indicated and particularly in circumstances in which changes in trabecular bone are being followed over time. The higher metabolic rate of trabecular bone compared to...

Differences In Spinal Pathways

Once transmission has occurred at a spinal level, the information must be passed to higher sites of processing. There is good evidence that visceral pain follows pathways that are different from those used for the perception of superficial pain. There now exist at least 10 clinical reports from six different neurosurgical groups in the United States, Europe, and Asia who have demonstrated that a midline myelotomy of the spinal cord (ablation of dorsal midline region) produces analgesia for visceral pain related to pelvic and lower abdominal organs (30-37) and for upper abdominal organs such as the stomach, pancreas, and hepatobiliary systems (38,39). Traditionally, it has been taught that the primary pathways for pain-related information from the dorsal horn of the spinal cord to the brain are via the ventrolateral quadrant white matter of the spinal cord. Tracts located within the ventrolateral quadrant include the classic spinothalamic and spinoreticular tracts as well as the...

The European Spine Phantom

The development of the European Spine Phantom (ESP) resulted from efforts to develop a more perfect spine phantom that could be used on all central devices. It was developed independently of any manufacturer under the direction of the Committee d'Actions Concertes-Biomedical Engineering (COMAC-BME) (6). The ESP is a semi-anthropomorphic phantom. Its three vertebrae are made of hydroxyapatite and vary in density, with standardized BMDs of 500, 1000, and 1500 mg cm2 (7). The vertebrae are encased in a plastic and epoxy-resin material equivalent to about 10 fat that is molded into an oval shape with flattened sides measuring 28 cm by 18 cm. The use of the ESP has generally been restricted to clinical research trials, primarily because of its expense. It was originally hoped that the ESP could be used to standardize BMD on any central bone densitometer. Unfortunately, this has not proven to be the case. It is an excellent phantom for cross-calibration of central DXA densitometers however.

The Hologic Spine and Hip Phantoms

The Hologic anthropomorphic spine phantom, although intended for use with Hologic DXA devices, is often used with DXA devices from other manufacturers. The phantom itself consists of four anatomically correct vertebrae made of calcium hydroxyapatite. The vertebrae are encased in an epoxy resin to simulate soft tissue. The four vertebrae have similar densities and areas and the soft tissue simulation of the epoxy-resin approaches 60 fat. Each Hologic spine phantom will have a factory-specified L1-L4 BMD. Consistent daily calibration can be obtained with the Hologic anthropomorphic spine phantom, although the lack of a range of BMD values make it less suitable for cross-calibration of central DXA devices. The Hologic anthropomorphic hip phantom has found less of a role in clinical medicine. It does not offer any quality control testing capabilities to the clinician that cannot be obtained with the anthropomorphic spine phantom other than proximal femur edge detection, which is under the...

The Lunar Spine Phantom

The Lunar spine phantom is a rectangular aluminum bar which is intended to replicate the lower half of T12, all of L1, L2, L3, and L4, and the upper half of L5. Each vertebra has a different density that is achieved by varying the thickness of the aluminum. The area of each vertebra is different as well. The densities of L1 to L4 are 0.92, 1.076, 1.239, and 1.403 g cm2, respectively. The L2-L4 BMD is 1.256 g cm2. To simulate soft tissue, the aluminum phantom is submerged in a water bath with a depth of approximately 15 cm. The aluminum phantom is also available encased in an epoxy-resin block, avoiding the necessity of a water bath and improving ease of use.

Cerebrospinal Fluid Protein Electrophoresis

Cerebrospinal fluid (CSF), a clear colorless fluid with a viscosity similar to water, is produced at a rate of approx 500 mL p d. The volume averages 135-150 mL in an adult and approx 40 mL in neonates with a turnover rate of 6 h. Approximately two-thirds of the CSF is secreted by the choroid plexuses, whereas the rest comes from leakage of plasma from the capillary bed found in the central nervous system (CNS) and the metabolism of glucose by cells in the CNS.

Dissimilar Spine and Femoral BMDs in Perimenopausal Women

Eighty-five Caucasian women between the ages of 45 to 60 who were within 6 months to 3 years past menopause underwent spine and proximal femur bone density testing using DXA (Lunar DPX) (15). These values were compared with reference values (mean and SD) from a group of 30 healthy women between the ages of 40 to 45. Thirty-nine women had both spine and femoral neck z-scores that were better than -1. Seventeen women had both spine and femoral neck z-scores that were both poorer than -1. Out of the 85 women, 22 (26 ) had dissimilar spine and femoral neck z-scores. Eight had spine z-scores that were better than -1 but femoral neck z-scores that were poorer than -1. Fourteen had femoral neck z-scores that were better than -1 but spine z-scores that were poorer than -1. In a similar study, Lai et al. (16) evaluated 88 Caucasian women, ages 44 to 59, who were within 5 years past menopause. BMD measurements of the lumbar spine and proximal femur were made using DXA (Hologic QDR-1000). The...

Divergence of Visceral Afferents in the Spinal Cord

Figure 1 The sensory innervation of the gastrointestinal tract. The splanchnic afferent Innervation Is shown on the left, the vagal pelvic afferent innervation is shown on the right. The splanchnic afferent nerves have cell bodies in the thoracolumbar dorsal root ganglia (DRG) and project centrally through the dorsal roots into the spinal cord. The vagal pelvic afferents that innervate the esophagus to the middle of the transverse colon project in the vagus nerve with cell bodies in the nodose ganglia. These afferents project centrally to the nucleus tractus solitarius. Pelvic afferents innervating the lower bowel have cell bodies in the lumbosacral DRG and project centrally into the lumbosacral spinal cord. Source From Ref. 16. Figure 1 The sensory innervation of the gastrointestinal tract. The splanchnic afferent Innervation Is shown on the left, the vagal pelvic afferent innervation is shown on the right. The splanchnic afferent nerves have cell bodies in the thoracolumbar dorsal...

Pharmacology Of Spinal Processing Of Visceral Pain Excitatory Amino Acid Receptors and Visceral Pain

It is generally accepted that the excitatory amino acid acid (AMPA) receptors, but not NMDA receptors, are involved in signaling acute noxious and innocuous somatic stimuli in the spinal cord. Following persistent noxious stimulation (inflammation following injury and neuropathic injury), a cascade of events including activation of signal transduction pathways, protein kinases and phosphatases, and NMDA receptor activation induce central sensitization and hyperalgesia (141,142). In contrast to somatic stimuli, experimental data support a role for NMDA receptor activity in addition to AMPA receptor activity in spinal processing of acute innocuous and noxious visceral stimuli. NMDA receptor antagonists attenuate the pressor response evoked by noxious ureter distention, but have no effect on the pressor response evoked by noxious somatic stimulation (143). Likewise, NMDA receptor antagonists attenuate changes in mean arterial pressure and the visceromotor response to urinary bladder...

Spinal Cord Injury Models

A large number of SCI paradigms have been developed over the past 100 years. As shown in Table 1, the current rodent models that are used to evaluate neuroprotective agents involve contusion, compression, ischemic, and excitotoxic injury mechanisms. By far, the contusion models predominate in the experimental acute SCI field, and in particular the New York University (NYU)12 and University of Kentucky (UK)13 controlled contusion devices dominate acute SCI research. For strategies that may influence axonal regeneration in the injured spinal cord, the usual models involve either complete transaction or hemisection of the spinal cord or dorsal roots (rhizotomy) followed by histological

Paravertebral Paraspinal Blocks

Paravertebral injections, both into the musculature and close to the spine, are frequently used to treat low back pain and sciatica. There is a lack of evidence for efficacy for these injections 18 . Two case reports concerning significant complications of these techniques have appeared recently documenting extensive abscess formation involving the entire paravertebral musculature descending to the level of the mid thighs after repeated paravertebral injection of local anesthetics, corticosteroid and botulinum toxin 25 and spinal abscesses and meningitis 1 . Reports of such adverse outcomes are rare however, there are no available systematic data to show how often such adverse effects occur.

Spinal Cord Stimulation

Spinal cord stimulation involves placement of an electrode or electrodes in the epidural space overlying the spinal cord, usually in the lower thoracic or cervical regions. It is used in a number of conditions including failed back surgery syndrome, CRPS, angina, lower limb ischemia and peripheral neuropathic pain syndromes. There is limited evidence from systematic reviews in favor of spinal cord stimulation (SCS) for failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS) in follow-up of 6-12 months. There is insufficient evidence to assess the benefits and harms of SCS for the relief of other types of chronic pain 39, 40 . A recent RCT of FBSS versus conventional medical management demonstrated better pain relief and improved health-related quality of life and functional capacity for SCS 41 .

Spinal and Supra Spinal Modulation of Pain Perception

Working with rats and using simple withdrawal reflexes as pain measures, Reynolds (31) showed that stimulation of a specific region of the midbrain periaqueductal gray (PAG) inhibited behavioral responses to noxious stimulation, giving rise to the term stimulation produced analgesia.'' Stimulation of these sites inhibited responses of spinal neurons to noxious stimuli suggesting that the brain could modulate spinal activity. The PAG receives direct inputs from the hypothalamus and from the limbic forebrain, including several regions of the frontal neocortex and the central nucleus of the amygdala (Fig. 3). The PAG controls nocicep-tive transmission by means of connections through neurons in the rostral ventromedial medulla (RVM) and the dorsolateral pontine tegmentum (DLPT). These two regions project through the spinal cord dorsolateral funiculus and selectively target the dorsal horn laminae that accommodate nociceptive relay neurons. This circuit can therefore selectively modulate...

Spinal Cord Compression And Radiculopathy

Extension of vertebral body plasmacytoma and collapse of bony structures lead to compression of the spinal cord or dorsal roots by epidural tumors. Occasionally, paravertebral tumor invades the spinal canal through intervertebral foramina. The incidence of this complication is about 15 .58 59 The thoracic spine is more commonly involved. IgA myeloma and extensive cortical bone involvement appear to pose a greater risk.59 Plain radiographs of the spine may reveal vertebral collapse and or vertebral or paravertebral masses. Uncommon neurologic manifestations may occur with cranial plasmacytoma, either as a part of multiple myeloma or as a solitary lesion.

Schwannomas of the Spinal Nerve Roots

The tumors constitute about 15 to 30 of spinal tumors. They are more common on the sensory roots, preferentially occurring on the cauda equina. Clinically, they present with pain and sensory and motor deficits in a radicular distribution. If they reach a large size, symptoms and signs of spinal cord compression develop. Hourglass or dumbbell schwannoma refers to extension of the tumor through the intervertebral foramen into the mediastinum or peritoneal cavity. Intraparenchymal schwannomas are rare in the brain or spinal cord. They derive from Schwann cells of the nerves that supply small arteries or from ectopic Schwann cells.

Spinal and Spinal Cord Defects

Vertebral Defects

Dysraphic disorders of the spine and spinal cord comprise a broad spectrum of malformations, ranging from total absence of the cord to asymptomatic bony defects and cord anomalies. Familial occurrences are common. The clinical manifestations vary from mild motor and sensory deficits to paraplegia with severe sensory impairment and loss of sphincter control. Amyelia, total absence of the spinal cord occurs with anencephaly (see Fig. 13.2). The cord is replaced with a mixture of fibrous tissue, blood vessels, and neural elements (area myelovasculosa). Meningocele and meningomyelocele consist of her-niations of the meninges or meninges, spinal cord, and Schematic drawing of a lumbar meningomyelocele. The cystic sac covered with skin contains the spinal cord, meninges, and nerve roots. Schematic drawing of a lumbar meningomyelocele. The cystic sac covered with skin contains the spinal cord, meninges, and nerve roots. In tethered spinal cord, the conus is fixed to a bony defect by a...

Adverse Reactions to Spinal Manipulation

The reported incidence of adverse reactions to spinal manipulation is high, with a frequency as high as one of every two patients, but these reactions are generally reported to be mild and self-resolving. In one of the largest studies examining the incidence of side effects from SMT, Senstead (28) reported that the most common side effect was local discomfort (53 ) of mild or moderate intensity (85 ) that resolved within 24 hours (74 ). No serious injuries or complications were reported during the study (28). Similarly,

Artifacts in PA or AP Spine Densitometry

The PA lumbar spine has been, and continues to be, used extensively in densitometry for diagnosis, fracture prediction, and monitoring. Unfortunately, it is also the skeletal site most often affected by structural changes and artifacts that may limit its utility. The BMD of a fractured vertebra will be increased because of the fracture itself. This increase in density could erroneously lead the physician to conclude that the bone strength is better and the risk for fracture, lower, than is the case. Vertebral fractures in osteoporosis frequently occur in the T7-T9 region and in the T12-L2 region (14,15). Because DXA measurements of the lumbar spine are often employed in patients with osteoporosis, osteoporotic fractures in the lumbar spine, particularly at L1 and L2, are a common problem, rendering the measurement of BMD inaccurate if the fractured vertebrae are included. An increased precision error would also be expected if the fractured vertebrae were included in BMD measurements...

Cerebrospinal Fluid

A rise or fall from normal of the cerebrospinal fluid pressure is associated with headache. When the pressure of the cerebrospinal fluid is raised, the patient usually experiences a bursting pain, which can interrupt sleep or appear in the early morning. It tends to be intermittent and is made worse by coughing or lying down. It can also, of course, be accompanied by

Spinal Cord Injury

The glucocorticoid steroids (e.g., dexamethasone and methylprednisolone (MP) Figure 2) were extensively employed in the clinical treatment of SCI beginning in the mid-1960s and continuing throughout the 1970s. The mechanistic rationale for their use in that era was centered on the expectation that they would reduce posttraumatic spinal cord edema. This notion was based on the rather remarkable reduction of peritumoral brain edema induced by glucocorticoids in brain tumor patients. Furthermore, steroid pretreatment became a standard of care prior to neurosurgical procedures to prevent intra- and postoperative brain swelling. In the mid-1970s a randomized, multicenter clinical trial, the National Acute Spinal Cord Injury Study (NASCIS I), was initiated to determine if steroid dosing was beneficial in improving neurological recovery in humans after SCI. It compared the efficacy of 'low-dose' MP (100 mg i.v. bolus per day for 10 days) and 'high-dose' MP (1000 mg i.v. bolus per day for 10...

Tumors of the Central Nervous System

Tumors of the Pituitary Gland and Sellar Region 235 Germ Cell Tumors 237 Tumors of the Cranial and Spinal Nerves 238 Maldevelopmental Tumors and Cysts 240 Hemangiomas 244 Lymphomas and Hematopoietic Tumors 245 Primary Central Nervous System Lymphomas 246 Metastatic Tumors 246 Tumors of the Spinal Cord, Nerve Roots, and Meninges 249 Tumors of the Cranium and the Spine 251 Primary Intracranial Tumors in Children 251 Hereditary Tumor Syndromes 253 Nervous System Complications of Radiation

Estimated Time To Complete

Quantitative spine morphometry. The vertebrae on this lateral lumbar spine X-ray demonstrate marked accentuation of the vertical trabecular pattern and thinning of the cortical shell. This is a Grade 2 spine. Fig. 1-1. Quantitative spine morphometry. The vertebrae on this lateral lumbar spine X-ray demonstrate marked accentuation of the vertical trabecular pattern and thinning of the cortical shell. This is a Grade 2 spine. Qualitative Spinal Morphometry Qualitative morphometric techniques for the assessment of bone density have been in limited use for more than 50 years. Grading systems for the spine relied on the appearance of the trabecular patterns within the vertebral body and the appearance and thickness of the cortical shell (4). Vertebrae were graded from IV down to I as the vertical trabecular pattern became more pronounced with the loss of the horizontal trabeculae and the cortical shell became progressively thinned. The spine shown in Fig. 1-1 demonstrates a...

Introduction to Clinical Neuropathology

The objectives of the neuropathologic examination are twofold First, to identify and localize any lesion(s), interpret histologic changes and ultimately, formulate a diagnosis. Second, to correlate the location and histopathologic features of the lesion(s) with the clinical presentation. Fulfilling these goals requires familiarity with the anatomy and histology of the nervous system. For this purpose, photographs of representative brain and spinal cord slices and myelin-stained sections are provided (Figs. 1.1 through 1.5). Myelin-stained sections of the spinal cord. Myelin-stained sections of the spinal cord.

Neuroanatomy Of Visceral Pain

Basic science studies have demonstrated that from the level of gross anatomy to the microscopic determination of both peripheral and central afferent terminals, visceral sensory pathways are diffusely organized and distributed (diagrammatic summary in Fig. 1). Rather than mimicking the precise organization of cutaneous sensory afferent pathways, which travel in defined peripheral nerves and extend into a limited number of spinal segmental nerves organized in a unilateral, somatotopic fashion, visceral sensory afferent nerve fibers originate from multiple branchings of nerve fascicles organized into weblike plexuses scattered through the thoracic and abdominal cavities that extend from the prevertebral region to reach the viscera by predominantly perivascular routes. Injection of neuronal tracing agents into focal sites within viscera may easily result in the labeling of cell bodies in the dorsal root ganglia of 10 or more spinal levels in a bilaterally distributed fashion (27). The...

Descending Modulating Systems

A large number of structures appear to be part of the descending pathways, including the cortex, the subcortical centers, basal ganglia, the thalamic-hypothalamic system, the midbrain, pons, and medulla, and the dorsal horn of the spinal cord. shows the importance of the pathways between the midbrain and the dorsal horn. There appear to be three pathways from the brain stem one arises from the nucleus raphe magnus and releases serotonin (5-HT) when activated (see following text) another arises from the locus ceruleus of the pons and releases norepinephrine (see following text). The third pathway arises from the Edinger-Westphal nucleus and releases cholecystokinin (see following text). These pathways inhibit pain-responsive neurons in the dorsal horn. The periaqueductal gray (PAG) connects to all three pathways. The PAG is extremely rich in opiate receptors, and when activated, it activates the three pathways noted to modulate or inhibit pain impulses entering the dorsal horn. The...

Immunological Procedures

A bacterial agglutination test is available for the detection of Streptococcus pneumoniae, S. agalactiae, Haemophilus influenzae type B, and Neisseria meningitidis. The assay uses latex particles coated with specific antibodies to structural antigens and can detect soluble antigens in urine, cerebrospinal fluid (CSF), and serum. The sensitivity and specificity of these tests in urine samples is extremely unreliable, and the tests should not be used on this specimen. For sterile body fluids, the tests are highly sensitive and specific for H. influenzae, but their sensitivity for other bacteria is much lower, particularly for N. meningitidis. It is important to note that the sensitivity of this assay was essentially identical to Gram stain smears prepared using a cytospin preparation of the fluid. Most laboratories have discontinued the use of this test. Those laboratories that still offer the latex particle agglutination tests will usually perform the procedure only on patients with...

The Central System 51 The Dorsal Horn

Spinal cord input, and local interneurons that are predominantly inhibitory. These inhibitory interneurons contain y-aminobutyric acid (GABA) and glycine. The main transmitter between peripheral afferents and the dorsal horn is a-amino-3-hydroxyl-5-methyl-4-isoxazole proprionic acid. Subunits of the a-amino-3-hydroxyl-5-methyl-4-isoxazole proprionic acid receptor have been shown to play a role in central sensitization and decreased pain thresholds (32).

Are All Visceral Pains The Same

Organization of structures related to most, if not all, viscera follows a similar pattern of diffuseness at a peripheral level and utilizes similar spinal mechanisms of processing and transmission. Visceral structures with a matched pair (i.e., ovaries, kidneys), based on clinical symptomatology, appear to have some lateralization of their afferents to the central nervous system. The chemical and mechanical stimuli adequate to activate primary afferents of differing organ systems appear to vary according to organ and according to afferent pathway (64). This is logical, given the differing functions performed by these organs and their exposure to the external world (i.e., the bladder is sterile, whereas the lower GI tract is full of coliform bacteria). Ascending pathways of sensation that utilize the dorsal midline region of the spinal cord appear to vary in their distance from the midline. All in all, every organ system is unique in some ways, but systems related to the various...

Effect of Artifacts on BMD in the Forearm

The forearm sites are relatively free from the confounding effects of most of the types of artifacts that are often seen in the lumbar spine. The presence of a prior fracture in the forearm will affect the BMC or BMD measurements in the forearm close to the prior fracture site. A study from Akesson et al. (43), suggested that in women with a prior fracture of the distal radius, the BMC was increased by 20 at the distal radius of the fractured arm in comparison to the nonfractured arm, irrespective of arm dominance. It is obviously important for the technologist to ask if the patient has experienced a prior wrist or forearm fracture. Unfortunately, this same study from Akesson et al. noted that in a group of older women who were known to have previously had a distal radial fracture, many of the women did not recall the fracture or incorrectly recalled which arm was fractured. It was noted however, that the forearm most often fractured was the dominant forearm.

Neurochemicalanatomical Correlates

Neurochemical-anatomical correlates exist in the peripheral nervous system, spinal cord, and supraspinal pathways. Spinal Cord Primary afferents with SP, angiotensin II, and somatostatin travel to the substantia gelatinosa and the trigeminal nucleus caudalis. CCK-8, neurotensin, enkephalins, and dynorphin are found in the same regions. 5-HT and NEP are found in all Rexed laminae. Dopamine is not found in the spinal cord. have wide distribution, especially to the amygdala, and a high density of enkephalins, dynorphins, and neurotensin are found in the amygdala and the thalamus. Neurotensin and dynorphin also are found in the pituitary. Fibers from the monoamine neurotransmitter systems arise from a small number of nuclei within the brain stem and are distributed widely, but not uniformly, to the spinal cord and brain.

The Immune Reaction in a Tumor Developing in an Immuno Priviledged Site The Case of Primary Intraocular Lymphoma

Some tumors can develop in the eye, among which are retinoblastoma, choroid ocular melanoma, and primary intraocular lymphoma (PIOL). PIOL is a rare disease from the group of Diffuse Large B-cell Lymphoma (DLCBL) and is usually called uveitis masquerade syndrome as it frequently displays misleading symptoms with forms of infectious uveitis. PIOL is genetically very similar to central nervous system lymphoma of other locations such as intra-cerebral, spinal cord, and lepto-meningeal lymphomas. Like other tumors developing in immune-privileged sites or in immune-compromised individuals, PIOLs are very aggressive with a 5-year survival rate of less than 5 . In addition, PIOLs have very peculiar invading characteristics with 85 developing cerebral lymphoma and 80 metastasing to the controlateral eye (Nussenblatt et al. 2006). The question therefore arose to the existence of immune surveillance toward PIOL in the eye. The presence of T cells in tumoral eyes has been reported and we...

Tiziana Lazzarotto Maria Paola Landini

After an initial foetal viraemic stage (dissemination stage), the virus can invade and productively replicate in target organs like the central nervous system, liver, inner ear, spinal cord, kidney, duct epithelium and vascular epithelium, etc. In particular, the tubular epithelium within the kidney appears to be a major site of viral replication. Cleared by foetal diuresis into the amniotic fluid (AF), the virus can be newly ingested by the foetus and replicate in the oropharyngeal epithelium giving rise to more extensive dissemination via the blood (Fig. 2).

Neurochemical Systems

The mechanisms of the monoamine system (MAS) are initiated in the brain but carry out their antinociceptive action at the spinal cord level via descending pathways. Serotonergic cell bodies in the nucleus raphe magnus descend via the DLF to end in the 5-HT fields of the Rexed laminae. The release of 5-HT inhibits neurons specifically excited by nociceptive inputs. The spinal effects of a similar system involving NEP are dose dependent, alpha-receptor mediated, and separate from opioid mechanisms or vasoconstrictive effects. Stimulation-produced analgesia (SPA) in the nucleus raphe magnus or local CNS opioid injections can activate the MAS. The interaction with the opioid system occurs both supraspinally and in the dorsal horn of the spinal cord. SPA, as the words indicate, occurs when a specific part of the CNS is electrically stimulated. A positive correlation exists between brain dopamine and SPA from the peri-aqueductal gray region. 5-HT has a similar correlation. With...

Trans Synaptic Degeneration

Degeneration of the fasciculus graci-lis from compression of the sensory nerve roots by a meta-static carcinoma in the lumbar spine (myelin stain). Wallerian degeneration. Degeneration of the fasciculus graci-lis from compression of the sensory nerve roots by a meta-static carcinoma in the lumbar spine (myelin stain). (b) the mammillary body following degeneration of the fornix (Fig. 2.15) and (c) the neurons of the gracile and cuneate nuclei of the medulla following degeneration of the posterior columns in the spinal cord.

Standard Scores on Bone Density Reports

T-scores and z-scores are found on the computer-generated bone densitometry printouts from virtually every manufacturer of bone density equipment. Figure 3-2 is the printout from a spine bone density study performed on an older Lunar DPX device. The individual BMD values for each vertebra are listed as well as the BMD values for each possible combination of contiguous vertebrae. The two columns adjacent to the BMD values reflect z-scores. One column is entitled young-adult z and the other, age-matched z. Based on an understanding of the z-score, it is clear that these z-scores indicate how many standard deviations above or below the mean value, the patient's BMD value lies. But what mean value and SD were used to calculate these z-scores The young-adult z-score was calculated using the average peak bone density and SD for the young adult. The column entitled age-matched z reflects the use of the average bone density that would have been predicted on the basis of the patient's age. In...

Nmethyldaspartate Receptors

It is known that the spinal delivery of N-methyl-D-aspartate receptor (NMDAR) antagonists inhibits the hyperexcitability of spinal cord nociceptive neurons induced by C-fiber stimulation. Activation of NMDARs after tissue injury and inflammation enables facilitated processing in the spinal cord (1,2). Evidence exists that development of spinal hyperexcitability and persistent pain involves activation of NMDARs (1 ). Increased NMDAR function is expressed as an increase in channel openings and may involve transcriptional, translational, and post-translational modulation. Observed changes in the NR subunit expression may represent an adaptive response aimed to reduce excessive neuronal excitability resulting from tissue injury. The dose-response curve of NMDAR currents were consistent with a relative increase in NR2B expression, which is important in neuropathic pain (21). Peripheral inflammation may alter the properties of NMDARs in the spinal dorsal horn (22). After Complete Freund's...

Mitochondria Aging and Human Disease

In 1988, Harding and colleagues (44) and Wallace et al. (45) reported the first mitochondrial mutations causing human disease. Since then, many other mi-tochondrial diseases caused by mitochondrial point mutations or multiple mito-chondrial deletions have been identified (46). There are a number of typical presentations of mitochondrial disease in humans, including (1) Kearns-Sayre syndrome, characterized by ptosis, ophthalmoplegia, retinitis pigmentosa, hearing loss, cardiac conduction defects, short stature, and elevated cerebrospinal fluid protein (2) mitochondrial encephalopathy with lactic acidosis and strokes (MELAS) (3) myoclonic epilepsy with ragged red fibers (MERRF) (4) Leber hereditary optic neuropathy (LHON) with sudden unilateral or bilateral painless central visual loss and (5) Leigh syndrome, or subacute necrotizing en-cephalomyopathy. The pleiotropic manifestations of mitochondrial disease may include, for example, diabetes mellitus, hearing loss, bone marrow aplasia,...

Prevalence and Incidence

Both these measures of prevalence are considered rates. The point prevalence is the more commonly used measure of the two. If the term prevalence is used without a modifier, it is reasonable to assume that point prevalence is being discussed. For example, Melton et al. (2) reported that the prevalence of a bone density more than 2 SD below the young-adult mean in the spine in Caucasian women aged 50 and over was 31.8 . This figure is based on a one-time measurement of BMD at the spine in a group of women from Rochester, Minnesota with extrapolation of the figures to the entire population of Caucasian women over age 50 in the United States in 1990. This is a point prevalence rate.

Clusterin Expression in the Adult Brain of Mammals

We, as well as two other groups, have reported on the distribution of clusterin mRNA in the CNS of young adult rats.26,32,38 Transcripts for clusterin were found to be distributed throughout the CNS, although regional differences in their prevalence were readily observed (Fig. 2.1). A strikingly high level of expression was observed in the ependymal lining of the ventricles and the choroid plexus (Figs. 2.1 and 2.2). In keeping with clusterin as a secretion product in other tissues, these results suggest that the protein is secreted locally into the cerebrospinal fluid (CSF), where the demand or turnover rate may be high. Several neuron-rich cell layers and nuclei contained high levels of clusterin mRNA. These included the pyramidal and granule cell layers of the hippocampal formation, the habenular complex, the hypothalamus, several brainstem nuclei, and some motor neurons in the ventral horns of the spinal cord (Figs. 2.1-2.3). Within most of these areas, much heterogeneity in the...

Mechanisms of Sensitization Structural Changes

Structural changes in primary afferent neurons may also contribute to the manifestation of injury-induced increases in excitability. While sensitization of transducers or changes in the properties of ion channels may contribute to an increase in receptive field size, there is also evidence of a sprouting in peripheral terminals. In the presence of inflammation, increases in neuropeptides such as calcitonin gene-related peptide (CGRP) have been reported, as well as the growth-associated protein, GAP-43 (102,103). Sprouting within central terminals would also be manifest as an increase in receptive field size, and there is evidence for sprouting of central terminals in the presence of (104,105), or in response to (106,107) inflammation and nerve injury (108). Another structural change that may contribute to an increased pain associated with tissue injury or disease has been referred to as a phenotypic switch.'' This term has been applied to sensory neurons that begin to express...

Pathology General Aspects

Selective regional vulnerability determines the anatomic distribution of the lesions. Most vulnerable are the hippocampus, the neocortex, the cerebellar cortex, the thalamus, and the basal ganglia. The hypothalamus, the brainstem, and the spinal cord are the least vulnerable. In the hippocampus, the pyramidal neurons in the CA1 zone (Sommer's sector) are primarily affected (Fig. 3.1) in the neocortex, laminae 3, 5, and 6 in the cerebellum, the Purkinje cells . in the thalamus, the anterior and dorsomedial nuclei and, in the basal ganglia, the spiny neurons. Carbon monoxide poisoning has an affinity for the iron-rich globus palli-dus and the reticular zone of the substantia nigra.

Mechanisms of SensitizationCNS Changes

Many of the processes underlying central sensitization are analogous to those observed in the peripheral nervous system. For example, there is evidence that central sensitization reflects an increase in synaptic strength (analogous to transduction in the periphery), which reflects changes in the biophysical properties (144), density (145-148), and or distribution of receptors critical to enabling postsynaptic neurons in the spinal cord dorsal horn (or at higher sites) to respond to excitatory input from nociceptive afferents. Similarly, there is evidence of changes in VGSCs (149) and VGPCs (150) associated with tissue injury, which mediate increases in the excitability of dorsal horn neurons. Interestingly, upregulation of a VGSC a subunit NaV1.3 occurs in both the spinal cord and the thalamus following spinal cord injury, where it appears to be critical for mediating sensitization of these CNS neurons (151). There is also evidence of phenotypic changes in CNS neurons following injury...

Neurochemical Milieu Of Muscle Nociceptors Or Afferent Units

As is commonly seen, SP appears to coexist in primary thin myelinated and unmyelinated muscle afferent units with CGRP (7,8). Beta-endorphin also resides in hypothalamic neurons along with adrenocorticotropic hormone (ACTH) These peptides are interactive, in that CGRP, in the spinal cord, prolongs the activity of SP by inhibiting its breakdown (9).

Sensitivity and Specificity

Sensitivity and specificity are easily illustrated by considering a population of 1000 women in whom the spine bone density has been measured. A cut point can be chosen, most simply by picking a T-score such as -2.5 to determine the exact percentages of women with spine T-scores of -2.5 or poorer and spine T-scores better than -2.5. The women with T-scores of -2.5 or poorer are considered diseased. Based on World Health Organization (WHO) criteria,2 they have osteoporosis. The women with T-scores better than -2.5 are considered nondiseased in this example. They do not have osteoporosis, although many of them may be osteopenic. By using the T-score to pick a cut point that defines the categories of diseased and nondiseased, quantitative continuous bone density data has been converted into two qualitative nominal data categories.

Projections to the Central Nervous System

Unlike somatic (i.e., nonvisceral) tissue, the viscera are innervated by two sets of primary afferent fibers that project to distinct regions of the CNS. Innervation of the GI tract from the esophagus through the transverse colon is provided by vagal afferent fibers originating in the nodose ganglia and projecting centrally to the nucleus of the solitary tract. The remaining lower bowel is innervated by pelvic nerve afferent fibers, originating in the sacral (human lumbosacral in rat) dorsal root ganglia, and projecting centrally to the sacral spinal cord. The entire GI tract is also innervated by afferent fibers in the splanchnic nerves projecting to the T5-L2 segments of the spinal cord. For example, colonic afferent fibers project in both the pelvic and the splanchnic nerves (3,4). Because these afferents run in mixed-nerve bundles that contain the autonomic outflow from the CNS, they are often referred to as parasympathetic and sympathetic afferents. This terminology is a misnomer...

Pathways in the Anterolateral Quadrant

Pathways ascending in the ALQ of the spinal cord, such as the STT, are known to be important in transmitting signals evoked by noxious cutaneous stimuli and have been proposed to carry nociceptive information of visceral origin (19). The role of the ALQ in cutaneous nociception is supported by a large amount of experimental and clinical evidence however, the data pertinent to the role of the ALQ in processing noxious visceral information is not conclusive. Transection of the ventral quadrant of the spinal cord in the dog raised the threshold for cutaneous nociception (20) this observation was used as an experimental basis for the introduction of cordotomy as a treatment of pain in humans (21). Several investigators have found that ventrolateral cordotomy produced somatic analgesia on the side contralateral to the lesion in monkeys (22-24). It is interesting, however, that reactions to painful stimuli applied to one side of the body in cats are not prevented by hemisecting the...

Fetal Vm Tissue Transplants

Several studies transplanted fetal nondopaminergic cerebellar tissue or striatal eminence into the striatum of dopamine-depleted monkeys. Not surprisingly, they found no change in motor impairments, and no synaptic connections were made between the host and the atypical tissue grafts (17,52,66,70,71). Another study found that cerebellar tissue, when transplanted with spinal cord cografts, initiated a dopaminergic sprouting into the striatum from the olfactory bulb and nucleus accumbens (70). Most likely, the dopaminergic sprouting resulted from the presence of the spinal cord cografts and was independent of the cerebellar graft. Like the sural nerve cografts transplanted with adrenal tissue (41), the spinal cord would be a source of Schwann cell-derived NGF (46-49). Regardless, the authors suggested that replenishing the striatum with dopamine may not necessarily have to rely on transplanting dopamine-secreting cells, but the striatum could be reinnervated from neighboring...

Pathways in the Dorsal Funiculus

Classical teaching holds that the dorsal column subserves graphesthesia, two-point discrimination, and kinesthesia. This concept was adopted at the turn of the 20th century (33,66-68) and was based on the pathologic alterations observed in certain disease states associated with dorsal column lesions and on the skimpy knowledge of spinal tracts available at that time. On the other hand, the evidence for the importance of the dorsal column pathway in the transmission of visceral nociceptive information is compelling. It rests on the great effectiveness of limited midline myelotomy in reducing intractable pelvic cancer pain in humans (69-74) and on a number of groundbreaking experimental observations (12-15,17,18). In an early report on visceral nociceptive fibers in the dorsal column, awake human subjects experienced unbearable, excruciating pain when the dorsal column or medial aspect of the nucleus gracilis was probed mechanically (75). The pain was referred to the sacral region and...

The CRF hypothesis and stress

CRF is synthesized in the hypothalamus and elicits the release of adrenocorticotropic hormone (ACTH) from the pituitary. CRF was isolated from sheep hypothalamus and its structure as a 41-amino-acid peptide determined.96 The hypothalamic paraventricular nucleus (PVN) is the major region in the brain of CRF-containing cell bodies and through axonal projections to the capillaries of the median eminence can secrete CRF directly into the portal system where it acts at the pituitary to regulate ACTH secretion into the circulation. The principal role of ACTH is to stimulate the release of cortisol from the adrenal gland, thus completing the HPA axis, a primary component of the neuroendocrine response to stress. Similarly, projections from the PVN to the lower brainstem and spinal cord have been demonstrated to regulate autonomic function and help to further mediate the behavioral responses to stress. High densities of CRF-containing neurons are localized in particular to prefrontal,...

Early clinical experience

As the preclinical data have suggested, gemcitabine is indeed a potent radiosensitizer. There are notable case reports in the literature of normal tissue toxicities occurring in patients that are felt to be related either to the drug alone (e.g., acute interstitial pneumonitis) (36,37) or to the combination of gemcitabine and radiation. Radiation recall dermatitis is one of those toxicities reported to have occurred in relation to the combination of the two agents (38,39). In one of the reported cases (38) a patient who had initial treatment with a lumpectomy, axillary node dissection, ipsilateral breast radiation, and adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) chemotherapy for breast cancer presented 3 yr later with metastatic disease in the spine for which she received localized radiotherapy to the lumbosacral spine prior to starting systemic therapies. In the course of her illness she developed a confluent erythematous maculopapular rash on her back exactly...

Steroids and Lipoproteins in the CNS

Likewise, the hippocampal CA1 also undergoes transient estrogen-induced synaptic remodeling.25 In the stratium radiatum of the CA1 both dendritic spine and synaptic density are increased on proestrus, and apoE mRNA levels also appear to be under estrogenic control in this region. On proestrus, when circulating estrogen levels are highest, apoE mRNA levels were found to be 30 to 70 higher than on other cycle days.26 In the same study, however, apoE mRNA levels were highest on diestrus in the CA3, when circulating estrogen levels are considerably lower. These results are not surprising as specialized subpopulations of astrocytes occur with different frequencies in the CA1 and CA3.27 This would suggest differential regulation of apoE mRNA levels in different astrocyte subpopulations different brain regions. These findings, however, do not constitute direct evidence that estrogen influences apoE mRNA in vivo, as levels of several other hormones also differ between cycle days (Fig. 3.1).28

Irritable Bowel Syndrome

Neurons, and modulation of the brain responses to information signalled by the gut. Recent evidence from behavioral and functional imaging studies of patients with IBS suggests that changes occur at the level of the primary afferent neuron and or spinal cord but not in higher cortical centers (16,17), thereby supporting the notion that peripheral mechanosensation plays an important role in the etiology of this disease. In particular, there is circumstantial evidence suggesting that hypersensitivity of lumbar splanchnic afferents induces hyperalgesia in IBS patients (16,18). Consistent with the role of peripheral mechanisms, subsets of IBS patients have increased numbers of inflammatory cells in the colonic mucosa (19), while activated mast cells have been found in close proximity to colonic nerves, which correlate with abdominal pain in IBS patients (15), suggesting that activation or sensitization of extrinsic sensory endings within the gut wall may play a key role in IBS. Recent...

Sensory Innervation Of The Gastrointestinal Tract

The sensory, or afferent, innervation of the gastrointestinal tract mediates sensations from the gut and initiates reflex control of digestive function. The afferent fibers innervating the gastrointestinal tract follow two main anatomical branches, the vagal pathway and the spinal pathway. Vagal afferents have axons which project directly into the brainstem to the nucleus tractus solitarius whereas their cell bodies are located in the nodose ganglia. Vagal afferents are important in the sensory innervation of the upper gastrointestinal tract, in particular the esophagus and stomach (27,28). However, the vagal innervation decreases down the length of the gastrointestinal tract and is sparse in the distal colon (27,29). As such, vagal fibers are asso-ciated with sensation in the upper gut such as fullness, bloating, and nausea, and induce vomiting. In contrast, pain evoked from the upper gut is probably mediated via spinal nerves. Spinal afferent endings are distributed throughout the...

Neuronal Development

Nervous system development occurs in three stages with the formation of neurons from neural stem cells (neurogenesis), the guidance of axons to target cells, and the formation of synapses. Heparan sulfate proteoglycans have been shown to play a significant role in these stages of neural development due to their regulation of growth factor signaling, cell adhesion, and assembly of the extracellular matrix. Syndecan-2 has been shown to be involved in the morphogenesis of dendritic spines during synaptogenesis. Dendritic spines are small protusions on the surface of dendrites and are the sites of synapse formation, and receive the majority of excitatory synapse information. The lack of dendritic spine formation results in mental retardation as illustrated by fragile X syndrome (63). The C2 domain EFYA tetrapeptide of syndecan-2 binds to the synaptic PDZ domain protein CASK. Ethell and Yamaguchi (64) showed that in vitro transfec-tion of syndecan-2 in rhippocampal neurons results in early...

Predicting rate of bone loss

If bone turnover markers could reliably predict the rate of bone loss, they would provide a cheap and easy way of screening women at high risk of developing osteoporosis. Unfortunately, there are major methodological problems that arise when trying to examine the association of bone markers with bone mineral density (BMD) in longitudinal studies 8 . For example, the magnitude of the error associated with BMD measurements over time (in the region of a few per cent) is similar to the annual changes that are seen in BMD. Therefore, it is difficult to make a valid assessment of the relationship between the rate of bone turnover and the subsequent rate of bone loss in individual postmenopausal women. Studies have previously given conflicting results 8-11 , but two recent studies suggest that bone markers cannot be used to predict the rate of bone loss. Yoshimura et al. 12 examined eight bone markers and their relationship with BMD change at the hip and femoral neck over 3 years in 400...

Replacing a densitometer

Kalender W, Felsenberg D, Genant HK, Fischer M, Dequeker J, Reeve J. The European spine phan-tom a tool for standardization and quality control in spine bone mineral measurements by DXA and QCT. Eur J Radiol 1995 20 83-92. 7. Pearson J, Dequeker J, Henley M, et al. European semi-anthropomorphic spine phantom for the calibration of bone densitometers assessment of precision, stability and accuracy. The European Quantitation of Osteoporosis Study group. Osteoporos Int 1995 5 174-184.

Neuroanatomy for Literati Cortical and Subcortical Regions

On the large scale the nervous system is divided into several major territories the cerebrum (composed of the left and right cerebral hemispheres, joined by the corpus callosum), the cerebellum (little brain), the diencephalon, the midbrain, the pons (bridge, so-called because it connects the cerebrum with the spinal cord and cerebellum), and the spinal cord. These are shown schematically in Figure 4-6. Inside the brain small islands of neurons are clustered together in a sea of white matter or CSF. Many of these territories or islands were given poetic names in Greek or Latin by early neuroanatomists. (See Table 4-2.)

Studies in MS and Other Conditions

Musculoskeletal conditions that are seen in MS may respond favorably to chiropractic therapy. Most notably, multiple studies have evaluated the chiropractic treatment of low back pain, which may occur in people with MS. Of note, besides chiropractors, physical therapists and osteopaths also perform spinal manipulation. In addition, low back pain may resolve with no therapy at all and may respond to nonmanipulative forms of therapy given by primary care doctors, orthopedic physicians, neurologists, and physical therapists. The relative effectiveness and expense of these different approaches is debatable. In 1994, the Agency for Health care Policy and Research endorsed chiropractic therapy for low back pain that is recent and not longstanding. Chiropractic therapy has been investigated in other conditions. Among neurologic disorders, small or single-case studies note beneficial responses in people with headaches and spinal cord injury. These studies are too small to be conclusive....

Predicting response to treatment

Relatively short period of time, however, would be a great advance over the current use of BMD measurements. Hesley et al. 25 found that those subjects identified as having a high bone turnover (baseline Dpd levels greater than two standard deviations above the group mean) showed a greater response to therapy, with the gain in lumbar spine BMD (2.8 increase) being significantly greater than the lumbar spine BMD increase for those individuals classified as low turnover (0.7 increase). A second study 26 found that baseline NTx levels in women treated with alendronate were correlated with alkaline phosphatase and lateral spine BMD at 12-18 months (r 0.28 and r 0.27, respectively p 0.05). Chesnut et al. 24 carried out a detailed analysis of the effect of hormone replacement therapy (HRT) on urine NTx levels and its value in predicting response to treatment. They observed a significant correlation between baseline NTx levels and lumbar spine BMD at 1 year. The percentage change in NTx at 6...

Monitoring response to therapy

Hesley et al. 25 have investigated the effects of treatment with 17-0 oestradiol (0.05 mg day) on urinary Dpd excretion in 91 women who had recently undergone a surgical menopause. Despite the low number of subjects in this study, the results are in agreement with other studies that have shown that short-term changes in Dpd response to antiresorptive treatment are inversely correlated with long-term changes in BMD 37, 38 . In this study, the changes in Dpd at just 6 months were correlated (r 0.47, p 0.05), with changes in lumbar spine BMD at 6 months in the subgroup of patients on the 0.05 mg therapy. Additionally, urinary Dpd levels decreased into the premenopausal range in 95 (59 62) of those subjects taking HRT (dose ranged from 0.025 to 0.1 mg day). Delmas et al. 39 investigated the change in BAP, osteocalcin and CTx in response to different doses of transdermal 17 0-oestradiol patches in 569 women. They found that all markers decreased significantly after 3 and 6 months of...

Binding to intracellular targets

An association and correctly time the conditioned response. The hippocampus is involved in the association of temporal events, and timing of the eye-blink response is crucial it is suggested that in trace eye-blink conditioning, the animal is likely to learn that a tone followed by an empty interval means to blink (41). The observed positive correlation of the increase in PKCy-ir and the number of correct behavioral CRs may suggest that alterations in PKCy are related to the proper timing of the eye-blink response and that a certain amount of previously immunonegative PKCy becomes available for binding of 36G9 and C19 in relation to each successfully timed eye-blink. This increase in PKCy-ir could take place at one given set of synapses, or at more and more synapses that are recruited as training continues, or a combination of both. Hippocampal input corresponding to the CS and US pathways most likely stimulates receptors coupled to PKCy. If the increase in PKCy-ir is a consequence of...

Hologic DXA and Lunar DPA

Kelly et al. (1) evaluated the relationship between BMD values in the spine in 85 individuals ranging in age from 21 to 78 years using the Lunar DP4, a 153Gd DPA device, and the Hologic QDR-1000, a pencil-beam DXA device. The correlation for the measurement of spine BMD between the two devices was extremely good with r 0.98. Not surprisingly, however, the two instruments did not give exactly the same results. Values obtained on the QDR-1000 were consistently lower than those obtained on the DP4. The equation that was derived to predict the DXA QDR-1000 values from the DPA DP4 values was Pacifici et al. (2) evaluated lumbar spine BMD in 52 women using the Hologic QDR-1000 and the Lunar DP4. Again, the results were correlated with a statistically significant r value of 0.94. The values in the spine obtained with the QDR-1000 were approximately 6.8 lower than those obtained with the DP4. The equation for predicting the DP4 spine value from the measurement of spine BMD with the QDR-1000...

Lunar DXA and Lunar DPA

BMD values in the spine obtained with the Lunar DPX, the first clinically available DXA device from what is now GE Medical Systems, were originally reported as being approximately 3 lower than those that would be obtained with a Lunar DP3. This finding was based on an initial study of 41 subjects by Mazess et al. (4). Lees and Stevenson (5) studied 70 subjects (2 men and 68 women) who underwent PA spine and proximal femur bone density studies using the Lunar DPX and Lunar DP3. The results between the two instruments were statistically significantly correlated. The r value ranged from 0.96 at Ward's area in the proximal femur to 0.98 for the L2-4 BMD. The BMD values in the lumbar spine were again lower on the DXA than on the DPA device. The equation for predicting the L2-4 BMD for the DPX from a measurement of L2-4 on the DP3 was There was less difference between the BMD values in the femoral neck, Ward's area and the trochanter obtained on the DPX and DP3 than in the lumbar spine....

Muscular Mucosal Afferents

Muscular mucosal afferents, a class of afferent that responds to both circumferential stretch and low-intensity mucosal stroking (10 mg), comprise 23 of the pelvic nerve afferent innervation of the mouse colon (80) and display similar properties to the vagal tension mucosal afferents recorded from the ferret esophagus (71). Muscular mucosal afferents are found only in the pelvic nerves, not in the LSN, and are clustered in the lower distal colon and rectum. In response to fine mucosal stroking, these afferents display similar graded responses to mucosal receptors. However, a proportion of them display greater responses to circumferential stretch than muscular afferents. Thus these afferents are able to detect both low-threshold events in the lumen plus distension of the rectum. In order to achieve this, it is likely that the muscular mucosal afferent has two receptive fields. Overall, these data suggest that pelvic muscular mucosal and mucosal afferents contribute equally in the...

Serosal Mesenteric Afferents

Spinal afferent fibers with endings within the serosa and mesenteric attachment of the colon have been reported in the cat, rat, and mouse (65,67,74,76,77,80). These afferents have endings that are located close to or on blood vessels or branching points of capillaries supplying the serosa and can have between one and seven punctate receptive fields (36,65,67,69,73,74,76,83). Recordings from the LSN show that punctate mechanical stimulation or stretch of the mesentery elicits afferent firing (65,67). These afferents are also capable of responding to distension with a rapidly adapting response, particularly at noxious intensities of distension (67), and are polymodal as the majority respond to chemical stimuli including 5-HT, NaCl, HCl, bile, bra-dykinin, and capsaicin (73,76,77). Recent in vitro studies in rat colon have demonstrated that serosal mesenteric afferents account for between 50 and 80 of the afferents recorded from the LSN (76,77). These afferents are classified by their...

Hologic DXA Lunar DXA and Lunar DPA

The general relationship between Lunar DP4 values, Hologic QDR-1000, and Lunar DPX values is summarized in a study from McClung and Roberts (6). Ninety-three subjects underwent bone density measurement on all three machines at the PA spine and proximal femur. The ratio of mean values obtained for each combination of machines is shown in Table 5-1. Note that the PA spine values obtained with either DXA device are lower than those obtained with the DP4. The three regions in the proximal femur are lower when obtained with the QDR-1000 compared to the DP4 but are slightly higher than the DP4 in the femoral neck and Ward's area when obtained with the DPX. The Hologic QDR-1000 values are consistently lower than the Lunar DPX values at all sites. Although these equations can be used to predict DXA values from earlier DPA measurements and vice-versa, the margin of error in these equations limits their utility to exactly predict BMD. They can be used to approximate the BMD, however. This is...

Nociception How It Works

Almost all parts of the body are covered with nerve endings that are each programmed to respond to a specific kind of unpleasant sensation. They require a certain intensity of stimulation before they react and will lie silent until this level is reached. When stimulated they create an electrical pulse known as an action potential, which is transmitted along the attached nerve on the first stage of a long but very rapid journey to the spinal cord and then to the brain. The nerves are composed of thousands of tiny filaments called axons, lying alongside each other like strands of copper wire in a domestic electrical cable. Axons are classified according to the type of receptor they connect to and their diameter. Some are myelinated , that is, covered with an insulating sheath made from a fatty material called myelin. This protects and nourishes the axon and keeps the electrical pulse within it, resulting in faster transmission of the signal. Large diameter axons are heavily myelinated...

Dxa from lunar to hologic to norland

The Hologic QDR-1000, the Lunar DPX and the Norland XR-26 were compared in an in vitro study by Arai et al. (7). Solutions of various concentrations of potassium phosphate enclosed in an acrylic resin and submerged in water were used to simulate bone and soft tissue. The various concentrations of potassium phosphate were measusred on each of the three machines to determine both the accuracy of the machines and the correlation between the BMDs measured by each of the machines. Each machine accurately measured the BMD. The correlation between each pair of machines was highly statistically significant with an r value of 0.9999. The measured values were not identical however. Values obtained with the Lunar DPX were 8.08 higher than those obtained with the Norland XR-26 and 4.96 higher than those obtained with the Hologic QDR-1000. The QDR-1000 values were 2.96 higher than those obtained with the XR-26. An anthropomorphic Hologic spine phantom was also used in this study to compare the...

Morphology and Populations of Dendritic Cells

Dendritic cells (DCs) are present in lymphoid organs, in the epithelia of the skin and gastrointestinal and respiratory tracts, and in the interstitium of most parenchymal organs. These cells (introduced in Chapter 2) are identified morphologically by their membranous or spine-like projections (Fig. 6-4). All DCs are thought to arise from bone marrow precursors, and most are related in lineage to mononuclear phagocytes (see Fig. 2-2). Several subsets of DCs have been identified that may be distinguished by the expression of various cell surface markers and may play different roles in immune responses. The two main types are called conventional DCs and plasmacytoid DCs (Table 6-3).

Chemical Mediators of Pain

Nociceptors also release other types of compounds that act as transmitters or as modulators of nerve excitability. Perhaps the best documented and understood is substance P, an 11 amino acid peptide identified first by Gaddum and von Euler as an extract in 1932, and termed substanz P, for powder. Substance P is released from one type of pain transmitting nerve fiber in response to intense peripheral stimulation and leads to selective amplification of pain pathways in the spinal cord. Other compounds including amino acids such as GABA and glycine, peptides such as enkephalin and dynorphin, and the nucleoside adenosine act to turn down the nociceptive signal. What have been described thus far are events that take place in nerve tissues, but important scientific discoveries about pain transmission have been made by focussing down further, to events taking place within and around individual nerve cells. Calcium plays a major role in short-term and long-term events...

Hologic DXA and Norland DXA

In vivo comparisons of spine measurements made using the Norland XR-26 and the Hologic QDR-1000 were conducted by Lai et al. (8) in 65 subjects. The correlation for BMD at the spine was 0.990 and was highly significant. BMDs obtained on the Norland XR-26 tended to be lower than those obtained on the QDR-1000. The equation for predicting the Hologic BMD from the measurement of BMD on the Norland XR-26 was Hologic QDR 1000 SpineBMD -0.1 + (1.09 x Norland XR-26 SpineBMD)

Contribution of Non Neuronal Cells to Nociception

Recently, we have become aware that direct neuronal signaling to other neurones is not the only process that leads to long-term changes. Immune cells within the spinal cord, which were long thought to only have a protective and nutritive role, have also recently been found to contribute to alterations in neuronal hyperexcit-ability -5-6 - These immune cells, mainly microglia and astrocytes, are activated from their normal quiescent state by injury to peripheral nerves and also by inflammation or injury within the spinal cord or brain. In fact, rather than increasing excitability of spinal nociceptive neurones the processes thought to occur are through removal of an inhibitory influence, or disinhibition 7 .

Lunar DXA and Hologic DXA

The Lunar DPX and the Hologic QDR-1000 were compared in a study of 46 women by Pocock et al. (9). These women underwent lumbar spine and proximal femur studies on both machines on the same day. The correlations were extremely good with r values of 0.98, 0.94, 0.96, and 0.96 for the lumbar spine, femoral neck, Ward's area, and the trochanter, respectively. The absolute BMD values were 16 lower on the QDR-1000 Conversion Formulas for BMDs of the AP Spine Between DXA Devices Hologic QDR-2000 Spinebmd Hologic QDR-2000 SpineBMD Lunar DPX-L SpineBMD Lunar DPX-L SpineBMD Norland XR-26 SpineBMD Norland XR-26 SpineBMD (0.906 x Lunar DPX-L SpineBMD) - 0.025 (0.912 x Norland XR 26 SpineBMD) + 0.088 (1.074 x Hologic QDR 2000 SpineBMD) + 0.054 (0.995 x Norland XR 26 SpineBMD) + 0.135 (0.983 x Lunar DPX-L SpineBMD) - 0.112 (1.068 x Hologic QDR 2000 SpineBMD) - 0.070 in the spine when compared to the DPX and 17 lower in the femoral neck. The equation for predicting the QDR BMD in the femoral neck...

Standardization of absolute bmd results

It is clear from the extremely good correlations between DXA measurements of BMD at the spine and proximal femur using the central devices from the major manufacturers in the United States that these devices are indeed measuring the same thing. The measured BMD values obtained on the various machines may differ markedly because of differences in calibration and bone edge detection algorithms among the machines. Because of this, there has been a great deal of interest in developing a standardized BMD to which all DXA results could be converted, regardless of which manufacturer's machine was used.

Diffuse Cortical Dementias Alzheimers Disease

Specific laboratory tests are used to eliminate endocrine dysfunction and vitamin deficiency. Cerebrospinal fluid (CSF) examination is indicated when an infectious etiology of dementia is suspected. Commercially available biomarkers for AD are not used routinely in the evaluation of patients. A definite diagnosis is based on the clinical criteria of probable AD (Clinical diagnosis of Alzheimer's disease report of the NINCDS, ADRDA Work Group, 1984) along with histologic verification by autopsy, rarely by biopsy.

Standardization of Central DXA Absolute BMD Values

In November 1990, the major manufacturers of DXA equipment agreed to work together in the area of standards as part of an international committee, known as the International Committee for Standards in Bone Measurement. Under the auspices of this committee, a study of 100 healthy women (10) was performed in which each of the women underwent PA spine and proximal femur studies on the Hologic QDR-2000, the Norland XR-26 Mark II, and the Lunar DPX-L. The women ranged in age from 20 to 80, with an average age of 52.6 years. The difference in PA lumbar spine BMD was greatest between the Norland XR-26 and the Lunar DPX-L, averaging 0.118 g cm2 or 12.2 . The average difference between the Lunar DPX-L and the Hologic QDR-2000 was 0.113 g cm2 or 11.7 . The average difference in BMD at the PA lumbar spine between the Norland XR-26 and the Hologic QDR-2000 was the smallest at only 0.012 g cm2 or 1.3 . Based on this data, equations were derived for the conversion of PA lumbar spine BMD obtained on...

Standardization of Dxa Bmd Results for the Femoral Neck Trochanter and Wards Area

In 2001, Lu et al. (13) developed equations for an sBMD for the femoral neck, trochanter, and Ward's area based on information obtained from studies of the same 100 women whose data was previously used to create formulas for the sBMD of the spine and total femur (10,12). The authors developed site-specific standardization formulas for the hip subre-gions. They compared the utility of the subregion formulas in reducing the disparity in BMD results among the three manufacturers' devices to that of the total femur standardization formulas developed previously when both sets of formulas were applied to the hip subregions. The authors applied the formulas to bone density data from a multicenter clinical trial involving 3139 postmenopausal women. Bone density data was acquired on 51 Hologic, 17 Lunar, and 2 Norland DXA scanners. Table 5-6 shows the difference between scanners for each subregion depending on whether no calibration, the total femur, or subregion calibration was used. The...

Regulation Thermography

The functions of the human body depend largely on its temperature. In order to maintain an optimal distribution of temperature throughout the body, it possesses a complex control and regulating system, the center of which is located in the hypotha-lamic region of the brain. For example, in reaction to incoming impulses in this region from cold or warm receptors, the production of heat in the organism can be regulated by increasing or decreasing metabolic activity. Regulatory impulses run from the brain to the skin as well, where they can influence the amount of heat that is perspired through contraction of blood vessels. The nerves through which these impulses pass can interact with nerves running within the spinal column from the internal organs to the brain. In this way a pathological disturbance within an organ can lead to a change in thermal regulation of the skin this is referred to as a reflex arc.

Novel chemotherapeutic agents

Temozolomide, a novel oral, second-generation alkylating agent, has shown significant promise as a cytotoxic agent in the treatment of a variety of solid tumors including melanoma, glioma, mycosis fungoides. Temozolomide is a prodrug of the active alkylating agent (MTIC) that is spontaneously converted to the active form under physiologic conditions. The drug demonstrates 100 oral bioavailability and excellent tissue distribution including penetration of the blood-brain barrier and into cerebrospinal fluid (51). Phase I II studies have shown significant antineoplastic effect in patients with recurrent malignant glioma (52,53). A randomized phase II trial comparing PCV to temozolomide in patients with supraten-torial GBM at first relapse demonstrated improved progression free survival, overall survival, tumor response, and quality of life among the patients treated with temozolomide compared to those treated with PCV (54). In a study of 33 patients with newly diagnosed GBM or AA,...

Frontotemporal Lobar Dementias

The pathology has a widespread distribution. Neuronal degeneration in the frontotemporal cortex is associated with neuronal losses in the basal ganglia, midbrain, brainstem, and spinal cord, in various combinations. The neurons and glial cells display distinctive neuronal and glial inclusions that immunoreact for tau protein or ubiquitin (Table 5.6).

The Utility of the sBMD

The sBMD is attractive as a means of comparing a BMD value obtained on one manufacturer's device with a BMD value obtained on another. This is useful in large population studies and clinical trials in which devices from several manufacturers must be used. The root-mean-square (RMS) error in the calculation of the sBMD is estimated to be 4 for the PA spine and total femur and even larger for the proximal femur subregion (13). This error is simply too large to base important clinical decisions on the comparison of sBMD values obtained on different devices for an individual.

From dxa machine to dxa machine within manufacturers

It is not uncommon for patients to have had a DXA study at another facility that must be compared to a DXA study at a second facility. Even if the studies have been performed on DXA machines from the same manufacturer, the results may vary slightly. If the machines have been properly calibrated and maintained using good quality control measures, the differences should be minimal. In a study performed at three different locations, three men and two women underwent duplicate total body and lumbar spine bone density studies at each location (15). The studies were performed on a Lunar DPX-L at one site and on a Lunar DPX at the other two locations. The differences in total body BMD among the three locations were less than 1.2 and the differences in lumbar spine BMD were less than 1.7 . When this is expressed as the CV7 between testing locations, the CV for total body BMD between sites was 0.7 and for the lumbar spine, 1.4 . Two similar studies using the Hologic QDR-1000 also demonstrated...

Myofascial Pain Syndrome

The localized, hypersensitive regions of muscle associated with trigger points are secondary, at least in part, to sensitization of the afferent peripheral nerve endings in the muscle by prostoglandins, bradykinin, histamine, substance P, and other nociceptive or algetic neurochemicals. Histologically and conceptually, there is evidence of an energy crisis found, which is identified by a decrease in high-energy phosphates and an associated increase in low-energy phosphates, as well as local hypoxia, secondary to local vascular and microvascular disturbances. The local, peripheral sensitization also is associated with a central, spinal cord sensitization in regions of the dorsal horn. As noted earlier, referred pain from trigger points may be mediated by any of four experimentally postulated mechanisms (i) convergence-projection, in which pain may be initiated by muscle nociceptors but then referred to another area served by other somatic receptors, which converge on the same region of...

Dementias Lacking Distinctive Histologic Features

Amyotrophic Lateral Sclerosis Spinal muscular The clinical presentation is characterized by a concurrence of symptoms and signs involving both the lower and upper motor neurons. The disease usually begins in the spinal cord, with weakness in extremities, increased or diminished to absent tendon reflexes, Babinski sign, increased or diminished muscle tone, muscle wasting, and fasciculations. Bulbar symptoms usually develop late in the course of the disease but, in

Disease State Diagnosis

Biomarkers are also necessitated for improved diagnosis and medical management of AD. Ab, tau, and phosphorylated tau (ptau) proteins are potential biomarkers, and clinical studies over the course of the past decade have shown that monitoring the levels of Ab42 and ptau (pthr231, pthr181, pser199) in cerebrospinal fluid (CSF) can potentially serve to discriminate AD from normal aging and other neurological disorders and can predict conversion of patients from MCI to AD, with low Ab42 levels associated with both high total and ptau levels being a distinguishing feature.10 These biomarkers are not robust in being able to distinguish AD from other forms of dementias, and alternate biomarkers are being sought using quantitative proteomic analysis to identify a panel of proteins, a molecular fingerprint that can differentiate AD and be used diagnostically - a major challenge. The National Institute of Health's BIOCARD study (Biomarkers in Older Controls at Risk for Dementia) reported...

Bone Density in Children

In a cross-sectional study of 110 boys and 124 girls ranging in age from 8 to 17 years, BMD in the proximal femur, PA lumbar spine, and total body was measured using DXA (Hologic QDR-2000, Bedford, MA) (1). For both the boys and girls, BMC and BMD increased at the spine, proximal femur, and total body between the ages of 8 and 17. The BMD values of the 17-year-old girls were also compared to BMD values from a separate group of healthy 21-year-old women. No significant difference was seen in BMD at any site between the 17-year-old girls and the 21-year-old women, suggesting that peak bone density had been reached by the age of 17 in the girls. In a cross-sectional study of266 subjects (136 boys, 130 girls) ages 4 to 27 years, BMD was measured in the total body, PA spine, and femoral neck using DXA (Lunar DPX. Madison, WI) (2). The average age of the subjects was 13 years. BMD increased at all sites in boys until the age of17.5 years. In girls, BMD increased at the total body and spine...

Changing Therapeutics in the Management of Intractable Pain in Children at the End of Life 19952005

A retrospective study published in 1995 examined the opioid requirements of children with terminal malignancy (27). Twelve (6 ) of the patients in this study required therapies beyond conventional pediatric opioid dosing. The majority of the patients had neuropathic pain related to tumor location as the basis of their intractability. Eleven patients had spinal cord compression, solid tumor metastatic to the spinal nerve roots, nerve plexus, or large peripheral nerves. Of the patients, 50 had adequate analgesia with either regional anesthesia or high-dose opioid infusion alone. The remaining patients required the prescription of sedation to control refractory pain.

Bone Density in Premenopausal Women

Mazess and Barden studied 300 young women between the ages of 20 and 40 (7). BMD was measured in the PA spine and proximal femur using DPA and at the ultradistal and 33 radial sites using SPA. BMD did not change significantly with age at any site. BMD tended to decrease with age at the femoral neck and Ward's area, but the change was not statistically significant. Additional BMD measurements were obtained at the spine and midradius after 2 years (8). In this longitudinal extension of the original study, there was no evidence of age-related bone loss at either the spine or 33 radial site. Hansen (9) evaluated 249 healthy premenopausal women whose average age was 39 years, measuring BMD at the distal forearm using SPA and at the PA spine and proximal femur using DXA (Hologic QDR-1000). In this study, no decline in BMD was seen at any site after age 30 and peak BMD appeared to be reached prior to age 30. Two other large cross-sectional studies have suggested that BMD in the proximal...

Hemorrhagic Shock And Trauma

With respect to trauma, another recent study has demonstrated the role of PARP in a head trauma model in the mouse. PARP-deficient mice had a faster recovery and better neurological performance than wild-type animals subjected to severe head trauma induced by a blunt device.40 Similarly, the activation of PARP has been demonstrated in spinal cord trauma.41 Although an in vitro study points toward the possibility that PARP activation plays a central role in the process,42 the effect of PARP inhibition or PARP deficiency in this latter model remains to be tested in vivo.

Dissimilar BMDs Between Skeletal Sites at Peak and Prior to Menopause

Two hundred thirty-seven premenopausal women between the ages of 20 and 45 were evaluated with DXA (Lunar DPX) measurements of the PA spine and proximal femur to determine if differences exist in z-scores for the spine and proximal femur (11). The reference population for the calculation of the mean BMD and the SD were the 20- to 29-year-old women of the study population. Twenty to 24 of the 20 to 29-year-old women had differences in z-scores of more thanl between the lumbar spine and any of the three sites in the proximal femur (neck, Ward's, trochanter). In the 30- to 45-year-old women, however, this percentage increased to 32 to 46 . In the younger age group, the percentage of women having higher z-scores in the spine or higher z-scores in the proximal femur was roughly equally split. In the older age group, however, there was clearly a shift in percentages favoring a higher z-score in the spine. This appeared to be due to the earlier onset of bone loss from the proximal femur in...

Bone Density in Perimenopausal Women

Changes in spine BMD in pre-, peri- and postmenopausal women were evaluated in a longitudinal study by Pouilles et al. (13). The subjects were 230 Caucasian women ranging in age from 45 to 66 years. Menopausal status was determined by menstrual history and estradiol and LH levels. Based on these determinants, 71 women ages 45-51 were premenopausal throughout the study, 42 women ages 47-57 experienced menopause during the study and were considered perimenopausal, and 117 women were postmenopausal throughout the study. BMD in the PA spine was assessed using DPA. The women were followed for an average of 27 months. Bone loss in the premenopausal women averaged 0.8 per year. In the perimenopausal women, bone loss was 2.3 per year. In the postmenopausal women, bone loss was again 0.5 per year. The authors noted that approximately half the bone loss observed in the first 10 years after menopause was seen in the first 3 years after menopause. There was no difference in the rates of bone loss...

Changes in Bone Density in Postmenopausal Women

BMD of the PA and lateral spine and proximal femur was measured in 353 Caucasian women ranging in age from 20 to 84 using DXA (Lunar DPX-L) (17). Of these women, 154 were age 50 or older. Between 50 and 80 years of age, BMD in the PA spine and femoral neck decreased 18 or 0.6 per year. BMD in the lateral spine decreased 35 to 40 or 1.4 per year, whereas BMD in Ward's area decreased 30 or 1.1 per year. As in young adults and perimenopausal women, dissimilarities in BMD among skeletal sites have also been reported in elderly women. Davis et al. (18) studied 744 women with a mean age of 66.6 years. BMD was measured in the PA spine, calcaneus, distal, and proximal radius. A combination of SPA and DPA was used to obtain these measurements. The women were classified by tertiles of BMD at each of the four skeletal sites. Of these women, 15 demonstrated marked heterogeneity in BMD among the four sites, having one or more sites in both the lowest and highest tertiles. Fourteen percent were in...

Changes in Bone Density in

BMD measurements of the PA spine (n 315) and proximal femur (n 282) were made in men ranging in age from 20 to 89 using DPA (20). The rate of loss from the PA spine was extremely small at 0.001 g cm2 per year, or approximately 1 per decade. Losses from the trochanteric region were also very small at 0.002 g cm2 per year or approximately 2 per decade. In the femoral neck and Ward's area, the rate of loss was greater at 0.005 g cm2 and 0.007 g cm2 per year, respectively. This would result in a decrease of 21 from the femoral neck and 34 from Ward's area between the ages of 20 and 70 in men.

Bone markers and fracture risk

With the emergence of effective - but rather expensive - treatments, it is essential to detect those women at higher risk of fracture. Several prospective studies have shown that a standard deviation (SD) decrease of bone mineral density (BMD) measured by dual X-ray absorptiometry (DXA) or heel ultrasound is associated with a 2-4-fold increase in relative fracture risk including of the hip, spine and forearm. In this context, the question arises as to what extent bone markers can add to bone mass measurements in order to improve the assessment of fracture risk.

Ankylosing Spondylitis

Low bone density has been frequently observed in ankylosing spondylitis although its etiology remains uncertain. For 2 years Maillefert et al (23) followed 54 patients with ankylosing spondylitis to determine the prevalence of osteopenia and osteoporosis and the relationship of any observed bone loss to therapy, physical impairment, or inflammation. There were 35 men and 19 women in the study with an average age of 37.3 years and average disease duration of 12.4 years. In 23 patients, the disease duration was less than 10 years. Bone density was measured at baseline and 2 years with DXA at the PA lumbar spine and proximal femur (Hologic QDR 2000). The mean PA lumbar spine baseline T-score and z-score for the group was -1.24 and -0.98, respectively. At the proximal femur, the baseline T-score and z-score was -1.07 and 0.46, respectively. Seventeen percent had T-scores at the PA lumbar spine of -2.5 or poorer and 39 had T-scores between -1 and -2.5. At the femoral neck, 11 had T-scores...

Bone markers to monitor antiresorptive therapy

Monitoring the efficacy of treatment of osteoporosis is a challenge. The goal of treatment is to reduce the occurrence of fragility fractures. Measurement of BMD by DXA is a surrogate marker of treatment efficacy that has been widely used in clinical trials. Its use in the monitoring of treatment efficacy in the individual patient, however, has not been validated. Given a short-term precision error of 1-1.5 of BMD measurement at the spine and hip, the individual change must be greater than 3-5 to be seen as significant. With bisphosphonates such as alendronate, repeating BMD 2 years after initiating therapy will determine if a patient is responding to therapy, i.e. shows a significant increase in BMD - at least at the lumbar spine which is the most responsive site. With treatments such as raloxifene or nasal calcitonin that induce much smaller increases in BMD, DXA is not appropriate to monitor therapy and, with any treatment, DXA does not allow the identification of all responders...

Central Nervous System Barriers

The neurons of the brain communicate with each other using chemical and electrical signals that depend on fine control of the local ionic microenvironment moreover such communication requires greater protection from circulating toxins than found in most other tissues of the body.1-3 Barriers at three interfaces separate the blood from the brain interstitial fluid (ISF, also called extracellular fluid, ECF) (Figure 1) the blood-brain barrier (BBB), formed by the endothelial cells lining the microvessels (Figure 2) the blood-CSF barrier, formed by the choroid plexus epithelium, which also secretes cerebrospinal fluid (CSF) and the arachnoid epithelium, which forms part of the meningeal covering.4 At each of these layers, tight junctions between cells form the 'physical' barrier, specific transport proteins transcytosis mechanisms mediate uptake and efflux ('transport' barrier), and enzymes add a 'metabolic' barrier. Together these mechanisms regulate molecular traffic between blood and...

From Single Analyte to Multi Analyte Testing

A promising alternative approach to the clinical work-up is the use of biochemical markers (biomarkers) present in the cerebrospinal fluid (CSF). As such, there is a growing need for laboratories to have access to rapid, automated, multiplexed, and cost-efficient measurement tools for key AD biomarkers. CSF is a continuum of the interstitial fluid from the brain and spinal cord (Figure 2). Neuropathological changes in the brain or modified biochemical processes affecting major functional pathways will be reflected in the CSF. The parallel involvement of several metabolic processes (e.g., inflammation, cholesterol homeostasis, hippocampal atrophy, neurofibrillary tangles in hippocampus and entorhinal cortex, senile plaques in the neocortex, synapse loss, oxidative stress) in the pathology of neurodegeneration precludes the use of one single biomarker for all applications areas. The selected biomarker panel will depend in part on the required clinical classification ( clinical question...

Routes Across the Blood Brain Barrier

Blood-brain barrier (BBB), (2) the arachnoid epithelium forming the middle layer of the meninges, and (3) the choroid plexus epithelium which secretes cerebrospinal fluid (CSF). In each site, the physical barrier is caused by tight junctions that reduce the permeability of the paracellular (intercellular cleft) pathway. In circumventricular organs (CVO), containing neurons specialized for neurosecretion and or chemosensitivity, the endothelium is leaky. This allows tissue-blood exchange, but as these sites are separated from the rest of the brain by an external glial barrier, and from CSF by a barrier at the ependyma, CVOs do not form a leak across the BBB. (Reproduced with permission from Abbott, N. J. Drug Disc. Today Technol. 2004, 1, 407-416 (with permission from Elsevier), based on Figure 1.1 in Segal, M. B. Zlokomic, B. V. The Blood-Brain Barrier, Amino Acids and Peptides Kluwer Dordrecht, 1990, with kind permission of Springer Science and Business Media.)

Capillary Hemangioblastoma

A WHO grade 1 tumor of stromal cells and abundant capillaries, uncertain histogenesis, and a preferential cerebellar location, capillary hemangioblastoma, has been reported in the brainstem, spine, and, rarely, supratentorially. When associated with VHL, these tumors are frequently multiple in number. They occur with increasing frequency during development, the peak incidence occurring in middle age (30-39 years). Success of surgical resection means that life-limiting tumor problems of VHL relate to malignancy at other sites (e.g., renal cell carcinoma), justifying surveillance at regular intervals.

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