The pathogenesis of orbital changes seen in patients with thyroid associated orbitopathy (TAO) has been matter of research since decades 12. One theory that has eluded confirmation is the proposal of a low level inflammation of the connective tissue 345. The original idea put forth in 1995 by the research group of Jack R. Wall 3 has found limited resonance in the scientific literature (citation analysis done with SCOPUS, Elsevier B.V.). On the other hand, the topic of low grade inflammation is found more frequently in relation to the metabolic syndrome, to abdominal obesity and to cardiovascular disease as well as in relation to decreased muscle mass and elevated cytokine levels, e.g. of IL-6 and TNF 6789. A common denominator found both in TAO as well as in these metabolic situations is the elevation of cytokines 10111213. It is interesting to emphasize, that effective treatment of the thyroid condition related to TAO, i.e. hyperthyroidism, does not lead to a normalization of IL-6 levels in these patients 11 which suggests that IL-6 might not originate from the thyroid 14. On the other hand, physiology research has demonstrated that muscle tissue can indeed produce IL-6 and TNF 15. In spite of this fact, the role of peripheral skeletal muscle function has been seldom evaluated in TAO. None the less muscular changes have been quantified in thyroid diseases showing a situation of diminished strength 161718. Therapeutical consequences, however, have not been derived from these dynamometric findings.

Elevation of glycosaminoglycans (GAGs) has also been described to occur in TAO 1920, however the mechanisms linking GAGs to inflammation are intricate 21 and elevated GAGs can be found in patients with other autoimmune diseases 22. In cases of recurrent of eye disease levels of GAGs can again be elevated 23. A recent publication on TAO concluded that "the elevations in urinary GAGs in these patients appear to reflect widespread stimulation of fibroblast metabolic processes, as might occur in the setting of systemic connective tissue inflammation" 24. Mechanisms leading to GAGs elevation in relation to connective tissue can be the scarring of fasciae 25 as well as endoplasmatic reticulum (ER) stress 26. GAGs are also related to the extra cellular superoxide dismutase system (EC-SOD) 27. SOD has been found to be elevated in GD, and remains so even after an euthyroid state has been achieved 28.

Due to the involvement of extra ocular muscles (EOM) in TAO, investigators have also studied the role of these tissues as a potential antigenic target. Based on serological methods, putative muscle antigens have been identified in EOM as well as in peripheral muscle tissue 2930. On clinical grounds, Graves' disease can present features such as myalgia, swelling of the calves and fasciitis 31. Symptomatology of amyotrophic lateral sclerosis has also been reported in association with thyroid disease 323334. The evaluation of muscle strength in hyperthyroid patients has revealed a situation of reduced strength which can be regained after therapy 1618. In 1977 Delporte et al. found an association with musculoskeletal components such as with polymyositis 3536. In another study an eosinophilic fasciitis was found 37. In 1977 one report described manifestations of muscular and neurological origin in hyperthyroidism. The authors called the situation hyperthyroid myopathy, a condition which was not necessarily proportional to the hyperthyroid state, and proposed also a polysystemic nature of Grave's disease 38. Finally, motor neuron alterations have also been described in connection with hyperthyroidism 3439.

Two recent findings clearly emphasize the relation of TAO to musculoskeletal structures. In the first place antibodies directed against a muscle antigen which is involved in Ca²⁺ release, i.e. myocardial calsequestrin, have also been described 40. Ca²⁺ release is an immediate regulator of muscle contraction 414243. In the second place, antibodies directed against collagen type XIII have also been found 44. Collagen type XIII is found at the myotendinous junctions 45.

Besides these clinical and serological aspects, imaging methods have also provided hints regarding the involvement of musculoskeletal structures. Recently it has been shown that muscles of patients with Graves' disease present increased peripheral glucose utilization, i.e. ¹⁸F-fluorodeoxyglucose uptake 46. Increased peripheral glucose metabolism can either signalize inflammatory changes 47 or increased tissue metabolism such as in oncological conditions 48. Indirect evidence on the presence of inflammation in muscles of TAO patients, e.g. neck muscles and shank, can be seen through the use of radioactive labeled octreotide, a somatostatin analog 4950. Furthermore it should be kept in mind that posture – a neuronal and musculoskeletal function – is intimately related to gaze 5152, and gaze is altered in TAO. Again, these lines of evidence suggest an interaction with the musculoskeletal system in TAO. One possible explanation for the scarcity of clinical evaluations in this direction is the lack of sufficient clinical expertise in the field of musculoskeletal diseases 5354.

Considering the compelling amount of evidence mentioned above it appears that both the musculoskeletal system and the connective tissue system can be involved in TAO. The aims of the study were to analyze and characterize musculoskeletal elements in TAO patients using a simple functional manual clinical examination method. The elements in this analysis were derived from features of biomechanical functions that relate the feet to eye function 515255. The presence of potential somatic dysfunction was studied using a propioceptive stretch test 56. Finally erythrocyte levels of Zn and Cu, which are closely related to the function of superoxide dismutase (SOD) 575859, as well as the levels of Mg and Ca²⁺, which are important in muscle action, were also analyzed.

The clinical and laboratory study included 13 patients with TAO, 12 females and 1 male, age range 10–46 years and 16 controls, 11 females and 5 males, age range 15 to 58 years. According to the Werner classification 60, all patients were in stages I or II. Mild signs of inflammatory activity in the form of conjunctivitis were present in 3 cases. All patients provided written consent for participation and for their identities to be revealed. At the time of the investigation, latent hyperthyroidism was present in 5 patients. Informed consent was provided. The investigation was carried out in accordance with the Declaration of Helsinki. The institutional ethics committee approved the study. The investigation was done by endocrinologists trained also in musculoskeletal methods (Applied Kinesiology) as well as in acupuncture. Additional expertise on sports physiology and physical training was contributed by RM (Master of Advanced Studies Health and Fitness, University of Salzburg, Austria). Neither specialized biomechanical methods nor a biomechanical research facility were available.

The initial clinical examination started with the patient sitting and then standing in front of the investigator. For the observations on posture the 3D coordinates were defined as follows: the positive x direction was the forward orientation, the positive y direction was the rightward orientation, and the positive z direction was the upward orientation (Figure 1). Some facial characteristics such as the inter-pupillary angle and the head on neck orientation 61 were quantitatively evaluated using digital photographic material.

Symmetry of foot movement during gait was observed in the frontal plane. For this the patient was asked to walk an aisle of 10 meters length. After observing the gait pattern the patient was asked to repeat the procedure and to stop on command during the stance phase of the representative side. While standing the angular deviation of the foot in relation to the straight direction of motion was measured. This procedure was adapted from the method described by Schmid 62.

The last part of the examination was conducted with the patient in an unloaded supine position where the orientation of the legs and of the feet was evaluated. This unloaded supine position has been described as being adequate for the mobilization of the stretch reflex pathway 63 where propioceptive stimuli from both the skin and the joint are activated 64. The clinical testing was done using passive inversion and active rotation of each foot. The effect of the stretch procedures was evaluated using standard methods of Applied Kinesiology (AK) as described elsewhere 6566. In this context, the propioceptive provocation can elicit a so-called therapy localization (TL) which provokes a change in muscle tonicity as documented by EMG analysis 67. The change in muscle tonicity can be evidenced by the manual examination 68. The response pattern can thus be reduced to binary elements, 0 = absent, or 1 = present. The identification of a TL site indicates a local structural change. Based on the experience gained through the investigation and treatment of the index case of this model two acupuncture points were chosen for the correction of the TL by applying acupressure on them. The points correspond to elements of the bladder and gall bladder meridians, Bl62 or Shen mai, and GB26 or Dai mai, respectively, which have been recently shown to be related to tendinomuscular structures by in-vivo MRI imaging of gold acupuncture needles inserted at these sites (submitted to BMC in March 2006). The examination procedure is summarized in Table 1.

Laboratory examinations included the determination of erythrocyte levels of Zn, Cu, Mg, Ca²⁺, Na, K, and Fe. The determinations were carried out at a specialized laboratory (Labor Bayer, Stuttgart, Germany). In a previous study we had demonstrated that patients with thyroid disease present lower levels of Se as compared to non-thyroid disease controls (submitted to BMC, 2006). For this reason this parameter was not evaluated again in this study.

Based on the close relation between vision and posture control 5152 we hypothesized that elements related to biomechanical features of posture and gait could be present in TAO patients and that such changes could be related to a low grade systemic inflammation 338. In this study we have been able to show that TAO patients present facial asymmetry with deviation of the inter-pupillary axis as well as of the head-on-neck position (Figures 8, 9) together with axial rotation of the legs and feet. Active foot rotation was found to be coupled to an altered neurological response producing the phenomenon of moving toes in the contra-lateral foot. Until now, moving toes have only been described in neurological patients 6970717273. Due to the lack of a resting phase in the contra lateral foot, one can expect that propioceptive stimuli produce altered signals in the brain, thus affecting the areas involved in their coordination 7475. This feature is new in TAO.

In addition to the moving toes phenomenon, active foot rotation or foot inversion were associated with an altered propioceptive response during manual examination which could be compensated by using acupressure on 2 specific acupuncture points. The manual examination procedure constitutes a simple binary evaluation approach where either altered musculoskeletal regulation is found or not. Based on our results we propose that TAO patients present alterations of whole body axial changes as shown in Figure 10. The most complex situation of axial misalignment resembles an arch-type body posture which we have called lateral tension. This term represents the eccentric muscle positions of the foot and leg, as well as that of the neck muscles due to a contra-lateral head tilt (Figure 11). Recent publications by the group of Milias et al. 7677 include a photograph of normal subject that presents the typical outward rotation of the foot as we describe here. These studies were centered on the actions of Se on muscle function tests and included dynamometric analysis. This postural alteration, however, was not characterized by the authors. Literature evidence on the potential interactions of these musculoskeletal changes on posture is summarized in Table 4.

On the biochemical side, our study has confirmed the finding of diminished erythrocyte Zn levels in hyperthyroidism 7879. Zinc plays an important role in the maintenance of multiple body functions. One general function is that of providing site-specific antioxidative protection together with Se 80. In a recent study we have also demonstrated that patients with thyroid disease have diminished levels of Se (submitted to BMC, 2006). We will mention some aspects that appear relevant to TAO. Low erythrocyte levels of Zn are characteristic of hyperthyroidism and not of subacute thyroiditis 81, thus suggesting that different pathogenetic mechanisms are involved in these entities. Zn availability is a key factor for the development and function of the immune system 828384. Fraker et al. have pointed out the importance of Zn supplementation in order to overcome "the dismantling of the immune system" 85. Studies on TAO have seldom considered Zn even though it is an important regulator of retinal function 868788. Neuritis of the optic nerve has also been described as being associated with low Zn levels 89. Smoking, which is a known risk factor for TAO 9091, can lead to diminished Zn levels in serum 92. Muscle and tendon function are also related to Zn. Zn uptake has been located to the connective tissue space of muscle 93. Lack of Zn could diminish collagenase activity leading to a hardening of tendon tissue resulting in the characteristic snapping we have documented. Regarding the other biochemical parameters, we have not found any studies that have analyzed erythrocyte Ca²⁺ and Mg levels in TAO patients. Further implications of these findings will be discussed below.

The scientific literature has abundant data on biomechanical evaluations of gait and posture, but none has been carried out in TAO patients. In the majority of studies, normal subjects restricted through the use of a bracing apparatus have been evaluated. Under these conditions, the innate posture cannot be characterized. Quantitative approaches, i.e. dynamometry, have revealed that muscle strength is diminished in patients with hyperthyroidism. In spite of having quantitative data on muscle strength, these studies 161718 have not attempted to derive corrective procedures as we have done. A beneficial role of muscle strength for the prevention of falls was mentioned by Brennan 16. We will comment on this in the outlook section.

The description of new features of TAO patients arising from this study is a consequence of the philosophy of our Institution WOMED. Here we are committed to deliver an integral approach to disease in each individual. Within this frame we have previously described therapeutical measures for treating periorbital edema in TAO 67 or daily stress burden in hyperthyroidism 94. For this reason, we have chosen to call our results and observations the WOMED concept of lateral tension. This concept includes components of musculoskeletal function, endocrine function, and nutrition.

The following discussion will expand to deal with the following topics: 1) muscle involvement in Graves' disease and TAO, 2) effects of eccentric muscle action on muscle inflammation, 3) calsequestrin and the Ca²⁺ regulation system, 4) involvement of the connective tissue and superoxide dismutase (SOD), 5) propioception and biomechanical implications, 6) functional imaging data in relation to the model, and 7) summary of the WOMED concept of lateral tension in the context of inflammation and IL-6.

The WOMED concept of lateral tension which is centered around the abdominal muscles might be applicable to other conditions of musculoskeletal diseases. It is important to point out that our proposed use of acupuncture to treat fascial changes in the WOMED model of lateral tension coincides with the expectations from Shah et al. 187. They propose the used of microdialysis needles as surrogates for acupuncture needles to treat myofascial trigger points. By our means of manual clinical investigation, relevant myofascial trigger points can be found easily. For analytical scientific research procedures such as dynamometry, body surface scanning, and in-vivo microdialysis will provide figures and numbers related to our model. It can be expected that 2D separation of serum proteins will allow a closer insight into the changes in the proteome in selected diseases 194. Our clinical experience in patients with TAO, multiple sclerosis, fibromyalgia and similar conditions suggests that successful treatment can rely on acupuncture techniques that aim at correcting the integration of neurophysiological inputs.

We are involved with musculoskeletal function every day and take it for granted. For this reason every day use might not appear to be relevant to disease in the first place. Terry F. Davies, Editor in Chief of Thyroid, has made reference to this situation while commenting on the pathogenesis of TAO: "It maybe very well be true that there is nothing new under the sun – it is just that we have either forgotten it or never understood it" 195. While this applies to daily motor accomplishments, unusual musculoskeletal exercise with repetitive eccentric muscle action can produce an acute situation similar to the one we describe. The impressions of Lance Armstrong after the N.Y. marathon in November 2006 illustrates this: "Even after experiencing one of the hardest days of the Tour nothing has ever left me feeling this bad," he said at a post-race news conference. " [My shins] started to hurt in the second half, but the bigger problem the last 7 or 8 miles was the tightness in my calves and thighs. My calves really knotted up. I can barely walk right now." Figure 18 presents a graphical summary of the model together with potential every day stressors such as bicycle riding and running.

The author(s) declare that they have no competing interests.

RM and HM contributed equally to the development of the concepts of this work. RM did the art work and the Mind Maps. All authors read and approved the final manuscript.

The WOMED concept of lateral tension Changes in muscle and connective tissue due to eccentric muscle exercise 209210211212

1 Sarcomere damage 108 213 214 215

1.1 Potential bias in biopsy studies 216 217

1.2 Weaker sarcomeres absorb more stretch 214

1.2.1 sarcomere damage in myofibrils 107109

1.2.2 Desmin, titin, junctin 218

force reduction 219220

stiffness 221

increased levels of CK and LDH. Increased hydroyproline and hydroxylysine excretion 222

muscle fragments and myosin 108223

Desmin, titin, junctin 109

Troponin I 224

1.2.3 progressive weakness and low muscle tone 220225

1.2.4 over stretched sarcomeres 226227

disruption of EC 228229

increased number of sarcomeres 230

failure to reconnect and shortening 231

swelling 105223225232

stimulation of ankyrin 233

connection of ankyrin to obscurin and titin 234 235

ECM disruption 236

Siehe auch:

Connective tissue

1.2.5 active contractile fibers turn into passive elastic tissue

altered nociceptor sensitation and neurological accomodation

passive tension 237 and mechanical laxity 180

involvement of tendons 112238239

decreased ankle ROM 76

fascial compartments 240

1.3 Inflammation mediators 104 241

1.3.1 IL-6, TNF 15117242

1.3.2 IL-6 polymorphism and Increased inflammatory response by -174 G>C 243

1.3.3 IL-6 regulates the Zn transporter Zip-14 244

pro-inflammatory cytokines

1.3.4 Influence of aging 245

1.3.5 granulocytes and neutrophils 106246

1.3.6 c-Fos and lipocortin II 215

1.3.7 induction of histidine decarboxylase 118119

1.3.8 increased levels of bradykinin 116

1.3.9 interactions in nociception 247

1.3.10 ubiquitin proteosome proteolysis 246

1.3.11 role of gender 248

1.3.12 Antioxidants diminish cytokine response 249

1.3.13 activation of the c-Jun NH(2)-terminal kinase (JNK) 250

1.4 Elements of Ca regulation 251 252 and EC coupling 253

1.4.1 reduced Ca levels 253254

1.4.2 ryanodine receptor, calmodulin 251255

1.4.3 calsequestrin 42133253

1.4.4 parvalbumin (in motoneuron) 137

excitoxicity 256

1.4.5 Ca, SERCA 254

SERCA 1 in fast twitch fibers 251

SERCA 2 in slow twitch fibers 251

SERCA in EOM 257

Relation to thyroid hormones 258259

Relation to extraocular muscles 257

1.4.6 Triadin 253

1.4.7 Junctin in myocyte 218

1.5 Muscle repair processes

1.5.1 mTOR 260261

1.5.2 Satellite cells 262263264

1.5.3 Zn, MMP and remodelling 265266

1.5.4 Telomerase in fatigue associated myopathy 267

2 Connective tissue 236

2.1 mechanosensory effects 268 269

2.2 mechanosensation of the skin 270

2.3 Structural changes

2.3.1 SOD changes ? 271

2.3.2 release of glycosaminoglycans ? 27

2.3.3 GAGs in ER 26

2.3.4 Scarred fascia and GAGs 25

2.4 interactions with collagen

2.4.1 collagen degrading enzymes: TIMP-1, TIMP2- MMP2, MMP-9 110265272273

2.4.2 procollagen processing 111

2.5 Potential interaction with fasciae 240

2.6 increased levels of bradykinin and adenosine 115 116

3 Neuromuscular dysfunction 120 122 124 125

3.1 Reduced reflex sensitivity 121

3.2 Alpha motoneuron pool recruitment 122

3.3 Alteration in sense of effort and motor command 123

3.4 C-FOS expression in anterior pretectal nucleus in relation to pain 274

3.5 C-FOS in the dorsal horn due to compression 275

3.6 sensory control and inflammatory mediators 247

3.7 Neuromuscular activity modulates myonuclear domain size 263

3.8 Nervous system strategies 276

3.8.1 Eccentric exercise and brain activation

3.8.2 Brain activation and ECC

3.8.3 Brain control of coordinated movements

4 Nutritional and endocrine factors

4.1 Mg and Ca

4.1.1 Decrease of the ion dependent binding of spin labeled ATP 277

4.2 Selenium 55

4.2.1 Decreased levels in thyroid disease (Moncayo 2006)

4.2.2 Se in the pituitary 278

4.2.3 Se and muscle 279

4.2.4 Se and heart 280

4.2.5 Se, mTOR and muscle hypertrophy 281

4.3 Selenoproteins

4.3.1 Selenoprotein S influences inflammatory response 282

4.3.2 Selenoprotein K – a cardiac antioxidant 280

4.3.3 Selenoprotein N – muscular dystrophies 283

4.3.4 Selenoprotein N1 – insulin resistance 284

4.3.5 Selenoprotein W and muscle growth 285

4.4 Zinc

4.4.1 Calsequestrin 133

4.4.2 Bradykinin 286

4.4.3 Zn and Cu and Ca binding proteins 287

4.4.4 Influence on TRH processing 288

4.4.5 Zn and MMP in muscle repair 265

4.4.6 Zn and mTOR 289

4.4.7 Synaptic activity 290

4.4.8 Inhibitory activity in the spinal cord 146

4.4.9 Sciatic nerve lesions and Zn transport 291

4.5 Se and Zn

4.5.1 Zn-Se nanocrystals in the pituitary 292

4.6 Vitamin E 293

4.7 Thyroid hormones 294 295

4.7.1 Regulation of muscle gene expression 294

4.7.2 SERCA 259296

4.7.3 SERCA and thermogenesis 258

4.7.4 Satellite cells 297

4.7.5 Change in Myosin and SERCA isoforms 295

4.7.6 Force reduction 298

4.7.7 Changes in Ca uptake 299

4.8 Insulin resistance 300 301

4.9 Altered glycogen accumulation 302

5 Muscle action of extraocular muscles

5.1 Consideration of muscle volume

5.1.1 EOM 100101

5.1.2 Volume of limb and abdominal muscles 102103

5.2 Inapparent TAO 303 304

5.3 Thyroid hormone receptors in EOM 305 306

5.4 Satellite cells 307 308

5.4.1 Activated satellite cells in overacting EOM 309

5.5 Alterations in gaze 310

5.6 SERCA in extraocular muscles 257

5.7 Muscle overaction and Ca uptake 127

5.8 Neck vibration in strabismus 311 associated with changes in congruent muscle propioceptive information

5.9 Head and eye movement in MRI 312

5.10 Influence of waist disturbance on gait 313

5.11 Ocular motility 314

5.12 Layer specific EOM structure 128 315 316 317

6 Role of brain integration in movement coordination

6.1 Interlimb coordination 318

6.2 Lateralization of lower limb movements 151

6.3 Coordination of ankle movements 150

6.4 Active and passive ankle movements 319

Regulation of Ca Release 320

1. Ca cycling 254

2. SERCA

2.1. SERCA 1 fast fibers

2.1.1. Sarcolipin (SLN) 321322

2.1.2. Brody disease 320

2.2. SERCA 2 slow fibers

2.2.1. Phospholamban (PLB) 321322

3. Calsequestrin (high capacity – low affinity)

3.1. CSQ1 fast

3.2. CSQ2 slow

3.2.1. CSQ2 deletion > catecholaminergic tachycardia 323

3.3. β Dystroglygan and CSQ assembly

4. Calreticulin 263

4.1. cardiac myofibrillogenesis 324

5. Na Ca exchanger 325

6. IP3 43 326

6.1. Involvement in redox echange regulation 326

7. Dihydropyridine receptor DHPR 251

7.1. Voltage sensor

7.2. Linked to CSQ via junctional protein 45 327

7.3. Subtype 1

7.3.1. Malignant Hyperthermia

8. Ryanodine 3 gene products and splicing variants

8.1. RYR1 skeletal

8.1.1. minicore ophthalmoplegia

8.1.2. multi minicore disease

8.1.3. central core disease

8.1.4. malignant hyperthermia

8.2. RyR2 cardiac

8.2.1. arrhythmias

8.3. RyR3 cephalic muscles

8.4. Regulation by thiols 328

8.5. Importance of glutathione 329

8.6. Importance of Se 330

8.7. Junctin in the structure 331

9. Ca buffers

9.1. Parvalbumin 41

9.2. Troponin C

9.3. Calmodulin 332

9.4. Histidin-rich calcium binding protein

9.5. Junctate

9.6. Sarcolumenin

9.7. Mitochondria

9.8. S100 333

10. Role of thyroid hormones 334

10.1. Hyperthyroidisim

10.1.1. Upregulates Na Ca exchanger

10.1.2. IP3

10.1.3. RyR

10.1.4. Myosin heavy chains

10.1.5. Gender specific action via βERB

10.1.6. Low levels of Zn 79

11. Role of Selenium and selenoproteins 279

11.1. Regulates functional thiols of RyR

11.1.1. oxidation > open

11.1.2. reduction > closed

11.2. Selenoprotein N 335

11.2.1. Related to rigid spine 283

11.2.2. Minicore ophthalmoplegia 336

11.3. Selenoprotein K

11.3.1. Cardiac antioxidant 280

11.4. Selenoprotein W 337 338

11.4.1. Oxidative stress 285

12. Role of Zn

12.1. Modulation of activation and inactivation of Ca on RyR 339

12.2. Associated with T-tubules 340

12.3. CSQ structure 133 135

12.4. Ca Zn binding to calmodulin

12.5. Ca Zn and MMP 341

12.6. HRP regulation 135

12.7. Higher levels in red muscle 342 343

Interactions of Se with cytokines in inflammation and insulin resistance

1. Aging, inflammation, and muscle function

1.1. Sarcopenia 344

1.2. increased levels of IL-6 together with reduced muscle mass 9

1.3. low level inflammation 345 346

1.4. increased mortality when Se levels are low 182

1.5. cognitive decline and IL-6 347

1.5.1. improved psychomotor performance after Se 348

1.6. high IL-6 as a marker of disability 349

1.7. IL-6 release from muscle depends on glucose and glycogen homeostasis 184 350

1.8. low IL-6 levels as marker of regular physical activity 351

2. Insulin resistance

2.1. TNF induces SCOS-3 which reduces insulin receptor substrate 1 352

2.2. Influence of IL-6 (-174) G–>C polymorphism 353

3. Selenium

3.1. controls COX-2 levels 354

3.2. regulation of PPAR and Zn dependence for immune regulation of TNF 355

3.3. regulation of NF-kappaB 356

Siehe auch:

controls COX-2 levels

3.4. Insulin-like activity improving GLUT1 expression 357

3.4.1. GLUT1 and GLUT3 transport dehydroascorbic acid 358

3.4.2. Vitamin C and neutrophil physiology 359

3.5. modulation of inflammation through SePS 282

3.6. high s-Se predicts reduced levels of oxidative stress and subclinical COX mediated inflammation in males 360

3.7. Insulin resistance and increased GPX1

4. IL-6

4.1. IL-6 promoter haplotype influences ex vivo IL-6 response to endotoxin. functional effect of 174 G–>C 243 361

4.2. production in muscle 362 and adipocytes 363

4.3. Ca and IL-6 185

4.4. relation to CRP 364 and TNF

4.5. negative correlation with DHEA and DHEA-S 365

4.6. response to psychological stress 366

4.7. low methallothionein expression when IL-6 is elevated 367

4.7.1. low Zn and immune deficiency

4.8. hypoferremia in inflammation: IL-6 – hepcidin 368 and Zip14 244

4.9. CC genotype and PMR relapse 369