Fibromyalgia beyond reductionism. Heart rhythm fractal analysis to assess autonomic nervous system resilience.

OBJECTIVES: The prevailing linear reductionist medical model seems unable to explain complex multisymptomatic illnesses such as fibromyalgia (FM) and similar maladies. Paradigms derived from the complexity theory may provide a coherent framework for these elusive illnesses. Along these lines is the proposal that FM represents a degradation of our main complex adaptive system (the autonomic nervous system, ANS), in a failed effort to adjust to a hostile environment. Healthy complex systems have fractal structures. Heart rate fractal-like variability reflects resilient ANS performance. Our aim was to measure the heart rate variability (HRV) fractal scaling index in FM patients and to correlate this index with clinical symptoms. METHOD: We studied 30 women with FM and 30 controls. All participants filled out questionnaires assessing the severity of FM. The HRV fractal scaling index was estimated during 24 h using detrended fluctuation analysis (DFA). RESULTS: The fractal scaling index alpha-1 was higher in FM patients than in controls (mean ± sd: 1.22 ± 0.10 vs. 1.16 ± 0.09; p = 0.031). There was a positive correlation between the fractal scaling index alpha-1 and the visual analogue scale (VAS) for depression (Spearman's ρ = 0.36, p = 0.04). CONCLUSIONS: The heart rate fractal exponent alpha-1 is altered in FM patients, suggesting a rigid ANS performance. This tangible non-linear finding supports the notion that FM may represent a degradation of our main complex adaptive system, namely the ANS.

Kidney involvement in Takayasu arteritis.

OBJECTIVE: To evaluate whether the presence of glomerulonephritis is or is not associated with the extent of arterial wall inflammatory cell infiltrate in Takayasu arthritis (TA). METHODS: Retrospective chart and pathology review of large artery and kidney specimens of TA autopsy cases. Kidney specimens were classified, according to their histopathological findings, in those with specific glomerular entities and those with non-specific, ischemic and/or hypertensive, glomerular changes. A control group of autopsy kidney specimens was utilized for comparison. Morphometric analysis was used to assess the extent of the arterial inflammatory infiltrates; results were compared among the different groups with kidney lesions. RESULTS: We included 25 kidney specimens from 25 autopsies. Specific glomerular entities were present in 14 specimens; 10 (40%) were classified as diffuse mesangial proliferative glomerulonephritis (DMPG [Group A]), and 4 (16%) as other associated glomerulopathies (Group B). Non-specific changes were observed in 11 (44%) specimens (Group C). The arterial inflammatory infiltrate proportion was 9.4 % for group A, 1.4% for group B, and 2.7% for group C. Furthermore, a larger proportion of vascular inflammation was confirmed for group A when compared with the other groups (p<0.05). Group A patients were younger than those in groups B and C (p<0.005) and exhibited shorter disease duration. CONCLUSION: The presence of DMPG was associated with a larger extent of vascular inflammatory cell infiltrate, suggesting a relationship between both phenomena.

Osteopoikilosis in an ancient skeleton: more than a medical curiosity.

We describe the palaeopathologic and radiographic findings of the human skeletal remains that belonged to a female who lived in Mexico's viceroyship period (seventeenth and eighteenth centuries A.D.). Radiographic studies showed numerous, radiodense, ovoid, small and well-defined foci in the long tubular bones, sacrum, scapulae and iliac bones. Computed tomography (CT) examination revealed multiple hyperdense foci located in the central marrow portion of the bones. Measurements of attenuation coefficient revealed +1548 HU. The findings are consistent with osteopoikilosis, an uncommon, benign sclerosing bone dysplasia transmitted in an autosomal dominant fashion, which in the clinical setting is important to set apart from different bone pathologies to avoid unnecessary interventions and treatments. To the best of our knowledge, this is the first report of osteopoikilosis in ancient human remains.

Noninvasive cerebrovascular assessment of Takayasu arteritis.

BACKGROUND AND PURPOSE: Despite prominent neurological symptoms reported in Takayasu arteritis (TA), a complete evaluation of the cerebral circulation has not been consistently performed. The purpose of this study is to describe MR angiography (MRA), color Doppler flow imaging, and transcranial Doppler (TCD) findings in the extracranial and intracranial cerebral arteries in TA. METHODS: MRA, color Doppler flow imaging, and TCD were performed in 21 patients with TA. Intima-media thickness was measured in the common carotid artery. The correlation between noninvasive studies and panaorto-arteriography was examined for supraortic vessels. Cerebral angiography findings were compared with the noninvasive methods in 7 patients. Intracranial hemodynamic changes detected by TCD were compared with extracranial circulation lesions assessed by panaorto-arteriography. RESULTS: Noninvasive vascular techniques showed at least 1 abnormality in the extracranial and/or intracranial cerebral arteries in 20 of 21 patients (95%). Both MRA and color Doppler flow imaging showed a substantial correlation in the ability to detect obstructive lesions in supra-aortic vessels compared with panaorto-arteriography. High-resolution ultrasonography displayed common carotid artery wall thickening in 5 vessels that were considered normal by arteriography. In 24% of patients, MRA and TCD showed abnormalities consistent with stenosis of the basal cerebral arteries. In 10 patients with severe extracranial circulation involvement (detected by arteriography), TCD displayed intracranial hemodynamic changes consisting of dampened or blunted waveforms with low pulsatility. CONCLUSIONS: The comprehensive assessment of cerebral circulation in TA patients by noninvasive methods allowed the detection of a high rate of diverse vascular abnormalities in both extracranial and intracranial circulation.

Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs: study in mitochondria, submitochondrial particles, cells, and whole heart.

The effects of the anti-inflammatory drugs diclofenac, piroxicam, indomethacin, naproxen, nabumetone, nimesulide, and meloxicam on mitochondrial respiration, ATP synthesis, and membrane potential were determined. Except for nabumetone and naproxen, the other drugs stimulated basal and uncoupled respiration, inhibited ATP synthesis, and collapsed membrane potential in mitochondria incubated in the presence of either glutamate + malate or succinate. Plots of membrane potential versus ATP synthesis (or respiration) showed proportional variations in both parameters, induced by different concentrations of nimesulide, meloxicam, piroxicam, or indomethacin, but not by diclofenac. The activity of the adenine nucleotide translocase was blocked by diclofenac and nimesulide; diclofenac also slightly inhibited mitochondrial ATPase activity. Naproxen did not affect any of the mitochondrial parameters measured. Nabumetone inhibited respiration, ATP synthesis, and membrane potential in the presence of glutamate + malate, but not with succinate. NADH oxidation in submitochondrial particles also was inhibited by nabumetone. Nabumetone inhibited O2 uptake in intact cells and in whole heart, whereas the other five drugs stimulated respiration. These observations revealed that in situ mitochondria are an accessible target. Except for diclofenac, a negative inotropic effect on cardiac contractility was induced by the drugs. The data indicated that nimesulide, meloxicam, piroxicam, and indomethacin behaved as mitochondrial uncouplers, whereas nabumetone exerted a specific inhibition of site 1 of the respiratory chain. Diclofenac was an uncoupler too, but it also affected the adenine nucleotide translocase and the H+-ATPase.

Gerodermia osteodysplastica hereditaria: report of three affected brothers and literature review.

Gerodermia osteodysplastica hereditaria was diagnosed in three Mexican brothers 6, 7, and 8 years old, respectively, who had the distinct facial appearance with sagging cheeks, premature wrinkling of the skin of face, abdomen, and dorsum of hands and feet; malocclusion, span greater than height; hyperextensibility; winging of the scapulae; stooped posture with kyphoscoliosis; protuberant abdomen; and pes planus. Radiologically they had generalized osteoplorosis, platyspondily due to multiple compression fractures, pseudoepiphyses of second metacarpals, and dislocated hips. Three other families with a total of 14 affected individuals have been reported. Inter- and intrafamilial variability can be recognized, particularly regarding the tendency to fractures, upper:lower segment ratio abnormalities, and results of skin biopsies, which have shown fragmentation of the elastic fibers in some cases (including the present family) and not in others. Although inheritance was considered to be X-linked recessive in the first reported family, an analysis of that pedigree together with those of the other reported families, including the present one, suggests that gerodermia osteodrysplastica is inherited in an autosomal recessive manner.

Primary hypertrophic osteoarthropathy.

We describe seven patients with primary HOA and review 125 cases reported in the English, French, and German literature. The salient clinical features of primary HOA are: a bimodal distribution of disease onset with one peak during the first year of life and the other at age 15, a male predominance (nine to one), uncommon benign joint effusion, and a variety of skin abnormalities resulting from cutaneous hypertrophy or glandular dysfunction. We concluded that HOA is not a synovial disease. It is suggested that synovial effusions, when present, are perhaps a sympathetic reaction to the neighboring periostitis. Proposed diagnostic criteria for HOA, including digital clubbing and radiographic periostitis, appear 86% sensitive. The clinical features, age of onset, and sex distribution suggest that a genetically controlled growth promoting factor, different from growth hormone, plays a role in the pathogenesis of this syndrome.

The skeletal manifestations of clubbing: a study in patients with cyanotic congenital heart disease and hypertrophic osteoarthropathy.

The skeletal manifestations of clubbing of the digits have been occasionally noted and only briefly discussed in the literature. We investigated the radiographic features of digital clubbing in 37 patients with diverse diseases including cyanotic congenital heart disease, lung malignancy-associated hypertrophic osteoarthropathy, and idiopathic cases. We identified two types of bone changes--osteolysis or bone dissolution, and bone formation or hypertrophy. The changes were more evident in the feet than in the hands, and the degree of soft tissue change did not always reflect the underlying osseous abnormalities. The relationship of these changes (ie, osteolysis, hypertrophy) to each other appear to depend in part on the underlying disease as well as the time course or disease duration. Thus, clubbing and hypertrophic osteoarthropathy may not represent distinct entities; our data suggest that they may be stages in an evolving, more generalized process of new bone formation or hypertrophy followed by osteolysis or atrophy affecting many parts of the skeleton.

Acute rheumatic fever.

The diagnosis of acute rheumatic fever has become difficult. A growing number of diseases that were not recognized in the past could fulfill its diagnostic criteria. We emphasize its changing incidence, current knowledge of its pathogenesis, and lesser known clinical features such as pneumonitis, encephalitis and glomerulonephritis.

Cardiogenic hypertrophic osteoarthropathy.

It has been a generally held notion that the association of cyanotic congenital heart diseases with hypertrophic osteoarthropathy (HOA) is exceptional. However, recent prospective studies have demonstrated the opposite to be true. More than a third of patients with cyanotic heart diseases have HOA. The skeletal changes are more prevalent, more persistent and more severe than in any other internal illness. The clinical features of cardiogenic HOA are here discussed.

Pathogenesis of hypertrophic osteoarthropathy.

The systematic study of patients with cyanotic heart diseases has led to a better understanding of the pathogenesis of hypertrophic osteoarthropathy (HOA). Current evidence suggests that in cases of right-to-left shunts of blood, HOA develops as a result of faulty pulmonary clearance of macrothrombocytes. There are theoretical grounds to suggest that a platelet-derived growth factor is also responsible for the acropachy associated with other types of internal illnesses.

Is fibromyalgia a generalized reflex sympathetic dystrophy?

Fibromyalgia and reflex sympathetic dystrophy share defining characteristics, namely chronic pain and allodynia, as well as other important clinical features such as onset after trauma, female predominance, paresthesias, vasomotor instability, response to sympathetic blockade and anxiety/depression. Recent research using heart rate variability analysis demonstrated that patients with fibromyalgia have changes consistent with relentless circadian sympathetic hyperactivity. I propose that fibromyalgia is a sympathetically maintained pain syndrome in which ongoing sympathetic hyperactivity sensitises the primary nociceptors and induces widespread pain and allodynia.

Macrothrombocytes in the peripheral circulation of patients with cardiogenic hypertrophic osteoarthropathy.

The objectives of this study were: first, to determine the platelet morphology in the peripheral circulation of patients with cyanotic congenital heart diseases and thus its possible link to the development of hypertrophic osteoarthropathy. Second: to test the mathematical model which proposes that in normal individuals megakaryocytes are fragmented in the lungs. We prospectively studied 14 patients with cyanotic heart disease and clubbing of the 20 digits, and compared them with 14 randomly assigned controls. We measured the platelet count, mean platelet volume (MPV) and platelet volume distribution curve (PVDC). Patients had a significantly lower platelet count (x +/- SD, 171,528 +/- 81,810 vs 319,929 +/- 69,460, p less than 0.001) and larger MPV (11.028 +/- 3.09 vs 8.414 +/- 0.79, p less than 0.005). The PVDC of the controls were uniform, in all cases showing a log-normal configuration. The patient's curves were different; they lost the log-normal shape and demonstrated a heterogeneous platelet population. These findings agree with the mathematical model which proposes that in normal individuals platelets are generated in the lungs, and also suggest a role for the macrothrombocytes in the pathogenesis of cardiogenic hypertrophic osteoarthropathy.

Antiphospholipid syndrome in patients with cyanotic congenital heart disease.

Patients with cyanotic congenital heart disease exhibit an increased incidence of thrombotic episodes and are frequently thrombocytopenic. We studied the sera of 15 patients with this type of heart malformation, searching for anticardiolipin antibodies. 3/15 had positive results. The three of them were adult females; two had thrombotic episodes and a false positive VDRL. Thus, cyanotic congenital heart disease may be another disease entity associated with the antiphospholipid syndrome.

Vascular endothelial growth factor and hypertrophic osteoarthropathy.

OBJECTIVE: Hypertrophic osteoarthropathy (HOA) is characterized by the coexistence of digital clubbing and periosteal proliferation of the tubular bones. Localized vascular proliferation associated with platelet/endothelial cell activation are recognized features of this syndrome. Current knowledge suggests that HOA develops from the presence in the systemic circulation of one or more growth factors that are normally inactivated in the lungs. The nature of these purported growth factors has not yet been identified. Vascular endothelial growth factor (VEGF) has several features that may fit in with the pathogenesis of HOA. The objective of our study was to measure serum and plasma levels of VEGF in different groups of patients with HOA. METHODS: We studied 24 patients with HOA; of these, in 12 the HOA was secondary to cyanotic congenital heart disease and in 7 to lung cancer, while 5 represented primary cases. As controls we studied 28 individuals without HOA; of these, 12 were apparently healthy individuals, 7 had cyanosis secondary to chronic obstructive pulmonary disease, and 9 had lung cancer. ELISA was used to measure serum and plasma levels of VEGF. RESULTS: Plasma levels of VEGF were significantly higher in the patients with primary HOA (median 46.2; range 19.4-398.8 pg/ml) and in those with lung cancer-HOA (median 75.5; range 24.6-166.7), compared to healthy controls (median 7.4; range: 0-26.1), p < 0.05. Serum VEGF levels were higher in patients with lung cancer and HOA (median 411.4; range 164.2-959.5 pg/ml) compared with lung cancer patients without HOA (median 74.5; range 13.2-205.4), p < 0.001. CONCLUSIONS: Patients with primary HOA and those with HOA and lung cancer have increased circulating levels of VEGF. This cytokine may play a role in the pathogenesis of HOA.