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Background: Structural bone allografts are an established treatment method for long-bone structural defects resulting from such conditions as traumatic injury and sarcoma. The functional lifetime of structural allografts depends on resistance to cyclic loading (cyclic fatigue life), which can lead to fracture at stress levels well below the yield strength. Raman spectroscopy biomarkers can be used to non-destructively assess the 3 primary components of bone (collagen, mineral, and water), and may aid in optimizing allograft selection to decrease fatigue fracture risk. We studied the association of Raman biomarkers with the cyclic fatigue life of human allograft cortical bone., Methods: Twenty-one cortical bone specimens were machined from the femoral diaphyses of 4 human donors (a 63-year old man, a 61-year-old man, a 51-year-old woman, and a 48-year-old woman) obtained from the Musculoskeletal Transplant Foundation. Six Raman biomarkers were analyzed: collagen disorganization, mineral maturation, matrix mineralization, and 3 water compartments. The specimens underwent cyclic fatigue testing under fully reversed conditions (35 and 45 MPa), during which they were tested to fracture or to 30 million cycles ("runout"), simulating 15 years of moderate activity. A tobit censored linear regression model for cyclic fatigue life was created., Results: The multivariate model explained 60% of the variance in the cyclic fatigue life (R = 0.604, p < 0.001). Increases in Raman biomarkers for disordered collagen (coefficient: -2.74×10, p < 0.001) and for loosely collagen-bound water compartments (coefficient: -2.11×10, p < 0.001) were associated with a decreased cyclic fatigue life. Increases in Raman biomarkers for mineral maturation (coefficient: 3.50×10, p < 0.001), matrix mineralization (coefficient: 2.32×10, p < 0.001), tightly collagen-bound water (coefficient: 1.19×10, p < 0.001), and mineral-bound water (coefficient: 3.27×10, p < 0.001) were associated with an increased cyclic fatigue life. Collagen disorder accounted for 44% of the variance in the cyclic fatigue life, mineral maturation accounted for 6%, and all bound water compartments accounted for 3%., Conclusions: Increasing baseline collagen disorder was associated with a decreased cyclic fatigue life and had the strongest correlation with the cyclic fatigue life of human cortical donor bone. This model should be prospectively validated., Clinical Relevance: Raman analysis is a promising tool for the non-destructive evaluation of structural bone allograft quality for load-bearing applications.

Collagenous gastritis is a rare entity, characterized by the deposition of a subepithelial collagenous band with an inflammatory infiltrate in the mucosa. We report the first Tunisian case revealed by severe anemia. Lesions were limited to the stomach and remained unchanged on 3 series biopsies during a 24 month follow up despite treatment with corticosteroids. The cause of the disease remains unknown; our findings suggest that lesions of collagenous gastritis may result from a local immune process.

Background and Purpose: There is concern that patients with collagen vascular disease (CVD) are at higher risk of developing radiation toxicity. We analyzed radiation toxicities in patients with intrathoracic malignancy and CVD treated using modern radiotherapy., Materials and Methods: This single-institution retrospective study included 31 patients with CVD and 825 patients without CVD treated from 1998 to 2014. Radiation esophagitis (RE) and radiation pneumonitis (RP) were scored by RTOG scales. RE was analyzed with logistic regression and RP with Cox regression., Results: CVD patients experienced similar grade ≥3 RE compared to control patients (23% vs. 19%, p = 0.64) but more grade ≥3 RP (26% vs. 10%, p = 0.01). There was no significant association between CVD subtype and toxicities. In multivariate analysis, CVD and lung V20 >30% were associated with grade ≥3 RP. We identified V20 ≤30%, V5 ≤50%, and MLD ≤18 Gy as dose thresholds in patients with CVD. CVD patients with mild severity disease and only 1 organ system involved were at low risk for RP., Conclusions: Patients with CVD may be at higher risk of RP. However, CVD patients may be offered curative thoracic RT with particular attention to risk-reduction strategies and maintaining recommended dose constraints as described in this study., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: Virtual touch tissue quantification (VTTQ) has been developed to evaluate tissue elasticity. Our previous study using delivered placentas showed increased elasticity in fetal growth restriction (FGR). Therefore, we investigated changes in placental elasticity during pregnancy, including complicated pregnancies., Methods: Based on complications, 199 women were divided into 5 groups (normal, FGR, pregnancy induced hypertension (PIH), diabetes mellitus and collagen disease), and shear wave velocity (SWV) of the placenta, measured using VTTQ, was compared. A cross-sectional study was performed with the 143 normal cases to construct the reference range. The association between placental SWV and the expression ratio of collagen fibers in the placenta stained with Masson's trichrome was determined., Results: The SWV was safely measured for all participants. The correlation between SWV and gestational weeks was not significant. The mean ± SD SWVs in the normal, FGR, and PIH groups were 0.98 ± 0.21, 1.28 ± 0.39, and 1.60 ± 0.45 m/sec, respectively. The FGR and PIH groups had significantly higher SWVs than that of the normal group. SWV and the expression ratio of collagen fibers were significantly correlated., Discussion: Based on the present findings, changes in SWV during pregnancy were associated with placental fibrosis, and increased SWV in PIH and/or FGR cases might be influenced by infarction, ischemic changes, and inflammation, as well as fibrosis. In conclusion, the measurement of placental SWV is potentially useful to evaluate the condition of the placenta during pregnancy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The aims of this study were to determine whether arterial hypertension could affect the venous system of brain and to find out the consequent pathologic changes of cerebral veins., Methods: Thirty male Sprague-Dawley rats were divided into 2 groups: a sham-clipped group and a stroke-prone renovascular hypertensive rat group. A 2-kidney 2-clip rat model was used to induce renovascular hypertension in the hypertensive group. Systolic blood pressure was measured by tail cuff once each week. Susceptibility-weighted imaging (SWI) was performed at 12, 16, and 20 weeks after surgery. All the rats were sacrificed after the SWI examination at 20 weeks after surgery. The brains were extracted and embedded in paraffin for histologic examination. Masson trichrome staining was performed to identify venous collagenosis., Results: The sham group demonstrated less prominence of cerebral veins compared with hypertensive groups (P < .01); the hypertensive group showed significant venous collagenosis in cerebral venous walls compared with the sham group (P < .01)., Conclusions: The increased visibility of cerebral veins on SWI as a sign of venous hypertension and the thickened cerebral venous walls (venous collagenosis), which may play a role in cerebral ischemia and/or infarction, are both consequences of long-term hypertension in hypertensive rats., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Purpose: We retrospectively analyzed patients with clinically diagnosed interstitial pneumonia to investigate the factors which contribute to the difference in prognosis from the initiation of long-term oxygen therapy (LTOT) among subtypes., Methods: Seventy-six patients with clinically diagnosed idiopathic interstitial pneumonia (IIP; n = 49) or interstitial pneumonia associated with collagen vascular disease (CVD-IP; n = 27) in whom LTOT was initiated in our facility from January 1999 to December 2012 were analyzed., Results: Patients with CVD-IP had significantly longer survival time from the initiation of LTOT than those with IIP with the median survival of 51.7 months versus 18.8 months, respectively. The 1-year survival rate was 92.4% for patients with CVD-IP versus 76.5% for those with IIP, and 2-year survival was 88.6 versus 36.0%, respectively. The patterns classified with high-resolution computed tomography (HRCT) were not associated with prognosis. The association between pulmonary hypertension and prognosis was unclear. In results of the multivariate Cox analysis which included factors demonstrating p < 0.1 in the univariate Cox analysis, male gender, low body mass index, and the absence of collagen vascular disease (CVD) were significantly associated with poor prognosis., Conclusions: After the initiation of LTOT, patients with IIP had poor prognosis regardless of the patterns classified with HRCT, while those with CVD-IP survived longer. Male gender, low body mass index, and the absence of CVD were the independent negative prognostic factors in patients with interstitial pneumonia receiving LTOT.

Background: Osteoporotic fractures commonly occur after low-energy trauma in postmenopausal women with reduced bone quantity documented by low bone mineral density (BMD). Low-energy fractures, however, have also been reported to occur in premenopausal women with normal or near-normal BMD, suggesting the existence of a bone quality abnormality., Methods: Bone quality and quantity were evaluated in a cross-sectional study of three groups of premenopausal white females: (1) twenty-five subjects with low-energy fracture(s) and BMD in the normal range (t-scores &gt; -2.0), (2) eighteen subjects with low-energy fracture(s) and BMD in the osteoporotic range (t-scores ≤ -2.5), and (3) fourteen healthy volunteers (controls). Bone quality was assessed with use of Fourier transform infrared spectroscopy and histomorphometry in iliac crest bone samples obtained from all subjects; bone quantity was assessed by dual x-ray absorptiometry and histomorphometry., Results: The collagen crosslinking ratio in the non-low-BMD subjects with fractures was 13% greater than the ratio in the low-BMD subjects with fractures and 14% greater than the ratio in the controls (p &lt; 0.001 for both). Cancellous bone volume was 29% greater (p &lt; 0.01) and trabecular separation was 31% less (p &lt; 0.01) in the non-low-BMD subjects with fractures than in the low-BMD subjects with fractures; the values in the non-low-BMD subjects did not differ from those in the controls. Bone turnover did not differ among the groups, and osteomalacia was not present in any subject. Thus, the non-low-BMD subjects with fractures maintained bone quantity, but the collagen crosslinking ratio, a parameter of bone quality, was abnormal. In contrast, the low-BMD subjects with fractures did not have this collagen crosslinking abnormality but did have abnormal bone quantity., Conclusions: This study highlights a collagen crosslinking abnormality in patients with low-energy fractures and nonosteoporotic t-scores. Reports have indicated that altered collagen crosslinking is associated with subnormal fracture resistance. A finding of nonosteoporotic bone mass in a patient with low-energy fractures would justify assessment of bone material quality, which currently requires a bone biopsy. Further studies are needed to search for possible noninvasive tests to diagnose abnormal crosslinking. Since no specific therapies for abnormal collagen crosslinking are currently available, studies are also needed to explore novel therapeutic modalities to reverse the underlying collagen crosslinking abnormality., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Collagen diseases are a large group of systemic inflammatory diseases of autoimmune etiology. The etiopathogenesis of collagen diseases is multifactorial. There is genetic susceptibility, as many connective tissue disorders show family history, and environmental factors may trigger the disease. Collagen diseases can affect almost all the organs of the body. The respiratory system is one of the most frequently affected, although the prevalence of pulmonary disease is not precisely known for the different collagen disorders. Any structure of the respiratory tract can be affected, but perhaps the most frequent is pulmonary parenchymal disease in the form of pneumonitis, which can be produced in any of the idiopathic interstitial pneumonitis patterns. The pleura, pulmonary vessels, airways and respiratory muscles may also be affected. The frequency of lung disease associated with collagen diseases is on the rise. This due in part to the better diagnostic methods that are available to us today (such as high-resolution computed tomography) and also to the appearance of new forms of pneumonitis associated with the new treatments that are currently used. The objective of this article is to offer a global vision of how collagen diseases can affect the lungs according to the latest scientific evidence., (Copyright © 2012 SEPAR. Published by Elsevier España, S.L. All rights reserved.)

Although headaches are common in the general population and have many causes, headaches secondary to inflammatory processes in the blood vessels in the Central Nervous System (CNS) are not so common. The most common types of vasculitis that are associated with headaches include primary CNS vasculitis, systemic necrotizing arteritis, granulomatous vasculitis, and systemic collagen diseases. It is important to differentiate between "true" vasculitides and a condition known and reversible cerebral vasoconstriction syndrome (RCVS). While treatment for many of the vasculitides consists of anti-inflammatory medications, this approach may produce significant complications in RCVS. It is up to the clinician to judiciously use imaging and laboratory data to reach the proper diagnosis and therefore offer the correct treatment to these patients.

Objectives: Pulmonary involvement of varying etiology is common in collagen vascular diseases (CVDs). Bronchoalveolar lavage fluid (BALF) cell differentials reveal information on the immune mechanisms involved in the CVDs. The aim of the present study was to evaluate BALF cell populations in CVD-associated ILD and to investigate possible correlation with pulmonary function., Methods: Fifty-seven patients (26 male and 31 female, mean age ± SD: 54.68±12.18 years) with CVD-associated interstitial lung disease were studied. Patients were divided into 6 groups based on underlying CVD. The study population also included a group of 10 healthy controls. BALF was examined in all individuals. Cell density, total cell number and differential cell count were recorded. BALF lymphocyte subsets were analysed by dual flow cytometry. Pulmonary function was assessed in all patients., Results: BALF differential cell count did not differ significantly among the different groups. Scleroderma patients showed the highest percentage of CD19 cells (p<0.001). The NK and NKT cell percentages were significantly higher in systemic lupus erythematosus and in Sjögren, respectively, compared to other CVDs and controls (p=0.001 and p<0.001). Also BALF neutrophil percentage correlated negatively with FVC (r=-0.356, p=0.011) and FEV1 (r=-0.336, p=0.017) and BALF NKT cell percentage correlated negatively with pO2 (r=-0.415, p=0.003)., Conclusions: Important variations observed in BALF cell populations suggest the implication of NK and NKT cells in the pathogenesis of lung involvement in CVDs.

The recent concept of pulse wave encephalopathy helps understanding the cerebral venous remodeling in aging. This so-called periventricular venous collagenosis is an expected mechanical consequence of the age-related changes in arterial pulsations and the mechanical fatigue of vascular smooth muscles. Unlike arteriolar mechanical stress, venular mechanical stress depends on both the blood pulse wave amplitude and the mechanical properties of the environment tissue. Thereby, there is a preferential periventricular location of venous collagenosis and a mechanistic link between venous collagenosis and foci of white matter rarefaction or leukoaraiosis. The recent concept of pulse wave encephalopathy also helps understanding the widening of retinal venules, the "mirror" of cerebral venules, in various manifestations of pulse wave encephalopathy, including progressive leukoara�osis, lacunar and hemorrhagic "pulse wave" strokes, and dementia. Indeed, the age-related chronic increase in arterial pulsations explains subsequent arteriolar myogenic "fatigue", marked attenuation in the arteriolar myogenic tone and abnormal penetration of the insufficiently dampened arterial pulse wave into the venules. Thus, retinal venular widening, a biomarker of advanced pulse wave encephalopathy, is also increasingly recognized as a biomarker for high cardiovascular risk. All these data support a shift in the concept of chronic cerebrovascular disease, from the classical model which is restricted to steno-occlusive cerebrovascular diseases to an enlarged model which would include the pulse wave encephalopathy concept. Thereby, preventing damage to the cerebral microvasculature by an undampened arterial pulse wave will become a logical target for the prevention and treatment of late-onset cognitive decline.

Background: Bone quantity, quality, and turnover contribute to whole bone strength. Although bone mineral density, or bone quantity, is associated with increased fracture risk, less is known about bone quality. Various conditions, including disorders of mineral homeostasis, disorders in bone remodeling, collagen disorders, and drugs, affect bone quality., Questions/purposes: The objectives of this review are to (1) identify the conditions and diseases that could adversely affect bone quality besides osteoporosis, and (2) evaluate how these conditions influence bone quality., Methods: We searched PubMed using the keywords "causes" combined with "secondary osteoporosis" or "fragility fracture." After identifying 20 disorders/conditions, we subsequently searched each condition to evaluate its effect on bone quality., Results: Many disorders or conditions have an effect on bone metabolism, leading to fragility fractures. These disorders include abnormalities that disrupt mineral homeostasis, lead to an alteration of the mineralization process, and ultimately reduce bone strength. The balance between bone formation and resorption is also essential to prevent microdamage accumulation and maintain proper material and structural integrity of the bone. As a result, diseases that alter the bone turnover process lead to a reduction of bone strength. Because Type I collagen is the most abundant protein found in bone, defects in Type I collagen can result in alterations of material property, ultimately leading to fragility fractures. Additionally, some medications can adversely affect bone., Conclusions: Recognizing these conditions and diseases and understanding their etiology and pathogenesis is crucial for patient care and maintaining overall bone health.

Multisystem autoimmune diseases occurring after allogeneic hematopoietic stem cell transplantation are infrequent, late-onset manifestations that resemble well-defined collagen vascular disorders. Because the lung is frequently involved in the course of connective tissue disorders, we focused on lung manifestations occurring in autoimmune diseases following allogeneic stem cell transplantation. In the present series, we report 6 patients with systemic lupus erythematous, mixed connective tissue disease, Sjögren syndrome, polymyositis, and ANCA-positive vasculitis who presented with a spectrum of pulmonary manifestations affecting the airways, lung parenchyma, and probably respiratory muscles. We identified 3 different histopathologic patterns of interstitial pneumonia consistent with the underlying autoimmune disorder: lymphocytic interstitial pneumonia and non-specific interstitial pneumonia in 2 patients with Sjögren syndrome and diffuse alveolar damage in 1 patient with ANCA-positive vasculitis. These lung manifestations had poor prognoses. Further studies are needed to determine the optimal therapy for these complications.

Summary: While the majority of this session will deal with selected inherited vascular abnormalities that may manifest as a haemorrhagic disorder, the initial discussion by Dr Key will focus on the interplay between the vessel wall and components of the coagulation system, with a focus on haemophilia A and B. Although it is generally accepted that physiological haemostasis is triggered by contact of blood with tissue factor (TF), there remains some controversy regarding the cellular origin of TF in vivo. In addition, the initiation and propagation of thrombin generation are highly dependent on the balance of pro- and anticoagulant functions of endothelium, a profile that varies significantly throughout the vasculature. Drs De Paepe and Malfait address heritable collagen disorders such as the Ehlers-Danlos syndromes (EDS), a heterogeneous group of diseases involving the skin, ligaments and joints, blood vessels and internal organs. Most EDS subtypes are caused by mutations in genes encoding fibrillar collagens, or in genes coding for enzymes involved in posttranslational modifications of collagens. Accurate biochemical and molecular testing is now available for most EDS subtypes and can direct genetic counselling and medical management for these disorders. Dr Shovlin reviews recent developments in hereditary haemorrhagic telengiectasia (HHT), a frequently undiagnosed disorder characterized by arteriovenous malformations in multiple organs. These abnormal blood vessels are the result of mutations in one of a number of genes whose protein products influence TGF-beta signalling in vascular endothelial cells. Several HHT management guidelines have been published and are discussed.

Objective: We speculated that distinct angiogenic profiles are involved in idiopathic interstitial pneumonias (IIPs) in comparison with interstitial pneumonias associated with collagen vascular disease (CVD-IPs). This hypothesis was investigated by measuring the expression of a cardinal biologic axis, the vascular endothelial growth factor (VEGF)-stromal derived growth factor [SDF-1alpha, transcripts 1 and 2 (TR1 and TR2)] and receptor, CXCR4 and the angiogenetic receptors CXCR2 and CXCR3 in bronchoalveolar lavage fluid (BALF) in both conditions., Methods: We studied prospectively 25 patients with fibrotic IIPs (f-IIPs) [20 with idiopathic pulmonary fibrosis (IPF) and 5 with idiopathic non-specific interstitial pneumonia (NSIP)] and 16 patients with CVD-IPs. mRNA expression was measured by Real-Time RT-PCR and protein was evaluated by Western Blotting., Results: A significantly greater value has been detected in SDF-1alpha-TR1 mRNA expression levels of CVD-IPs (p=0.05) in comparison with IPF group. A similar trend has been also detected in protein expression in favor of CVD-IP group. In addition, VEGF mRNA levels have been found significantly increased in CVD-IPs in comparison with the NSIP group (p=0.05). No significant difference has been found in SDF-1alpha-TR2-CXCR4 mRNA and CXCR2-CXCR3 between the two groups., Conclusion: These results showed increased expression of SDF-1alpha in CVD-IPs, suggesting different angiogenic procedures. Further studies are needed in order to better explore the angiogenetic pathway in these disorders., (Copyright 2009 Elsevier Ltd. All rights reserved.)

In this paper the mechanical response of soft collagenous tissues with regular fiber arrangement (RSCTs) is described by means of a nanoscale model and a two-step micro-macro homogenization technique. The non-linear collagen constitutive behavior is modeled at the nanoscale by a novel approach accounting for entropic mechanisms as well as stretching effects occurring in collagen molecules. Crimped fibers are reduced to equivalent straight ones at the microscale and the constitutive response of RSCTs at the macroscale is formulated by homogenizing a fiber reinforced material. This approach has been applied to different RSCTs (tendon, periodontal ligament and aortic media), resulting effective and accurate as proved by the excellent agreement with available experimental data. The model is based on few parameters, directly related to histological and morphological evidences and whose sensitivity has been widely investigated. Applications to simulation of some physiopathological mechanisms are also proposed, providing confirmation of clinical evidences and quantitative indications helpful for clinical practice., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Collagen-vascular diseases could be defined as 'chronic', 'inflammatory', 'multiorgan diseases' 'with immunological derangement'. It is important to know that these diseases frequently involve locomotorium, skin, and vessels, of which symptoms or signs are easily sensed by patient herself or observed by herself or a doctor from her body surface. Even among routine laboratory findings, cytopenia, lymphocytopenia, inflammatory reactant level increase, serum total protein level increase could be indicative of these diseases. When considering a substantial number of patients with these diseases or with their subclinical status, routine medical check for rheumatoid factor or anti-nuclear antibody would be better recommended. In case that differential diagnosis is difficult or a strong intervention may be necessary, visiting a rheumatologist at least once would be a choice for early diagnosis or to avoid iatrogenic adverse events induced by irrelevant steroid, disease-modifying anti-rheumatic drug or immunosuppressant. Socio-economically, the early diagnosis and early treatment for these diseases would be very effective showing a good cost-performance.

Systemic autoimmune diseases, such as vasculitis and collagen diseases, are characterized by chronic inflammation. Mutual interrelationship between angiogenesis and chronic inflammation has already been demonstrated. The aim of the study was to examine the effect of sera from patients with systemic autoimmune diseases on angiogenesis induced by human mononuclear cells. The study population consisted of 43 patients with a systemic autoimmune disease associated with pulmonary manifestations, divided into three groups: 14 with Wegener's granulomatosis (WG), 13 with systemic sclerosis (SS), and 16 with collagen vascular diseases (CVD) such as rheumatoid arthritis, systemic lupus erythematosus, and dermatomyositis. The control group consisted of 15 healthy volunteers. Clinical status was evaluated using a questionnaire. Standard chest radiographs were performed in all patients. Pulmonary function tests were performed according to the ERS standards. An animal model of a leukocyte-induced angiogenesis assay was used as an angiogenic test. Sera from WG and CVD patients significantly stimulated angiogenesis compared with healthy subjects (P<0.001). On the other hand, sera from healthy donors exerted a proangiogenic effect compared with PBS. In contrast, sera from SS patients significantly (P<0.001) inhibited angiogenesis compared with sera from healthy subjects and PBS. Proangiogenic effect of sera from systemic diseases patients depended on radiological changes. No significant correlation between a degree of dyspnea or functional pulmonary tests and the number of new vessels or angiogenesis index was found. Sera from patients with systemic autoimmune diseases and healthy people constitute the source of mediators modulating angiogenesis. These modulatory effects differ depending on the disease entity.

Objective: The collagen VI muscular dystrophies, Bethlem myopathy and Ullrich congenital muscular dystrophy, form a continuum of clinical phenotypes. Glycine mutations in the triple helix have been identified in both Bethlem and Ullrich congenital muscular dystrophy, but it is not known why they cause these different phenotypes., Methods: We studied eight new patients who presented with a spectrum of clinical severity, screened the three collagen VI messenger RNA for mutations, and examined collagen VI biosynthesis and the assembly pathway., Results: All eight patients had heterozygous glycine mutations toward the N-terminal end of the triple helix. The mutations produced two assembly phenotypes. In the first patient group, collagen VI dimers accumulated in the cell but not the medium, microfibril formation in the medium was moderately reduced, and the amount of collagen VI in the extracellular matrix was not significantly altered. The second group had more severe assembly defects: some secreted collagen VI tetramers were not disulfide bonded, microfibril formation in the medium was severely compromised, and collagen VI in the extracellular matrix was reduced., Interpretation: These data indicate that collagen VI glycine mutations impair the assembly pathway in different ways and disease severity correlates with the assembly abnormality. In mildly affected patients, normal amounts of collagen VI were deposited in the fibroblast matrix, whereas in patients with moderate-to-severe disability, assembly defects led to a reduced collagen VI fibroblast matrix. This study thus provides an explanation for how different glycine mutations produce a spectrum of clinical severity.

Systemic sclerosis is a complex multi-systemic disease with a mostly unresolved pathogenesis. Following an inflammatory reaction, overproduction of collagen and other extra-cellular matrix components leads to a characteristic fibrosis. It remains unclear why this overproduction by fibroblasts and myofibroblasts occurs. Micro-vascular disturbances and endothelial cells, as well as immunomodulation and inflammation are central factors. Besides intrinsic influences, such as genetic polymorphisms, multiple mediators with fibrotic effects such as Platelet Derived Growth Factor, Transforming Growth Factor-beta and Connective Tissue Growth Factor have been characterized. These have become targets for innovative therapeutic strategies that might lead to specific treatments for systemic sclerosis.

Background: Prostanoids are used in the treatment of Raynaud's phenomenon and acral perfusion disorders secondary to collagenosis. In subjective terms, intravenous administration of these agents produces success in more than 50% of patients. The therapeutic outcome of clinical administration of alprostadil or iloprost may vary from individual to individual., Patients and Methods: The following variables were analysed in a cross-over study in 27 patients with collagenosis and Raynaud's phenomenon: plasma viscosity and erythrocyte aggregation (rheological variables), partial pressure of oxygen and laser Doppler flowmetry in the finger region, and lymphocyte phenotyping and interleukin (IL) determinations (immunological variables)., Results: Laser Doppler flowmetry revealed significant differences between patients with secondary Raynaud's phenomenon and a control group of 25 healthy subjects. Laser Doppler readings did not change significantly as a result of the treatments. Therapy with iloprost produced a reduction in IL-1beta, L-selectin (CD 62 L) and IL-6., Conclusion: The change in immunological variables due to iloprost may explain the long-term effects of prostaglandins in the treatment of Raynaud's phenomenon. From our results it is not possible to infer any preference for iloprost or alprostadil.

Background: Hydrodistension is the first choice of treatment for interstitial cystitis because it allows for diagnosis, bladder biopsy and treatment. However, the method and efficacy of hydrodistension are variable. We performed adjuvant hydrodistension and examined the efficacy and factors that influence prognosis., Methods: Fifty-two patients participated in the present study as subjects; they satisfied the diagnostic inclusion and exclusion criteria established by the National Institute of Diabetes, Digestive and Kidney Disease (NIDDK) in 1987, USA. Under epidural anesthesia, the bladder was repeatedly distended up to the maximal bladder capacity for treatment, diagnosis and biopsy. Hydrodistension was performed again on the following day for approximately 30 min under epidural anesthesia in a ward until macroscopic hematuria disappeared., Results: Five patients were classified into the good, 30 into the moderate and 17 into the poor response group. In the good response group, three patients had type I allergy and one patient did not fulfil all of the positive factors in the NIDDK criteria. The poor response group included one patient with collagen disease. The poor response group was further divided into two subgroups based on bladder capacity. One subgroup included eight patients with a bladder capacity of less than 100 mL and vesicoureteral reflux (VUR). The other subgroup included nine patients with a bladder capacity of more than 100 mL. Among these nine patients there were five patients who lacked one or two positive factors in the NIDDK criteria., Conclusion: Adjuvant hydrodistension under epidural anesthesia is effective for about 70% of patients for more than 3 months. It can be performed in a ward without any serious complications. It was observed that patients lacking one or two positive factors were included in the good and poor response groups.

The diagnosis of patients with fever of unknown origin (FUO) is often problematic because the range of possible differential diagnoses is broad. We report on a case in which a patient presented with FUO and was subsequently found to have both a collagen vascular disease and an intercurrent infection. Treatment for the collagen vascular disease with corticosteroids exacerbated the intercurrent infection. The problems in the diagnosis and management of such cases are discussed.

A hypothesis on the existence of link between the changes in connective tissue in patients with genital descensus and impairments of their pulmonary function was made. In the sample of 40 patients, admitted to hospital for surgical correction of their genital descensus, their pulmonary ventilatory function was examined and compared with 40 matched female examinees without genital descensus. All the examinees were in premenopausis, nonsmokers and without history or clinical signs of the diseases that could affect their pulmonary function. Patients exhibited highly significant decrements in all expiratory flows, especially in the peak expiratory flow (-26%) and other flows at large lung volumes. The forced vital capacity and forced expired volume at 1 second were also decreased (-9% and -16%, respectively). The findings were typical for reduced strength of the expiratory muscles, suggesting the possible link between the lack of collagen and the impairments of pulmonary function in women with genital descensus.

The authors discuss cutaneous manifestations of some systemic diseases (collagenoses) and their connection with diseases of liver cells.

Purpose: Some patients with nonmalignant systemic diseases, like collagen vascular disease (CVD), hypertension, diabetes mellitus, and inflammatory bowel disease (IBD), tolerate radiation therapy poorly. Although the mechanisms of each of these disease processes are different, they share a common microvessel pathology that is potentially exacerbated by radiotherapy. This article reviews and evaluates available data examining the effects of these benign disease processes on radiation tolerance., Methods: We conducted a thorough review of the Anglo-American medical literature from 1960 to 2001 on the effects of radiotherapy on CVD, hypertension, diabetes mellitus, and IBD., Results: Fifteen studies were identified that examined the effects of radiation therapy for cancer in patients with CVDs. Thirteen of 15 studies documented greater occurrences of acute and late toxicities (range 7%-100%). Higher rates of complications were noted especially for nonrheumatoid arthritis CVDs. Nine studies evaluated the effects of hypertension and diabetes on radiation tolerance. All nine studies documented higher rates of late toxicities than in a "control" group (range 34%-100%). When patients had both diabetes and hypertension, the risk of late toxicities was even higher. Six studies examined radiation tolerance of patients with IBD irradiated to the abdomen and pelvis. Five of these six studies showed greater occurrences of acute and late toxicities for patients with IBD, even with precautionary measures like reduced fraction size and volume and patient immobilization (13%-29%)., Conclusion: The majority of published studies documented lower radiation tolerance for patients who have CVD, diabetes mellitus, hypertension, and IBD. This may reflect a publication bias, as the majority of these studies are retrospective with small numbers of patients and use different scoring scales for complications. These factors may contribute to an overestimation of true radiation-induced morbidity. Although the paucity of data makes precise estimates difficult, a subset of patients, in particular, those with active CVD, IBD, or a combination of uncontrolled hypertension with type I diabetes, is likely to be at higher risk. Future prospective trials need to document these disease entities when reporting treatment-related complications and also must monitor toxicities associated with quiescent versus active IBD and CVD, type I versus type II diabetes, and levels of hypertension (controlled versus uncontrolled) matched for radiation-specific treatment sites, field size, fractionation, and total dose.

The collagen superfamily of proteins plays a dominant role in maintaining the integrity of various tissues and also has a number of other important functions. The superfamily now includes more than 20 collagen types with altogether at least 38 distinct polypeptide chains, and more than 15 additional proteins that have collagen-like domains. Most collagens form polymeric assemblies, such as fibrils, networks and filaments, and the superfamily can be divided into several families based on these assemblies and other features. All collagens also contain noncollagenous domains, and many of these have important functions that are distinct from those of the collagen domains. Major interest has been focused on endostatin, a fragment released from type XVIII collagen, which potently inhibits angiogenesis and tumour growth. Collagen synthesis requires eight specific post-translational enzymes, some of which are attractive targets for the development of drugs to inhibit collagen accumulation in fibrotic diseases. The critical roles of collagens have been clearly illustrated by the wide spectrum of diseases caused by the more than 1,000 mutations that have thus far been identified in 22 genes for 12 out of the more than 20 collagen types. These diseases include osteogenesis imperfecta, many chondrodysplasias, several subtypes of the Ehlers-Danlos syndrome, Alport syndrome, Bethlem myopathy, certain subtypes of epidermolysis bullosa, Knobloch syndrome and also some cases of osteoporosis, arterial aneurysms, osteoarthrosis, and intervertebral disc disease. The characterization of mutations in additional collagen genes will probably add further diseases to this list. Mice with genetically engineered collagen mutations have proved valuable for defining the functions of various collagens and for studying many aspects of the related diseases.

Unlabelled: The purpose of this study was to detect disturbances in pulmonary circulation in collagen disease patients by means of a non-invasive technique., Methods: Ventilation/perfusion scans with 133Xe gas and 99mTc-macroaggregated albumin (MAA) were performed in 109 patients with various collagen diseases. Functional images of V, Vol, Q and V/Q ratio were obtained at total lung capacity. Wash-out time was calculated from the wash-out curve. Whole body scans were performed in 65 patients to evaluate intra-pulmonary shunts., Results: Increased V/Q areas were observed in 74 patients (67.9%), suggesting some impairment of pulmonary perfusion. Decreased perfusion, probably due to vasculitis or intravascular microcoagulation, was observed often, even in patients without pulmonary fibrosis. Shunt ratios over 10% were observed in 8 of the 65 patients (12.3%), indicating formation of PA-PV shunts secondary to peripheral vascular impairment. Wash-out time was prolonged in 37 patients (33.9%), shortened in 18 (16.5%), and within the normal range in 54 (49.6%). The prolonged and normal wash-out times in the patients with pulmonary fibrosis may represent obstructive changes in the small airways superimposed on the fibrosis., Conclusion: Ventilation/perfusion scans are a very useful tool for evaluating collagen lung diseases, and they might contribute to treatment decisions for the patients.

Background: It has been reported that carbohydrate antigen sialyl Lewis (a) (CA19-9) levels are elevated in serum as well as in bronchoalveolar lavage fluid (BALF) of patients with pulmonary fibrosis. However, the biological significance of CA19-9 is unclear., Objective: The purpose of the present study was to evaluate correlations between CA19-9 levels in BALF and several biochemical as well as clinical parameters in patients with pulmonary fibrosis. In addition, biological functions of CA19-9 were also examined., Methods: We studied 24 patients with a diagnosis of pulmonary fibrosis: 16 with idiopathic pulmonary fibrosis (IPF) and 8 with pulmonary fibrosis associated with a collagen vascular disorder (PF-CVD). In BALF, carbohydrate antigens sialyl Lewis (a) (CA19-9), elastase: alpha(1)-proteinase inhibitor complex (E-PI), hepatocyte growth factor (HGF), LDH, IgG, IgA, albumin, and cell differentiation were measured. We also evaluated the effects of CA19-9 on neutrophil functions., Results: CA19-9/albumin levels in BALF significantly correlated with HGF/albumin, elastase/albumin, LDH/albumin, total number of alveolar macrophages, and total number of neutrophils. Purified CA19-9 had a chemotactic activity for neutrophils. In addition, neutrophil chemotactic activity to C5a, fMLP, and interleukin 8 was significantly stimulated after incubation with purified CA19-9. Furthermore, CA19-9 increased the expression of CD15s on neutrophils., Conclusions: Our data demonstrated (i) CA19-9 in BALF correlated with other markers of inflammation in pulmonary fibrosis, and (ii) CA19-9 can modify neutrophil functions. These results suggest that CA19-9 may play a role in the process of lung injury in patients with pulmonary fibrosis., (Copyright 2000 S. Karger AG, Basel.)

Laser Doppler fluxmetry (LDF) is frequently used in research on microcirculation of blood. Usually LDF time series are analysed by conventional linear methods, mainly Fourier analysis. These methods may not be optimal for the investigation of nonlinear effects of vasomotion, heartbeat or vessels. Nonlinear methods are based on a reconstruction of the system trajectory in an embedding space describing not only the measured time series but the behaviour of the whole system. The fill factor is a tool for displaying the main properties of this attractor in two dimensions and for determining diverse parameters for further analysis. A quantitative characterization of the system is possible by the distribution of correlation dimensions in the embedding space. The singular value decomposition (SVD) can be used to display and characterize individual degrees of freedom. These methods were applied to LDF time series from nine healthy controls and nine patients with Raynaud's phenomenon due to connective tissue disease. The fill factor and the SVD indicate qualitatively that in the controls vasomotion and heartbeat are the main influences on blood flow and act fairly independently of each other. In the patients there was a mixture of strong but irregular degrees of freedom. The mean and the maximal local correlation dimensions were significantly higher in the patient group. Nonlinear analysis of LDF time series provides additional information which cannot be detected using conventional approaches.

The aim of this study was to evaluate pulmonary hemodynamic and gas exchange response to oxygen inhalation in patients with severe pulmonary hypertension primarily affecting the pulmonary vasculature. This study included 7 patients with primary pulmonary hypertension (PPH), 11 with pulmonary hypertension related to collagen vascular diseases (CoPH), and 18 with chronic thromboembolic pulmonary hypertension (CTEPH). All patients had mean pulmonary arterial pressure (PPAm) of greater than 25 mm Hg. We divided the patients into two groups: a PPH + CoPH group comprising the 7 PPH and 11 CoPH patients, and the CTEPH group. We measured cardiopulmonary variables after 10 min inhalation of various oxygen concentrations (FiO2 0.24, 0.28, 0.4, 1.0). In the PPH + CoPH group, PPAm significantly decreased after the inhalation of oxygen concentrations of 40% or more. This was associated with a significant reduction in pulmonary arteriolar resistance (PAR), and suggested active pulmonary vasodilation was caused by oxygen inhalation. In the CTEPH group, on the other hand, PPAm significantly decreased after the inhalation of oxygen concentrations of 28% or more, apparently in association with a significant fall of cardiac output. However, PAR was unchanged regardless of the inspired oxygen concentration, indicating an absence of pulmonary vasodilation in the CTEPH group. When breathing room air, 7 patients in the PPH + CoPH group (38.9%) and 10 in the CTEPH group (55.6%) demonstrated mixed venous oxygen tension (PvO2) values of less than 35 Torr. Extra attention should be paid to PvO2 when administering oxygen therapy to patients with severe pulmonary hypertension.

Membranous nephropathy, mesangial proliferative glomerulonephritis and renal amyloidosis are common renal pathology in RA patients. However, IgA nephropathy and diffuse thinning of glomerular basement membrane are described as common and characteristic renal lesions in Japanese RA patients. Glomerular filtration rate may decrease significantly in active lupus nephritis, but renal plasma flow does not change or even increase. These findings seem to be characteristic of SLE patients with active renal disorders. Therefore, filtration fraction may be a useful clinical parameter to evaluate SLE patients. Scleroderma renal crisis(SRC) has been believed to be the most serious renal disorder in systemic sclerosis (SSc). Recently, the presence of an antibody to RNA polymerase has been associated with a high prevalence of SRC.

Collagen vascular diseases are multisystem disorders that frequently affect the skin. At times, cutaneous disease is the initial manifestation. This article focuses on lupus erythematosus, dermatomyositis, and sclerodermoid syndromes.

We studied in vitro spontaneous and ultraviolet light (UV)-induced lymphocyte apoptosis in patients with systemic lupus erythematosus (SLE, n = 11), cutaneous lupus erythematosus (CLE, n = 8), and other collagen diseases (n = 6), as well as normal individuals (n = 6). Apoptosis was confirmed by the presence of a 180 bp DNA ladder on gel electrophoresis. UVB-induced apoptosis was observed in 4 of 11 patients with SLE (36.3%), 3 of 8 patients with CLE (37.5%) and 2 of 6 patients (33.3%) with other collagen diseases. There was no clinical correlation between clinical photosensitivity and UV-induced apoptosis. Similarly, spontaneous apoptosis was also found in lymphocytes from patients with diseases other than SLE. No apoptosis was found in normal subjects with or without UVB irradiation (25 mJ/cm2). These data suggest that UV-induced lymphocyte apoptosis may not be specific to SLE but may be common in collagen diseases.

Collagens can be divided into two groups, i.e., fibrillar and non-fibrillar collagens. Short-chain collagens, a subgroup of non-fibrillar collagens, comprises collagen type VIII and type X. These two collagen types show several similarities in structure and possibly also in function. Type VIII collagen appears to be secreted by rapidly proliferating cells. It can be found in basement membranes and may serve as a molecular bridge between different types of matrix molecules. In different tissues this collagen type may serve different functions. Stabilization of membranes, angiogenesis, and interactions with other extracellular matrix molecules. Since collagen type X is produced by hypertrophic chondrocytes, this collagen type can only be found in matrix of the hypertrophic zone of the epiphyseal growth plate cartilage. Collagen type X is probably involved in the process of mineralization, endochondral ossification, and is also proposed to play a role in angiogenesis. Collagen types VII and X may be involved in matrix and bone disorders. Their structure, function, and involvement in pathology are discussed in this review.

To evaluate the function of HTLV-I env-pX gene in vivo, we developed two lines of transgenic rats (env-pX rats) that expressed env-pX gene products, under control of own LTR promotor. In various tissues of the rats, env and pX mRNAs were constitutively expressed, irrespective of age. At age 5 weeks, swelling of the bilateral ankle joints histologically showing synovial lining hyperplasia, severe chronic inflammation, erosion of the joint cartilage, and bone destruction with pannus formation began to develop in these env-pX rats. These histologic features resemble those of rheumatoid arthritis (RA) in man. High titered rheumatoid factors and low anti-dsDNA antibodies and hyper-gamma globulinemia were detected. Necrotizing arteritis resembling polyarteritis nodosa, polymyositis, myocarditis and Sjögren syndrome-like sialoadenitis developed, together with RA-like arthritis even in one individual animal. Thymic atrophy with low body weight was also observed. The evidence indicates that env-pX rats appear to be suitable animal models for elucidating pathogenetic mechanisms involved in not only HTLV-I related diseases but also various collegen vascular and autoimmune diseases of unknown etiology in man.

The neurologic manifestations of the skeletal dysplasias are reviewed. Three important major groups are identified: Achondroplasia (cranio-cervical junction problems in infancy, spinal stenosis and neurogenic claudication in the adult). Type II collagenopathies (upper cervical spine anatomic and functional problems), and craniotubular and sclerosing bone dysplasias (osseous overgrowth with foraminal obstruction problems). The remainder of the well-identified 150 or so bone dysplasias are also evaluated in depth for their diverse neurologic abnormalities. The findings discussed are important both for the diagnosis and management of these patients.

Unlabelled: We studied 60 patients with collagen-vascular diseases with pulmonary manifestations (SLE-25; SSc-13; mixed connective tissue disease-12; RA-6; PD-DM-3; ankylosing spondylitis-1), 54 females and 6 males, mean age 42.4 +/- 9.9 years. We measured lung volumes (total lung capacity-TLC) by spirography (Flowscreen Jaeger) and body plethysmography (Bodyplethismograph Jaeger); compliance of the lungs (CL) and elastic recoil pressures at 100%, 80% and 70% TLC (PL,el 100%, 80%, 70% TLC) by the esophageal catheter method; diffusing capacity of the lungs by the single-breath method (DL,COSB) (Alveo-Diffusionstest Jaeger). DL,CO was diminished in 45 (75%) of cases. 11 patients (18.3%) had an increased elastic recoil, equally distributed between mild and severe decrease of DL,CO. Statistical significant correlations were found between TLC-DL,CO (r = 0.63; p < 0.001) and TL-CL (r = 0.49; p < 0.001). No correlations were found between DL,CO and PL,el 100, 80, 70% TLC. The results are expressed as percent of predicted value (% pred.). The mean values and standard deviation (X +/- sd) were calculated., Conclusions: I) DL,CO is the most frequent altered pulmonary function test in collagen-vascular diseases with pulmonary manifestations; it seems to be a sensible parameter for diagnosing these diseases. 2) The alteration of DL,CO,CL and PL,el appears to be rather as a result of "shrinking lungs" due to respiratory muscle involvement than to an interstitial lung disease. 3) Elastic recoil pressures and compliance should be considered as routine pulmonary function test, important for the evaluation of treatment and prognosis.