Increase In Ground Substance Research Articles

Mechanisms, Efficacy, and Clinical Applications of Platelet-Rich Plasma in Tendinopathy: A Comprehensive Review.

Tendinopathy poses a significant clinical challenge characterized by chronic tendon pain, swelling, and impaired function, affecting athletes and the general population. Current treatments often provide limited success, necessitating exploration into regenerative therapies such as platelet-rich plasma (PRP). PRP harnesses the regenerative potential of autologous platelets and growth factors to promote tendon healing. This review aims to comprehensively examine the mechanisms, efficacy, and clinical applications of PRPin tendinopathy. We discuss the pathophysiology of tendinopathy, highlighting collagen disorganization, increased ground substance, and inflammatory changes. PRP's action mechanism involves releasing bioactive molecules that stimulate cellular proliferation, collagen synthesis, and tissue remodeling. Clinical studies and trials evaluating PRP in various tendinopathies, including Achilles, patellar, and rotator cuff tendinopathy, are reviewed to assess its efficacy and effectiveness compared to traditional therapies. Practical aspects, such as preparation methods, injection techniques, and safety considerations, are discussed to provide insights into optimal PRP administration. Challenges, including protocol variability and evidence gaps, are addressed, and future research and clinical practice directions are proposed. By synthesizing current knowledge, this review aims to guide clinicians in enhancing treatment strategies and advancing the field of tendon regenerative medicine.

Cholesterol Diet Withdrawal Leads to an Initial Plaque Instability and Subsequent Regression of Accelerated Iliac Artery Atherosclerosis in Rabbits

Effect of long term cholesterol diet withdrawal on accelerated atherosclerosis in iliac artery of New Zealand White (NZW) rabbits has not been explored so far. Atherosclerosis was thus induced in rabbits by a combination of balloon injury and atherogenic diet (AD) (1% cholesterol and 6% peanut oil) feeding for 8 weeks (baseline) followed by chow diet (CD) feeding for 4, 8, 16, 32, 50 and 64 weeks. The plaque characterization was done using histology, real time RT-PCR and vasoreactivity studies. Significant elevation in plasma lipids with AD feeding was normalized following 16 weeks of CD feeding. However, baseline comparison showed advanced plaque features even after 8 weeks of CD period with significant elevation in intima/media thickness ratio and plaque area later showing reduction at 50 and 64 weeks CD periods. Lesion lipid accumulation and CD68 positivity was maintained till 16 weeks of CD feeding which significantly reduced from 32 to 64 weeks CD periods. Baseline comparison showed significant increase in ground substance, MMP-9 and significant decrease in α-actin and collagen content at 8 weeks CD period indicating features of unstable plaque. These features regressed up to 64 weeks of CD. Partial restoration of functional vasoconstriction and vasorelaxation was seen after 64 weeks of CD feeding. mRNA expression of MCP-1, VCAM-1, collagen type I and III, MMP-9, TIMP-1, IFN-γ, TNF-α, IL-10 and eNOS supported the above findings. The study thus reveals insights into initial plaque instability and subsequent regression on AD withdrawal in this model. These results are suggestive of an appropriate window for drug intervention for plaque stability/regression and restenosis as well as improves understanding of plaque regression phenomenon in this model.

UNDERSTANDING TENDON PAIN MECHANISMS THROUGH A SYSTEMATIC REVIEW OF WIDESPREAD MANIFESTATIONS OF UNILATERAL TENDINOPATHY

IntroductionTendinopathy is a clinical condition within or around the tendon that is thought to arise from high volume repetitive overuse, causing microtrauma.1 The local changes at the tissue have been...

Obstruction-Induced Pulmonary Vascular Remodeling

Pulmonary obstruction occurs in many common forms of congenital heart disease. In this study, pulmonary artery (PA) banding is used as a model for pulmonary stenosis. Significant remodeling of the vascular bed occurs as a result of a prolonged narrowing of the PAs, and here we quantify the biophysical and molecular changes proximal and distal to the obstruction. Main and branch PAs are harvested from banded and sham rabbits and their mechanical properties are assessed using a biaxial tensile tester. Measurements defined as initial and stiff slopes are taken, assuming a linear region at the start and end of the J-shaped stress-strain curves, along with a transitional knee point. Collagen, elastin assays, Movat's pentachrome staining, and Doppler protocols are used to quantify biochemical, structural, and physiological differences. The banded main PAs have significantly greater initial slopes while banded branch PAs have lower initial slopes; however, this change in mechanical behavior cannot be explained by the assay results as the elastin content in both main and branch PAs is not significantly different. The stiff slopes of the banded main PAs are higher, which is attributed to the significantly greater amounts of insoluble collagen. Shifting of the knee points reveals a decreased toe region in the main PAs but an opposite trend in the branch PAs. The histology results show a loss of integrity of the media, increase in ground substance, and dispersion of collagen in the banded tissue samples. This indicates other structural changes could have led to the mechanical differences in banded and normal tissue.

Central Pulmonary Artery Histopathology in Patients With Cyanotic Congenital Heart Diseases

This study evaluated the pulmonary arterial (PA) wall histopathology and the risk factors related to histopathology and inadequate pulmonary artery growth in patients with cyanotic congenital heart diseases (CHDs) undergoing primary or second-stage operations after different types of systemic-to-PA shunts with or without pulmonary arterioplasty. Operatively excised full-thickness PA tissue from 150 consecutive patients (mean age, 90.8 +/- 62.8 months; range, 6 months to 47 years) undergoing primary or second-stage procedures for different cyanotic CHDs were studied by light microscopy. The controls were 43 patients (23.8%) with normally developed central PAs and normal wall histology. The incidence of elastic fragmentation, increased ground substance, smooth muscle disarray, intimal thickening, and fibrosis was 61.3%, 36.6%, 34.6%, 39.3%, and 42% respectively. The risk of inadequate PA growth was 174.8, 64.7, and 45.5 times higher in patients with muscle disarray of the PA, abnormal lamellar count, and absence of palliative shunting procedures. Almost all PA walls in shunted patients undergoing primary/second-stage procedures for cyanotic CHD indicate significant lamellar loss and intrinsic pulmonary arteriopathy. These changes are present in infancy, are more pronounced in patients with deep cyanosis, and may account for or may coexist with a higher incidence of PA hypoplasia and inadequate PA growth encountered in these patients.

Histopathologic changes in ascending aorta and risk factors related to histopathologic conditions and aortic dilatation in patients with tetralogy of Fallot

The purposes of this study were to evaluate the histologic characteristics of the aortic wall and the risk factors related to histopathology and aortic dilatation in patients undergoing intracardiac repair of tetralogy of Fallot. Operatively excised full-thickness aortic wall tissue from 98 consecutive patients undergoing intracardiac repair of tetralogy of Fallot aged 6 months to 47 years (mean 104.5 +/- 102.8 months; median 72 months) were studied by light microscopy. The receiver operating characteristic curve analysis was done to quantify the diagnostic accuracy of loss of lamellar counts and multiple logistic regression models. Twenty-five (25.5%) aortic tissue specimens were indicated as histologically normal and were used as normal controls. The incidence of elastic fragmentation, increased ground substance, medionecrosis, smooth muscle disarray, and fibrosis was 74.5%, 54%, 39.8%, 26.5%, and 57.1%, respectively. A lamellar count of less than 60 was associated with a sensitivity of 80% and a specificity of 87.67%. Area under the receiver operating characteristic curve indicated that 93.37% (standard error +/- 0.039) of the time the value of lamellar count was lower for the abnormal histopathology group than for the normal group (P < .001). The risk of aortic dilatation was 15.97 times higher in patients with histopathologically abnormal aorta. The majority of aortic media of the ascending aorta in cyanotic tetralogy of Fallot indicates significant loss of lamellar units and pre-existing intrinsic aortopathy. The changes are present since infancy and are more pronounced in older patients subjected to long-standing cyanosis and volume overload and may account for or may coexist with the higher incidence of aortic dilatation encountered in these patients.

OP17. PATHOLOGIC FEATURES OF TAKAYASU'S ARTERITIS (NON SPECIFIC AORTOARTERITIS)

Takayasu's arteritis or Non-specific aortoarteritis (NSAA) is an uncommon form of large vessel vasculitis and has been known by various names. The morbid anatomical features of NSAA described here are based on the autopsy findings of 80 cases seen in a 30-year period. These autopsies were carried out at Seth GS Medical College & KEM hospital, Mumbai. With an active autopsy service, the incidence of NSAA is about 0.15%. 46.25% of these cases were in the pediatric age group. In the aorta the disease had 2 patterns of involvement: (a) Segmental lesions either single or multiple, with skip areas in between. (b) Diffuse extensive disease. Marked periadventitial and adventitial fibrous thickening with adhesions to neighboring structures with enlarged lymph nodes is often noted around the involved segments. The aorta is stiff and rigid, sometimes with dilated segments and aneurysms. Localised stenotic lesions is fairly common (37.5%), seen particularly in children and is noted in the descending thoracic (DTA) and abdominal aorta. In our material the DTA is the segment maximally affected. The lesion starts at the level of L subclavian or just beyond it to involve variable lengths of DTA. Abdominal aorta (renal artery segment) disease is more common in adults. This is often associated with renal artery stenosis. In diffuse disease the thoracic abdominal aorta is affected, sparing the ascending aorta. In autopsy material, isolated arch vessel disease is rare. When arch vessel is diseased, it involves mainly the L Subclavian and there is always associated aortic arch disease. Arch vessel disease is in the form of complete block or osteal narrowing with occlusive luminal thrombi. Coronary osteal stenosis is not uncommon. The intimal surface of the aorta is covered with gelatinous or whitish plaques or is diffusely thickened. Mural thrombi are sometimes present in the constricted segment. Histopathological features: Inflammation may be in the active or more commonly in the chronic healed phase. In the active phase, diffuse or granulomatous inflammation is seen consisting of Langhans giant cells, foreign body giant cells, mixed inflammatory cells and sometimes-fibrinoid necrosis. Inflammatory reaction is maximal at the junction of the media and adventitia and is marked around vasavasorum though there is no vasculitis. Adventitia shows increase in ground substance with acid mucopolysaccharides. Media shows neovascularization and inflammatory cells. Intima is thickened with increase in ground substance. There is no intimitis. In chronic phase there is sparse inflammation around vasavasorum, adventitial thickening, fibrosis, scarring in the media, disruption of elastic fibres and hyaline intimal thickening. Pulmonary artery and coronary artery involvement is infrequent. The commonest associated pathology noted at autopsy is tuberculous lymphadenitis (55%). Matted enlarged Para aortic and mediastinal lymph nodes are particularly present around the involved segments of aorta. It is not easy to reconstruct the natural course of the disease. Symptoms are related to well establish lesions in the aorta or its branches. The inflammatory process may be self limiting in most cases. Regression of lesions has been documented in a few case reports. Prognosis is influenced by clinical course, age of onset and complications like hypertension, rapid development of congestive cardiac failure, and left ventricular failure. As of today there is no specific disease activity marker and treatment should be aimed at preventing vital organ ischemia and cardiac failure.

Ullrich congenital muscular dystrophy: Connective tissue abnormalities in the skin support overlap with Ehlers–Danlos syndromes

Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in the three genes coding for the alpha chains of collagen VI and characterized by generalized muscle weakness, striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints, and normal intellectual development. The diagnosis is supported by abnormal immunoreactivity for collagen VI on muscle biopsies. As patients with UCMD show clinical characteristics typical of classical disorders of connective tissue such as Ehlers-Danlos syndromes (EDS), we investigated the ultrastructure of skin biopsy samples from patients with UCMD (n=5). Electron microscopy of skin biopsies revealed ultrastructural abnormalities in all cases, including alterations of collagen fibril morphology (variation in size and composite fibers) and increase in ground substance, which resemble those seen in patients with EDS. Our findings suggest that there is a true connective tissue component as part of the phenotypic spectrum of UCMD and that there is considerable clinical as well as morphological overlap between UCMD and classic connective tissue disorders.

Abnormal tenocyte morphology is more prevalent than collagen disruption in asymptomatic athletes’ patellar tendons

This study investigated the prevalence of each of the four features of patellar tendinosis in asymptomatic athletic subjects undergoing patellar tendon anterior cruciate ligament (ACL) reconstruction. Fifty subjects (39 males and 11 females) undergoing ACL reconstruction using a patellar tendon graft were screened for previous tendon symptoms, training and playing history and had their patellar tendons examined with ultrasound prior to surgery. During surgery, a small piece of proximal posterocentral tendon was harvested, fixed and examined under light microscopy. Histopathological changes were graded for severity. Results demonstrate that 18 tendons were abnormal on light microscopy and 32 were normal. There were no differences between subjects with and without pathology in respect of training, recovery after surgery and basic anthropometric measures. Three tendons were abnormal on ultrasound but only one had proximal and central changes. Tendons showed a consistent series of changes. Tenocyte changes were found in all but one of the abnormal tendons. In all but one of the tendons with increased ground substance there were tenocyte changes, and collagen separation was always associated with both tenocyte changes and increased ground substance. No tendons demonstrated neovascularization. It appears that cellular changes must be present if there is an increase in ground substance, or collagen and vascular changes. Further research is required to confirm these findings.

Familial intracranial aneurysms: an autopsy study.

Familial intracranial aneurysms are more common than has been appreciated, but systematic autopsy studies of affected individuals have not been reported. We reviewed the autopsy findings of a group of patients with familial aneurysms to elucidate the nature of the putative underlying arteriopathy. Using a computerized diagnostic index, we identified all patients with intracranial aneurysms in whom postmortem examination had been performed at the Mayo Clinic between January 1, 1992, and December 31, 1994. The medical records, radiographic studies, and autopsy findings of these patients were reviewed. Among the 28 patients with intracranial aneurysms, 3 (11%) had one or more first-degree relatives with documented intracranial aneurysms. The mean age of the three patients (two women and one man) was 54 years. Microscopic examination of the vascular system revealed medial changes, consisting of degeneration of elastic fibers and increased ground substance, in the systemic arteries of 2 of the 3 patients with familial aneurysms but in none of the 25 patients with sporadic aneurysms. These nonspecific medial changes involved both common and extracranial internal carotid arteries in one patient and the entire aorta as well as intracranial and common carotid arteries in the other patient. These observations suggest that an underlying arteriopathy in patients with familial intracranial aneurysms involves the tunica media and commonly may affect systemic (extracranial) arteries.

Nuclear scaffold organization in the X-ray sensitive Chinese hamster mutant cell line, xrs-5.

Nuclear organization was probed in the radiation-sensitive Chinese hamster ovary CHO) cell line, xrs-5, and compared with parental CHO K1 cells using the resinless section technique and DNase I digestions. The resinless section data showed no gross morphological differences in core filaments from the nuclear scaffolds of unirradiated CHO K1 and xrs-5 cells. However, the nuclear scaffolds of irradiated xrs-5 cells (1 Gy) had significantly increased ground substance. Irradiated and unirradiated CHO K1 cell nuclear scaffolds were morphologically identical. These data suggest that both CHO K1 and xrs-5 cell nuclear scaffolds had internal nuclear scaffolding networks that could provide DNA attachment sites. The rate of DNase I digestion of unirradiated CHO K1 and xrs-5 was not significantly different, but the extent of digestion was greater in unirradiated CHO K1 cells that in xrs-5 cells suggesting that less xrs-5 cell chromatin at DNA attachment points is accessible to the enzyme DNase I. The extents of digestion in irradiated (1 Gy) CHO K1 and xrs-5 cell nuclei also differed but the relationship was reversed. The irradiated xrs-5 cell samples were digested to a greater extent compared with CHO K1 cells. These chromatin digestion data suggest that the matrix attachment regions in xrs-5 cells are different from CHO K1 cells. The different DNA attachment organization in the xrs-5 cells may play a role in modulating radiation sensitivity.

Pyridoxine deficiency and antagonism produce increased ground substance viscosity with resulting seborrheic dermatitis and increased tumor resistance

Pyridoxine deficiency and 4′-deoxypyridoxine produce acrodynia in rats and seborrheic dermatitis in man. They also produce tumor inhibition in man and animals. Pyridoxine is extensively involved in metabolism and its relationship to the inhibitor 4′-deoxypyridoxine is complex. Pyridoxine deficiency and antagonism increases ground substance viscosity. This increase the inflammatory reactivity of the skin to produce acrodynia in rats and seborrheic dermatitis in man. The increase in ground substance viscosity would explain the increased resistance to tumors in man and animals. Pyridoxine is important in protein metabolism. The protein moiety of glycosaminoglycans in ground substance is small but plays a major role in tissue viscosity. Pyridoxine deficiency or antagonism by itself does not offer a definitive answer for tumors. Combined with substances that stimulate fibroblast or glycosaminoglycans production it may have a significant additive effect.

A mechanism of peripheral spread or localization of inflammatory reactions — Role of the localized ground substance adaptive phenomenon

It is known that connective tissue-active peptides (CTAP) are released at sites of inflammation. Some of this material diffuses to immediately adjacent tissue and increases ground substance viscosity and fibroblast proliferation. This contributes to host protection against spread of infections and tumors. In a person with normal inflammatory reactivity, it should prevent spread of mediators and products of local inflammation. However, the host with an increased reactivity in sites of increased ground substance viscosity or who is highly reactive to dilution of tissue fluid would respond with more inflammation. A non-infectious, non-malignant process in a host with a highly reactive inflammatory or immune response could end up with peripheral spread. This could occur in any tissue but it occurs with great vigor in the skin. It could present as a peripheral extension of a local disease process, such as psoriasis, or the migration of cyclic lesions with clearing of the central area. There are over a dozen variants of peripherally spreading, ringed lesions described in the dermatologic literature. This includes erythema marginatum of rheumatic fever, erythema gyratum repens associated with cancer, and erythema annulare centrificum associated with allergic reactions to fungi. Many of the ringed dermatologic lesions have an immunologic component. They tend to be associated with inflammatory immune reactions at distant sites. Dermatologists have been gathering information on the ringed phenomenon at least since Hebra in 1854. The acute localized ground substance adaptive phenomenon is a broadly beneficial biologic response. It is essentially the same process as walling off an infection but it is also important in localizing inflammation at times and causing peripheral extension at other times. There is a large number of substances released in acute inflammation, immune reactions, and tissue reactions. The explanation given for increased viscosity is probably an over simplification but the general phenomenon of localized increased ground substance viscosity is very likely to exist.

Ultrastructural studies of the human round window membrane.

An ultrastructural study of 14 round window membranes of seven human ears disclosed three basic layers: an outer epithelium lining the middle ear, a middle core of connective tissue, and an inner epithelium bordering the inner ear. Morphological evidence suggests that these layers participate in absorption and secretion of substances to and from the inner ear. A comparison of morphological features of round window membranes suggests that the average thickness of 70 microns does not change with advancing age. However, in the elderly, the connective tissue has a looser arrangement; there is an increase in ground substance; and elastic fibers thicken. Fibroblast nuclei become larger, rounder, and less uniform and have extensions. The ultrastructure of the "false round window membranes," with epithelial cells of the same type bounding both sides, suggests that these membranes consist of juxtaposed epithelial folds of the overlying promontory.

Non-immunologic enhancement and regression of self-healing squamous cell carcinoma (keratoacanthoma) — Ground substance and inflammation

Keratoacanthomas have many characteristics of squamous cell carcinoma and in the past were interpreted as squamous cell carcinomas. It is now known that these lesions spontaneously resolve if left untreated. In man the lesions occur on sunlight damaged areas or areas exposed to tar. Many of the experimental cancers of animals produced by topical carcinogens are keratoacanthomas. Ultraviolet light and tar are known to damage fibroblast and ground substance viscosity. It has recently been proposed that anything that decreases ground substance viscosity would encourage the spread of tumors, by weakening tissue resistance. The rapidly growing keratoacanthoma produces invasive pressure and moves into deeper, less damaged dermis. An inflammatory reaction occurs in the depth of the lesion and a very characteristic granulocytic response occurs. Granulocytes release connective tissue active peptides which stimulate fibroblast and ground substance formation. The fibroblast proliferation is followed by fibrosis and the shrinking and disappearance of the tumor. The characteristic pustule that spurts granulocytes into the depth of the tumor has been experimentally blocked by hyaluronidase and other substances that damage ground substance viscosity. Edema is essential to produce this inflammatory reaction. However, this inflammatory phenomenon occurs vigorously in keratoacanthoma. It is proposed that a keratoacanthoma is a tumor that does not produce hyaluronidase or other substances that decrease ground substance viscosity. It is a deviant cell that can only move through areas of decreased ground substance viscosity. When it reaches tissue of normal viscosity edema and an inflammatory reaction occurs. The granulocytic inflammation releases the connective tissue-active peptide which stimulates fibroblasts, increases ground substance viscosity and produces scar tissue much as an infectious process would be walled off. The wall of fibroblasts forces regression of the tumor. The body may be able to remove invasive growths that do not have hyaluronidase activity or other connective tissue lytic activity. The phenomena that occur in a spontaneously healing tumor may shed light on cancers that do not regress. It is known that persons with cancer have a relatively weak inflammatory response when challenged with irritants. A non-immunologic phase of cancer resistance is presented. Although cellular immunity is important in tumor resistance, non-immunologic factors may play an important role in cancer resistance. Increased ground substance viscosity, increased early cellular inflammation, and decreased production of hyaluronidase or other lytic factors from the tumors would all greatly benefit the host with a tumor. Without this phase it appears that the immunologic phase might be weakened.

Acute local inflammation causing generalized increased ground substance viscosity: Guttate psoriasis, Reiter's syndrome, adjuvant disease, cancer regression

It is known that at sites of acute inflammation there is increased ground substance formation and fibroblast proliferation. There is also increased serum gylcoprotein following localized acute inflammation. The author proposes that a severe acute inflammatory response in a localized area of the body induces a generalized increase in ground substance viscosity (generalized ground substance adaptive phenomenon). This would increase host resistance to invasion and heighten the inflammatory response. There are multiple clinical and experimental facts which could be explained by this response. These include guttate psoriasis, pustular psoriasis, pustular bacterid of Andrew's, Reiter's syndrome, and other. This response would include some aspects of adjuvant disease. Increased generalized ground substance viscosity could also explain the beneficial effects of streptococcal cell fractions and stretococcal infections on tumor regression. A number of other clinical observations could be explained. Connective tissue-activating peptide released at the inflammation site could be having a systemic effect. It could be generally beneficial to have generalized increased ground substance viscosity when acute inflammation is occurring in a localized area. A few patients who already have a highly reactive inflammatory level could develop excess inflammation especially at sites of trauma, or preexisting inflammation.

Intensification of ultraviolet-induced dermal damage by infrared radiation.

Abnormal dermal deposition of elastic fibers is the earliest and most striking effect of prolonged sun exposure (solar elastosis). The hyperplastic fibers are usually ascribed to ultraviolet (UV) rays. Nonetheless, other portions of the solar spectrum may play contributing roles. Heat, for example, enhances experimental UV tumorigenesis. Heat induces erythema ab igne in which the structural alterations resemble those of actinically damaged skin, including the development of premaligant and malignant lesions. In regions of high insulation, infrared radiation (IR) is a constant companion of UV. To assess the role of IR in actinic damage to the dermis, albino guinea pigs were irradiated for 45 weeks with UV-B and UV-A, with and without IR. Control animals received IR only or no irradiation at all. Unirradiated dermis contains small amounts of elastic fibers in the upper dermis with greater depositions around follicles and sebaceous glands. After irradiation with UV, the fibers became more numerous, thicker, and more twisted; IR alone produced many fine, feathery fibers. The addition of IR to UV resulted in dense matlike elastic fiber depositions that exceeded what was observed with either irradiation alone. In combination or alone UV and IR radiation produced a large increase in ground substance, a finding also seen in actinically damaged human skin. Infrared radiation, in the physiologic range, though pleasant is not innocuous.

Plasmapheresis and immunosuppressive drug therapy in scleroderma.

In an uncontrolled clinical trial, plasmapheresis combined with prednisone and cyclophosphamide therapy produced clinical improvement in 14 of 15 scleroderma patients with varying degrees of skin and internal organ involvement. All improved patients showed a gradual loosening of hide-bound skin, relaxation of contractures, and healing cutaneous ulcers, when present. Severe gastrointestinal symptoms were ameliorated in 4 patients, severe polymyositis was largely reversed in 2 patients, and pulmonary and cardiac function was improved in others. After initial improvement, however, 2 patients died during the period of study and another withdrew unimproved. Antinuclear antibody (ANA) titers declined relatively more than total IgG levels with plasmapheresis in 6 of the 9 patients who had elevated titers. Increased levels of endothelial cell cytotoxic activity found in 11 of the 15 patients were significantly reduced by plasmapheresis. Elevated levels of circulating immune complexes were found in only 4 of the 15 patients. Skin biopsies from adjacent sites taken before and after plasmapheresis in 10 patients all showed less swollen dermal collagen with increased ground substance between collagen bundles in the second biopsy. Although the effects of plasmapheresis cannot be dissociated from those of the immunosuppressive drug therapy, our results suggest that plasmapheresis combined with immunosuppressive drug therapy may find a place in the management of patients with moderate to severe scleroderma. This study implicates circulating factors in the pathogenesis of the disease.

Age dependent biochemical changes in dermal connective tissue. Relationship to histological and ultrastructural observations.

A biochemical study of skin biopsies of young normal subjects and two groups of aged subjects, one active and the other confined to bed, was made and the results compared with histological observations. Skin biopsies were incubated with 3H proline and 14C glucosamine and connective tissue components were sequentially extracted. In each extract the specific activity of total and collagenous protein was determined. With age a decrease was observed in both the amount of protein and the 3H proline incorporation of collagenous extracts. A parallel increase in 14C glucosamine incorporation was also noticed in extracts containing glycosaminoglycans and structural proteins. These results agree in part with the changes observed by light and electron microscopy, which revealed an increase in ground substance and fragmentation of collagen bundles in the dermis of older subjects.

VITAMIN D SCLEROSIS IN RATS

The early fine structural changes in the arteries of rats induced by excess vitamin D3 perorally or parenterally were essentially similar, except the latter had a more prominent toxic effect to the vascular wall. The ultrastructural features, incidental to calcification, included the appearance of increased ground substance with a separation of collagenous and elastic fibrils, and degenerative changes in smooth muscle cells. Atherosclerosis was greatly accelerated at the sites of vascular injury when cholesterol, cholic acid and thiouracil were added to the basal diet. Calcification was initially observed in relation to elastic fibrils or degenerated cells in the upper and middle layers of the arteries, although there were few such deposits in the thickened intima of the coronary arteries. Calcium deposition could not be a direct effect of hypercalcemia, but the functional activity of smooth muscle cells did seem to promote the mineralization of calcium and phosphate. Furthermore, vitamin D-induced sclerosis did not prevent intimal thickening of the arteries when vitamin D3 was withdrawn.