Intimal Sclerosis Research Articles

Intensive receptor blockade and plasma exchange to treat refractory scleroderma renal crisis in patients with agonistic autoantibodies targeting the angiotensin II type 1 and endothelin-1 type A receptors

Scleroderma renal crisis is a rare complication of systemic sclerosis characterized by a rapid decline in kidney function due to acute renal vascular injury. Recently, activating autoantibodies targeting the angiotensin II type 1 receptor and the endothelin-1 type A receptor have been implicated in the pathophysiology of scleroderma renal crisis by sensitizing the angiotensin II type 1 receptor and endothelin-1 type A receptor in renal resistance arteries to their natural ligands. Here, we describe a cohort of 10 patients with scleroderma renal crisis refractory to standard treatment, including blockade of the renin-angiotensin system. Multimodal therapy was initiated, targeting at the removal of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies by plasma exchange and the reduction of vasoconstrictive activity. Further treatment options included angiotensin II type 1 receptor and endothelin-1 type A receptor blockade, iloprost, intravenous immunoglobulins, and immunosuppression. Six patients were hypertensive. On kidney biopsy, concentric intimal sclerosis was present in all patients, whereas acute vascular injury was evident in eight. Levels of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies were significantly reduced by multimodal treatment. Kidney function improved in three patients with histological signs of severe acute renal vascular damage. This report demonstrates that intensive multimodal therapy taking account of potentially pathogenic anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies in concert with other vasodilatory interventions provides a salvage option for patients with refractory scleroderma renal crisis.

POS-004 ATYPICAL HEMOLYTIC UREMIC SYNDROME IN YOUNG FEMALE: CASE FOR DISCUSSION

POS-004 ATYPICAL HEMOLYTIC UREMIC SYNDROME IN YOUNG FEMALE: CASE FOR DISCUSSION

Structural features of the lower limb deep vein remodeling as a morphologic component in the pathogenesis of pulmonary thromboembolism in cancer patients

Oncological patients are at high risk of developing thromboembolic complications, which is a manifestation of a complex set of symptoms – cancer. At the same time, the analysis of the literature shows that the question of the involvement of structural changes of the vascular wall in the pathogenesis of possible primary thrombus formation in cancer patients remains open. The aim of the study – to study the structural features of remodeling of the deep vein of the lower extremity as a morphological link of pathogenesis of pulmonary embolism in cancer patients. Retrospective analysis of 54 protocols of autopsy of deaths from cardiopulmonary shock caused by pulmonary embolism in 2014-2018 was performed. In parallel, all patients were determined the number of free-circulating endothelial cells in the citrate blood by Hladovez J. method, in modification of Sivak V.V. and co-authors (2007). Statistical processing of digital data was performed using the software “Excel” and “STATISTICA” 6.0. In retrospective analysis of autopsy protocols, the highest proportion of pulmonary embolism was report in patients with cancer of the uterus and colon. Morphological changes of the deep vein of the lower extremities in cancer patients were manifested by endothelium desquamation and circular and focal muscular-fibrous hyperplasia of the intima, which caused disturbances of laminar flow of blood; muscular-fibrous atrophy with neovascularization of the middle membrane and sclerosis of vasa vasorum vessels of adventitia. The process of remodeling was also manifest by the inflammatory transformation of the vascular wall, the formation of obstructing and floating blood clots with their subsequent organization, vascularization and recanalization. The cause of intimal thickening, atrophy, and sclerosis with midbrain neovascularization is most likely a hypoxic mechanism of activation of transforming connective tissue growth factors that stimulate collagenogenesis and neoangiogenesis. Desquamation of endothelial cells can also be considered as a significant contributor to thrombus formation. Endothelial cells have a protective function aimed at eliminating damage to the vascular wall by thrombus formation and the development of fibrous intima hyperplasia. In addition, tumor cells are themselves capable of producing excess platelet growth factor, which causes intima proliferation. So, a component of pathomorphogenesis of pulmonary artery thromboembolism in cancer patients is a complex structural reconstruction of the wall of the deep vein of the lower extremity, which causes the development of its thrombosis. Deep vein remodeling in cancer patients is characterized by endothelial cell desquamation, intima and middle-membrane thickening and sclerosis in combination with vasa vasorum fibrous degeneration and perforant vein thrombosis. In response to hemodynamic disorders, compensatory remodeling develops: the combination of leiomyocyte atrophy with their hypertrophy and neovascularization of the middle membrane.

Medical renal disease in tumor nephrectomies: The silent killer.

In tumor nephrectomy specimens, the evaluation of the normal renal parenchyma is often overlooked. A patient with both end-stage renal diseases (ESRDs) with a renal cell carcinoma is more likely to die of the ESRD rather than cancer. At the time of nephrectomy, a pathologist has a large amount of tissue available to him to comment upon the presence of disease in the nonneoplastic kidney. Hence, this study was undertaken with the idea of characterizing disease in the nonneoplastic kidney at the time of tumor nephrectomy. A two-year retrospective study was carried out on all tumor nephrectomies and partial nephrectomies. Glomerular, tubulointerstitial, and vascular compartments were evaluated for abnormalities. Twenty-four cases were included in the study. A total of 17 cases showed abnormalities in the nonneoplastic renal parenchyma. In the glomeruli, two cases showed IgA nephropathy, one case showed segmental sclerosis, and one case showed the presence of cellular crescents. A single case showed diabetic glomerulosclerosis. Interstitial fibrosis and tubular atrophy were noted in seven cases. Fifteen cases showed intimal sclerosis and medial hypertrophy and six cases showed nodular hyalinosis. Tumor nephrectomy specimens may very often show the presence of various nonneoplastic diseases. Hypertensive and diabetic renal disease are the major contributors, although primary glomerular diseases may also be present. At the time of the evaluation of a renal tumor on nephrectomy specimen, the status of the nonneoplastic kidney may become as an important predictor of clinical outcome as the tumor itself.

Use of multidetector computed tomography angiography of upper limb circulation in patients undergoing coronary artery bypass grafting surgery.

Objective:This study aimed to evaluate the bilateral forehand circulation using a 64-channel multidetector computed tomography (MDCT) as a noninvasive method to define criteria for an upper extremity arterial anatomy and pathology prior to the use of arterial conduits.Materials and Methods:Fifty-five patients with coronary artery disease who underwent total arterial coronary artery bypass grafting (CABG) were randomly selected for this prospective study. MDCT angiography was performed for 110 examinations of forearm and hand arterial anatomy. Prior to MDCT, Allen tests were performed in all patients with a normal result, except four. Thirteen patients had diabetes mellitus (DM), 8 had peripheral artery occlusive disease, and 19 had a history of smoking.Results:All arteries, including axillary, ulnar artery (UA) and radial artery (RA), were clearly visualized in all patients. Upper extremity anatomical and pathological results were examined in 16 patients (29.1%). Severely calcified RA and/or UA were found in 6 patients who had a moderate renal failure. Nearly total occlusion of the RA was detected in another two patients. Focal intimal RA calcification was recorded in 1 female and 3 male patients. Ten patients who had severe calcification or intimal sclerosis of the upper extremity arteries had DM. The remaining patients had normal forehand arterial circulation. A persistent median artery with the absence of radial and ulnar arteries and a high bifurcation of RA from the brachial artery was detected as an anatomic variation in seven patients (12.7%).Conclusions:The major advantages of MDCT angiography are its non-invasiveness and the ability to detect calcific subadventitial plaques, which are difficult to diagnose using conventional angiography. MDCT may be used as a safe and non-invasive method to assess RA and UA prior to harvesting the upper limb artery. Preoperative imaging of forehand arteries is a means to avoid unnecessary forearm exploration or the use of an unsuitable arterial conduit in CABG operations, especially in patients with DM and moderate renal impairment.

Low-dose cyclosporine in treatment of membranous nephropathy with nephrotic syndrome: effectiveness and renal safety

Background: To observe effectiveness and renal safety of long-term low-dose cyclosporine in idiopathic membranous nephropathy (IMN).Methods: Sixty-eight patients were enrolled in this prospective cohort study. Renal endpoint was defined as a decrease in eGFR ≥50% from baseline and a development of eGFR ≤60 ml/min/1.73m2.Results: A cyclosporine dose of 2.0 ± 0.5 mg/kg/d and a prednisone of 0.3 ± 0.2 mg/kg/d were prescribed. The duration of cyclosporine treatment was 27 (3–80) months. The overall remission rate was 91% with a relapse rate of 42%. Fourteen patients had cyclosporine-related acute renal injury (CsA-ARI) within the first three months, and 16 patients had cyclosporine related chronic renal injury (CsA-CRI) within the first year. At the end of follow-up (50 ± 18 months), 16 patients (24%) reached renal endpoint. Presence of intimal fibrosis of small artery and higher time-averaged proteinuria were identified as independent risk factors for renal endpoint. RAS inhibition treatment decreased the risk of poor renal outcome. Patients in CsA-ARI group had the highest proteinuria at the third month, the highest time-average proteinuria and the highest proportion of cases reaching renal endpoint. Patients with CsA-CRI were of the oldest age and with the lowest baseline eGFR.Conclusions: Low-dose cyclosporine is effective in treating IMN. CsA-ARI and no response in proteinuria during the first three months of cyclosporine treatment had the lowest benefit/risk ratio, and these patients should be switched to non-calcineurin-inhibitor based regimen. Patients of older age, with lower baseline eGFR, or having intimal sclerosis of small artery, are more likely to develop progressive renal dysfunction.

The other end of spectrum in hypertension: ‘Idiopathic nodular glomerulosclerosis’

Dear Editor, Nodular glomerulosclerosis is observed in diabetes mellitus, dysproteinemias, lobular membranoproliferative glomerulonephritis, glomerular deposition disease, and chronic hypoxic states. Idiopathic nodular glomerulosclerosis (ING), which is a rare clinical entity, is diagnosed in the absence of these conditions. We report a case of ING in an elderly hypertensive lady. An 82-year-old woman was evaluated for chronic kidney disease. Her medical history included hypertension, permanent atrial fibrillation, and osteoarthritis. There was no personal or family history of diabetes mellitus, hepatitis, autoimmune, or connective tissue disease. She did not use any over-the-counter medications, herbal remedies, cigarettes, alcohol, or recreational drugs. On examination, her vitals revealed blood pressure of 140/93 mmHg, with an irregular heart rate of 74–86 beats/min. The rest of the physical examination was unremarkable. Laboratory parameters were significant for mild normocytic anemia with a hemoglobin level of 10.2 mg/dl, BUN of 65 mg/dl, and creatinine level of 1.7 mg/dl. Fasting blood glucose, 2-h glucose tolerance test, autoantibody screening, complements, hepatitis serology, and cryoglobulins were normal. Urinalysis was normal with random protein 18 mg/dl and creatinine 59.2 mg/dl. Serum protein electrophoresis confirmed by immunofixation revealed monoclonal IgM lambda quantitated at 0.11 g/dl; free kappa/lambda ratio was 1.17 (normal 0.26–1.65). Renal ultrasound demonstrated slightly asymmetric kidneys. Renal artery magnetic resonance angiography was normal. Light microscopy of left kidney biopsy showed 6 end-stage sclerotic glomeruli and 14 viable glomeruli. Nodular mesangial expansion, thickened peripheral capillary basement membranes, tubular atrophy, interstitial fibrosis, arteriolar intimal sclerosis, and patchy lymphoplasmacytic infiltrates were observed (Fig. 1). Congo red stain was negative. Immunofluorescence was positive for focal granular mesangial IgM deposits. Electron microscopy showed thickened glomerular basement membranes and expanded mesangial matrix, frequently forming mesangial matrix nodules. There were no electron dense deposits, and foot processes were fused in a patchy pattern. These findings were suggestive of diffuse and nodular glomerulosclerosis with moderate to severe arteriosclerosis. In the absence of other etiologies, it is possible that hypertension was responsible for nodular glomerulosclerosis in this patient. It is speculated that individuals with long standing hypertension have an increased or reset sensitivity to non-diabetic glycemic levels resulting in an exaggerated glomerulovascular response [1]. R. Kasmani (&) T. Thiyagarajan R. NarwalChadha K. Okoli F. Irani Department of Internal Medicine, St. Vincent Mercy Medical Center, Toledo, 2213, Cherry Street, Toledo, OH 43608, USA e-mail: rahilkasmani@hotmail.com

Sauropus androgynus-constrictive obliterative bronchitis/bronchiolitis--histopathological study of pneumonectomy and biopsy specimens with emphasis on the inflammatory process and disease progression.

The histopathology of the Sauropus androgynus (SA)-constrictive bronchiolitis obliterans (BO) is still controversial. A recent report using pneumonectomy specimens showed that the major histopathology was obliterative arteriopathy with segmental necrosis of small bronchi instead of constrictive BO as previously described. We analysed semiquantitatively and immunohistochemically the histopathology of one pneumonectomy and four biopsies specimens of SA-associated lung disease. We found a significant number of constrictive and obliterative bronchioles 1 mm or less in diameter and segmental inflammatory destruction with complete luminal obliteration of the bronchi less than 3 mm in diameter in the pneumonectomy specimen (37% and 25%, respectively). Fibromuscular intimal sclerosis of the bronchial arteries was identified in 15% of the bronchi 4 mm or less in diameter. The inflammation in these airways was composed predominantly of T-lymphocytes, macrophages, mast cells and eosinophils. They were present throughout the evolutionary stages of the bronchiolitis ranging from early oedematous to the late fibrotic obliterative stage. Double immunohistochemical stains revealed negative proliferative cell nuclear antigen for most of the T-lymphocytes and macrophages but positive for fibroblasts. A more accurate histopathological designation of the SA-associated lung disease should be constrictive obliterative bronchitis/bronchiolitis, with the participation of T-lymphocytes, macrophages, mast cells, eosinophils and fibroblasts in its morphogenesis. The persistent accumulation of inflammatory cells was mediated predominantly by continued recruitment to the site of injury from the bloodstream, resulting eventually in the irreversible fibrosis of the bronchioles and the bronchi less than 3 mm in diameter. Obliterative arteriopathy is suspected of being only an indirect contributing factor.

Incidence and morphology of endometrial angiopathies in mares in relationship to age and parity

The morphology of endometrial blood vessels in uterine biopsy specimens from mares of varying age and reproductive status was examined by light (n = 117) and electron microscopy (n = 13), and additionally after elastase digestion (n = 86). Inflammatory vascular alterations were observed in 20.5% of the specimens. Smaller and larger arterial and venous vessels demonstrated mild to severe degenerative lesions. Unaltered vessels were detected only in maiden mares. Vessels in older maiden mares were frequently affected by angiosclerotic changes, characterized by mild to moderate perivascular and intimal sclerosis. The incidence and severity of angiosis increased with the number of previous pregnancies and with advancing age. Changes in multiparous mares resembled the so-called "pregnancy-sclerosis" of other species, with fraying and disruption of the membrana elastica interna, medial atrophy intimal, medial and adventitial elastosis and fibrosis, and calcification processes within the media. Ultrastructural studies revealed characteristic arterial changes in post-parturient mares, namely, disruption of the membrana elastica interna, as well as activated smooth muscle cells and immature elastic fibres within the intima and inner media, suggesting a pregnancy-induced pathogenesis. Haemodynamic and hormonal alterations during pregnancy and the puerperium possibly induce active vascular remodelling. Cycles of vascular growth during pregnancy and subsequent involution post partum are thought to result in progressive degenerative vascular changes, as seen in multiparous mares. Ageing processes, chronic inflammation and short foaling intervals have to be considered as additional pathogenetic factors. Furthermore, severe angiosis was frequently combined with phlebectasia and lymphangiectasia. This may indicate a reduced ability of the vessels to adapt to the varying demands of uterine circulation, with a decrease of uterine perfusion and lymph drainage. Angiosis in older, multiparous mares might therefore be intimately related to infertility.

The pathology of combined heart-lung transplantation: an autopsy study.

Clinical heart-lung transplantation (HLT) began at Stanford University (Stanford, CA) in 1981, and since then, over 40 HLTs have been performed. There is now a worldwide total of 250 HLTs. While much of the pathology that occurs in patients receiving an HLT is similar to that which develops in patients with other transplanted organ systems, these patients also develop unique clinical complications and pathologic processes that deserve emphasis. We report the autopsy findings of 20 HLT recipients, of whom 12 died in hospital one day to 4 months post-HLT. A major contributing factor in five of these postoperative deaths was pleural hemorrhage from adhesions due to prior chest surgery. Overwhelming viral and fungal infections accounted for six deaths. The seventh patient died as a result of adult respiratory distress syndrome (ARDS). Two patients showed histologic evidence of the reimplantation response. Six long-term survivors died (mean survival, 22 months) with obliterative bronchiolitis (OB). In four patients, OB was the immediate cause of death, while one patient died of an intercurrent myocardial infarct, and the other patient died of complications from an appendectomy. Two long-term survivors died without OB, one of iatrogenic causes at 63 months and the second due to unexplained ARDS at 52 months. Both patients without OB had virtually normal underlying pulmonary parenchyma. All of the long-term survivors had either coronary arterial or pulmonary vascular intimal sclerosis, and renal lesions attributable to cyclosporine A toxicity. Although histologic features of mild acute pulmonary and cardiac rejection were observed in four patients overall, these did not contribute to the cause of death in any case. Although OB is a major threat to its success, HLT is a viable option for patients with endstage pulmonary disease.

Cardiovascular complications of chronic catheterization of the jugular vein in the dog.

Cardiovascular changes associated with indwelling catheters were evaluated in 51 adult beagle dogs catheterized for 4 to 9 weeks. Pathologic changes consistent with traumatic injury were in the vena cava and endocardium of the right atrium of 88% of cannulated dogs. Lesions were characterized by surface denudation and diffuse intimal thickening due to myointimal hyperplasia and deposition of extracellular matrix. Affected intima was lined by hyperplastic, poorly differentiated endothelial cells and contained round to oval cells with characteristics of smooth muscle cells. After 9 weeks, thickened intima was vascularized and composed of spindle-shaped cells and fibrillar stroma. Intimal sclerosis and localized proliferative papillary projections in the vena cava cranial to areas of myointimal hyperplasia occurred infrequently. Traumatic lesions, regardless of location or severity, did not extend below the internal elastic membrane. Inflammatory cellular responses, when present, were minimal. The location, distribution, and morphogenesis of catheter-related cardiovascular lesions distinguishes them from those induced by chemical toxicity or pharmacotoxicity.

The pathology and pathogenesis of malignant atrophic papulosis (Degos' disease): A case study with reference to other vascular disorders

The morphology and immunohistology in a case of malignant atrophic papulosis (Degos' disease), a rare vascular disorder of unknown etiology, are described. The vascular lesions affected middle class and small arteries and veins throughout the body and were histologically characterized by intimal proliferation in the absence of any appreciable inflammation. The lesions were categorized as early, intermediate or late. Early lesions consisted of cellular proliferation and edema of the intima with signs of immune complex deposition (IgM, C3). Thrombosis was occasionally present as a secondary phenomenon in the affected vessel segments. In intermediate lesions the edema decreased and smooth muscle proliferation became apparent. Late lesions consisted of acellular intimal sclerosis with hyalinization and narrowing or obliteration of the vascular lumen. The media of the vessels remained always intact. In comparing these features to the pathology and pathogenesis of other vascular disorders they resembled the vascular lesions in a murine model of lupus erythematodes in which also considerable intimal proliferation occurred with thrombotic occlusion, but without appreciable inflammation. The murine model is associated with sustained low levels of circulating immune complexes and it is tempting to assume the same for Degos' disease. The notion of an immune complex mediated non-inflammatory condition underlying this severe and often fatal vascular disorder of mainly young males may contribute to the eventual finding of a successful therapeutical regimen.

Renal artery occlusion and infarction with Sotradecol.

Sodium tetradecyl sulfate 3% (Sotradecol) was perfused into a proximally obstructed renal artery in ten random-source adult dogs. In all animals, the intra-arterial injections of Sotradecol produced immediate thrombosis of the renal arteries. Angiographic studies, lasting up to ten weeks, on eight dogs demonstrated persistent occlusion. In one dog, unintentional thrombosis occurred in the opposite renal artery due to reflux of Sotradecol. Histopathologic studies showed total obliteration of the renal arteries through organized thrombosis, intimal sclerosis, and luminal collapse. In all dogs, the kidneys were not visible, and diffuse renal infarction was confirmed by histologic studies of five dogs.

Increased collagen cross-linkages in experimental diabetes: reversal by beta-aminopropionitrile and D-penicillamine.

The effects of diabetes on collagen cross-link formation and solubility were investigated in granulation tissue collagen induced by polyester fabric implanted subcutaneously in rats at the same time diabetes was produced by injection of streptozotocin. Thus, all the collagen analyzed was formed in a diabetic milieu. Ten days later the implants were removed and the total collagen content as well as the fraction soluble in 0.5 M acetic acid was determined. Predominantly type I collagen accumulated in the implants. Total collagen content was the same in diabetics and controls; however, the acid-soluble fraction in diabetic animals was only half that of controls (8.5% and 17.7%, respectively), and the ratio of beta chains to alpha chains in the acid-soluble fraction was higher in diabetics (0.89) than in controls (0.69). In animals treated with beta-aminopropionitrile or D-penicillamine the acid-soluble fraction of collagen from diabetics equaled that from controls. These observations indicate that both intramolecular and intermolecular cross-links are increased in type I collagen from diabetic animals. Since these cross-links interfere with degradation of collagen by collagenase, they may contribute to accelerated intimal sclerosis of arteries and to capillary basement membrane thickening in diabetes.

The effect of hypercholesterolemia on the response patterns after different types of defined mechanical injury.

Different types of specific mechanical injury to the arterial wall elicit three characteristic and reproducible types of tissue responses. The morphology of these has many similarities with the three major changes in human arteries, i.e. progressive intimal thickening, medial sclerosis, and atherosclerosis. Hyperlipidemia is closely epidemiologically related to early human atherosclerotic disease. To test whether this relationship could be mediated by a modifying effect of hypercholesterolemia on the different arterial tissue responses, the three different types of specific injuries were induced in rabbits, which were kept on cholesterol-supplemented diet for different time periods.

Studie zur arteriosklerosegenese beim Hanford-Miniaturschwein unter normalen und experimentellen bedingungen: Teil 1. Pathologische anatomie und histologie

The Handford-miniature swine shows a pronounced inclination to develop spontaneous arteriosclerosis like other domestic porcine breeds. In the reported studies two groups of miniature swine were fed a standardized basic diet, which has been supplemented in one group by 10% palmoil-stearin of known chemical composition. One-half of the animals of each group was kept in stables under standardized climatic conditions and the second half in wooden field boxes with free runs. The results of the study show that the kind of climatic environment seems to have no significant influences on the development and severity of arteriosclerosic lesions in contrary to the different diets. Whereas the aortic lesions of the control groups had reached only a stage of merely uncomplicated intimal sclerosis (physiosclerosis!), in the experimental group the fat diet obviouslv has caused complicated lesions comparable to early human arteriosclerosis. After 38 months an atheromatous-necrotic stage has developed. The role of smooth muscle cells within the pathogenesis of intimal sclerosis as well as the problems of lipid and mucopolysaccharide metabolism of the arterial wall are discussed on the basis of histomorphology.

MODIFICATION OF THE VASCULAR LESIONS OF REJECTION IN CADAVERIC RENAL ALLOGRAFTS BY DIPYRIDAMOLE AND ANTICOAGULANTS

Dipyridamole together with heparin or phenindione seems to prevent not only thrombosis in vessels in acute rejection but also the progressive narrowing of vessels so characteristic of so-called chronic rejection in cadaveric renal allografts. This supports the view that the intimal sclerosis which causes narrowing in the vessels of renal allografts results from deposition and organisation of mural thrombi. Damage to the internal elastic lamina and media is also common in arteries in renal allografts, and such damage was very slight in patients given antithrombotic and anticoagulant treatment. A similar process of deposition and incorporation of thrombi and their breakdown products into the glomerular capillary wall seems to cause the apparent glomerular-basement-membrane thickening in renal allografts. Preliminary observations suggest that this may also be modified by treatment with dipyridamole and anticoagulants. The main renal artery shows intimal thickening in almost all renal allografts, and commonly this causes radiographic evidence of stenosis. The only three renal arteries which have shown no evidence of intimal thickening were those from patients treated early and continuously with dipyridamole and anticoagulants. The similarity between the glomerular and vascular lesions of rejection and many other forms of renal disease may mean that antithrombotic and anticoagulant drugs have a wide application in the treatment of renal diseases in which narrowing and occlusion of arteries and glomerular capillaries cause renal failure.

Intrahepatic portal vein occlusion. A cause of portal hypertension.

Intrahepatic portal vein occlusion has recently been postulated as a primary cause of portal hypertension (1, 10). This was based on the presence of intimal sclerosis or organized thrombi partially obstructing the intrahepatic portal radicles of patients in whom other causes of portal hypertension were excluded. Splenoportography in some of these cases has shown obliteration of the segmental or other large branches of the intrahepatic portal vein. Although occasionally similar splenoportograms may be demonstrated in schistosomiasis or cirrhosis, this abnormal intrahepatic vascular pattern was most common in the group of patients with portal hypertension, patent extrahepatic portal vein, and liver biopsies showing normal architecture with varying degrees of portal fibrosis (1). Five patients with portal hypertension of uncertain etiology have recently been studied at the Yale-New Haven Medical Center, and their radiographic and hemodynamic findings form the basis of this report. Particular attention is directed to the radiographic appearance of the larger intrahepatic portal veins. Materials and Methods The clinical features of the 5 patients are presented in Table 1. The portal venous system was visualized by several technics: percutaneous splenoportography with serial filming in 2 patients, single-film percutaneous splenoportography in 1, direct operative portography in 1, and superior mesenteric arteriography with serial filming in 1 patient who had undergone previous splenectomy. Wedged hepatic venous pressure was obtained by the standard method in 3 patients, followed by wedged hepatic venography using 15 ml of contrast material injected by hand with serial filming. Splenic pulp or direct portal pressure was measured in all 5. Discussion In 1965 Mikkelsen et al. (10) reported a series of cases of portal hypertension in which the cause of the obstruction appeared to be intrahepatic portal phlebosclerosis. These authors termed the syndrome “hepatoportal sclerosis.” Their report was significant because it provided a reasonable explanation for the development of portal hypertension in patients without cirrhosis or extrahepatic portal vein occlusion. Previously many such cases were called idiopathic or primary portal hypertension (8, 13, 14). Subsequently, Boyer et al. (1) reported similar findings in 21 patients from India. These patients characteristically present with upper gastrointestinal bleeding or splenomegaly without a history of alcoholism, hepatitis, or other liver disease. Physical signs of cirrhosis are usually absent, and results of liver function tests are either normal or only mildly deranged. Esophageal varices are consistently demonstrated. The gross appearance of the liver is normal, or the capsule may have areas of nodulation. Liver biopsy reveals only portal fibrosis and no evidence of cirrhosis.

Histologic features of renal biopsies from patients with essential hypertension and from the aged.

In order to clarify the vascular changes involved in the kidneys in essential hypertension, a histological study was performed on the renal biopsy materials obtained from 15 patients with juvenile form of essential hypertension, 30 elderly patients with essential hypertension, and 10 ordinary aged persons without hypertension, who admitted in the third medical clinic of Kyoto University Hospital between 1959 and 1963. It was found that the renal vascular disease in essential hypertension was predominantly in the small arteries and arterioles, especially in the media of arterioles, and included spasm, hypertrophy with or without vacuolation, hyperplasia, degeneration, atrophy with fibrosis and fibrinoid degeneration or necrosis of the medial smooth muscle. Intimal proliferation appeared to follow the changes in the media, while in the ordinary aged persons intimal sclerosis occurred from larger arteries with milder degree of severity. These flndings suggest that fundamental importance in the development of systemic hypertension should be attached to the problems on the contraction of the smooth muscle cells of the peripheral small arteries and arterioles.

The natural history of atherosclerosis.

In order to complete the fragmentary knowledge of the natural history of atherosclerosis, the authors examined the coronary arteries of 403 captive and 146 wild vertebrates living in freedom, as well as the aortas of 134 of them. In 88 of the captive animals and in 51 of the free individuals, lipidogram, total cholesterol, beta-cholesterol and cholesterol/phospholipid ratio were also determined. In this material, spontaneous atherosclerosis always developed in arteries already impaired by intimal sclerosis, and intimal sclerosis seems to be a basic condition for spontaneous atherogenesis. Lipid deposits were found in the intima of 29 per cent of the examined aortas, but coronary atherosclerosis was present in only 2 per cent of the captive specimens. The discovery of coronary atherosclerosis in free tunny fishes, caught in the Bay of Biscay, brings proof that atherosclerosis is neither the privilege of warm-blooded vertebrates nor a consequence of captivity. Unfortunately, the material collected does not permit even a rough estimate of the influence of captivity on the development of atherosclerosis. It was observed in any case that captivity significantly alters some aspects of the lipidic metabolism in animals, and especially the beta-lipoprotein levels as well as the beta-cholesterol fraction. Spontaneous atherosclerosis may develop in fishes living in their natural habitat, feeding on a diet rich in unsaturated fats; in captive birds whose dietary fats are mostly unsaturated (crane, tree duck, pelican); and in wild mammals whose diet is free of animal fats, in freedom as well as in captivity (deer, camel, tapir).